instruction stringlengths 34 186 | input stringlengths 2.02k 93.8k | output stringlengths 2 418 | meta_questiontype stringclasses 6
values | meta_inputlicense stringclasses 6
values | meta_pmid stringlengths 8 8 | meta_safetyreportid int64 9.51M 21M | meta_articlepubdate stringlengths 4 10 |
|---|---|---|---|---|---|---|---|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Peripherally Inserted Central Catheter-Associated Nocardia nova Endocarditis in a Patient Receiving Intravenous Antibiotics for Chronic Lyme Disease.
Long-term antibiotics are not effective for the therapy of patients with persistent symptoms and a history of Lyme disease. However, some clinicians still prescribe these therapies. We present a case of peripherally inserted central catheter-associated Nocardia nova endocarditis in a patient who had been receiving intravenous antibiotics for the management of chronic Lyme disease. This case highlights an important risk associated with the unscientific use of indwelling peripheral catheters and intravenous antibiotics for the management of such patients.
PRESENTATION OF CASE
A 34-year-old female from New England presented with a 1-month history of daily low-grade fevers, dry cough, loss of appetite, and a 5-pound weight loss. She received 2 separate 5-day courses of azithromycin as an outpatient with no improvement in her symptoms. Ten years before presentation, the patient was diagnosed with Lyme disease. A Western blot for Borrelia burgdorferi-specific immunoglobulin IgM antibodies detected 2 of 3 bands and was interpreted as positive, but a Western blot for IgG antibodies was negative. She was treated with doxycycline for 3 weeks. The patient continued to have polyarthralgia and fatigue and reported that she was diagnosed with chronic Lyme disease 5 years before presentation. She had an indwelling peripherally inserted central catheter (PICC) in place for the previous 22 months for the administration of intravenous (IV) antibiotics that were prescribed to treat chronic Lyme disease. She received a 10-month course of IV ceftriaxone and then a 6-month course of IV doxycycline. She was also prescribed intermittent courses of other agents, such as oral disulfuram and oral doxycycline, for the treatment of chronic Lyme disease. The patient has a history of Ehlers-Danlos syndrome, gastrointestinal malabsorption, which necessitates enteral feeding through a nasogastric tube, postural orthostatic tachycardia syndrome, and psychogenic nonepileptic seizures. She reported that the administration of sulfa drugs caused hives when she was a child. On the day of presentation, the patient had a temperature of 38.1°C and a heart rate of 103 beats per minute. A PICC line was in place in the right arm. The rest of her physical exam was normal. Kidney function, serum glucose, a complete blood count with differential, and liver enzyme tests were all within the normal range. Tests for SARS-CoV-2 and human immunodeficiency virus were negative. A chest x-ray was normal. A chest computed tomography (CT) scan showed multiple scattered pulmonary nodules concerning for emboli (Figure 1). Branching, Gram-positive bacilli grew in 4 of 4 blood cultures bottles taken on the day of her admission to the hospital (Figure 2). The organism stained with a modified acid-fast bacilli stain and was identified as Nocardia nova (Figure 3). The multiple, bilateral small nodular opacities seen on CT scan of the chest were consistent with septic pulmonary emboli. A transthoracic echocardiogram was normal, but transesophageal echocardiogram showed a 3-mm × 1-mm mobile vegetation on the mitral valve. A magnetic resonance image of the brain was normal. Thus, this patient was diagnosed with PICC-associated N nova septic pulmonary emboli and endocarditis.
Figure 1. Computed tomography of the patient’s chest. Multiple scattered nodules in the periphery of the lungs (arrow) were identified.
Figure 2. Gram stain of the organism growing in blood culture.
Figure 3. A modified acid-fast bacilli stain of the organism growing in blood culture.
PATIENT CONSENT
Consent to publish to this case report was obtained from the patient. The article type (“ID Teaching Cases”) does not require formal approval by an ethics committee.
DISCUSSION
In this study, we present the case of a patient with a severe complication associated with the unscientific use of IV antibiotics for management of persistent symptoms and a diagnosis of Lyme disease. Several randomized controlled trials have compared long-term antibiotics with placebo for the treatment of these patients [1–4]. In each of these studies, longer term antibiotic treatment did not improve symptoms in patients compared with placebo. However, complications of long-term antibiotic treatment for Lyme disease include PICC-line associated bacteremia, which can be life threatening [5]. Despite these data and a recommendation from the Infectious Diseases Society of America against the use of extended courses of antibiotics in this setting [6], some clinicians still prescribe such therapies [7, 8].
The patient was initially diagnosed with Lyme disease when an immunoblot for B burgdorferi-specific IgM antibodies was positive; however, the immunoblot for IgG antibodies was negative. Borrelia burgdorferi IgM immunoblots have poor specificity, particularly when the IgG test is negative, and can lead to the misdiagnosis of Lyme disease [9]. Thus, an isolated positive B burgdorferi IgM immunoblot should not be used to diagnose Lyme disease in patients who have had symptoms for more than 6 weeks.
Nocardia sp are Gram-positive, beaded, weakly acid-fast, branching bacilli that are uncommon causes of bacteremia and endocarditis [10]. It is interesting to note that N nova was the most common pathogen in a case series of patients with Nocardia sp bacteremia and an underlying cancer, recovered in 6 of 17 cases [11]. Ten of 17 patients in this study had central catheter-associated bacteremia, and the authors found that Nocardia sp promoted biofilm formation on central venous catheters in vitro [11]. Patients with central venous catheter-associated Nocardia sp bacteremia responded well to catheter removal and antibiotic therapy [11].
Data from randomized controlled trials are not available to guide treatment for nocardiosis. Based on cumulative clinical experience, trimethoprim-sulfamethoxazole is the mainstay of therapy for patients with nocardiosis. Patients who are allergic to trimethoprim-sulfamethoxazole should be desensitized to enable treatment with this agent. Most authorities recommend that severe infection with Nocardia sp, such as endocarditis in this patient, be managed with combination therapy. For severe disease outside the central nervous system, the combination of trimethoprim-sulfamethoxazole and amikacin for initial therapy is recommended until antimicrobial susceptibility data are available. The combination of imipenem and amikacin is also used in this setting. The optimal duration of therapy for patients with nocardiosis is not known. Shorter antibiotic courses for Nocardia sp infection are associated with a high risk of relapse, even in immunocompetent hosts. Thus, most infectious disease clinicians recommend that patients with severe nocardiosis be treated with antibiotics for 6 to 12 months.
FOLLOW-UP
The patient’s PICC line was removed and she was started on imipenem, given her history of a severe allergy to trimethoprim-sulfamethoxazole. On the second hospital day, the patient’s fever resolved, and her symptoms improved markedly. During her hospital stay, she was desensitized to trimethoprim-sulfamethoxazole. She was discharged on trimethoprim-sulfamethoxazole and amikacin while awaiting the identification and susceptibility of the Nocardia sp. Ten days into therapy, the patient developed a diffuse maculopapular drug rash. The trimethoprim-sulfamethoxazole was discontinued, imipenem was restarted, and the amikacin therapy continued. Her rash resolved. After 4 weeks of empiric antibiotic treatment, the organism was identified as N nova that was sensitive to trimethoprim-sulfamethoxazole, amikacin, ceftriaxone, imipenem, and linezolid, but resistant to tetracyclines, fluoroquinolones, and amoxicillin/clavulanate. Imipenem and amikacin were discontinued, and the patient was started on ceftriaxone, given her history of malabsorption and inability to tolerate oral antibiotics. A 6-month course of ceftriaxone is planned for this patient, after which a CT scan of the chest will be obtained to ensure resolution of the septic emboli. The PICC line used to administer ceftriaxone will then be removed.
Acknowledgments
Financial support. R. P.-W.’s research is funded by R01 AI130289 from the National Institute of Allergy and Infectious Diseases and an Innovator Award from the Kenneth Rainin Foundation.
Potential conflicts of interests. All authors have no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | AMIKACIN, AZITHROMYCIN ANHYDROUS, CEFTRIAXONE, DISULFIRAM, DOXYCYCLINE, SULFAMETHOXAZOLE\TRIMETHOPRIM | DrugsGivenReaction | CC BY-NC-ND | 33728358 | 19,724,199 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Endocarditis'. | Peripherally Inserted Central Catheter-Associated Nocardia nova Endocarditis in a Patient Receiving Intravenous Antibiotics for Chronic Lyme Disease.
Long-term antibiotics are not effective for the therapy of patients with persistent symptoms and a history of Lyme disease. However, some clinicians still prescribe these therapies. We present a case of peripherally inserted central catheter-associated Nocardia nova endocarditis in a patient who had been receiving intravenous antibiotics for the management of chronic Lyme disease. This case highlights an important risk associated with the unscientific use of indwelling peripheral catheters and intravenous antibiotics for the management of such patients.
PRESENTATION OF CASE
A 34-year-old female from New England presented with a 1-month history of daily low-grade fevers, dry cough, loss of appetite, and a 5-pound weight loss. She received 2 separate 5-day courses of azithromycin as an outpatient with no improvement in her symptoms. Ten years before presentation, the patient was diagnosed with Lyme disease. A Western blot for Borrelia burgdorferi-specific immunoglobulin IgM antibodies detected 2 of 3 bands and was interpreted as positive, but a Western blot for IgG antibodies was negative. She was treated with doxycycline for 3 weeks. The patient continued to have polyarthralgia and fatigue and reported that she was diagnosed with chronic Lyme disease 5 years before presentation. She had an indwelling peripherally inserted central catheter (PICC) in place for the previous 22 months for the administration of intravenous (IV) antibiotics that were prescribed to treat chronic Lyme disease. She received a 10-month course of IV ceftriaxone and then a 6-month course of IV doxycycline. She was also prescribed intermittent courses of other agents, such as oral disulfuram and oral doxycycline, for the treatment of chronic Lyme disease. The patient has a history of Ehlers-Danlos syndrome, gastrointestinal malabsorption, which necessitates enteral feeding through a nasogastric tube, postural orthostatic tachycardia syndrome, and psychogenic nonepileptic seizures. She reported that the administration of sulfa drugs caused hives when she was a child. On the day of presentation, the patient had a temperature of 38.1°C and a heart rate of 103 beats per minute. A PICC line was in place in the right arm. The rest of her physical exam was normal. Kidney function, serum glucose, a complete blood count with differential, and liver enzyme tests were all within the normal range. Tests for SARS-CoV-2 and human immunodeficiency virus were negative. A chest x-ray was normal. A chest computed tomography (CT) scan showed multiple scattered pulmonary nodules concerning for emboli (Figure 1). Branching, Gram-positive bacilli grew in 4 of 4 blood cultures bottles taken on the day of her admission to the hospital (Figure 2). The organism stained with a modified acid-fast bacilli stain and was identified as Nocardia nova (Figure 3). The multiple, bilateral small nodular opacities seen on CT scan of the chest were consistent with septic pulmonary emboli. A transthoracic echocardiogram was normal, but transesophageal echocardiogram showed a 3-mm × 1-mm mobile vegetation on the mitral valve. A magnetic resonance image of the brain was normal. Thus, this patient was diagnosed with PICC-associated N nova septic pulmonary emboli and endocarditis.
Figure 1. Computed tomography of the patient’s chest. Multiple scattered nodules in the periphery of the lungs (arrow) were identified.
Figure 2. Gram stain of the organism growing in blood culture.
Figure 3. A modified acid-fast bacilli stain of the organism growing in blood culture.
PATIENT CONSENT
Consent to publish to this case report was obtained from the patient. The article type (“ID Teaching Cases”) does not require formal approval by an ethics committee.
DISCUSSION
In this study, we present the case of a patient with a severe complication associated with the unscientific use of IV antibiotics for management of persistent symptoms and a diagnosis of Lyme disease. Several randomized controlled trials have compared long-term antibiotics with placebo for the treatment of these patients [1–4]. In each of these studies, longer term antibiotic treatment did not improve symptoms in patients compared with placebo. However, complications of long-term antibiotic treatment for Lyme disease include PICC-line associated bacteremia, which can be life threatening [5]. Despite these data and a recommendation from the Infectious Diseases Society of America against the use of extended courses of antibiotics in this setting [6], some clinicians still prescribe such therapies [7, 8].
The patient was initially diagnosed with Lyme disease when an immunoblot for B burgdorferi-specific IgM antibodies was positive; however, the immunoblot for IgG antibodies was negative. Borrelia burgdorferi IgM immunoblots have poor specificity, particularly when the IgG test is negative, and can lead to the misdiagnosis of Lyme disease [9]. Thus, an isolated positive B burgdorferi IgM immunoblot should not be used to diagnose Lyme disease in patients who have had symptoms for more than 6 weeks.
Nocardia sp are Gram-positive, beaded, weakly acid-fast, branching bacilli that are uncommon causes of bacteremia and endocarditis [10]. It is interesting to note that N nova was the most common pathogen in a case series of patients with Nocardia sp bacteremia and an underlying cancer, recovered in 6 of 17 cases [11]. Ten of 17 patients in this study had central catheter-associated bacteremia, and the authors found that Nocardia sp promoted biofilm formation on central venous catheters in vitro [11]. Patients with central venous catheter-associated Nocardia sp bacteremia responded well to catheter removal and antibiotic therapy [11].
Data from randomized controlled trials are not available to guide treatment for nocardiosis. Based on cumulative clinical experience, trimethoprim-sulfamethoxazole is the mainstay of therapy for patients with nocardiosis. Patients who are allergic to trimethoprim-sulfamethoxazole should be desensitized to enable treatment with this agent. Most authorities recommend that severe infection with Nocardia sp, such as endocarditis in this patient, be managed with combination therapy. For severe disease outside the central nervous system, the combination of trimethoprim-sulfamethoxazole and amikacin for initial therapy is recommended until antimicrobial susceptibility data are available. The combination of imipenem and amikacin is also used in this setting. The optimal duration of therapy for patients with nocardiosis is not known. Shorter antibiotic courses for Nocardia sp infection are associated with a high risk of relapse, even in immunocompetent hosts. Thus, most infectious disease clinicians recommend that patients with severe nocardiosis be treated with antibiotics for 6 to 12 months.
FOLLOW-UP
The patient’s PICC line was removed and she was started on imipenem, given her history of a severe allergy to trimethoprim-sulfamethoxazole. On the second hospital day, the patient’s fever resolved, and her symptoms improved markedly. During her hospital stay, she was desensitized to trimethoprim-sulfamethoxazole. She was discharged on trimethoprim-sulfamethoxazole and amikacin while awaiting the identification and susceptibility of the Nocardia sp. Ten days into therapy, the patient developed a diffuse maculopapular drug rash. The trimethoprim-sulfamethoxazole was discontinued, imipenem was restarted, and the amikacin therapy continued. Her rash resolved. After 4 weeks of empiric antibiotic treatment, the organism was identified as N nova that was sensitive to trimethoprim-sulfamethoxazole, amikacin, ceftriaxone, imipenem, and linezolid, but resistant to tetracyclines, fluoroquinolones, and amoxicillin/clavulanate. Imipenem and amikacin were discontinued, and the patient was started on ceftriaxone, given her history of malabsorption and inability to tolerate oral antibiotics. A 6-month course of ceftriaxone is planned for this patient, after which a CT scan of the chest will be obtained to ensure resolution of the septic emboli. The PICC line used to administer ceftriaxone will then be removed.
Acknowledgments
Financial support. R. P.-W.’s research is funded by R01 AI130289 from the National Institute of Allergy and Infectious Diseases and an Innovator Award from the Kenneth Rainin Foundation.
Potential conflicts of interests. All authors have no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | CEFTRIAXONE, DISULFIRAM, DOXYCYCLINE | DrugsGivenReaction | CC BY-NC-ND | 33728358 | 19,670,043 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nocardia sepsis'. | Peripherally Inserted Central Catheter-Associated Nocardia nova Endocarditis in a Patient Receiving Intravenous Antibiotics for Chronic Lyme Disease.
Long-term antibiotics are not effective for the therapy of patients with persistent symptoms and a history of Lyme disease. However, some clinicians still prescribe these therapies. We present a case of peripherally inserted central catheter-associated Nocardia nova endocarditis in a patient who had been receiving intravenous antibiotics for the management of chronic Lyme disease. This case highlights an important risk associated with the unscientific use of indwelling peripheral catheters and intravenous antibiotics for the management of such patients.
PRESENTATION OF CASE
A 34-year-old female from New England presented with a 1-month history of daily low-grade fevers, dry cough, loss of appetite, and a 5-pound weight loss. She received 2 separate 5-day courses of azithromycin as an outpatient with no improvement in her symptoms. Ten years before presentation, the patient was diagnosed with Lyme disease. A Western blot for Borrelia burgdorferi-specific immunoglobulin IgM antibodies detected 2 of 3 bands and was interpreted as positive, but a Western blot for IgG antibodies was negative. She was treated with doxycycline for 3 weeks. The patient continued to have polyarthralgia and fatigue and reported that she was diagnosed with chronic Lyme disease 5 years before presentation. She had an indwelling peripherally inserted central catheter (PICC) in place for the previous 22 months for the administration of intravenous (IV) antibiotics that were prescribed to treat chronic Lyme disease. She received a 10-month course of IV ceftriaxone and then a 6-month course of IV doxycycline. She was also prescribed intermittent courses of other agents, such as oral disulfuram and oral doxycycline, for the treatment of chronic Lyme disease. The patient has a history of Ehlers-Danlos syndrome, gastrointestinal malabsorption, which necessitates enteral feeding through a nasogastric tube, postural orthostatic tachycardia syndrome, and psychogenic nonepileptic seizures. She reported that the administration of sulfa drugs caused hives when she was a child. On the day of presentation, the patient had a temperature of 38.1°C and a heart rate of 103 beats per minute. A PICC line was in place in the right arm. The rest of her physical exam was normal. Kidney function, serum glucose, a complete blood count with differential, and liver enzyme tests were all within the normal range. Tests for SARS-CoV-2 and human immunodeficiency virus were negative. A chest x-ray was normal. A chest computed tomography (CT) scan showed multiple scattered pulmonary nodules concerning for emboli (Figure 1). Branching, Gram-positive bacilli grew in 4 of 4 blood cultures bottles taken on the day of her admission to the hospital (Figure 2). The organism stained with a modified acid-fast bacilli stain and was identified as Nocardia nova (Figure 3). The multiple, bilateral small nodular opacities seen on CT scan of the chest were consistent with septic pulmonary emboli. A transthoracic echocardiogram was normal, but transesophageal echocardiogram showed a 3-mm × 1-mm mobile vegetation on the mitral valve. A magnetic resonance image of the brain was normal. Thus, this patient was diagnosed with PICC-associated N nova septic pulmonary emboli and endocarditis.
Figure 1. Computed tomography of the patient’s chest. Multiple scattered nodules in the periphery of the lungs (arrow) were identified.
Figure 2. Gram stain of the organism growing in blood culture.
Figure 3. A modified acid-fast bacilli stain of the organism growing in blood culture.
PATIENT CONSENT
Consent to publish to this case report was obtained from the patient. The article type (“ID Teaching Cases”) does not require formal approval by an ethics committee.
DISCUSSION
In this study, we present the case of a patient with a severe complication associated with the unscientific use of IV antibiotics for management of persistent symptoms and a diagnosis of Lyme disease. Several randomized controlled trials have compared long-term antibiotics with placebo for the treatment of these patients [1–4]. In each of these studies, longer term antibiotic treatment did not improve symptoms in patients compared with placebo. However, complications of long-term antibiotic treatment for Lyme disease include PICC-line associated bacteremia, which can be life threatening [5]. Despite these data and a recommendation from the Infectious Diseases Society of America against the use of extended courses of antibiotics in this setting [6], some clinicians still prescribe such therapies [7, 8].
The patient was initially diagnosed with Lyme disease when an immunoblot for B burgdorferi-specific IgM antibodies was positive; however, the immunoblot for IgG antibodies was negative. Borrelia burgdorferi IgM immunoblots have poor specificity, particularly when the IgG test is negative, and can lead to the misdiagnosis of Lyme disease [9]. Thus, an isolated positive B burgdorferi IgM immunoblot should not be used to diagnose Lyme disease in patients who have had symptoms for more than 6 weeks.
Nocardia sp are Gram-positive, beaded, weakly acid-fast, branching bacilli that are uncommon causes of bacteremia and endocarditis [10]. It is interesting to note that N nova was the most common pathogen in a case series of patients with Nocardia sp bacteremia and an underlying cancer, recovered in 6 of 17 cases [11]. Ten of 17 patients in this study had central catheter-associated bacteremia, and the authors found that Nocardia sp promoted biofilm formation on central venous catheters in vitro [11]. Patients with central venous catheter-associated Nocardia sp bacteremia responded well to catheter removal and antibiotic therapy [11].
Data from randomized controlled trials are not available to guide treatment for nocardiosis. Based on cumulative clinical experience, trimethoprim-sulfamethoxazole is the mainstay of therapy for patients with nocardiosis. Patients who are allergic to trimethoprim-sulfamethoxazole should be desensitized to enable treatment with this agent. Most authorities recommend that severe infection with Nocardia sp, such as endocarditis in this patient, be managed with combination therapy. For severe disease outside the central nervous system, the combination of trimethoprim-sulfamethoxazole and amikacin for initial therapy is recommended until antimicrobial susceptibility data are available. The combination of imipenem and amikacin is also used in this setting. The optimal duration of therapy for patients with nocardiosis is not known. Shorter antibiotic courses for Nocardia sp infection are associated with a high risk of relapse, even in immunocompetent hosts. Thus, most infectious disease clinicians recommend that patients with severe nocardiosis be treated with antibiotics for 6 to 12 months.
FOLLOW-UP
The patient’s PICC line was removed and she was started on imipenem, given her history of a severe allergy to trimethoprim-sulfamethoxazole. On the second hospital day, the patient’s fever resolved, and her symptoms improved markedly. During her hospital stay, she was desensitized to trimethoprim-sulfamethoxazole. She was discharged on trimethoprim-sulfamethoxazole and amikacin while awaiting the identification and susceptibility of the Nocardia sp. Ten days into therapy, the patient developed a diffuse maculopapular drug rash. The trimethoprim-sulfamethoxazole was discontinued, imipenem was restarted, and the amikacin therapy continued. Her rash resolved. After 4 weeks of empiric antibiotic treatment, the organism was identified as N nova that was sensitive to trimethoprim-sulfamethoxazole, amikacin, ceftriaxone, imipenem, and linezolid, but resistant to tetracyclines, fluoroquinolones, and amoxicillin/clavulanate. Imipenem and amikacin were discontinued, and the patient was started on ceftriaxone, given her history of malabsorption and inability to tolerate oral antibiotics. A 6-month course of ceftriaxone is planned for this patient, after which a CT scan of the chest will be obtained to ensure resolution of the septic emboli. The PICC line used to administer ceftriaxone will then be removed.
Acknowledgments
Financial support. R. P.-W.’s research is funded by R01 AI130289 from the National Institute of Allergy and Infectious Diseases and an Innovator Award from the Kenneth Rainin Foundation.
Potential conflicts of interests. All authors have no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | CEFTRIAXONE, DISULFIRAM, DOXYCYCLINE | DrugsGivenReaction | CC BY-NC-ND | 33728358 | 19,670,043 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rash maculo-papular'. | Peripherally Inserted Central Catheter-Associated Nocardia nova Endocarditis in a Patient Receiving Intravenous Antibiotics for Chronic Lyme Disease.
Long-term antibiotics are not effective for the therapy of patients with persistent symptoms and a history of Lyme disease. However, some clinicians still prescribe these therapies. We present a case of peripherally inserted central catheter-associated Nocardia nova endocarditis in a patient who had been receiving intravenous antibiotics for the management of chronic Lyme disease. This case highlights an important risk associated with the unscientific use of indwelling peripheral catheters and intravenous antibiotics for the management of such patients.
PRESENTATION OF CASE
A 34-year-old female from New England presented with a 1-month history of daily low-grade fevers, dry cough, loss of appetite, and a 5-pound weight loss. She received 2 separate 5-day courses of azithromycin as an outpatient with no improvement in her symptoms. Ten years before presentation, the patient was diagnosed with Lyme disease. A Western blot for Borrelia burgdorferi-specific immunoglobulin IgM antibodies detected 2 of 3 bands and was interpreted as positive, but a Western blot for IgG antibodies was negative. She was treated with doxycycline for 3 weeks. The patient continued to have polyarthralgia and fatigue and reported that she was diagnosed with chronic Lyme disease 5 years before presentation. She had an indwelling peripherally inserted central catheter (PICC) in place for the previous 22 months for the administration of intravenous (IV) antibiotics that were prescribed to treat chronic Lyme disease. She received a 10-month course of IV ceftriaxone and then a 6-month course of IV doxycycline. She was also prescribed intermittent courses of other agents, such as oral disulfuram and oral doxycycline, for the treatment of chronic Lyme disease. The patient has a history of Ehlers-Danlos syndrome, gastrointestinal malabsorption, which necessitates enteral feeding through a nasogastric tube, postural orthostatic tachycardia syndrome, and psychogenic nonepileptic seizures. She reported that the administration of sulfa drugs caused hives when she was a child. On the day of presentation, the patient had a temperature of 38.1°C and a heart rate of 103 beats per minute. A PICC line was in place in the right arm. The rest of her physical exam was normal. Kidney function, serum glucose, a complete blood count with differential, and liver enzyme tests were all within the normal range. Tests for SARS-CoV-2 and human immunodeficiency virus were negative. A chest x-ray was normal. A chest computed tomography (CT) scan showed multiple scattered pulmonary nodules concerning for emboli (Figure 1). Branching, Gram-positive bacilli grew in 4 of 4 blood cultures bottles taken on the day of her admission to the hospital (Figure 2). The organism stained with a modified acid-fast bacilli stain and was identified as Nocardia nova (Figure 3). The multiple, bilateral small nodular opacities seen on CT scan of the chest were consistent with septic pulmonary emboli. A transthoracic echocardiogram was normal, but transesophageal echocardiogram showed a 3-mm × 1-mm mobile vegetation on the mitral valve. A magnetic resonance image of the brain was normal. Thus, this patient was diagnosed with PICC-associated N nova septic pulmonary emboli and endocarditis.
Figure 1. Computed tomography of the patient’s chest. Multiple scattered nodules in the periphery of the lungs (arrow) were identified.
Figure 2. Gram stain of the organism growing in blood culture.
Figure 3. A modified acid-fast bacilli stain of the organism growing in blood culture.
PATIENT CONSENT
Consent to publish to this case report was obtained from the patient. The article type (“ID Teaching Cases”) does not require formal approval by an ethics committee.
DISCUSSION
In this study, we present the case of a patient with a severe complication associated with the unscientific use of IV antibiotics for management of persistent symptoms and a diagnosis of Lyme disease. Several randomized controlled trials have compared long-term antibiotics with placebo for the treatment of these patients [1–4]. In each of these studies, longer term antibiotic treatment did not improve symptoms in patients compared with placebo. However, complications of long-term antibiotic treatment for Lyme disease include PICC-line associated bacteremia, which can be life threatening [5]. Despite these data and a recommendation from the Infectious Diseases Society of America against the use of extended courses of antibiotics in this setting [6], some clinicians still prescribe such therapies [7, 8].
The patient was initially diagnosed with Lyme disease when an immunoblot for B burgdorferi-specific IgM antibodies was positive; however, the immunoblot for IgG antibodies was negative. Borrelia burgdorferi IgM immunoblots have poor specificity, particularly when the IgG test is negative, and can lead to the misdiagnosis of Lyme disease [9]. Thus, an isolated positive B burgdorferi IgM immunoblot should not be used to diagnose Lyme disease in patients who have had symptoms for more than 6 weeks.
Nocardia sp are Gram-positive, beaded, weakly acid-fast, branching bacilli that are uncommon causes of bacteremia and endocarditis [10]. It is interesting to note that N nova was the most common pathogen in a case series of patients with Nocardia sp bacteremia and an underlying cancer, recovered in 6 of 17 cases [11]. Ten of 17 patients in this study had central catheter-associated bacteremia, and the authors found that Nocardia sp promoted biofilm formation on central venous catheters in vitro [11]. Patients with central venous catheter-associated Nocardia sp bacteremia responded well to catheter removal and antibiotic therapy [11].
Data from randomized controlled trials are not available to guide treatment for nocardiosis. Based on cumulative clinical experience, trimethoprim-sulfamethoxazole is the mainstay of therapy for patients with nocardiosis. Patients who are allergic to trimethoprim-sulfamethoxazole should be desensitized to enable treatment with this agent. Most authorities recommend that severe infection with Nocardia sp, such as endocarditis in this patient, be managed with combination therapy. For severe disease outside the central nervous system, the combination of trimethoprim-sulfamethoxazole and amikacin for initial therapy is recommended until antimicrobial susceptibility data are available. The combination of imipenem and amikacin is also used in this setting. The optimal duration of therapy for patients with nocardiosis is not known. Shorter antibiotic courses for Nocardia sp infection are associated with a high risk of relapse, even in immunocompetent hosts. Thus, most infectious disease clinicians recommend that patients with severe nocardiosis be treated with antibiotics for 6 to 12 months.
FOLLOW-UP
The patient’s PICC line was removed and she was started on imipenem, given her history of a severe allergy to trimethoprim-sulfamethoxazole. On the second hospital day, the patient’s fever resolved, and her symptoms improved markedly. During her hospital stay, she was desensitized to trimethoprim-sulfamethoxazole. She was discharged on trimethoprim-sulfamethoxazole and amikacin while awaiting the identification and susceptibility of the Nocardia sp. Ten days into therapy, the patient developed a diffuse maculopapular drug rash. The trimethoprim-sulfamethoxazole was discontinued, imipenem was restarted, and the amikacin therapy continued. Her rash resolved. After 4 weeks of empiric antibiotic treatment, the organism was identified as N nova that was sensitive to trimethoprim-sulfamethoxazole, amikacin, ceftriaxone, imipenem, and linezolid, but resistant to tetracyclines, fluoroquinolones, and amoxicillin/clavulanate. Imipenem and amikacin were discontinued, and the patient was started on ceftriaxone, given her history of malabsorption and inability to tolerate oral antibiotics. A 6-month course of ceftriaxone is planned for this patient, after which a CT scan of the chest will be obtained to ensure resolution of the septic emboli. The PICC line used to administer ceftriaxone will then be removed.
Acknowledgments
Financial support. R. P.-W.’s research is funded by R01 AI130289 from the National Institute of Allergy and Infectious Diseases and an Innovator Award from the Kenneth Rainin Foundation.
Potential conflicts of interests. All authors have no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | AMIKACIN, AZITHROMYCIN ANHYDROUS, CEFTRIAXONE, DISULFIRAM, DOXYCYCLINE, SULFAMETHOXAZOLE\TRIMETHOPRIM | DrugsGivenReaction | CC BY-NC-ND | 33728358 | 19,724,199 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vascular device infection'. | Peripherally Inserted Central Catheter-Associated Nocardia nova Endocarditis in a Patient Receiving Intravenous Antibiotics for Chronic Lyme Disease.
Long-term antibiotics are not effective for the therapy of patients with persistent symptoms and a history of Lyme disease. However, some clinicians still prescribe these therapies. We present a case of peripherally inserted central catheter-associated Nocardia nova endocarditis in a patient who had been receiving intravenous antibiotics for the management of chronic Lyme disease. This case highlights an important risk associated with the unscientific use of indwelling peripheral catheters and intravenous antibiotics for the management of such patients.
PRESENTATION OF CASE
A 34-year-old female from New England presented with a 1-month history of daily low-grade fevers, dry cough, loss of appetite, and a 5-pound weight loss. She received 2 separate 5-day courses of azithromycin as an outpatient with no improvement in her symptoms. Ten years before presentation, the patient was diagnosed with Lyme disease. A Western blot for Borrelia burgdorferi-specific immunoglobulin IgM antibodies detected 2 of 3 bands and was interpreted as positive, but a Western blot for IgG antibodies was negative. She was treated with doxycycline for 3 weeks. The patient continued to have polyarthralgia and fatigue and reported that she was diagnosed with chronic Lyme disease 5 years before presentation. She had an indwelling peripherally inserted central catheter (PICC) in place for the previous 22 months for the administration of intravenous (IV) antibiotics that were prescribed to treat chronic Lyme disease. She received a 10-month course of IV ceftriaxone and then a 6-month course of IV doxycycline. She was also prescribed intermittent courses of other agents, such as oral disulfuram and oral doxycycline, for the treatment of chronic Lyme disease. The patient has a history of Ehlers-Danlos syndrome, gastrointestinal malabsorption, which necessitates enteral feeding through a nasogastric tube, postural orthostatic tachycardia syndrome, and psychogenic nonepileptic seizures. She reported that the administration of sulfa drugs caused hives when she was a child. On the day of presentation, the patient had a temperature of 38.1°C and a heart rate of 103 beats per minute. A PICC line was in place in the right arm. The rest of her physical exam was normal. Kidney function, serum glucose, a complete blood count with differential, and liver enzyme tests were all within the normal range. Tests for SARS-CoV-2 and human immunodeficiency virus were negative. A chest x-ray was normal. A chest computed tomography (CT) scan showed multiple scattered pulmonary nodules concerning for emboli (Figure 1). Branching, Gram-positive bacilli grew in 4 of 4 blood cultures bottles taken on the day of her admission to the hospital (Figure 2). The organism stained with a modified acid-fast bacilli stain and was identified as Nocardia nova (Figure 3). The multiple, bilateral small nodular opacities seen on CT scan of the chest were consistent with septic pulmonary emboli. A transthoracic echocardiogram was normal, but transesophageal echocardiogram showed a 3-mm × 1-mm mobile vegetation on the mitral valve. A magnetic resonance image of the brain was normal. Thus, this patient was diagnosed with PICC-associated N nova septic pulmonary emboli and endocarditis.
Figure 1. Computed tomography of the patient’s chest. Multiple scattered nodules in the periphery of the lungs (arrow) were identified.
Figure 2. Gram stain of the organism growing in blood culture.
Figure 3. A modified acid-fast bacilli stain of the organism growing in blood culture.
PATIENT CONSENT
Consent to publish to this case report was obtained from the patient. The article type (“ID Teaching Cases”) does not require formal approval by an ethics committee.
DISCUSSION
In this study, we present the case of a patient with a severe complication associated with the unscientific use of IV antibiotics for management of persistent symptoms and a diagnosis of Lyme disease. Several randomized controlled trials have compared long-term antibiotics with placebo for the treatment of these patients [1–4]. In each of these studies, longer term antibiotic treatment did not improve symptoms in patients compared with placebo. However, complications of long-term antibiotic treatment for Lyme disease include PICC-line associated bacteremia, which can be life threatening [5]. Despite these data and a recommendation from the Infectious Diseases Society of America against the use of extended courses of antibiotics in this setting [6], some clinicians still prescribe such therapies [7, 8].
The patient was initially diagnosed with Lyme disease when an immunoblot for B burgdorferi-specific IgM antibodies was positive; however, the immunoblot for IgG antibodies was negative. Borrelia burgdorferi IgM immunoblots have poor specificity, particularly when the IgG test is negative, and can lead to the misdiagnosis of Lyme disease [9]. Thus, an isolated positive B burgdorferi IgM immunoblot should not be used to diagnose Lyme disease in patients who have had symptoms for more than 6 weeks.
Nocardia sp are Gram-positive, beaded, weakly acid-fast, branching bacilli that are uncommon causes of bacteremia and endocarditis [10]. It is interesting to note that N nova was the most common pathogen in a case series of patients with Nocardia sp bacteremia and an underlying cancer, recovered in 6 of 17 cases [11]. Ten of 17 patients in this study had central catheter-associated bacteremia, and the authors found that Nocardia sp promoted biofilm formation on central venous catheters in vitro [11]. Patients with central venous catheter-associated Nocardia sp bacteremia responded well to catheter removal and antibiotic therapy [11].
Data from randomized controlled trials are not available to guide treatment for nocardiosis. Based on cumulative clinical experience, trimethoprim-sulfamethoxazole is the mainstay of therapy for patients with nocardiosis. Patients who are allergic to trimethoprim-sulfamethoxazole should be desensitized to enable treatment with this agent. Most authorities recommend that severe infection with Nocardia sp, such as endocarditis in this patient, be managed with combination therapy. For severe disease outside the central nervous system, the combination of trimethoprim-sulfamethoxazole and amikacin for initial therapy is recommended until antimicrobial susceptibility data are available. The combination of imipenem and amikacin is also used in this setting. The optimal duration of therapy for patients with nocardiosis is not known. Shorter antibiotic courses for Nocardia sp infection are associated with a high risk of relapse, even in immunocompetent hosts. Thus, most infectious disease clinicians recommend that patients with severe nocardiosis be treated with antibiotics for 6 to 12 months.
FOLLOW-UP
The patient’s PICC line was removed and she was started on imipenem, given her history of a severe allergy to trimethoprim-sulfamethoxazole. On the second hospital day, the patient’s fever resolved, and her symptoms improved markedly. During her hospital stay, she was desensitized to trimethoprim-sulfamethoxazole. She was discharged on trimethoprim-sulfamethoxazole and amikacin while awaiting the identification and susceptibility of the Nocardia sp. Ten days into therapy, the patient developed a diffuse maculopapular drug rash. The trimethoprim-sulfamethoxazole was discontinued, imipenem was restarted, and the amikacin therapy continued. Her rash resolved. After 4 weeks of empiric antibiotic treatment, the organism was identified as N nova that was sensitive to trimethoprim-sulfamethoxazole, amikacin, ceftriaxone, imipenem, and linezolid, but resistant to tetracyclines, fluoroquinolones, and amoxicillin/clavulanate. Imipenem and amikacin were discontinued, and the patient was started on ceftriaxone, given her history of malabsorption and inability to tolerate oral antibiotics. A 6-month course of ceftriaxone is planned for this patient, after which a CT scan of the chest will be obtained to ensure resolution of the septic emboli. The PICC line used to administer ceftriaxone will then be removed.
Acknowledgments
Financial support. R. P.-W.’s research is funded by R01 AI130289 from the National Institute of Allergy and Infectious Diseases and an Innovator Award from the Kenneth Rainin Foundation.
Potential conflicts of interests. All authors have no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | CEFTRIAXONE, DISULFIRAM, DOXYCYCLINE | DrugsGivenReaction | CC BY-NC-ND | 33728358 | 19,670,043 | 2021-03 |
What was the administration route of drug 'CEFTRIAXONE'? | Peripherally Inserted Central Catheter-Associated Nocardia nova Endocarditis in a Patient Receiving Intravenous Antibiotics for Chronic Lyme Disease.
Long-term antibiotics are not effective for the therapy of patients with persistent symptoms and a history of Lyme disease. However, some clinicians still prescribe these therapies. We present a case of peripherally inserted central catheter-associated Nocardia nova endocarditis in a patient who had been receiving intravenous antibiotics for the management of chronic Lyme disease. This case highlights an important risk associated with the unscientific use of indwelling peripheral catheters and intravenous antibiotics for the management of such patients.
PRESENTATION OF CASE
A 34-year-old female from New England presented with a 1-month history of daily low-grade fevers, dry cough, loss of appetite, and a 5-pound weight loss. She received 2 separate 5-day courses of azithromycin as an outpatient with no improvement in her symptoms. Ten years before presentation, the patient was diagnosed with Lyme disease. A Western blot for Borrelia burgdorferi-specific immunoglobulin IgM antibodies detected 2 of 3 bands and was interpreted as positive, but a Western blot for IgG antibodies was negative. She was treated with doxycycline for 3 weeks. The patient continued to have polyarthralgia and fatigue and reported that she was diagnosed with chronic Lyme disease 5 years before presentation. She had an indwelling peripherally inserted central catheter (PICC) in place for the previous 22 months for the administration of intravenous (IV) antibiotics that were prescribed to treat chronic Lyme disease. She received a 10-month course of IV ceftriaxone and then a 6-month course of IV doxycycline. She was also prescribed intermittent courses of other agents, such as oral disulfuram and oral doxycycline, for the treatment of chronic Lyme disease. The patient has a history of Ehlers-Danlos syndrome, gastrointestinal malabsorption, which necessitates enteral feeding through a nasogastric tube, postural orthostatic tachycardia syndrome, and psychogenic nonepileptic seizures. She reported that the administration of sulfa drugs caused hives when she was a child. On the day of presentation, the patient had a temperature of 38.1°C and a heart rate of 103 beats per minute. A PICC line was in place in the right arm. The rest of her physical exam was normal. Kidney function, serum glucose, a complete blood count with differential, and liver enzyme tests were all within the normal range. Tests for SARS-CoV-2 and human immunodeficiency virus were negative. A chest x-ray was normal. A chest computed tomography (CT) scan showed multiple scattered pulmonary nodules concerning for emboli (Figure 1). Branching, Gram-positive bacilli grew in 4 of 4 blood cultures bottles taken on the day of her admission to the hospital (Figure 2). The organism stained with a modified acid-fast bacilli stain and was identified as Nocardia nova (Figure 3). The multiple, bilateral small nodular opacities seen on CT scan of the chest were consistent with septic pulmonary emboli. A transthoracic echocardiogram was normal, but transesophageal echocardiogram showed a 3-mm × 1-mm mobile vegetation on the mitral valve. A magnetic resonance image of the brain was normal. Thus, this patient was diagnosed with PICC-associated N nova septic pulmonary emboli and endocarditis.
Figure 1. Computed tomography of the patient’s chest. Multiple scattered nodules in the periphery of the lungs (arrow) were identified.
Figure 2. Gram stain of the organism growing in blood culture.
Figure 3. A modified acid-fast bacilli stain of the organism growing in blood culture.
PATIENT CONSENT
Consent to publish to this case report was obtained from the patient. The article type (“ID Teaching Cases”) does not require formal approval by an ethics committee.
DISCUSSION
In this study, we present the case of a patient with a severe complication associated with the unscientific use of IV antibiotics for management of persistent symptoms and a diagnosis of Lyme disease. Several randomized controlled trials have compared long-term antibiotics with placebo for the treatment of these patients [1–4]. In each of these studies, longer term antibiotic treatment did not improve symptoms in patients compared with placebo. However, complications of long-term antibiotic treatment for Lyme disease include PICC-line associated bacteremia, which can be life threatening [5]. Despite these data and a recommendation from the Infectious Diseases Society of America against the use of extended courses of antibiotics in this setting [6], some clinicians still prescribe such therapies [7, 8].
The patient was initially diagnosed with Lyme disease when an immunoblot for B burgdorferi-specific IgM antibodies was positive; however, the immunoblot for IgG antibodies was negative. Borrelia burgdorferi IgM immunoblots have poor specificity, particularly when the IgG test is negative, and can lead to the misdiagnosis of Lyme disease [9]. Thus, an isolated positive B burgdorferi IgM immunoblot should not be used to diagnose Lyme disease in patients who have had symptoms for more than 6 weeks.
Nocardia sp are Gram-positive, beaded, weakly acid-fast, branching bacilli that are uncommon causes of bacteremia and endocarditis [10]. It is interesting to note that N nova was the most common pathogen in a case series of patients with Nocardia sp bacteremia and an underlying cancer, recovered in 6 of 17 cases [11]. Ten of 17 patients in this study had central catheter-associated bacteremia, and the authors found that Nocardia sp promoted biofilm formation on central venous catheters in vitro [11]. Patients with central venous catheter-associated Nocardia sp bacteremia responded well to catheter removal and antibiotic therapy [11].
Data from randomized controlled trials are not available to guide treatment for nocardiosis. Based on cumulative clinical experience, trimethoprim-sulfamethoxazole is the mainstay of therapy for patients with nocardiosis. Patients who are allergic to trimethoprim-sulfamethoxazole should be desensitized to enable treatment with this agent. Most authorities recommend that severe infection with Nocardia sp, such as endocarditis in this patient, be managed with combination therapy. For severe disease outside the central nervous system, the combination of trimethoprim-sulfamethoxazole and amikacin for initial therapy is recommended until antimicrobial susceptibility data are available. The combination of imipenem and amikacin is also used in this setting. The optimal duration of therapy for patients with nocardiosis is not known. Shorter antibiotic courses for Nocardia sp infection are associated with a high risk of relapse, even in immunocompetent hosts. Thus, most infectious disease clinicians recommend that patients with severe nocardiosis be treated with antibiotics for 6 to 12 months.
FOLLOW-UP
The patient’s PICC line was removed and she was started on imipenem, given her history of a severe allergy to trimethoprim-sulfamethoxazole. On the second hospital day, the patient’s fever resolved, and her symptoms improved markedly. During her hospital stay, she was desensitized to trimethoprim-sulfamethoxazole. She was discharged on trimethoprim-sulfamethoxazole and amikacin while awaiting the identification and susceptibility of the Nocardia sp. Ten days into therapy, the patient developed a diffuse maculopapular drug rash. The trimethoprim-sulfamethoxazole was discontinued, imipenem was restarted, and the amikacin therapy continued. Her rash resolved. After 4 weeks of empiric antibiotic treatment, the organism was identified as N nova that was sensitive to trimethoprim-sulfamethoxazole, amikacin, ceftriaxone, imipenem, and linezolid, but resistant to tetracyclines, fluoroquinolones, and amoxicillin/clavulanate. Imipenem and amikacin were discontinued, and the patient was started on ceftriaxone, given her history of malabsorption and inability to tolerate oral antibiotics. A 6-month course of ceftriaxone is planned for this patient, after which a CT scan of the chest will be obtained to ensure resolution of the septic emboli. The PICC line used to administer ceftriaxone will then be removed.
Acknowledgments
Financial support. R. P.-W.’s research is funded by R01 AI130289 from the National Institute of Allergy and Infectious Diseases and an Innovator Award from the Kenneth Rainin Foundation.
Potential conflicts of interests. All authors have no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33728358 | 19,724,199 | 2021-03 |
What was the administration route of drug 'DISULFIRAM'? | Peripherally Inserted Central Catheter-Associated Nocardia nova Endocarditis in a Patient Receiving Intravenous Antibiotics for Chronic Lyme Disease.
Long-term antibiotics are not effective for the therapy of patients with persistent symptoms and a history of Lyme disease. However, some clinicians still prescribe these therapies. We present a case of peripherally inserted central catheter-associated Nocardia nova endocarditis in a patient who had been receiving intravenous antibiotics for the management of chronic Lyme disease. This case highlights an important risk associated with the unscientific use of indwelling peripheral catheters and intravenous antibiotics for the management of such patients.
PRESENTATION OF CASE
A 34-year-old female from New England presented with a 1-month history of daily low-grade fevers, dry cough, loss of appetite, and a 5-pound weight loss. She received 2 separate 5-day courses of azithromycin as an outpatient with no improvement in her symptoms. Ten years before presentation, the patient was diagnosed with Lyme disease. A Western blot for Borrelia burgdorferi-specific immunoglobulin IgM antibodies detected 2 of 3 bands and was interpreted as positive, but a Western blot for IgG antibodies was negative. She was treated with doxycycline for 3 weeks. The patient continued to have polyarthralgia and fatigue and reported that she was diagnosed with chronic Lyme disease 5 years before presentation. She had an indwelling peripherally inserted central catheter (PICC) in place for the previous 22 months for the administration of intravenous (IV) antibiotics that were prescribed to treat chronic Lyme disease. She received a 10-month course of IV ceftriaxone and then a 6-month course of IV doxycycline. She was also prescribed intermittent courses of other agents, such as oral disulfuram and oral doxycycline, for the treatment of chronic Lyme disease. The patient has a history of Ehlers-Danlos syndrome, gastrointestinal malabsorption, which necessitates enteral feeding through a nasogastric tube, postural orthostatic tachycardia syndrome, and psychogenic nonepileptic seizures. She reported that the administration of sulfa drugs caused hives when she was a child. On the day of presentation, the patient had a temperature of 38.1°C and a heart rate of 103 beats per minute. A PICC line was in place in the right arm. The rest of her physical exam was normal. Kidney function, serum glucose, a complete blood count with differential, and liver enzyme tests were all within the normal range. Tests for SARS-CoV-2 and human immunodeficiency virus were negative. A chest x-ray was normal. A chest computed tomography (CT) scan showed multiple scattered pulmonary nodules concerning for emboli (Figure 1). Branching, Gram-positive bacilli grew in 4 of 4 blood cultures bottles taken on the day of her admission to the hospital (Figure 2). The organism stained with a modified acid-fast bacilli stain and was identified as Nocardia nova (Figure 3). The multiple, bilateral small nodular opacities seen on CT scan of the chest were consistent with septic pulmonary emboli. A transthoracic echocardiogram was normal, but transesophageal echocardiogram showed a 3-mm × 1-mm mobile vegetation on the mitral valve. A magnetic resonance image of the brain was normal. Thus, this patient was diagnosed with PICC-associated N nova septic pulmonary emboli and endocarditis.
Figure 1. Computed tomography of the patient’s chest. Multiple scattered nodules in the periphery of the lungs (arrow) were identified.
Figure 2. Gram stain of the organism growing in blood culture.
Figure 3. A modified acid-fast bacilli stain of the organism growing in blood culture.
PATIENT CONSENT
Consent to publish to this case report was obtained from the patient. The article type (“ID Teaching Cases”) does not require formal approval by an ethics committee.
DISCUSSION
In this study, we present the case of a patient with a severe complication associated with the unscientific use of IV antibiotics for management of persistent symptoms and a diagnosis of Lyme disease. Several randomized controlled trials have compared long-term antibiotics with placebo for the treatment of these patients [1–4]. In each of these studies, longer term antibiotic treatment did not improve symptoms in patients compared with placebo. However, complications of long-term antibiotic treatment for Lyme disease include PICC-line associated bacteremia, which can be life threatening [5]. Despite these data and a recommendation from the Infectious Diseases Society of America against the use of extended courses of antibiotics in this setting [6], some clinicians still prescribe such therapies [7, 8].
The patient was initially diagnosed with Lyme disease when an immunoblot for B burgdorferi-specific IgM antibodies was positive; however, the immunoblot for IgG antibodies was negative. Borrelia burgdorferi IgM immunoblots have poor specificity, particularly when the IgG test is negative, and can lead to the misdiagnosis of Lyme disease [9]. Thus, an isolated positive B burgdorferi IgM immunoblot should not be used to diagnose Lyme disease in patients who have had symptoms for more than 6 weeks.
Nocardia sp are Gram-positive, beaded, weakly acid-fast, branching bacilli that are uncommon causes of bacteremia and endocarditis [10]. It is interesting to note that N nova was the most common pathogen in a case series of patients with Nocardia sp bacteremia and an underlying cancer, recovered in 6 of 17 cases [11]. Ten of 17 patients in this study had central catheter-associated bacteremia, and the authors found that Nocardia sp promoted biofilm formation on central venous catheters in vitro [11]. Patients with central venous catheter-associated Nocardia sp bacteremia responded well to catheter removal and antibiotic therapy [11].
Data from randomized controlled trials are not available to guide treatment for nocardiosis. Based on cumulative clinical experience, trimethoprim-sulfamethoxazole is the mainstay of therapy for patients with nocardiosis. Patients who are allergic to trimethoprim-sulfamethoxazole should be desensitized to enable treatment with this agent. Most authorities recommend that severe infection with Nocardia sp, such as endocarditis in this patient, be managed with combination therapy. For severe disease outside the central nervous system, the combination of trimethoprim-sulfamethoxazole and amikacin for initial therapy is recommended until antimicrobial susceptibility data are available. The combination of imipenem and amikacin is also used in this setting. The optimal duration of therapy for patients with nocardiosis is not known. Shorter antibiotic courses for Nocardia sp infection are associated with a high risk of relapse, even in immunocompetent hosts. Thus, most infectious disease clinicians recommend that patients with severe nocardiosis be treated with antibiotics for 6 to 12 months.
FOLLOW-UP
The patient’s PICC line was removed and she was started on imipenem, given her history of a severe allergy to trimethoprim-sulfamethoxazole. On the second hospital day, the patient’s fever resolved, and her symptoms improved markedly. During her hospital stay, she was desensitized to trimethoprim-sulfamethoxazole. She was discharged on trimethoprim-sulfamethoxazole and amikacin while awaiting the identification and susceptibility of the Nocardia sp. Ten days into therapy, the patient developed a diffuse maculopapular drug rash. The trimethoprim-sulfamethoxazole was discontinued, imipenem was restarted, and the amikacin therapy continued. Her rash resolved. After 4 weeks of empiric antibiotic treatment, the organism was identified as N nova that was sensitive to trimethoprim-sulfamethoxazole, amikacin, ceftriaxone, imipenem, and linezolid, but resistant to tetracyclines, fluoroquinolones, and amoxicillin/clavulanate. Imipenem and amikacin were discontinued, and the patient was started on ceftriaxone, given her history of malabsorption and inability to tolerate oral antibiotics. A 6-month course of ceftriaxone is planned for this patient, after which a CT scan of the chest will be obtained to ensure resolution of the septic emboli. The PICC line used to administer ceftriaxone will then be removed.
Acknowledgments
Financial support. R. P.-W.’s research is funded by R01 AI130289 from the National Institute of Allergy and Infectious Diseases and an Innovator Award from the Kenneth Rainin Foundation.
Potential conflicts of interests. All authors have no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33728358 | 19,670,043 | 2021-03 |
What was the dosage of drug 'AZITHROMYCIN ANHYDROUS'? | Peripherally Inserted Central Catheter-Associated Nocardia nova Endocarditis in a Patient Receiving Intravenous Antibiotics for Chronic Lyme Disease.
Long-term antibiotics are not effective for the therapy of patients with persistent symptoms and a history of Lyme disease. However, some clinicians still prescribe these therapies. We present a case of peripherally inserted central catheter-associated Nocardia nova endocarditis in a patient who had been receiving intravenous antibiotics for the management of chronic Lyme disease. This case highlights an important risk associated with the unscientific use of indwelling peripheral catheters and intravenous antibiotics for the management of such patients.
PRESENTATION OF CASE
A 34-year-old female from New England presented with a 1-month history of daily low-grade fevers, dry cough, loss of appetite, and a 5-pound weight loss. She received 2 separate 5-day courses of azithromycin as an outpatient with no improvement in her symptoms. Ten years before presentation, the patient was diagnosed with Lyme disease. A Western blot for Borrelia burgdorferi-specific immunoglobulin IgM antibodies detected 2 of 3 bands and was interpreted as positive, but a Western blot for IgG antibodies was negative. She was treated with doxycycline for 3 weeks. The patient continued to have polyarthralgia and fatigue and reported that she was diagnosed with chronic Lyme disease 5 years before presentation. She had an indwelling peripherally inserted central catheter (PICC) in place for the previous 22 months for the administration of intravenous (IV) antibiotics that were prescribed to treat chronic Lyme disease. She received a 10-month course of IV ceftriaxone and then a 6-month course of IV doxycycline. She was also prescribed intermittent courses of other agents, such as oral disulfuram and oral doxycycline, for the treatment of chronic Lyme disease. The patient has a history of Ehlers-Danlos syndrome, gastrointestinal malabsorption, which necessitates enteral feeding through a nasogastric tube, postural orthostatic tachycardia syndrome, and psychogenic nonepileptic seizures. She reported that the administration of sulfa drugs caused hives when she was a child. On the day of presentation, the patient had a temperature of 38.1°C and a heart rate of 103 beats per minute. A PICC line was in place in the right arm. The rest of her physical exam was normal. Kidney function, serum glucose, a complete blood count with differential, and liver enzyme tests were all within the normal range. Tests for SARS-CoV-2 and human immunodeficiency virus were negative. A chest x-ray was normal. A chest computed tomography (CT) scan showed multiple scattered pulmonary nodules concerning for emboli (Figure 1). Branching, Gram-positive bacilli grew in 4 of 4 blood cultures bottles taken on the day of her admission to the hospital (Figure 2). The organism stained with a modified acid-fast bacilli stain and was identified as Nocardia nova (Figure 3). The multiple, bilateral small nodular opacities seen on CT scan of the chest were consistent with septic pulmonary emboli. A transthoracic echocardiogram was normal, but transesophageal echocardiogram showed a 3-mm × 1-mm mobile vegetation on the mitral valve. A magnetic resonance image of the brain was normal. Thus, this patient was diagnosed with PICC-associated N nova septic pulmonary emboli and endocarditis.
Figure 1. Computed tomography of the patient’s chest. Multiple scattered nodules in the periphery of the lungs (arrow) were identified.
Figure 2. Gram stain of the organism growing in blood culture.
Figure 3. A modified acid-fast bacilli stain of the organism growing in blood culture.
PATIENT CONSENT
Consent to publish to this case report was obtained from the patient. The article type (“ID Teaching Cases”) does not require formal approval by an ethics committee.
DISCUSSION
In this study, we present the case of a patient with a severe complication associated with the unscientific use of IV antibiotics for management of persistent symptoms and a diagnosis of Lyme disease. Several randomized controlled trials have compared long-term antibiotics with placebo for the treatment of these patients [1–4]. In each of these studies, longer term antibiotic treatment did not improve symptoms in patients compared with placebo. However, complications of long-term antibiotic treatment for Lyme disease include PICC-line associated bacteremia, which can be life threatening [5]. Despite these data and a recommendation from the Infectious Diseases Society of America against the use of extended courses of antibiotics in this setting [6], some clinicians still prescribe such therapies [7, 8].
The patient was initially diagnosed with Lyme disease when an immunoblot for B burgdorferi-specific IgM antibodies was positive; however, the immunoblot for IgG antibodies was negative. Borrelia burgdorferi IgM immunoblots have poor specificity, particularly when the IgG test is negative, and can lead to the misdiagnosis of Lyme disease [9]. Thus, an isolated positive B burgdorferi IgM immunoblot should not be used to diagnose Lyme disease in patients who have had symptoms for more than 6 weeks.
Nocardia sp are Gram-positive, beaded, weakly acid-fast, branching bacilli that are uncommon causes of bacteremia and endocarditis [10]. It is interesting to note that N nova was the most common pathogen in a case series of patients with Nocardia sp bacteremia and an underlying cancer, recovered in 6 of 17 cases [11]. Ten of 17 patients in this study had central catheter-associated bacteremia, and the authors found that Nocardia sp promoted biofilm formation on central venous catheters in vitro [11]. Patients with central venous catheter-associated Nocardia sp bacteremia responded well to catheter removal and antibiotic therapy [11].
Data from randomized controlled trials are not available to guide treatment for nocardiosis. Based on cumulative clinical experience, trimethoprim-sulfamethoxazole is the mainstay of therapy for patients with nocardiosis. Patients who are allergic to trimethoprim-sulfamethoxazole should be desensitized to enable treatment with this agent. Most authorities recommend that severe infection with Nocardia sp, such as endocarditis in this patient, be managed with combination therapy. For severe disease outside the central nervous system, the combination of trimethoprim-sulfamethoxazole and amikacin for initial therapy is recommended until antimicrobial susceptibility data are available. The combination of imipenem and amikacin is also used in this setting. The optimal duration of therapy for patients with nocardiosis is not known. Shorter antibiotic courses for Nocardia sp infection are associated with a high risk of relapse, even in immunocompetent hosts. Thus, most infectious disease clinicians recommend that patients with severe nocardiosis be treated with antibiotics for 6 to 12 months.
FOLLOW-UP
The patient’s PICC line was removed and she was started on imipenem, given her history of a severe allergy to trimethoprim-sulfamethoxazole. On the second hospital day, the patient’s fever resolved, and her symptoms improved markedly. During her hospital stay, she was desensitized to trimethoprim-sulfamethoxazole. She was discharged on trimethoprim-sulfamethoxazole and amikacin while awaiting the identification and susceptibility of the Nocardia sp. Ten days into therapy, the patient developed a diffuse maculopapular drug rash. The trimethoprim-sulfamethoxazole was discontinued, imipenem was restarted, and the amikacin therapy continued. Her rash resolved. After 4 weeks of empiric antibiotic treatment, the organism was identified as N nova that was sensitive to trimethoprim-sulfamethoxazole, amikacin, ceftriaxone, imipenem, and linezolid, but resistant to tetracyclines, fluoroquinolones, and amoxicillin/clavulanate. Imipenem and amikacin were discontinued, and the patient was started on ceftriaxone, given her history of malabsorption and inability to tolerate oral antibiotics. A 6-month course of ceftriaxone is planned for this patient, after which a CT scan of the chest will be obtained to ensure resolution of the septic emboli. The PICC line used to administer ceftriaxone will then be removed.
Acknowledgments
Financial support. R. P.-W.’s research is funded by R01 AI130289 from the National Institute of Allergy and Infectious Diseases and an Innovator Award from the Kenneth Rainin Foundation.
Potential conflicts of interests. All authors have no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | RECEIVED TWO 5DAYS COURSES OF AZITHROMYCIN | DrugDosageText | CC BY-NC-ND | 33728358 | 19,724,199 | 2021-03 |
What was the dosage of drug 'CEFTRIAXONE'? | Peripherally Inserted Central Catheter-Associated Nocardia nova Endocarditis in a Patient Receiving Intravenous Antibiotics for Chronic Lyme Disease.
Long-term antibiotics are not effective for the therapy of patients with persistent symptoms and a history of Lyme disease. However, some clinicians still prescribe these therapies. We present a case of peripherally inserted central catheter-associated Nocardia nova endocarditis in a patient who had been receiving intravenous antibiotics for the management of chronic Lyme disease. This case highlights an important risk associated with the unscientific use of indwelling peripheral catheters and intravenous antibiotics for the management of such patients.
PRESENTATION OF CASE
A 34-year-old female from New England presented with a 1-month history of daily low-grade fevers, dry cough, loss of appetite, and a 5-pound weight loss. She received 2 separate 5-day courses of azithromycin as an outpatient with no improvement in her symptoms. Ten years before presentation, the patient was diagnosed with Lyme disease. A Western blot for Borrelia burgdorferi-specific immunoglobulin IgM antibodies detected 2 of 3 bands and was interpreted as positive, but a Western blot for IgG antibodies was negative. She was treated with doxycycline for 3 weeks. The patient continued to have polyarthralgia and fatigue and reported that she was diagnosed with chronic Lyme disease 5 years before presentation. She had an indwelling peripherally inserted central catheter (PICC) in place for the previous 22 months for the administration of intravenous (IV) antibiotics that were prescribed to treat chronic Lyme disease. She received a 10-month course of IV ceftriaxone and then a 6-month course of IV doxycycline. She was also prescribed intermittent courses of other agents, such as oral disulfuram and oral doxycycline, for the treatment of chronic Lyme disease. The patient has a history of Ehlers-Danlos syndrome, gastrointestinal malabsorption, which necessitates enteral feeding through a nasogastric tube, postural orthostatic tachycardia syndrome, and psychogenic nonepileptic seizures. She reported that the administration of sulfa drugs caused hives when she was a child. On the day of presentation, the patient had a temperature of 38.1°C and a heart rate of 103 beats per minute. A PICC line was in place in the right arm. The rest of her physical exam was normal. Kidney function, serum glucose, a complete blood count with differential, and liver enzyme tests were all within the normal range. Tests for SARS-CoV-2 and human immunodeficiency virus were negative. A chest x-ray was normal. A chest computed tomography (CT) scan showed multiple scattered pulmonary nodules concerning for emboli (Figure 1). Branching, Gram-positive bacilli grew in 4 of 4 blood cultures bottles taken on the day of her admission to the hospital (Figure 2). The organism stained with a modified acid-fast bacilli stain and was identified as Nocardia nova (Figure 3). The multiple, bilateral small nodular opacities seen on CT scan of the chest were consistent with septic pulmonary emboli. A transthoracic echocardiogram was normal, but transesophageal echocardiogram showed a 3-mm × 1-mm mobile vegetation on the mitral valve. A magnetic resonance image of the brain was normal. Thus, this patient was diagnosed with PICC-associated N nova septic pulmonary emboli and endocarditis.
Figure 1. Computed tomography of the patient’s chest. Multiple scattered nodules in the periphery of the lungs (arrow) were identified.
Figure 2. Gram stain of the organism growing in blood culture.
Figure 3. A modified acid-fast bacilli stain of the organism growing in blood culture.
PATIENT CONSENT
Consent to publish to this case report was obtained from the patient. The article type (“ID Teaching Cases”) does not require formal approval by an ethics committee.
DISCUSSION
In this study, we present the case of a patient with a severe complication associated with the unscientific use of IV antibiotics for management of persistent symptoms and a diagnosis of Lyme disease. Several randomized controlled trials have compared long-term antibiotics with placebo for the treatment of these patients [1–4]. In each of these studies, longer term antibiotic treatment did not improve symptoms in patients compared with placebo. However, complications of long-term antibiotic treatment for Lyme disease include PICC-line associated bacteremia, which can be life threatening [5]. Despite these data and a recommendation from the Infectious Diseases Society of America against the use of extended courses of antibiotics in this setting [6], some clinicians still prescribe such therapies [7, 8].
The patient was initially diagnosed with Lyme disease when an immunoblot for B burgdorferi-specific IgM antibodies was positive; however, the immunoblot for IgG antibodies was negative. Borrelia burgdorferi IgM immunoblots have poor specificity, particularly when the IgG test is negative, and can lead to the misdiagnosis of Lyme disease [9]. Thus, an isolated positive B burgdorferi IgM immunoblot should not be used to diagnose Lyme disease in patients who have had symptoms for more than 6 weeks.
Nocardia sp are Gram-positive, beaded, weakly acid-fast, branching bacilli that are uncommon causes of bacteremia and endocarditis [10]. It is interesting to note that N nova was the most common pathogen in a case series of patients with Nocardia sp bacteremia and an underlying cancer, recovered in 6 of 17 cases [11]. Ten of 17 patients in this study had central catheter-associated bacteremia, and the authors found that Nocardia sp promoted biofilm formation on central venous catheters in vitro [11]. Patients with central venous catheter-associated Nocardia sp bacteremia responded well to catheter removal and antibiotic therapy [11].
Data from randomized controlled trials are not available to guide treatment for nocardiosis. Based on cumulative clinical experience, trimethoprim-sulfamethoxazole is the mainstay of therapy for patients with nocardiosis. Patients who are allergic to trimethoprim-sulfamethoxazole should be desensitized to enable treatment with this agent. Most authorities recommend that severe infection with Nocardia sp, such as endocarditis in this patient, be managed with combination therapy. For severe disease outside the central nervous system, the combination of trimethoprim-sulfamethoxazole and amikacin for initial therapy is recommended until antimicrobial susceptibility data are available. The combination of imipenem and amikacin is also used in this setting. The optimal duration of therapy for patients with nocardiosis is not known. Shorter antibiotic courses for Nocardia sp infection are associated with a high risk of relapse, even in immunocompetent hosts. Thus, most infectious disease clinicians recommend that patients with severe nocardiosis be treated with antibiotics for 6 to 12 months.
FOLLOW-UP
The patient’s PICC line was removed and she was started on imipenem, given her history of a severe allergy to trimethoprim-sulfamethoxazole. On the second hospital day, the patient’s fever resolved, and her symptoms improved markedly. During her hospital stay, she was desensitized to trimethoprim-sulfamethoxazole. She was discharged on trimethoprim-sulfamethoxazole and amikacin while awaiting the identification and susceptibility of the Nocardia sp. Ten days into therapy, the patient developed a diffuse maculopapular drug rash. The trimethoprim-sulfamethoxazole was discontinued, imipenem was restarted, and the amikacin therapy continued. Her rash resolved. After 4 weeks of empiric antibiotic treatment, the organism was identified as N nova that was sensitive to trimethoprim-sulfamethoxazole, amikacin, ceftriaxone, imipenem, and linezolid, but resistant to tetracyclines, fluoroquinolones, and amoxicillin/clavulanate. Imipenem and amikacin were discontinued, and the patient was started on ceftriaxone, given her history of malabsorption and inability to tolerate oral antibiotics. A 6-month course of ceftriaxone is planned for this patient, after which a CT scan of the chest will be obtained to ensure resolution of the septic emboli. The PICC line used to administer ceftriaxone will then be removed.
Acknowledgments
Financial support. R. P.-W.’s research is funded by R01 AI130289 from the National Institute of Allergy and Infectious Diseases and an Innovator Award from the Kenneth Rainin Foundation.
Potential conflicts of interests. All authors have no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | UNKNOWN | DrugDosageText | CC BY-NC-ND | 33728358 | 19,512,742 | 2021-03 |
What was the dosage of drug 'DISULFIRAM'? | Peripherally Inserted Central Catheter-Associated Nocardia nova Endocarditis in a Patient Receiving Intravenous Antibiotics for Chronic Lyme Disease.
Long-term antibiotics are not effective for the therapy of patients with persistent symptoms and a history of Lyme disease. However, some clinicians still prescribe these therapies. We present a case of peripherally inserted central catheter-associated Nocardia nova endocarditis in a patient who had been receiving intravenous antibiotics for the management of chronic Lyme disease. This case highlights an important risk associated with the unscientific use of indwelling peripheral catheters and intravenous antibiotics for the management of such patients.
PRESENTATION OF CASE
A 34-year-old female from New England presented with a 1-month history of daily low-grade fevers, dry cough, loss of appetite, and a 5-pound weight loss. She received 2 separate 5-day courses of azithromycin as an outpatient with no improvement in her symptoms. Ten years before presentation, the patient was diagnosed with Lyme disease. A Western blot for Borrelia burgdorferi-specific immunoglobulin IgM antibodies detected 2 of 3 bands and was interpreted as positive, but a Western blot for IgG antibodies was negative. She was treated with doxycycline for 3 weeks. The patient continued to have polyarthralgia and fatigue and reported that she was diagnosed with chronic Lyme disease 5 years before presentation. She had an indwelling peripherally inserted central catheter (PICC) in place for the previous 22 months for the administration of intravenous (IV) antibiotics that were prescribed to treat chronic Lyme disease. She received a 10-month course of IV ceftriaxone and then a 6-month course of IV doxycycline. She was also prescribed intermittent courses of other agents, such as oral disulfuram and oral doxycycline, for the treatment of chronic Lyme disease. The patient has a history of Ehlers-Danlos syndrome, gastrointestinal malabsorption, which necessitates enteral feeding through a nasogastric tube, postural orthostatic tachycardia syndrome, and psychogenic nonepileptic seizures. She reported that the administration of sulfa drugs caused hives when she was a child. On the day of presentation, the patient had a temperature of 38.1°C and a heart rate of 103 beats per minute. A PICC line was in place in the right arm. The rest of her physical exam was normal. Kidney function, serum glucose, a complete blood count with differential, and liver enzyme tests were all within the normal range. Tests for SARS-CoV-2 and human immunodeficiency virus were negative. A chest x-ray was normal. A chest computed tomography (CT) scan showed multiple scattered pulmonary nodules concerning for emboli (Figure 1). Branching, Gram-positive bacilli grew in 4 of 4 blood cultures bottles taken on the day of her admission to the hospital (Figure 2). The organism stained with a modified acid-fast bacilli stain and was identified as Nocardia nova (Figure 3). The multiple, bilateral small nodular opacities seen on CT scan of the chest were consistent with septic pulmonary emboli. A transthoracic echocardiogram was normal, but transesophageal echocardiogram showed a 3-mm × 1-mm mobile vegetation on the mitral valve. A magnetic resonance image of the brain was normal. Thus, this patient was diagnosed with PICC-associated N nova septic pulmonary emboli and endocarditis.
Figure 1. Computed tomography of the patient’s chest. Multiple scattered nodules in the periphery of the lungs (arrow) were identified.
Figure 2. Gram stain of the organism growing in blood culture.
Figure 3. A modified acid-fast bacilli stain of the organism growing in blood culture.
PATIENT CONSENT
Consent to publish to this case report was obtained from the patient. The article type (“ID Teaching Cases”) does not require formal approval by an ethics committee.
DISCUSSION
In this study, we present the case of a patient with a severe complication associated with the unscientific use of IV antibiotics for management of persistent symptoms and a diagnosis of Lyme disease. Several randomized controlled trials have compared long-term antibiotics with placebo for the treatment of these patients [1–4]. In each of these studies, longer term antibiotic treatment did not improve symptoms in patients compared with placebo. However, complications of long-term antibiotic treatment for Lyme disease include PICC-line associated bacteremia, which can be life threatening [5]. Despite these data and a recommendation from the Infectious Diseases Society of America against the use of extended courses of antibiotics in this setting [6], some clinicians still prescribe such therapies [7, 8].
The patient was initially diagnosed with Lyme disease when an immunoblot for B burgdorferi-specific IgM antibodies was positive; however, the immunoblot for IgG antibodies was negative. Borrelia burgdorferi IgM immunoblots have poor specificity, particularly when the IgG test is negative, and can lead to the misdiagnosis of Lyme disease [9]. Thus, an isolated positive B burgdorferi IgM immunoblot should not be used to diagnose Lyme disease in patients who have had symptoms for more than 6 weeks.
Nocardia sp are Gram-positive, beaded, weakly acid-fast, branching bacilli that are uncommon causes of bacteremia and endocarditis [10]. It is interesting to note that N nova was the most common pathogen in a case series of patients with Nocardia sp bacteremia and an underlying cancer, recovered in 6 of 17 cases [11]. Ten of 17 patients in this study had central catheter-associated bacteremia, and the authors found that Nocardia sp promoted biofilm formation on central venous catheters in vitro [11]. Patients with central venous catheter-associated Nocardia sp bacteremia responded well to catheter removal and antibiotic therapy [11].
Data from randomized controlled trials are not available to guide treatment for nocardiosis. Based on cumulative clinical experience, trimethoprim-sulfamethoxazole is the mainstay of therapy for patients with nocardiosis. Patients who are allergic to trimethoprim-sulfamethoxazole should be desensitized to enable treatment with this agent. Most authorities recommend that severe infection with Nocardia sp, such as endocarditis in this patient, be managed with combination therapy. For severe disease outside the central nervous system, the combination of trimethoprim-sulfamethoxazole and amikacin for initial therapy is recommended until antimicrobial susceptibility data are available. The combination of imipenem and amikacin is also used in this setting. The optimal duration of therapy for patients with nocardiosis is not known. Shorter antibiotic courses for Nocardia sp infection are associated with a high risk of relapse, even in immunocompetent hosts. Thus, most infectious disease clinicians recommend that patients with severe nocardiosis be treated with antibiotics for 6 to 12 months.
FOLLOW-UP
The patient’s PICC line was removed and she was started on imipenem, given her history of a severe allergy to trimethoprim-sulfamethoxazole. On the second hospital day, the patient’s fever resolved, and her symptoms improved markedly. During her hospital stay, she was desensitized to trimethoprim-sulfamethoxazole. She was discharged on trimethoprim-sulfamethoxazole and amikacin while awaiting the identification and susceptibility of the Nocardia sp. Ten days into therapy, the patient developed a diffuse maculopapular drug rash. The trimethoprim-sulfamethoxazole was discontinued, imipenem was restarted, and the amikacin therapy continued. Her rash resolved. After 4 weeks of empiric antibiotic treatment, the organism was identified as N nova that was sensitive to trimethoprim-sulfamethoxazole, amikacin, ceftriaxone, imipenem, and linezolid, but resistant to tetracyclines, fluoroquinolones, and amoxicillin/clavulanate. Imipenem and amikacin were discontinued, and the patient was started on ceftriaxone, given her history of malabsorption and inability to tolerate oral antibiotics. A 6-month course of ceftriaxone is planned for this patient, after which a CT scan of the chest will be obtained to ensure resolution of the septic emboli. The PICC line used to administer ceftriaxone will then be removed.
Acknowledgments
Financial support. R. P.-W.’s research is funded by R01 AI130289 from the National Institute of Allergy and Infectious Diseases and an Innovator Award from the Kenneth Rainin Foundation.
Potential conflicts of interests. All authors have no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | HAD BEEN PRESCRIBED WITH INTERMITTENT COURSES | DrugDosageText | CC BY-NC-ND | 33728358 | 19,724,199 | 2021-03 |
What was the outcome of reaction 'Drug eruption'? | Peripherally Inserted Central Catheter-Associated Nocardia nova Endocarditis in a Patient Receiving Intravenous Antibiotics for Chronic Lyme Disease.
Long-term antibiotics are not effective for the therapy of patients with persistent symptoms and a history of Lyme disease. However, some clinicians still prescribe these therapies. We present a case of peripherally inserted central catheter-associated Nocardia nova endocarditis in a patient who had been receiving intravenous antibiotics for the management of chronic Lyme disease. This case highlights an important risk associated with the unscientific use of indwelling peripheral catheters and intravenous antibiotics for the management of such patients.
PRESENTATION OF CASE
A 34-year-old female from New England presented with a 1-month history of daily low-grade fevers, dry cough, loss of appetite, and a 5-pound weight loss. She received 2 separate 5-day courses of azithromycin as an outpatient with no improvement in her symptoms. Ten years before presentation, the patient was diagnosed with Lyme disease. A Western blot for Borrelia burgdorferi-specific immunoglobulin IgM antibodies detected 2 of 3 bands and was interpreted as positive, but a Western blot for IgG antibodies was negative. She was treated with doxycycline for 3 weeks. The patient continued to have polyarthralgia and fatigue and reported that she was diagnosed with chronic Lyme disease 5 years before presentation. She had an indwelling peripherally inserted central catheter (PICC) in place for the previous 22 months for the administration of intravenous (IV) antibiotics that were prescribed to treat chronic Lyme disease. She received a 10-month course of IV ceftriaxone and then a 6-month course of IV doxycycline. She was also prescribed intermittent courses of other agents, such as oral disulfuram and oral doxycycline, for the treatment of chronic Lyme disease. The patient has a history of Ehlers-Danlos syndrome, gastrointestinal malabsorption, which necessitates enteral feeding through a nasogastric tube, postural orthostatic tachycardia syndrome, and psychogenic nonepileptic seizures. She reported that the administration of sulfa drugs caused hives when she was a child. On the day of presentation, the patient had a temperature of 38.1°C and a heart rate of 103 beats per minute. A PICC line was in place in the right arm. The rest of her physical exam was normal. Kidney function, serum glucose, a complete blood count with differential, and liver enzyme tests were all within the normal range. Tests for SARS-CoV-2 and human immunodeficiency virus were negative. A chest x-ray was normal. A chest computed tomography (CT) scan showed multiple scattered pulmonary nodules concerning for emboli (Figure 1). Branching, Gram-positive bacilli grew in 4 of 4 blood cultures bottles taken on the day of her admission to the hospital (Figure 2). The organism stained with a modified acid-fast bacilli stain and was identified as Nocardia nova (Figure 3). The multiple, bilateral small nodular opacities seen on CT scan of the chest were consistent with septic pulmonary emboli. A transthoracic echocardiogram was normal, but transesophageal echocardiogram showed a 3-mm × 1-mm mobile vegetation on the mitral valve. A magnetic resonance image of the brain was normal. Thus, this patient was diagnosed with PICC-associated N nova septic pulmonary emboli and endocarditis.
Figure 1. Computed tomography of the patient’s chest. Multiple scattered nodules in the periphery of the lungs (arrow) were identified.
Figure 2. Gram stain of the organism growing in blood culture.
Figure 3. A modified acid-fast bacilli stain of the organism growing in blood culture.
PATIENT CONSENT
Consent to publish to this case report was obtained from the patient. The article type (“ID Teaching Cases”) does not require formal approval by an ethics committee.
DISCUSSION
In this study, we present the case of a patient with a severe complication associated with the unscientific use of IV antibiotics for management of persistent symptoms and a diagnosis of Lyme disease. Several randomized controlled trials have compared long-term antibiotics with placebo for the treatment of these patients [1–4]. In each of these studies, longer term antibiotic treatment did not improve symptoms in patients compared with placebo. However, complications of long-term antibiotic treatment for Lyme disease include PICC-line associated bacteremia, which can be life threatening [5]. Despite these data and a recommendation from the Infectious Diseases Society of America against the use of extended courses of antibiotics in this setting [6], some clinicians still prescribe such therapies [7, 8].
The patient was initially diagnosed with Lyme disease when an immunoblot for B burgdorferi-specific IgM antibodies was positive; however, the immunoblot for IgG antibodies was negative. Borrelia burgdorferi IgM immunoblots have poor specificity, particularly when the IgG test is negative, and can lead to the misdiagnosis of Lyme disease [9]. Thus, an isolated positive B burgdorferi IgM immunoblot should not be used to diagnose Lyme disease in patients who have had symptoms for more than 6 weeks.
Nocardia sp are Gram-positive, beaded, weakly acid-fast, branching bacilli that are uncommon causes of bacteremia and endocarditis [10]. It is interesting to note that N nova was the most common pathogen in a case series of patients with Nocardia sp bacteremia and an underlying cancer, recovered in 6 of 17 cases [11]. Ten of 17 patients in this study had central catheter-associated bacteremia, and the authors found that Nocardia sp promoted biofilm formation on central venous catheters in vitro [11]. Patients with central venous catheter-associated Nocardia sp bacteremia responded well to catheter removal and antibiotic therapy [11].
Data from randomized controlled trials are not available to guide treatment for nocardiosis. Based on cumulative clinical experience, trimethoprim-sulfamethoxazole is the mainstay of therapy for patients with nocardiosis. Patients who are allergic to trimethoprim-sulfamethoxazole should be desensitized to enable treatment with this agent. Most authorities recommend that severe infection with Nocardia sp, such as endocarditis in this patient, be managed with combination therapy. For severe disease outside the central nervous system, the combination of trimethoprim-sulfamethoxazole and amikacin for initial therapy is recommended until antimicrobial susceptibility data are available. The combination of imipenem and amikacin is also used in this setting. The optimal duration of therapy for patients with nocardiosis is not known. Shorter antibiotic courses for Nocardia sp infection are associated with a high risk of relapse, even in immunocompetent hosts. Thus, most infectious disease clinicians recommend that patients with severe nocardiosis be treated with antibiotics for 6 to 12 months.
FOLLOW-UP
The patient’s PICC line was removed and she was started on imipenem, given her history of a severe allergy to trimethoprim-sulfamethoxazole. On the second hospital day, the patient’s fever resolved, and her symptoms improved markedly. During her hospital stay, she was desensitized to trimethoprim-sulfamethoxazole. She was discharged on trimethoprim-sulfamethoxazole and amikacin while awaiting the identification and susceptibility of the Nocardia sp. Ten days into therapy, the patient developed a diffuse maculopapular drug rash. The trimethoprim-sulfamethoxazole was discontinued, imipenem was restarted, and the amikacin therapy continued. Her rash resolved. After 4 weeks of empiric antibiotic treatment, the organism was identified as N nova that was sensitive to trimethoprim-sulfamethoxazole, amikacin, ceftriaxone, imipenem, and linezolid, but resistant to tetracyclines, fluoroquinolones, and amoxicillin/clavulanate. Imipenem and amikacin were discontinued, and the patient was started on ceftriaxone, given her history of malabsorption and inability to tolerate oral antibiotics. A 6-month course of ceftriaxone is planned for this patient, after which a CT scan of the chest will be obtained to ensure resolution of the septic emboli. The PICC line used to administer ceftriaxone will then be removed.
Acknowledgments
Financial support. R. P.-W.’s research is funded by R01 AI130289 from the National Institute of Allergy and Infectious Diseases and an Innovator Award from the Kenneth Rainin Foundation.
Potential conflicts of interests. All authors have no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | Recovered | ReactionOutcome | CC BY-NC-ND | 33728358 | 19,724,199 | 2021-03 |
What was the outcome of reaction 'Endocarditis bacterial'? | Peripherally Inserted Central Catheter-Associated Nocardia nova Endocarditis in a Patient Receiving Intravenous Antibiotics for Chronic Lyme Disease.
Long-term antibiotics are not effective for the therapy of patients with persistent symptoms and a history of Lyme disease. However, some clinicians still prescribe these therapies. We present a case of peripherally inserted central catheter-associated Nocardia nova endocarditis in a patient who had been receiving intravenous antibiotics for the management of chronic Lyme disease. This case highlights an important risk associated with the unscientific use of indwelling peripheral catheters and intravenous antibiotics for the management of such patients.
PRESENTATION OF CASE
A 34-year-old female from New England presented with a 1-month history of daily low-grade fevers, dry cough, loss of appetite, and a 5-pound weight loss. She received 2 separate 5-day courses of azithromycin as an outpatient with no improvement in her symptoms. Ten years before presentation, the patient was diagnosed with Lyme disease. A Western blot for Borrelia burgdorferi-specific immunoglobulin IgM antibodies detected 2 of 3 bands and was interpreted as positive, but a Western blot for IgG antibodies was negative. She was treated with doxycycline for 3 weeks. The patient continued to have polyarthralgia and fatigue and reported that she was diagnosed with chronic Lyme disease 5 years before presentation. She had an indwelling peripherally inserted central catheter (PICC) in place for the previous 22 months for the administration of intravenous (IV) antibiotics that were prescribed to treat chronic Lyme disease. She received a 10-month course of IV ceftriaxone and then a 6-month course of IV doxycycline. She was also prescribed intermittent courses of other agents, such as oral disulfuram and oral doxycycline, for the treatment of chronic Lyme disease. The patient has a history of Ehlers-Danlos syndrome, gastrointestinal malabsorption, which necessitates enteral feeding through a nasogastric tube, postural orthostatic tachycardia syndrome, and psychogenic nonepileptic seizures. She reported that the administration of sulfa drugs caused hives when she was a child. On the day of presentation, the patient had a temperature of 38.1°C and a heart rate of 103 beats per minute. A PICC line was in place in the right arm. The rest of her physical exam was normal. Kidney function, serum glucose, a complete blood count with differential, and liver enzyme tests were all within the normal range. Tests for SARS-CoV-2 and human immunodeficiency virus were negative. A chest x-ray was normal. A chest computed tomography (CT) scan showed multiple scattered pulmonary nodules concerning for emboli (Figure 1). Branching, Gram-positive bacilli grew in 4 of 4 blood cultures bottles taken on the day of her admission to the hospital (Figure 2). The organism stained with a modified acid-fast bacilli stain and was identified as Nocardia nova (Figure 3). The multiple, bilateral small nodular opacities seen on CT scan of the chest were consistent with septic pulmonary emboli. A transthoracic echocardiogram was normal, but transesophageal echocardiogram showed a 3-mm × 1-mm mobile vegetation on the mitral valve. A magnetic resonance image of the brain was normal. Thus, this patient was diagnosed with PICC-associated N nova septic pulmonary emboli and endocarditis.
Figure 1. Computed tomography of the patient’s chest. Multiple scattered nodules in the periphery of the lungs (arrow) were identified.
Figure 2. Gram stain of the organism growing in blood culture.
Figure 3. A modified acid-fast bacilli stain of the organism growing in blood culture.
PATIENT CONSENT
Consent to publish to this case report was obtained from the patient. The article type (“ID Teaching Cases”) does not require formal approval by an ethics committee.
DISCUSSION
In this study, we present the case of a patient with a severe complication associated with the unscientific use of IV antibiotics for management of persistent symptoms and a diagnosis of Lyme disease. Several randomized controlled trials have compared long-term antibiotics with placebo for the treatment of these patients [1–4]. In each of these studies, longer term antibiotic treatment did not improve symptoms in patients compared with placebo. However, complications of long-term antibiotic treatment for Lyme disease include PICC-line associated bacteremia, which can be life threatening [5]. Despite these data and a recommendation from the Infectious Diseases Society of America against the use of extended courses of antibiotics in this setting [6], some clinicians still prescribe such therapies [7, 8].
The patient was initially diagnosed with Lyme disease when an immunoblot for B burgdorferi-specific IgM antibodies was positive; however, the immunoblot for IgG antibodies was negative. Borrelia burgdorferi IgM immunoblots have poor specificity, particularly when the IgG test is negative, and can lead to the misdiagnosis of Lyme disease [9]. Thus, an isolated positive B burgdorferi IgM immunoblot should not be used to diagnose Lyme disease in patients who have had symptoms for more than 6 weeks.
Nocardia sp are Gram-positive, beaded, weakly acid-fast, branching bacilli that are uncommon causes of bacteremia and endocarditis [10]. It is interesting to note that N nova was the most common pathogen in a case series of patients with Nocardia sp bacteremia and an underlying cancer, recovered in 6 of 17 cases [11]. Ten of 17 patients in this study had central catheter-associated bacteremia, and the authors found that Nocardia sp promoted biofilm formation on central venous catheters in vitro [11]. Patients with central venous catheter-associated Nocardia sp bacteremia responded well to catheter removal and antibiotic therapy [11].
Data from randomized controlled trials are not available to guide treatment for nocardiosis. Based on cumulative clinical experience, trimethoprim-sulfamethoxazole is the mainstay of therapy for patients with nocardiosis. Patients who are allergic to trimethoprim-sulfamethoxazole should be desensitized to enable treatment with this agent. Most authorities recommend that severe infection with Nocardia sp, such as endocarditis in this patient, be managed with combination therapy. For severe disease outside the central nervous system, the combination of trimethoprim-sulfamethoxazole and amikacin for initial therapy is recommended until antimicrobial susceptibility data are available. The combination of imipenem and amikacin is also used in this setting. The optimal duration of therapy for patients with nocardiosis is not known. Shorter antibiotic courses for Nocardia sp infection are associated with a high risk of relapse, even in immunocompetent hosts. Thus, most infectious disease clinicians recommend that patients with severe nocardiosis be treated with antibiotics for 6 to 12 months.
FOLLOW-UP
The patient’s PICC line was removed and she was started on imipenem, given her history of a severe allergy to trimethoprim-sulfamethoxazole. On the second hospital day, the patient’s fever resolved, and her symptoms improved markedly. During her hospital stay, she was desensitized to trimethoprim-sulfamethoxazole. She was discharged on trimethoprim-sulfamethoxazole and amikacin while awaiting the identification and susceptibility of the Nocardia sp. Ten days into therapy, the patient developed a diffuse maculopapular drug rash. The trimethoprim-sulfamethoxazole was discontinued, imipenem was restarted, and the amikacin therapy continued. Her rash resolved. After 4 weeks of empiric antibiotic treatment, the organism was identified as N nova that was sensitive to trimethoprim-sulfamethoxazole, amikacin, ceftriaxone, imipenem, and linezolid, but resistant to tetracyclines, fluoroquinolones, and amoxicillin/clavulanate. Imipenem and amikacin were discontinued, and the patient was started on ceftriaxone, given her history of malabsorption and inability to tolerate oral antibiotics. A 6-month course of ceftriaxone is planned for this patient, after which a CT scan of the chest will be obtained to ensure resolution of the septic emboli. The PICC line used to administer ceftriaxone will then be removed.
Acknowledgments
Financial support. R. P.-W.’s research is funded by R01 AI130289 from the National Institute of Allergy and Infectious Diseases and an Innovator Award from the Kenneth Rainin Foundation.
Potential conflicts of interests. All authors have no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33728358 | 19,724,199 | 2021-03 |
What was the outcome of reaction 'Endocarditis'? | Peripherally Inserted Central Catheter-Associated Nocardia nova Endocarditis in a Patient Receiving Intravenous Antibiotics for Chronic Lyme Disease.
Long-term antibiotics are not effective for the therapy of patients with persistent symptoms and a history of Lyme disease. However, some clinicians still prescribe these therapies. We present a case of peripherally inserted central catheter-associated Nocardia nova endocarditis in a patient who had been receiving intravenous antibiotics for the management of chronic Lyme disease. This case highlights an important risk associated with the unscientific use of indwelling peripheral catheters and intravenous antibiotics for the management of such patients.
PRESENTATION OF CASE
A 34-year-old female from New England presented with a 1-month history of daily low-grade fevers, dry cough, loss of appetite, and a 5-pound weight loss. She received 2 separate 5-day courses of azithromycin as an outpatient with no improvement in her symptoms. Ten years before presentation, the patient was diagnosed with Lyme disease. A Western blot for Borrelia burgdorferi-specific immunoglobulin IgM antibodies detected 2 of 3 bands and was interpreted as positive, but a Western blot for IgG antibodies was negative. She was treated with doxycycline for 3 weeks. The patient continued to have polyarthralgia and fatigue and reported that she was diagnosed with chronic Lyme disease 5 years before presentation. She had an indwelling peripherally inserted central catheter (PICC) in place for the previous 22 months for the administration of intravenous (IV) antibiotics that were prescribed to treat chronic Lyme disease. She received a 10-month course of IV ceftriaxone and then a 6-month course of IV doxycycline. She was also prescribed intermittent courses of other agents, such as oral disulfuram and oral doxycycline, for the treatment of chronic Lyme disease. The patient has a history of Ehlers-Danlos syndrome, gastrointestinal malabsorption, which necessitates enteral feeding through a nasogastric tube, postural orthostatic tachycardia syndrome, and psychogenic nonepileptic seizures. She reported that the administration of sulfa drugs caused hives when she was a child. On the day of presentation, the patient had a temperature of 38.1°C and a heart rate of 103 beats per minute. A PICC line was in place in the right arm. The rest of her physical exam was normal. Kidney function, serum glucose, a complete blood count with differential, and liver enzyme tests were all within the normal range. Tests for SARS-CoV-2 and human immunodeficiency virus were negative. A chest x-ray was normal. A chest computed tomography (CT) scan showed multiple scattered pulmonary nodules concerning for emboli (Figure 1). Branching, Gram-positive bacilli grew in 4 of 4 blood cultures bottles taken on the day of her admission to the hospital (Figure 2). The organism stained with a modified acid-fast bacilli stain and was identified as Nocardia nova (Figure 3). The multiple, bilateral small nodular opacities seen on CT scan of the chest were consistent with septic pulmonary emboli. A transthoracic echocardiogram was normal, but transesophageal echocardiogram showed a 3-mm × 1-mm mobile vegetation on the mitral valve. A magnetic resonance image of the brain was normal. Thus, this patient was diagnosed with PICC-associated N nova septic pulmonary emboli and endocarditis.
Figure 1. Computed tomography of the patient’s chest. Multiple scattered nodules in the periphery of the lungs (arrow) were identified.
Figure 2. Gram stain of the organism growing in blood culture.
Figure 3. A modified acid-fast bacilli stain of the organism growing in blood culture.
PATIENT CONSENT
Consent to publish to this case report was obtained from the patient. The article type (“ID Teaching Cases”) does not require formal approval by an ethics committee.
DISCUSSION
In this study, we present the case of a patient with a severe complication associated with the unscientific use of IV antibiotics for management of persistent symptoms and a diagnosis of Lyme disease. Several randomized controlled trials have compared long-term antibiotics with placebo for the treatment of these patients [1–4]. In each of these studies, longer term antibiotic treatment did not improve symptoms in patients compared with placebo. However, complications of long-term antibiotic treatment for Lyme disease include PICC-line associated bacteremia, which can be life threatening [5]. Despite these data and a recommendation from the Infectious Diseases Society of America against the use of extended courses of antibiotics in this setting [6], some clinicians still prescribe such therapies [7, 8].
The patient was initially diagnosed with Lyme disease when an immunoblot for B burgdorferi-specific IgM antibodies was positive; however, the immunoblot for IgG antibodies was negative. Borrelia burgdorferi IgM immunoblots have poor specificity, particularly when the IgG test is negative, and can lead to the misdiagnosis of Lyme disease [9]. Thus, an isolated positive B burgdorferi IgM immunoblot should not be used to diagnose Lyme disease in patients who have had symptoms for more than 6 weeks.
Nocardia sp are Gram-positive, beaded, weakly acid-fast, branching bacilli that are uncommon causes of bacteremia and endocarditis [10]. It is interesting to note that N nova was the most common pathogen in a case series of patients with Nocardia sp bacteremia and an underlying cancer, recovered in 6 of 17 cases [11]. Ten of 17 patients in this study had central catheter-associated bacteremia, and the authors found that Nocardia sp promoted biofilm formation on central venous catheters in vitro [11]. Patients with central venous catheter-associated Nocardia sp bacteremia responded well to catheter removal and antibiotic therapy [11].
Data from randomized controlled trials are not available to guide treatment for nocardiosis. Based on cumulative clinical experience, trimethoprim-sulfamethoxazole is the mainstay of therapy for patients with nocardiosis. Patients who are allergic to trimethoprim-sulfamethoxazole should be desensitized to enable treatment with this agent. Most authorities recommend that severe infection with Nocardia sp, such as endocarditis in this patient, be managed with combination therapy. For severe disease outside the central nervous system, the combination of trimethoprim-sulfamethoxazole and amikacin for initial therapy is recommended until antimicrobial susceptibility data are available. The combination of imipenem and amikacin is also used in this setting. The optimal duration of therapy for patients with nocardiosis is not known. Shorter antibiotic courses for Nocardia sp infection are associated with a high risk of relapse, even in immunocompetent hosts. Thus, most infectious disease clinicians recommend that patients with severe nocardiosis be treated with antibiotics for 6 to 12 months.
FOLLOW-UP
The patient’s PICC line was removed and she was started on imipenem, given her history of a severe allergy to trimethoprim-sulfamethoxazole. On the second hospital day, the patient’s fever resolved, and her symptoms improved markedly. During her hospital stay, she was desensitized to trimethoprim-sulfamethoxazole. She was discharged on trimethoprim-sulfamethoxazole and amikacin while awaiting the identification and susceptibility of the Nocardia sp. Ten days into therapy, the patient developed a diffuse maculopapular drug rash. The trimethoprim-sulfamethoxazole was discontinued, imipenem was restarted, and the amikacin therapy continued. Her rash resolved. After 4 weeks of empiric antibiotic treatment, the organism was identified as N nova that was sensitive to trimethoprim-sulfamethoxazole, amikacin, ceftriaxone, imipenem, and linezolid, but resistant to tetracyclines, fluoroquinolones, and amoxicillin/clavulanate. Imipenem and amikacin were discontinued, and the patient was started on ceftriaxone, given her history of malabsorption and inability to tolerate oral antibiotics. A 6-month course of ceftriaxone is planned for this patient, after which a CT scan of the chest will be obtained to ensure resolution of the septic emboli. The PICC line used to administer ceftriaxone will then be removed.
Acknowledgments
Financial support. R. P.-W.’s research is funded by R01 AI130289 from the National Institute of Allergy and Infectious Diseases and an Innovator Award from the Kenneth Rainin Foundation.
Potential conflicts of interests. All authors have no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33728358 | 19,670,043 | 2021-03 |
What was the outcome of reaction 'Nocardia sepsis'? | Peripherally Inserted Central Catheter-Associated Nocardia nova Endocarditis in a Patient Receiving Intravenous Antibiotics for Chronic Lyme Disease.
Long-term antibiotics are not effective for the therapy of patients with persistent symptoms and a history of Lyme disease. However, some clinicians still prescribe these therapies. We present a case of peripherally inserted central catheter-associated Nocardia nova endocarditis in a patient who had been receiving intravenous antibiotics for the management of chronic Lyme disease. This case highlights an important risk associated with the unscientific use of indwelling peripheral catheters and intravenous antibiotics for the management of such patients.
PRESENTATION OF CASE
A 34-year-old female from New England presented with a 1-month history of daily low-grade fevers, dry cough, loss of appetite, and a 5-pound weight loss. She received 2 separate 5-day courses of azithromycin as an outpatient with no improvement in her symptoms. Ten years before presentation, the patient was diagnosed with Lyme disease. A Western blot for Borrelia burgdorferi-specific immunoglobulin IgM antibodies detected 2 of 3 bands and was interpreted as positive, but a Western blot for IgG antibodies was negative. She was treated with doxycycline for 3 weeks. The patient continued to have polyarthralgia and fatigue and reported that she was diagnosed with chronic Lyme disease 5 years before presentation. She had an indwelling peripherally inserted central catheter (PICC) in place for the previous 22 months for the administration of intravenous (IV) antibiotics that were prescribed to treat chronic Lyme disease. She received a 10-month course of IV ceftriaxone and then a 6-month course of IV doxycycline. She was also prescribed intermittent courses of other agents, such as oral disulfuram and oral doxycycline, for the treatment of chronic Lyme disease. The patient has a history of Ehlers-Danlos syndrome, gastrointestinal malabsorption, which necessitates enteral feeding through a nasogastric tube, postural orthostatic tachycardia syndrome, and psychogenic nonepileptic seizures. She reported that the administration of sulfa drugs caused hives when she was a child. On the day of presentation, the patient had a temperature of 38.1°C and a heart rate of 103 beats per minute. A PICC line was in place in the right arm. The rest of her physical exam was normal. Kidney function, serum glucose, a complete blood count with differential, and liver enzyme tests were all within the normal range. Tests for SARS-CoV-2 and human immunodeficiency virus were negative. A chest x-ray was normal. A chest computed tomography (CT) scan showed multiple scattered pulmonary nodules concerning for emboli (Figure 1). Branching, Gram-positive bacilli grew in 4 of 4 blood cultures bottles taken on the day of her admission to the hospital (Figure 2). The organism stained with a modified acid-fast bacilli stain and was identified as Nocardia nova (Figure 3). The multiple, bilateral small nodular opacities seen on CT scan of the chest were consistent with septic pulmonary emboli. A transthoracic echocardiogram was normal, but transesophageal echocardiogram showed a 3-mm × 1-mm mobile vegetation on the mitral valve. A magnetic resonance image of the brain was normal. Thus, this patient was diagnosed with PICC-associated N nova septic pulmonary emboli and endocarditis.
Figure 1. Computed tomography of the patient’s chest. Multiple scattered nodules in the periphery of the lungs (arrow) were identified.
Figure 2. Gram stain of the organism growing in blood culture.
Figure 3. A modified acid-fast bacilli stain of the organism growing in blood culture.
PATIENT CONSENT
Consent to publish to this case report was obtained from the patient. The article type (“ID Teaching Cases”) does not require formal approval by an ethics committee.
DISCUSSION
In this study, we present the case of a patient with a severe complication associated with the unscientific use of IV antibiotics for management of persistent symptoms and a diagnosis of Lyme disease. Several randomized controlled trials have compared long-term antibiotics with placebo for the treatment of these patients [1–4]. In each of these studies, longer term antibiotic treatment did not improve symptoms in patients compared with placebo. However, complications of long-term antibiotic treatment for Lyme disease include PICC-line associated bacteremia, which can be life threatening [5]. Despite these data and a recommendation from the Infectious Diseases Society of America against the use of extended courses of antibiotics in this setting [6], some clinicians still prescribe such therapies [7, 8].
The patient was initially diagnosed with Lyme disease when an immunoblot for B burgdorferi-specific IgM antibodies was positive; however, the immunoblot for IgG antibodies was negative. Borrelia burgdorferi IgM immunoblots have poor specificity, particularly when the IgG test is negative, and can lead to the misdiagnosis of Lyme disease [9]. Thus, an isolated positive B burgdorferi IgM immunoblot should not be used to diagnose Lyme disease in patients who have had symptoms for more than 6 weeks.
Nocardia sp are Gram-positive, beaded, weakly acid-fast, branching bacilli that are uncommon causes of bacteremia and endocarditis [10]. It is interesting to note that N nova was the most common pathogen in a case series of patients with Nocardia sp bacteremia and an underlying cancer, recovered in 6 of 17 cases [11]. Ten of 17 patients in this study had central catheter-associated bacteremia, and the authors found that Nocardia sp promoted biofilm formation on central venous catheters in vitro [11]. Patients with central venous catheter-associated Nocardia sp bacteremia responded well to catheter removal and antibiotic therapy [11].
Data from randomized controlled trials are not available to guide treatment for nocardiosis. Based on cumulative clinical experience, trimethoprim-sulfamethoxazole is the mainstay of therapy for patients with nocardiosis. Patients who are allergic to trimethoprim-sulfamethoxazole should be desensitized to enable treatment with this agent. Most authorities recommend that severe infection with Nocardia sp, such as endocarditis in this patient, be managed with combination therapy. For severe disease outside the central nervous system, the combination of trimethoprim-sulfamethoxazole and amikacin for initial therapy is recommended until antimicrobial susceptibility data are available. The combination of imipenem and amikacin is also used in this setting. The optimal duration of therapy for patients with nocardiosis is not known. Shorter antibiotic courses for Nocardia sp infection are associated with a high risk of relapse, even in immunocompetent hosts. Thus, most infectious disease clinicians recommend that patients with severe nocardiosis be treated with antibiotics for 6 to 12 months.
FOLLOW-UP
The patient’s PICC line was removed and she was started on imipenem, given her history of a severe allergy to trimethoprim-sulfamethoxazole. On the second hospital day, the patient’s fever resolved, and her symptoms improved markedly. During her hospital stay, she was desensitized to trimethoprim-sulfamethoxazole. She was discharged on trimethoprim-sulfamethoxazole and amikacin while awaiting the identification and susceptibility of the Nocardia sp. Ten days into therapy, the patient developed a diffuse maculopapular drug rash. The trimethoprim-sulfamethoxazole was discontinued, imipenem was restarted, and the amikacin therapy continued. Her rash resolved. After 4 weeks of empiric antibiotic treatment, the organism was identified as N nova that was sensitive to trimethoprim-sulfamethoxazole, amikacin, ceftriaxone, imipenem, and linezolid, but resistant to tetracyclines, fluoroquinolones, and amoxicillin/clavulanate. Imipenem and amikacin were discontinued, and the patient was started on ceftriaxone, given her history of malabsorption and inability to tolerate oral antibiotics. A 6-month course of ceftriaxone is planned for this patient, after which a CT scan of the chest will be obtained to ensure resolution of the septic emboli. The PICC line used to administer ceftriaxone will then be removed.
Acknowledgments
Financial support. R. P.-W.’s research is funded by R01 AI130289 from the National Institute of Allergy and Infectious Diseases and an Innovator Award from the Kenneth Rainin Foundation.
Potential conflicts of interests. All authors have no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33728358 | 19,670,043 | 2021-03 |
What was the outcome of reaction 'Nocardiosis'? | Peripherally Inserted Central Catheter-Associated Nocardia nova Endocarditis in a Patient Receiving Intravenous Antibiotics for Chronic Lyme Disease.
Long-term antibiotics are not effective for the therapy of patients with persistent symptoms and a history of Lyme disease. However, some clinicians still prescribe these therapies. We present a case of peripherally inserted central catheter-associated Nocardia nova endocarditis in a patient who had been receiving intravenous antibiotics for the management of chronic Lyme disease. This case highlights an important risk associated with the unscientific use of indwelling peripheral catheters and intravenous antibiotics for the management of such patients.
PRESENTATION OF CASE
A 34-year-old female from New England presented with a 1-month history of daily low-grade fevers, dry cough, loss of appetite, and a 5-pound weight loss. She received 2 separate 5-day courses of azithromycin as an outpatient with no improvement in her symptoms. Ten years before presentation, the patient was diagnosed with Lyme disease. A Western blot for Borrelia burgdorferi-specific immunoglobulin IgM antibodies detected 2 of 3 bands and was interpreted as positive, but a Western blot for IgG antibodies was negative. She was treated with doxycycline for 3 weeks. The patient continued to have polyarthralgia and fatigue and reported that she was diagnosed with chronic Lyme disease 5 years before presentation. She had an indwelling peripherally inserted central catheter (PICC) in place for the previous 22 months for the administration of intravenous (IV) antibiotics that were prescribed to treat chronic Lyme disease. She received a 10-month course of IV ceftriaxone and then a 6-month course of IV doxycycline. She was also prescribed intermittent courses of other agents, such as oral disulfuram and oral doxycycline, for the treatment of chronic Lyme disease. The patient has a history of Ehlers-Danlos syndrome, gastrointestinal malabsorption, which necessitates enteral feeding through a nasogastric tube, postural orthostatic tachycardia syndrome, and psychogenic nonepileptic seizures. She reported that the administration of sulfa drugs caused hives when she was a child. On the day of presentation, the patient had a temperature of 38.1°C and a heart rate of 103 beats per minute. A PICC line was in place in the right arm. The rest of her physical exam was normal. Kidney function, serum glucose, a complete blood count with differential, and liver enzyme tests were all within the normal range. Tests for SARS-CoV-2 and human immunodeficiency virus were negative. A chest x-ray was normal. A chest computed tomography (CT) scan showed multiple scattered pulmonary nodules concerning for emboli (Figure 1). Branching, Gram-positive bacilli grew in 4 of 4 blood cultures bottles taken on the day of her admission to the hospital (Figure 2). The organism stained with a modified acid-fast bacilli stain and was identified as Nocardia nova (Figure 3). The multiple, bilateral small nodular opacities seen on CT scan of the chest were consistent with septic pulmonary emboli. A transthoracic echocardiogram was normal, but transesophageal echocardiogram showed a 3-mm × 1-mm mobile vegetation on the mitral valve. A magnetic resonance image of the brain was normal. Thus, this patient was diagnosed with PICC-associated N nova septic pulmonary emboli and endocarditis.
Figure 1. Computed tomography of the patient’s chest. Multiple scattered nodules in the periphery of the lungs (arrow) were identified.
Figure 2. Gram stain of the organism growing in blood culture.
Figure 3. A modified acid-fast bacilli stain of the organism growing in blood culture.
PATIENT CONSENT
Consent to publish to this case report was obtained from the patient. The article type (“ID Teaching Cases”) does not require formal approval by an ethics committee.
DISCUSSION
In this study, we present the case of a patient with a severe complication associated with the unscientific use of IV antibiotics for management of persistent symptoms and a diagnosis of Lyme disease. Several randomized controlled trials have compared long-term antibiotics with placebo for the treatment of these patients [1–4]. In each of these studies, longer term antibiotic treatment did not improve symptoms in patients compared with placebo. However, complications of long-term antibiotic treatment for Lyme disease include PICC-line associated bacteremia, which can be life threatening [5]. Despite these data and a recommendation from the Infectious Diseases Society of America against the use of extended courses of antibiotics in this setting [6], some clinicians still prescribe such therapies [7, 8].
The patient was initially diagnosed with Lyme disease when an immunoblot for B burgdorferi-specific IgM antibodies was positive; however, the immunoblot for IgG antibodies was negative. Borrelia burgdorferi IgM immunoblots have poor specificity, particularly when the IgG test is negative, and can lead to the misdiagnosis of Lyme disease [9]. Thus, an isolated positive B burgdorferi IgM immunoblot should not be used to diagnose Lyme disease in patients who have had symptoms for more than 6 weeks.
Nocardia sp are Gram-positive, beaded, weakly acid-fast, branching bacilli that are uncommon causes of bacteremia and endocarditis [10]. It is interesting to note that N nova was the most common pathogen in a case series of patients with Nocardia sp bacteremia and an underlying cancer, recovered in 6 of 17 cases [11]. Ten of 17 patients in this study had central catheter-associated bacteremia, and the authors found that Nocardia sp promoted biofilm formation on central venous catheters in vitro [11]. Patients with central venous catheter-associated Nocardia sp bacteremia responded well to catheter removal and antibiotic therapy [11].
Data from randomized controlled trials are not available to guide treatment for nocardiosis. Based on cumulative clinical experience, trimethoprim-sulfamethoxazole is the mainstay of therapy for patients with nocardiosis. Patients who are allergic to trimethoprim-sulfamethoxazole should be desensitized to enable treatment with this agent. Most authorities recommend that severe infection with Nocardia sp, such as endocarditis in this patient, be managed with combination therapy. For severe disease outside the central nervous system, the combination of trimethoprim-sulfamethoxazole and amikacin for initial therapy is recommended until antimicrobial susceptibility data are available. The combination of imipenem and amikacin is also used in this setting. The optimal duration of therapy for patients with nocardiosis is not known. Shorter antibiotic courses for Nocardia sp infection are associated with a high risk of relapse, even in immunocompetent hosts. Thus, most infectious disease clinicians recommend that patients with severe nocardiosis be treated with antibiotics for 6 to 12 months.
FOLLOW-UP
The patient’s PICC line was removed and she was started on imipenem, given her history of a severe allergy to trimethoprim-sulfamethoxazole. On the second hospital day, the patient’s fever resolved, and her symptoms improved markedly. During her hospital stay, she was desensitized to trimethoprim-sulfamethoxazole. She was discharged on trimethoprim-sulfamethoxazole and amikacin while awaiting the identification and susceptibility of the Nocardia sp. Ten days into therapy, the patient developed a diffuse maculopapular drug rash. The trimethoprim-sulfamethoxazole was discontinued, imipenem was restarted, and the amikacin therapy continued. Her rash resolved. After 4 weeks of empiric antibiotic treatment, the organism was identified as N nova that was sensitive to trimethoprim-sulfamethoxazole, amikacin, ceftriaxone, imipenem, and linezolid, but resistant to tetracyclines, fluoroquinolones, and amoxicillin/clavulanate. Imipenem and amikacin were discontinued, and the patient was started on ceftriaxone, given her history of malabsorption and inability to tolerate oral antibiotics. A 6-month course of ceftriaxone is planned for this patient, after which a CT scan of the chest will be obtained to ensure resolution of the septic emboli. The PICC line used to administer ceftriaxone will then be removed.
Acknowledgments
Financial support. R. P.-W.’s research is funded by R01 AI130289 from the National Institute of Allergy and Infectious Diseases and an Innovator Award from the Kenneth Rainin Foundation.
Potential conflicts of interests. All authors have no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33728358 | 19,724,199 | 2021-03 |
What was the outcome of reaction 'Rash maculo-papular'? | Peripherally Inserted Central Catheter-Associated Nocardia nova Endocarditis in a Patient Receiving Intravenous Antibiotics for Chronic Lyme Disease.
Long-term antibiotics are not effective for the therapy of patients with persistent symptoms and a history of Lyme disease. However, some clinicians still prescribe these therapies. We present a case of peripherally inserted central catheter-associated Nocardia nova endocarditis in a patient who had been receiving intravenous antibiotics for the management of chronic Lyme disease. This case highlights an important risk associated with the unscientific use of indwelling peripheral catheters and intravenous antibiotics for the management of such patients.
PRESENTATION OF CASE
A 34-year-old female from New England presented with a 1-month history of daily low-grade fevers, dry cough, loss of appetite, and a 5-pound weight loss. She received 2 separate 5-day courses of azithromycin as an outpatient with no improvement in her symptoms. Ten years before presentation, the patient was diagnosed with Lyme disease. A Western blot for Borrelia burgdorferi-specific immunoglobulin IgM antibodies detected 2 of 3 bands and was interpreted as positive, but a Western blot for IgG antibodies was negative. She was treated with doxycycline for 3 weeks. The patient continued to have polyarthralgia and fatigue and reported that she was diagnosed with chronic Lyme disease 5 years before presentation. She had an indwelling peripherally inserted central catheter (PICC) in place for the previous 22 months for the administration of intravenous (IV) antibiotics that were prescribed to treat chronic Lyme disease. She received a 10-month course of IV ceftriaxone and then a 6-month course of IV doxycycline. She was also prescribed intermittent courses of other agents, such as oral disulfuram and oral doxycycline, for the treatment of chronic Lyme disease. The patient has a history of Ehlers-Danlos syndrome, gastrointestinal malabsorption, which necessitates enteral feeding through a nasogastric tube, postural orthostatic tachycardia syndrome, and psychogenic nonepileptic seizures. She reported that the administration of sulfa drugs caused hives when she was a child. On the day of presentation, the patient had a temperature of 38.1°C and a heart rate of 103 beats per minute. A PICC line was in place in the right arm. The rest of her physical exam was normal. Kidney function, serum glucose, a complete blood count with differential, and liver enzyme tests were all within the normal range. Tests for SARS-CoV-2 and human immunodeficiency virus were negative. A chest x-ray was normal. A chest computed tomography (CT) scan showed multiple scattered pulmonary nodules concerning for emboli (Figure 1). Branching, Gram-positive bacilli grew in 4 of 4 blood cultures bottles taken on the day of her admission to the hospital (Figure 2). The organism stained with a modified acid-fast bacilli stain and was identified as Nocardia nova (Figure 3). The multiple, bilateral small nodular opacities seen on CT scan of the chest were consistent with septic pulmonary emboli. A transthoracic echocardiogram was normal, but transesophageal echocardiogram showed a 3-mm × 1-mm mobile vegetation on the mitral valve. A magnetic resonance image of the brain was normal. Thus, this patient was diagnosed with PICC-associated N nova septic pulmonary emboli and endocarditis.
Figure 1. Computed tomography of the patient’s chest. Multiple scattered nodules in the periphery of the lungs (arrow) were identified.
Figure 2. Gram stain of the organism growing in blood culture.
Figure 3. A modified acid-fast bacilli stain of the organism growing in blood culture.
PATIENT CONSENT
Consent to publish to this case report was obtained from the patient. The article type (“ID Teaching Cases”) does not require formal approval by an ethics committee.
DISCUSSION
In this study, we present the case of a patient with a severe complication associated with the unscientific use of IV antibiotics for management of persistent symptoms and a diagnosis of Lyme disease. Several randomized controlled trials have compared long-term antibiotics with placebo for the treatment of these patients [1–4]. In each of these studies, longer term antibiotic treatment did not improve symptoms in patients compared with placebo. However, complications of long-term antibiotic treatment for Lyme disease include PICC-line associated bacteremia, which can be life threatening [5]. Despite these data and a recommendation from the Infectious Diseases Society of America against the use of extended courses of antibiotics in this setting [6], some clinicians still prescribe such therapies [7, 8].
The patient was initially diagnosed with Lyme disease when an immunoblot for B burgdorferi-specific IgM antibodies was positive; however, the immunoblot for IgG antibodies was negative. Borrelia burgdorferi IgM immunoblots have poor specificity, particularly when the IgG test is negative, and can lead to the misdiagnosis of Lyme disease [9]. Thus, an isolated positive B burgdorferi IgM immunoblot should not be used to diagnose Lyme disease in patients who have had symptoms for more than 6 weeks.
Nocardia sp are Gram-positive, beaded, weakly acid-fast, branching bacilli that are uncommon causes of bacteremia and endocarditis [10]. It is interesting to note that N nova was the most common pathogen in a case series of patients with Nocardia sp bacteremia and an underlying cancer, recovered in 6 of 17 cases [11]. Ten of 17 patients in this study had central catheter-associated bacteremia, and the authors found that Nocardia sp promoted biofilm formation on central venous catheters in vitro [11]. Patients with central venous catheter-associated Nocardia sp bacteremia responded well to catheter removal and antibiotic therapy [11].
Data from randomized controlled trials are not available to guide treatment for nocardiosis. Based on cumulative clinical experience, trimethoprim-sulfamethoxazole is the mainstay of therapy for patients with nocardiosis. Patients who are allergic to trimethoprim-sulfamethoxazole should be desensitized to enable treatment with this agent. Most authorities recommend that severe infection with Nocardia sp, such as endocarditis in this patient, be managed with combination therapy. For severe disease outside the central nervous system, the combination of trimethoprim-sulfamethoxazole and amikacin for initial therapy is recommended until antimicrobial susceptibility data are available. The combination of imipenem and amikacin is also used in this setting. The optimal duration of therapy for patients with nocardiosis is not known. Shorter antibiotic courses for Nocardia sp infection are associated with a high risk of relapse, even in immunocompetent hosts. Thus, most infectious disease clinicians recommend that patients with severe nocardiosis be treated with antibiotics for 6 to 12 months.
FOLLOW-UP
The patient’s PICC line was removed and she was started on imipenem, given her history of a severe allergy to trimethoprim-sulfamethoxazole. On the second hospital day, the patient’s fever resolved, and her symptoms improved markedly. During her hospital stay, she was desensitized to trimethoprim-sulfamethoxazole. She was discharged on trimethoprim-sulfamethoxazole and amikacin while awaiting the identification and susceptibility of the Nocardia sp. Ten days into therapy, the patient developed a diffuse maculopapular drug rash. The trimethoprim-sulfamethoxazole was discontinued, imipenem was restarted, and the amikacin therapy continued. Her rash resolved. After 4 weeks of empiric antibiotic treatment, the organism was identified as N nova that was sensitive to trimethoprim-sulfamethoxazole, amikacin, ceftriaxone, imipenem, and linezolid, but resistant to tetracyclines, fluoroquinolones, and amoxicillin/clavulanate. Imipenem and amikacin were discontinued, and the patient was started on ceftriaxone, given her history of malabsorption and inability to tolerate oral antibiotics. A 6-month course of ceftriaxone is planned for this patient, after which a CT scan of the chest will be obtained to ensure resolution of the septic emboli. The PICC line used to administer ceftriaxone will then be removed.
Acknowledgments
Financial support. R. P.-W.’s research is funded by R01 AI130289 from the National Institute of Allergy and Infectious Diseases and an Innovator Award from the Kenneth Rainin Foundation.
Potential conflicts of interests. All authors have no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | Recovered | ReactionOutcome | CC BY-NC-ND | 33728358 | 19,724,199 | 2021-03 |
What was the outcome of reaction 'Septic pulmonary embolism'? | Peripherally Inserted Central Catheter-Associated Nocardia nova Endocarditis in a Patient Receiving Intravenous Antibiotics for Chronic Lyme Disease.
Long-term antibiotics are not effective for the therapy of patients with persistent symptoms and a history of Lyme disease. However, some clinicians still prescribe these therapies. We present a case of peripherally inserted central catheter-associated Nocardia nova endocarditis in a patient who had been receiving intravenous antibiotics for the management of chronic Lyme disease. This case highlights an important risk associated with the unscientific use of indwelling peripheral catheters and intravenous antibiotics for the management of such patients.
PRESENTATION OF CASE
A 34-year-old female from New England presented with a 1-month history of daily low-grade fevers, dry cough, loss of appetite, and a 5-pound weight loss. She received 2 separate 5-day courses of azithromycin as an outpatient with no improvement in her symptoms. Ten years before presentation, the patient was diagnosed with Lyme disease. A Western blot for Borrelia burgdorferi-specific immunoglobulin IgM antibodies detected 2 of 3 bands and was interpreted as positive, but a Western blot for IgG antibodies was negative. She was treated with doxycycline for 3 weeks. The patient continued to have polyarthralgia and fatigue and reported that she was diagnosed with chronic Lyme disease 5 years before presentation. She had an indwelling peripherally inserted central catheter (PICC) in place for the previous 22 months for the administration of intravenous (IV) antibiotics that were prescribed to treat chronic Lyme disease. She received a 10-month course of IV ceftriaxone and then a 6-month course of IV doxycycline. She was also prescribed intermittent courses of other agents, such as oral disulfuram and oral doxycycline, for the treatment of chronic Lyme disease. The patient has a history of Ehlers-Danlos syndrome, gastrointestinal malabsorption, which necessitates enteral feeding through a nasogastric tube, postural orthostatic tachycardia syndrome, and psychogenic nonepileptic seizures. She reported that the administration of sulfa drugs caused hives when she was a child. On the day of presentation, the patient had a temperature of 38.1°C and a heart rate of 103 beats per minute. A PICC line was in place in the right arm. The rest of her physical exam was normal. Kidney function, serum glucose, a complete blood count with differential, and liver enzyme tests were all within the normal range. Tests for SARS-CoV-2 and human immunodeficiency virus were negative. A chest x-ray was normal. A chest computed tomography (CT) scan showed multiple scattered pulmonary nodules concerning for emboli (Figure 1). Branching, Gram-positive bacilli grew in 4 of 4 blood cultures bottles taken on the day of her admission to the hospital (Figure 2). The organism stained with a modified acid-fast bacilli stain and was identified as Nocardia nova (Figure 3). The multiple, bilateral small nodular opacities seen on CT scan of the chest were consistent with septic pulmonary emboli. A transthoracic echocardiogram was normal, but transesophageal echocardiogram showed a 3-mm × 1-mm mobile vegetation on the mitral valve. A magnetic resonance image of the brain was normal. Thus, this patient was diagnosed with PICC-associated N nova septic pulmonary emboli and endocarditis.
Figure 1. Computed tomography of the patient’s chest. Multiple scattered nodules in the periphery of the lungs (arrow) were identified.
Figure 2. Gram stain of the organism growing in blood culture.
Figure 3. A modified acid-fast bacilli stain of the organism growing in blood culture.
PATIENT CONSENT
Consent to publish to this case report was obtained from the patient. The article type (“ID Teaching Cases”) does not require formal approval by an ethics committee.
DISCUSSION
In this study, we present the case of a patient with a severe complication associated with the unscientific use of IV antibiotics for management of persistent symptoms and a diagnosis of Lyme disease. Several randomized controlled trials have compared long-term antibiotics with placebo for the treatment of these patients [1–4]. In each of these studies, longer term antibiotic treatment did not improve symptoms in patients compared with placebo. However, complications of long-term antibiotic treatment for Lyme disease include PICC-line associated bacteremia, which can be life threatening [5]. Despite these data and a recommendation from the Infectious Diseases Society of America against the use of extended courses of antibiotics in this setting [6], some clinicians still prescribe such therapies [7, 8].
The patient was initially diagnosed with Lyme disease when an immunoblot for B burgdorferi-specific IgM antibodies was positive; however, the immunoblot for IgG antibodies was negative. Borrelia burgdorferi IgM immunoblots have poor specificity, particularly when the IgG test is negative, and can lead to the misdiagnosis of Lyme disease [9]. Thus, an isolated positive B burgdorferi IgM immunoblot should not be used to diagnose Lyme disease in patients who have had symptoms for more than 6 weeks.
Nocardia sp are Gram-positive, beaded, weakly acid-fast, branching bacilli that are uncommon causes of bacteremia and endocarditis [10]. It is interesting to note that N nova was the most common pathogen in a case series of patients with Nocardia sp bacteremia and an underlying cancer, recovered in 6 of 17 cases [11]. Ten of 17 patients in this study had central catheter-associated bacteremia, and the authors found that Nocardia sp promoted biofilm formation on central venous catheters in vitro [11]. Patients with central venous catheter-associated Nocardia sp bacteremia responded well to catheter removal and antibiotic therapy [11].
Data from randomized controlled trials are not available to guide treatment for nocardiosis. Based on cumulative clinical experience, trimethoprim-sulfamethoxazole is the mainstay of therapy for patients with nocardiosis. Patients who are allergic to trimethoprim-sulfamethoxazole should be desensitized to enable treatment with this agent. Most authorities recommend that severe infection with Nocardia sp, such as endocarditis in this patient, be managed with combination therapy. For severe disease outside the central nervous system, the combination of trimethoprim-sulfamethoxazole and amikacin for initial therapy is recommended until antimicrobial susceptibility data are available. The combination of imipenem and amikacin is also used in this setting. The optimal duration of therapy for patients with nocardiosis is not known. Shorter antibiotic courses for Nocardia sp infection are associated with a high risk of relapse, even in immunocompetent hosts. Thus, most infectious disease clinicians recommend that patients with severe nocardiosis be treated with antibiotics for 6 to 12 months.
FOLLOW-UP
The patient’s PICC line was removed and she was started on imipenem, given her history of a severe allergy to trimethoprim-sulfamethoxazole. On the second hospital day, the patient’s fever resolved, and her symptoms improved markedly. During her hospital stay, she was desensitized to trimethoprim-sulfamethoxazole. She was discharged on trimethoprim-sulfamethoxazole and amikacin while awaiting the identification and susceptibility of the Nocardia sp. Ten days into therapy, the patient developed a diffuse maculopapular drug rash. The trimethoprim-sulfamethoxazole was discontinued, imipenem was restarted, and the amikacin therapy continued. Her rash resolved. After 4 weeks of empiric antibiotic treatment, the organism was identified as N nova that was sensitive to trimethoprim-sulfamethoxazole, amikacin, ceftriaxone, imipenem, and linezolid, but resistant to tetracyclines, fluoroquinolones, and amoxicillin/clavulanate. Imipenem and amikacin were discontinued, and the patient was started on ceftriaxone, given her history of malabsorption and inability to tolerate oral antibiotics. A 6-month course of ceftriaxone is planned for this patient, after which a CT scan of the chest will be obtained to ensure resolution of the septic emboli. The PICC line used to administer ceftriaxone will then be removed.
Acknowledgments
Financial support. R. P.-W.’s research is funded by R01 AI130289 from the National Institute of Allergy and Infectious Diseases and an Innovator Award from the Kenneth Rainin Foundation.
Potential conflicts of interests. All authors have no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33728358 | 19,724,199 | 2021-03 |
What was the outcome of reaction 'Vascular device infection'? | Peripherally Inserted Central Catheter-Associated Nocardia nova Endocarditis in a Patient Receiving Intravenous Antibiotics for Chronic Lyme Disease.
Long-term antibiotics are not effective for the therapy of patients with persistent symptoms and a history of Lyme disease. However, some clinicians still prescribe these therapies. We present a case of peripherally inserted central catheter-associated Nocardia nova endocarditis in a patient who had been receiving intravenous antibiotics for the management of chronic Lyme disease. This case highlights an important risk associated with the unscientific use of indwelling peripheral catheters and intravenous antibiotics for the management of such patients.
PRESENTATION OF CASE
A 34-year-old female from New England presented with a 1-month history of daily low-grade fevers, dry cough, loss of appetite, and a 5-pound weight loss. She received 2 separate 5-day courses of azithromycin as an outpatient with no improvement in her symptoms. Ten years before presentation, the patient was diagnosed with Lyme disease. A Western blot for Borrelia burgdorferi-specific immunoglobulin IgM antibodies detected 2 of 3 bands and was interpreted as positive, but a Western blot for IgG antibodies was negative. She was treated with doxycycline for 3 weeks. The patient continued to have polyarthralgia and fatigue and reported that she was diagnosed with chronic Lyme disease 5 years before presentation. She had an indwelling peripherally inserted central catheter (PICC) in place for the previous 22 months for the administration of intravenous (IV) antibiotics that were prescribed to treat chronic Lyme disease. She received a 10-month course of IV ceftriaxone and then a 6-month course of IV doxycycline. She was also prescribed intermittent courses of other agents, such as oral disulfuram and oral doxycycline, for the treatment of chronic Lyme disease. The patient has a history of Ehlers-Danlos syndrome, gastrointestinal malabsorption, which necessitates enteral feeding through a nasogastric tube, postural orthostatic tachycardia syndrome, and psychogenic nonepileptic seizures. She reported that the administration of sulfa drugs caused hives when she was a child. On the day of presentation, the patient had a temperature of 38.1°C and a heart rate of 103 beats per minute. A PICC line was in place in the right arm. The rest of her physical exam was normal. Kidney function, serum glucose, a complete blood count with differential, and liver enzyme tests were all within the normal range. Tests for SARS-CoV-2 and human immunodeficiency virus were negative. A chest x-ray was normal. A chest computed tomography (CT) scan showed multiple scattered pulmonary nodules concerning for emboli (Figure 1). Branching, Gram-positive bacilli grew in 4 of 4 blood cultures bottles taken on the day of her admission to the hospital (Figure 2). The organism stained with a modified acid-fast bacilli stain and was identified as Nocardia nova (Figure 3). The multiple, bilateral small nodular opacities seen on CT scan of the chest were consistent with septic pulmonary emboli. A transthoracic echocardiogram was normal, but transesophageal echocardiogram showed a 3-mm × 1-mm mobile vegetation on the mitral valve. A magnetic resonance image of the brain was normal. Thus, this patient was diagnosed with PICC-associated N nova septic pulmonary emboli and endocarditis.
Figure 1. Computed tomography of the patient’s chest. Multiple scattered nodules in the periphery of the lungs (arrow) were identified.
Figure 2. Gram stain of the organism growing in blood culture.
Figure 3. A modified acid-fast bacilli stain of the organism growing in blood culture.
PATIENT CONSENT
Consent to publish to this case report was obtained from the patient. The article type (“ID Teaching Cases”) does not require formal approval by an ethics committee.
DISCUSSION
In this study, we present the case of a patient with a severe complication associated with the unscientific use of IV antibiotics for management of persistent symptoms and a diagnosis of Lyme disease. Several randomized controlled trials have compared long-term antibiotics with placebo for the treatment of these patients [1–4]. In each of these studies, longer term antibiotic treatment did not improve symptoms in patients compared with placebo. However, complications of long-term antibiotic treatment for Lyme disease include PICC-line associated bacteremia, which can be life threatening [5]. Despite these data and a recommendation from the Infectious Diseases Society of America against the use of extended courses of antibiotics in this setting [6], some clinicians still prescribe such therapies [7, 8].
The patient was initially diagnosed with Lyme disease when an immunoblot for B burgdorferi-specific IgM antibodies was positive; however, the immunoblot for IgG antibodies was negative. Borrelia burgdorferi IgM immunoblots have poor specificity, particularly when the IgG test is negative, and can lead to the misdiagnosis of Lyme disease [9]. Thus, an isolated positive B burgdorferi IgM immunoblot should not be used to diagnose Lyme disease in patients who have had symptoms for more than 6 weeks.
Nocardia sp are Gram-positive, beaded, weakly acid-fast, branching bacilli that are uncommon causes of bacteremia and endocarditis [10]. It is interesting to note that N nova was the most common pathogen in a case series of patients with Nocardia sp bacteremia and an underlying cancer, recovered in 6 of 17 cases [11]. Ten of 17 patients in this study had central catheter-associated bacteremia, and the authors found that Nocardia sp promoted biofilm formation on central venous catheters in vitro [11]. Patients with central venous catheter-associated Nocardia sp bacteremia responded well to catheter removal and antibiotic therapy [11].
Data from randomized controlled trials are not available to guide treatment for nocardiosis. Based on cumulative clinical experience, trimethoprim-sulfamethoxazole is the mainstay of therapy for patients with nocardiosis. Patients who are allergic to trimethoprim-sulfamethoxazole should be desensitized to enable treatment with this agent. Most authorities recommend that severe infection with Nocardia sp, such as endocarditis in this patient, be managed with combination therapy. For severe disease outside the central nervous system, the combination of trimethoprim-sulfamethoxazole and amikacin for initial therapy is recommended until antimicrobial susceptibility data are available. The combination of imipenem and amikacin is also used in this setting. The optimal duration of therapy for patients with nocardiosis is not known. Shorter antibiotic courses for Nocardia sp infection are associated with a high risk of relapse, even in immunocompetent hosts. Thus, most infectious disease clinicians recommend that patients with severe nocardiosis be treated with antibiotics for 6 to 12 months.
FOLLOW-UP
The patient’s PICC line was removed and she was started on imipenem, given her history of a severe allergy to trimethoprim-sulfamethoxazole. On the second hospital day, the patient’s fever resolved, and her symptoms improved markedly. During her hospital stay, she was desensitized to trimethoprim-sulfamethoxazole. She was discharged on trimethoprim-sulfamethoxazole and amikacin while awaiting the identification and susceptibility of the Nocardia sp. Ten days into therapy, the patient developed a diffuse maculopapular drug rash. The trimethoprim-sulfamethoxazole was discontinued, imipenem was restarted, and the amikacin therapy continued. Her rash resolved. After 4 weeks of empiric antibiotic treatment, the organism was identified as N nova that was sensitive to trimethoprim-sulfamethoxazole, amikacin, ceftriaxone, imipenem, and linezolid, but resistant to tetracyclines, fluoroquinolones, and amoxicillin/clavulanate. Imipenem and amikacin were discontinued, and the patient was started on ceftriaxone, given her history of malabsorption and inability to tolerate oral antibiotics. A 6-month course of ceftriaxone is planned for this patient, after which a CT scan of the chest will be obtained to ensure resolution of the septic emboli. The PICC line used to administer ceftriaxone will then be removed.
Acknowledgments
Financial support. R. P.-W.’s research is funded by R01 AI130289 from the National Institute of Allergy and Infectious Diseases and an Innovator Award from the Kenneth Rainin Foundation.
Potential conflicts of interests. All authors have no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33728358 | 19,670,043 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Death'. | Real-World Treatment Patterns and Outcomes Among Multiple Myeloma Patients with Asthma and COPD in the United States.
BACKGROUND
Multiple myeloma (MM) is the second most frequent hematologic malignancy after lymphoma, contributing to approximately 10% of all hematologic malignancies. The prognosis of patients with MM is impacted by the heterogeneity of the disease, with worse outcomes reported in patients classified as International Staging System stage III, those with high-risk cytogenetics and elevated serum lactate dehydrogenase, and among patients who are elderly and have comorbidities. Previous studies have demonstrated an association between the presence of lung disease and worse outcomes; however, this impact in a real-world setting is not well understood.
METHODS
This retrospective, observational, cohort study included data from the nationwide US Optum® de-identified electronic health record (EHR) database from January 1, 2006, to December 31, 2019. MM patients with asthma or chronic obstructive pulmonary disease (COPD) were compared with MM patients without asthma or COPD for time to next treatment and overall survival using one-sided log-rank tests stratified by age and multivariable Cox proportional hazard models.
RESULTS
Among 5186 patients with MM, approximately 15% had an asthma or COPD diagnosis (asthma/COPD) at baseline. The most commonly observed comorbidities among all MM patients and among those MM patients with asthma/COPD were cardiovascular disease, diabetes, and renal impairment. Time from first- to second-line treatment was significantly longer for patients with a diagnosis of COPD. Overall survival from first-line therapy was significantly worse among patients with COPD, with numerically worse overall survival from second-line therapy.
CONCLUSIONS
These real-world data suggest that patients with asthma or COPD do not experience a shorter time interval to next treatment, but have significantly worse overall survival from start of first-line therapy and numerically worse survival from the start of later lines. Future investigations with larger datasets may improve the understanding of the influence of individual treatments on outcomes in these patients.
Key Summary Points
Why carry out this study?
Comorbidities are known to impact outcomes in patients with multiple myeloma, but many patients with pulmonary disease are excluded from clinical trials; therefore, not much is known about this subgroup of patients.
Previous results have demonstrated an association between the presence of lung disease and worse outcomes; however, this impact in a real-world setting is not well understood.
The objective of the current study was to assess the prevalence of asthma and chronic obstructive pulmonary disease (COPD) in a real-world patient population with multiple myeloma, and to describe treatment patterns in patients with/without asthma/COPD, and time to next treatment and overall survival in patients with asthma/COPD.
What was learned from the study?
These real-world data suggest that patients with asthma or COPD experience prolonged time to next treatment from first to second line, but have significantly worse overall survival from start of first-line therapy and numerically worse survival from the start of later lines of therapy.
Future investigations with larger datasets may improve the understanding of the influence of individual treatments on outcomes in these patients.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article, go to https://doi.org/10.6084/m9.figshare.14113682.
Introduction
Multiple myeloma (MM) is the second most frequent hematologic malignancy after lymphoma, contributing to 1% of all cancers and approximately 10% of all hematologic malignancies [1, 2]. Despite the introduction of targeted therapies and combination regimens, patients with MM continue to experience multiple relapses and/or become refractory to treatment [3].
The prognosis of patients with MM has been shown to be impacted by the heterogeneity of the disease, with prognostic factors categorized by burden of disease, tumor biology, host factors, and depth of response to therapy [4]. Worse outcomes have been reported in patients classified as International Staging System stage III, those with high-risk cytogenetics and elevated serum lactate dehydrogenase, and among patients who are elderly and have comorbidities. Treatment decision-making may require consideration of preexisting comorbidities and organ dysfunction, which have been associated with an increased risk of treatment- and disease-related complications that contribute to high levels of mortality earlier in the treatment continuum.
In ICARIA-MM, a recent phase 3 study of isatuximab, an anti-CD38 monoclonal antibody that has been approved in combination with pomalidomide and dexamethasone in the United States, the European Union, Japan, and other countries for the treatment of adult patients with relapsed/refractory MM who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor (PI) [5–9], approximately 10% of patients had a previous history of asthma or chronic obstructive pulmonary disorder (COPD) [10]. However, previous MM studies investigating other molecules have used COPD/pulmonary disease as an exclusion criterion (e.g., POLLUX; ELOQUENT-2 [if uncontrolled]; CASTOR; CANDOR; MAIA; CASSIOPEIA) [11–16]. As a result, little is known from randomized controlled trials about treatment patterns and outcomes in MM patients with respiratory comorbidities. Although some retrospective studies have demonstrated an association between the presence of lung disease and worse outcome [17], and an independent association has been reported between pulmonary function abnormalities and worse outcome in patients with MM [18], the real-world impact of preexisting lung disease is not well understood.
Therefore, the objective of the current study was to assess the prevalence of asthma and COPD in a real-world patient population with MM, and to describe treatment patterns, time to next treatment, and overall survival in MM patients by asthma/COPD status.
Methods
This retrospective, observational, cohort study included data from the nationwide US Optum® de-identified electronic health record (EHR) database. The dataset includes all data collected from January 1, 2006, to December 31, 2019. The dataset is statistically deidentified under the Expert Determination method consistent with the Health Insurance Portability and Accountability Act and managed according to Optum’s customer data use agreements. This article is based on previously collected data and does not contain any studies with human participants or animals performed by any of the authors.
Inclusion Criteria
Inclusion and exclusion criteria are described in Table 1. In this study, patients were included if they had ≥ 2 medical records with a diagnosis of MM at least 30 days apart but no more than 365 days apart. The first of these two medical records was considered the diagnosis date. Patients were aged ≥ 18 years as of the first observed treatment for MM. Patients had ≥ 1 medical record for a medical service with a procedure code or a prescription for an MM treatment, including immunomodulatory drugs (i.e., thalidomide, lenalidomide, pomalidomide), proteasome inhibitors (PIs; i.e., bortezomib, carfilzomib, ixazomib), histone deacetylase inhibitors (i.e., panobinostat), monoclonal antibodies (i.e., daratumumab, elotuzumab, isatuximab), chemotherapy (i.e., bendamustine, cisplatin, cyclophosphamide, doxorubicin, etoposide, liposomal doxorubicin, melphalan), or other treatments (i.e., selinexor, an inhibitor of nuclear export). Patients were included if they initiated the first MM treatment ≤ 1 month prior to or any time after the MM diagnosis date, and if they initiated first-line therapy for first observed treatment for MM on or after January 1, 2012. Patients were enrolled in an integrated delivery network and must have had at least one medical activity within 12 months prior to the index date (date of initiation of the line of therapy) and at least one medical activity within 2 months after the index date.Table 1 Analysis population
n % Remaining
Inclusion criteria
Patients with ≥ 2 medical records with a diagnosis for MM at least 30 days apart but no more than 365 days apart 45,663 –
Patients with ≥ 1 medical record with a procedure code or a prescription fill for an MM treatment at anytime 21,324 47%
Patients who were initiated on the first MM treatment within 1 month prior to or any time after the first observed diagnosis for MM 20,177 95%
Patients with their first observed MM treatment (defined as the index date) on or after 2012 16,784 83%
Patients aged ≥ 18 years as of the first observed MM treatment 16,779 100%
Patient enrolled in an integrated delivery network (IDN) 10,939 65%
Exclusion criteria
Patients with an indicator of enrollment in a clinical trial on or after first observed treatment for MM 10,244 94%
Patients with ≥ 2 medical records on different days with a diagnosis for a blood cancer other than MM anytime 9354 91%
Patients with a diagnosis for neoplasms of unspecified behavior (ICD-9-CM: 239; ICD-10-CM: D49) on or after the first observed MM diagnosis 8732 93%
Patients with ≥ 2 medical records with a diagnosis for malignant neoplasm within 2 years prior to the index date 6468 74%
Patient with an indicator of SCT any time prior to the index date 5997 93%
Patients with ≥ 1 medical record with a diagnosis for relapse/remission MM (ICD-9-CM: 203.01 or 203.02; ICD-10-CM: C90.01 or C90.02) any time prior to the index date 5186 86%
MM multiple myeloma, SCT stem cell transplant
Exclusion Criteria
Patients were excluded if any of the following criteria were met: an indicator of enrollment in a clinical trial on or after the first observed treatment for MM, ≥ 2 medical records on different days with a diagnosis for a blood cancer other than MM at any time, ≥ 1 medical record with a diagnosis for neoplasm of unspecified nature on or after the first observed treatment for MM, ≥ 2 medical records with a diagnosis for malignant neoplasm ≤ 2 years prior to the first observed treatment for MM, an indicator of stem cell transplant (SCT) prior to the first observed treatment for MM, ≥ 1 medical record with a diagnosis for relapsed MM or MM in remission prior to the first observed treatment for MM, or first-line treatment with melphalan or doxorubicin (with or without corticosteroids) before an indicator of SCT.
Outcome Definitions
For time to next treatment, an event was defined as the start of the subsequent line of therapy, which was the date of the first occurrence of (a) treatment switch, (b) treatment add-on, (c) resumption of MM treatment (old or new regimen) after a treatment discontinuation (a drop of all therapeutic agents of the treatment regimen for > 90 days), or (d) death. For overall survival, an event was defined as death.
Subgroups
To be included in the asthma group, patients had ≥ 1 medical record with a diagnosis for asthma during the 12-month baseline period prior to initiating treatment. To be included in the COPD group, patients had ≥ 1 medical record with a diagnosis for COPD during the 12-month baseline period prior to initiating treatment. To be included in the asthma or COPD group, patients had ≥ 1 medical record with a diagnosis for asthma or COPD during the 12-month baseline period prior to initiating treatment.
Statistical Analysis
Patient characteristics were summarized by line of therapy for the first four lines of therapy and replicated separately among the following subgroups: (a) patients with COPD, (b) patients without COPD, (c) patients with asthma, (d) patients without asthma, (e) patients with either asthma or COPD (asthma/COPD), and (f) patients with neither asthma nor COPD. Mean, standard deviation, and median are presented for continuous variables, and the frequency and percentage are presented for categorical variables.
For time-to-next-treatment analyses, patients were observed from the line of therapy initiation to start of the subsequent line of therapy. Patients without a subsequent line of therapy were censored at the earliest of death, the date of their last medical activity, or the end of the study period. For overall survival analyses, patients were observed from the line of therapy initiation to date of death, or patients without an observed date of death were censored at the end of the study period or the date of last medical activity.
Patients with asthma, COPD, or asthma/COPD were compared with patients without asthma, COPD, or asthma/COPD for time to next treatment and overall survival using a one-sided log-rank test stratified by age. Cox proportional hazard models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for time to next treatment and overall survival, adjusted for age, sex, race, geographic region, insurance type, and Quan–Charlson comorbidity index (QCCI).
Results
Patient Characteristics
A total of 5186 patients with MM were included in the analysis (Table 2). Of these patients, 10.1% (n = 524) had a COPD diagnosis at baseline, 7.2% (n = 373) had an asthma diagnosis at baseline, and 15.4% (n = 799) had a diagnosis of asthma or COPD at baseline. The most commonly observed comorbidities among all MM patients and among those MM patients with asthma/COPD included cardiovascular disease, diabetes, and renal impairment. Both patients with asthma or COPD and patients without asthma or COPD had a median age of 69 years, and similar proportions were observed across the age categories.Table 2 Patient characteristics
First line
All
(N = 5186) COPD
(n = 524) No COPD
(n = 4662) Asthma
(n = 373) No asthma
(n = 4813) COPD or asthma
(n = 799) Neither COPD nor asthma
(n = 4387)
At the index datea
Age (years)
Mean (SD) 68.4 (11.0) 70.2 (9.8) 68.2 (11.1) 67.6 (10.2) 68.5 (11.0) 69.2 (10.0) 68.2 (11.1)
Median 69 70 69 68 69 69 69
Age categories, n (%)
< 50 267 (5) 7 (1) 260 (6) 17 (5) 250 (5) 21 (3) 246 (6)
50–54 258 (5) 18 (3) 240 (5) 19 (5) 239 (5) 34 (4) 224 (5)
55–59 488 (9) 49 (9) 439 (9) 40 (11) 448 (9) 75 (9) 413 (9)
60–64 814 (16) 78 (15) 736 (16) 62 (17) 752 (16) 122 (15) 692 (16)
65–69 833 (16) 92 (18) 741 (16) 75 (20) 758 (16) 150 (19) 683 (16)
70–74 814 (16) 88 (17) 726 (16) 57 (15) 757 (16) 133 (17) 681 (16)
75–79 775 (15) 86 (16) 689 (15) 57 (15) 718 (15) 127 (16) 648 (15)
80–84 709 (14) 74 (14) 635 (14) 31 (8) 678 (14) 95 (12) 614 (14)
≥ 85 228 (4) 32 (6) 196 (4) 15 (4) 213 (4) 42 (5) 186 (4)
Race, n (%)
Caucasian 3953 (76) 399 (76) 3554 (76) 258 (69) 3695 (77) 590 (74) 3363 (77)
African American 903 (17) 105 (20) 798 (17) 90 (24) 813 (17) 167 (21) 736 (17)
Asian 55 (1) 1 (0) 54 (1) 5 (1) 50 (1) 6 (1) 49 (1)
Other/unknown 275 (5) 19 (4) 256 (5) 20 (5) 255 (5) 36 (5) 239 (5)
Ethnicity, n (%)
Hispanic 201 (4) 15 (3) 186 (4) 18 (5) 183 (4) 33 (4) 168 (4)
Non-Hispanic 4725 (91) 486 (93) 4239 (91) 337 (90) 4388 (91) 730 (91) 3995 (91)
Unknown 260 (5) 23 (4) 237 (5) 18 (5) 242 (5) 36 (5) 224 (5)
Sex, n (%)
Female 2456 (47) 239 (46) 2217 (48) 206 (55) 2250 (47) 396 (50) 2060 (47)
Male 2724 (53) 285 (54) 2439 (52) 166 (45) 2558 (53) 402 (50) 2322 (53)
Unknown 6 (0) 6 (0) 1 (0) 5 (0) 1 (0) 5 (0)
Region of residence, n (%)
Northeast 708 (14) 63 (12) 645 (14) 49 (13) 659 (14) 96 (12) 612 (14)
Midwest 2808 (54) 310 (59) 2498 (54) 229 (61) 2579 (54) 472 (59) 2336 (53)
South 1147 (22) 99 (19) 1048 (22) 64 (17) 1083 (23) 152 (19) 995 (23)
West 414 (8) 41 (8) 373 (8) 23 (6) 391 (8) 61 (8) 353 (8)
Other/unknown 109 (2) 11 (2) 98 (2) 8 (2) 101 (2) 18 (2) 91 (2)
Calendar year, n (%)
2012 453 (8.74) 37 (7.06) 416 (8.92) 19 (5.09) 434 (9.02) 52 (6.51) 401 (9.14)
2013 570 (10.99) 52 (9.92) 518 (11.11) 34 (9.12) 536 (11.14) 79 (9.89) 491 (11.19)
2014 658 (12.69) 67 (12.79) 591 (12.68) 49 (13.14) 609 (12.65) 107 (13.39) 551 (12.56)
2015 707 (13.63) 68 (12.98) 639 (13.71) 41 (10.99) 666 (13.84) 99 (12.39) 608 (13.86)
2016 772 (14.89) 72 (13.74) 700 (15.02) 70 (18.77) 702 (14.59) 118 (14.77) 654 (14.91)
2017 768 (14.81) 94 (17.94) 674 (14.46) 67 (17.96) 701 (14.56) 141 (17.65) 627 (14.29)
2018 646 (12.46) 72 (13.74) 574 (12.31) 50 (13.40) 596 (12.38) 108 (13.52) 538 (12.26)
2019 612 (11.80) 62 (11.83) 550 (11.80) 43 (11.53) 569 (11.82) 95 (11.89) 517 (11.78)
Time from MM diagnosis to treatment line initiation (months)
Mean (SD) 9.1 (17.2) 6.9 (13.8) 9.4 (16.5) 7.3 (14.8) 9.3 (17.4) 7.2 (14.7) 9.5 (17.6)
Insurance type, n (%)
Commercial 1630 (31) 117 (22) 1513 (32) 128 (34) 1502 (31) 223 (28) 1407 (32)
Medicare 2755 (53) 314 (60) 2441 (52) 186 (50) 2569 (53) 449 (56) 2306 (53)
Medicaid 220 (4) 38 (7) 182 (4) 27 (7) 193 (4) 51 (6) 169 (4)
Other payor type 83 (2) 8 (2) 75 (2) 2 (1) 81 (2) 10 (1) 73 (2)
Uninsured 64 (1) 8 (2) 56 (1) 7 (2) 57 (1) 12 (2) 52 (1)
Unknown 275 (5) 32 (6) 243 (5) 19 (5) 256 (5) 45 (6) 230 (5)
Missing 159 (3) 7 (1) 152 (3) 4 (1) 155 (3) 9 (1) 150 (3)
Integrated patient, n (%)
Yes 1320 (25) 125 (24) 1195 (26) 119 (32) 1201 (25) 215 (27) 1105 (25)
No 3866 (75) 399 (76) 3467 (74) 254 (68) 3612 (75) 584 (73) 3282 (75)
During the baseline periodb
Quan–Charlson comorbidity index (excluding MM)
Mean (SD) 2.7 (3.1) 5.2 (3.2) 2.4 (3.0) 4.7 (3.2) 2.6 (3.1) 5 (3.2) 2.3 (3.0)
Comorbidities, n (%)
Anemia 751 (14) 115 (22) 636 (14) 79 (21) 672 (14) 166 (21) 585 (13)
Cardiovascular disease 2659 (51) 386 (74) 2273 (49) 279 (75) 2380 (49) 582 (73) 2077 (47)
Diabetes 1094 (21) 175 (33) 919 (20) 136 (36) 958 (20) 271 (34) 823 (19)
Hypercalcemia 648 (12) 74 (14) 574 (12) 55 (15) 593 (12) 123 (15) 525 (12)
Peripheral neuropathy 357 (7) 58 (11) 299 (6) 29 (8) 328 (7) 81 (10) 276 (6)
Renal impairment 1363 (26) 215 (41) 1148 (25) 134 (36) 1229 (26) 303 (38) 1060 (24)
Skeletal-related events 878 (17) 130 (25) 748 (16) 75 (20) 803 (17) 185 (23) 693 (16)
Thrombocytopenia 546 (11) 87 (17) 459 (10) 54 (14) 492 (10) 122 (15) 424 (10)
MM multiple myeloma, SD standard deviation
aIndex date was defined as the start for the treatment line
bBaseline period was defined as the 12-month period prior to each treatment start date, excluding the index date
The second-line analysis included 2386 patients (161 [6.7%] with asthma and 184 [7.7%] with COPD). The third-line analysis included 1064 patients (68 [6.4%] with asthma and 78 [7.3%] with COPD). The fourth-line analysis included 474 patients (33 [7.0%] with asthma and 28 [5.9%] with COPD).
A description of asthma/COPD and MM treatments are shown in Tables 3 and 4, respectively. The most common treatments for patients with asthma/COPD were systemic corticosteroids (76.7%, asthma; 72.7%, COPD), oral corticosteroids (70.5%, asthma; 70.0%, COPD), and short-acting beta agonists (56.6%, asthma; 55.7%, COPD) (Table 3).Table 3 Description of asthma and COPD treatments
First line
Asthma COPD
n = 373 n = 524
Asthma + COPD treatments, n (%)
SABA (Y/N) 211 (56.6) 292 (55.7)
LABA (Y/N) 18 (4.8) 32 (6.1)
ICS (Y/N) 31 (8.3) 33 (6.3)
ICS dose low 0 2 (0.4)
ICS dose medium 26 (7.0) 27 (5.2)
ICS dose high 7 (1.9) 8 (1.5)
Leukotriene modifiers (Y/N) 53 (14.2) 31 (5.9)
Theophylline (Y/N) 3 (0.8) 6 (1.1)
Tiotropium (Y/N) 26 (7.0) 69 (13.2)
OCS use (Y/N) 263 (70.5) 367 (70.0)
Systemic corticosteroids (Y/N) 286 (76.7) 381 (72.7)
Controller medication 131 (35.1) 171 (32.6)
1 type of controller mediation (Y/N) 91 (24.4) 119 (22.7)
2 types of controller medications (Y/N) 32 (8.6) 44 (8.4)
≥ 3 types of controller medications (Y/N) 8 (2.1) 8 (1.5)
ICS only 3 (0.8) 1 (0.2)
ICS + SABA 10 (2.7) 14 (2.7)
ICS + LABA 98 (26.3) 126 (24.0)
Triple or more therapy 13 (3.5) 16 (3.1)
COPD specific
LAMA (Y/N) 61 (16.4) 129 (24.6)
LAMA + LABA (Y/N) 5 (1.3) 9 (1.7)
Long-term oxygen use (Y/N) 1 (0.3) 8 (1.5)
Systematic antibiotics (Y/N) 217 (58.2) 303 (57.8)
ICS inhaled corticosteroid, LABA long-acting beta agonist, LAMA long-acting muscarinic antagonist, OCS oral corticosteroid, SABA short-acting beta agonist, Y/N yes or no response
Table 4 Description of multiple myeloma treatments
First line
All
(N = 5186) COPD
(n = 524) Asthma
(n = 373) COPD or asthma
(n = 799) Neither COPD nor asthma (n = 4387)
Type of treatment, n (%)
IMiDs 3071 (59.22) 288 (54.96) 223 (59.79) 460 (57.57) 2611 (59.52)
Thalidomide 173 (3.34) 18 (3.44) 16 (4.29) 28 (3.50) 145 (3.31)
Lenalidomide 2803 (54.05) 258 (49.24) 204 (54.69) 417 (52.19) 2386 (54.39)
Pomalidomide 126 (2.43) 17 (3.24) 5 (1.34) 21 (2.63) 105 (2.39)
PIs 2871 (55.36) 305 (58.21) 213 (57.10) 457 (57.20) 2414 (55.03)
Bortezomib 2684 (51.75) 299 (57.06) 205 (54.96) 445 (55.69) 2239 (51.04)
Carfilzomib 164 (3.16) 4 (0.76) 10 (2.68) 13 (1.63) 151 (3.44)
Ixazomib 61 (1.18) 3 (0.57) 2 (0.54) 4 (0.50) 57 (1.30)
HDAC inhibitors 1 (0.02) 1 (0.19) 0 (0) 1 (0.13) 0 (0)
Panobinostat 1 (0.02) 1 (0.19) 0 (0) 1 (0.13) 0 (0)
Monoclonal antibodies 111 (2.14) 9 (1.72) 4 (1.07) 11 (1.38) 100 (2.28)
Daratumumab 101 (1.95) 9 (1.72) 4 (1.07) 11 (1.38) 90 (2.05)
Elotuzumab 11 (0.21) 0 (0) 0 (0) 0 (0) 11 (0.25)
Isatuximab
Chemotherapy 1188 (22.91) 114 (21.76) 101 (27.08) 184 (23.03) 1004 (22.89)
Bendamustine 10 (0.19) 1 (0.19) 1 (0.27) 1 (0.13) 9 (0.21)
Cisplatin 63 (1.21) 6 (1.15) 4 (1.07) 8 (1.00) 55 (1.25)
Cyclophosphamide 1051 (20.27) 107 (20.42) 90 (24.13) 169 (21.15) 882 (20.10)
Doxorubicin 126 (2.43) 8 (1.53) 9 (2.41) 16 (2.00) 110 (2.51)
Etoposide 74 (1.43) 5 (0.95) 5 (1.34) 9 (1.13) 65 (1.48)
Liposomal doxorubicin 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Melphalan 129 (2.49) 7 (1.34) 9 (2.41) 13 (1.63) 116 (2.64)
Top 10 treatment regimens (mono or combination therapy), n (%)
1 Lenalidomide, 1657 (32.0) Lenalidomide, 160 (30.5) Lenalidomide, 116 (31.1) Lenalidomide, 250 (31.3) Lenalidomide, 1407 (32.1)
2 Bortezomib, 1041 (20.1) Bortezomib, 136 (26.0) Lenalidomide, bortezomib, 67 (18.0) Bortezomib, 180 (22.5) Bortezomib, 861 (19.6)
3 Lenalidomide, bortezomib, 831 (16.0) Lenalidomide, bortezomib, 77 (14.7) Bortezomib, 65 (17.4) Lenalidomide, bortezomib, 131 (16.4) Lenalidomide, bortezomib, 700 (16.0)
4 Bortezomib, cyclophosphamide, 516 (9.9) Bortezomib, cyclophosphamide, 61 (11.6) Bortezomib, cyclophosphamide, 48 (12.9) Bortezomib, cyclophosphamide, 92 (11.5) Bortezomib, cyclophosphamide, 424 (9.7)
5 Cyclophosphamide, 243 (4.7) Cyclophosphamide, 19 (3.6) Cyclophosphamide, 19 (5.1) Cyclophosphamide, 35 (4.4) Cyclophosphamide, 208 (4.7)
6 Pomalidomide, 81 (1.6) Pomalidomide, 12 (2.3) Thalidomide, 6 (1.6) Pomalidomide, 15 (1.9) Pomalidomide, 66 (1.5)
7 Thalidomide, 65 (1.3) Thalidomide, 8 (1.5) Bortezomib, cyclophosphamide, lenalidomide, 6 (1.6) Thalidomide, 11 (1.4) Carfilzomib, 57 (1.3)
8 Lenalidomide, bortezomib, cyclophosphamide, 65 (1.3) Bortezomib, cyclophosphamide, lenalidomide, 8 (1.5) Lenalidomide, bortezomib, cyclophosphamide, 5 (1.3) Bortezomib, cyclophosphamide, lenalidomide, 11 (1.4) Lenalidomide, bortezomib, cyclophosphamide, 56 (1.3)
9 Melphalan, 62 (1.2) Lenalidomide, bortezomib, cyclophosphamide, 5 (1.0) Melphalan, 5 (1.3) Lenalidomide, bortezomib, cyclophosphamide, 9 (1.1) Melphalan, 55 (1.3)
10 Carfilzomib, 60 (1.2) Melphalan, 4 (0.8) Lenalidomide, carfilzomib, 3 (0.8) Melphalan, 7 (0.9) Thalidomide, 54 (1.2)
Stem cell transplant (SCT)
Yes 319 (6.2) 14 (2.7) 18 (4.8) 30 (3.8) 289 (6.6)
No 4867 (93.8) 510 (97.3) 355 (95.2) 769 (96.2) 4098 (93.4)
Maintenance therapy, n (%) 186 (3.59) 13 (2.48) 14 (3.75) 24 (3.00) 162 (3.69)
Bortezomib 23 (0.44) 1 (0.19) 3 (0.80) 4 (0.50) 19 (0.43)
Lenalidomide 156 (3.01) 12 (2.29) 10 (2.68) 19 (2.38) 137 (3.12)
Thalidomide 7 (0.13) 0 (0) 1 (0.27) 1 (0.13) 6 (0.14)
Combination therapy, n (%)
2-agent combination 1614 (31.12) 151 (28.82) 127 (34.05) 245 (30.66) 1369 (31.21)
3-agent combination 189 (3.64) 20 (3.82) 21 (5.63) 34 (4.26) 155 (3.53)
4-agent combination 27 (0.52) 2 (0.38) 1 (0.27) 3 (0.38) 24 (0.55)
≥ 5-agent combination 63 (1.21) 4 (0.76) 4 (1.07) 7 (0.88) 56 (1.28)
Top 10 therapies by agent, n (%)
1 Lenalidomide, 2803 (54.05) Bortezomib, 299 (57.06) Bortezomib, 205 (54.96) Bortezomib, 445 (55.69) Lenalidomide, 2386 (54.39)
2 Bortezomib, 2684 (51.75) Lenalidomide, 258 (49.24) Lenalidomide, 204 (54.69) Lenalidomide, 417 (52.19) Bortezomib, 2239 (51.04)
3 Cyclophosphamide, 1051 (20.27) Cyclophosphamide, 107 (20.42) Cyclophosphamide, 90 (24.13) Cyclophosphamide, 169 (21.15) Cyclophosphamide, 882 (20.10)
4 Thalidomide, 173 (3.34) Thalidomide, 18 (3.44) Thalidomide, 16 (4.29) Thalidomide, 28 (3.50) Carfilzomib, 151 (3.44)
5 Carfilzomib, 164 (3.16) Pomalidomide, 17 (3.24) Carfilzomib, 10 (2.68) Pomalidomide, 21 (2.63) Thalidomide, 145 (3.31)
6 Melphalan, 129 (2.49) Daratumumab, 9 (1.72) Doxorubicin, 9 (2.41) Doxorubicin, 16 (2.00) Melphalan, 116 (2.64)
7 Pomalidomide, 126 (2.43) Doxorubicin, 8 (1.53) Melphalan, 9 (2.41) Carfilzomib, 13 (1.63) Doxorubicin, 110 (2.51)
8 Doxorubicin, 126 (2.43) Melphalan, 7 (1.34) Pomalidomide, 5 (1.34) Melphalan, 13 (1.63) Pomalidomide, 105 (2.39)
9 Daratumumab, 101 (1.95) Cisplatin, 6 (1.15) Etoposide, 5 (1.34) Daratumumab, 11 (1.38) Daratumumab, 90 (2.05)
10 Etoposide, 74 (1.43) Etoposide, 5 (0.95) Cisplatin, 4 (1.07) Etoposide, 9 (1.13) Etoposide, 65 (1.48)
Top 5 therapies by type, n (%)
1 IMiDs, 3102 (59.81) PIs, 306 (58.40) IMiDs, 225 (60.32) IMiDs, 466 (58.32) IMiDs, 2636 (60.09)
2 PIs, 2909 (56.09) IMiDs, 293 (55.92) PIs, 217 (58.18) PIs, 462 (57.82) PIs, 2447 (55.78)
3 Chemotherapy, 1453 (28.02) Chemotherapy, 134 (25.57) Chemotherapy, 118 (31.64) Chemotherapy, 216 (27.03) Chemotherapy, 1237 (28.20)
4 Monoclonal antibodies, 112 (2.16) Monoclonal antibodies, 9 (1.72) Monoclonal antibodies, 4 (1.07) Monoclonal antibodies, 11 (1.38) Monoclonal antibodies, 101 (2.30)
5 HDAC inhibitors, 1 (0.02) HDAC inhibitors, 1 (0.19) HDAC inhibitors, 1 (0.13)
Characteristics at the end of line of therapy, n (%)
Treatment augmentation (add-on) 300 (5.78) 25 (4.77) 24 (6.43) 44 (5.51) 256 (5.84)
Treatment switch 813 (15.68) 60 (11.45) 51 (13.67) 103 (12.89) 710 (16.18)
Treatment discontinuation 1214 (23.41) 96 (18.32) 84 (22.52) 166 (20.78) 1048 (23.89)
SCT 59 (1.14) 3 (0.57) 2 (0.54) 5 (0.63) 54 (1.23)
Death 120 (2.31) 22 (4.20) 15 (4.02) 30 (3.75) 90 (2.05)
Censored
Last date of medical activity 720 (13.88) 69 (13.17) 52 (13.94) 105 (13.14) 615 (14.02)
End of data availability 1960 (37.79) 249 (47.52) 145 (38.87) 346 (43.30) 1614 (36.79)
COPD chronic obstructive pulmonary disease, HDAC histone deacetylase, IMiDs immunomodulatory drugs, PI proteasome inhibitor
Approximately half of patients received first-line anti-myeloma treatment with bortezomib or lenalidomide (Table 4). Overall, 31.1% of patients received a two-agent combination. Evidence for receipt of SCT was low across the groups, particularly for patients with COPD. Steroids were assumed to be present in treatment lines due to concerns about adequate capture of steroid use.
Time to Next Treatment
First to Second Line
The median time to next treatment for patients with COPD was significantly longer compared with patients with no COPD (27.56 vs. 22.10 months; adjusted HR 0.71; 95% CI 0.61–0.83; p = 0.04; Fig. 1a). There was no significant difference in time to next treatment between patients with asthma and patients without asthma (25.83 vs. 22.56 months; adjusted HR 0.88; 95% CI 0.74–1.04). The median time to next treatment for patients with asthma or COPD was significantly longer compared with patients with no asthma nor COPD (25.83 vs. 22.38 months; adjusted HR 0.80; 95% CI 0.70–0.90).Fig. 1 Time to next treatment. Kaplan–Meier analyses were used to estimate time to next treatment from first to second line (a), second to third line (b), and third to fourth line (c). Patients were observed from the line of therapy initiation (index date) to the subsequent line of therapy initiation (event; earliest of second-line index date or date of death), or the observation period of patients without a subsequent line of therapy was censored at the end of follow-up (censoring; i.e., first event end of data availability, and end of continuous medical activity). Patients at risk were defined as the total number of patients who were still observed (no prior event and no censoring) at the specific time period (i.e., patients without the study event prior to that time point and who were still followed)
Second to Third Line
No significant differences in time to third-line treatment were observed in patients with/without COPD (18.93 vs. 18.66 months; HR 1.07; 95% CI 0.85–1.35), with/without asthma (19.03 vs. 18.66 months; HR 0.93; 95% CI 0.73–1.20), or with/without asthma or COPD (18.66 vs. 18.70 months; HR 1.02; 95% CI 0.85–1.22; Fig. 1b).
Third to Fourth Line
No significant differences in time to fourth-line treatment were observed in patients with/without asthma (15.90 vs. 14.46 months; HR 1.02; 95% CI 0.71–1.46), with/without COPD (15.73 vs. 14.46 months; HR 0.96; 95% CI 0.65–1.42), or with/without asthma or COPD (15.90 vs. 14.26 months; HR 0.98; 95% CI 0.74–1.30; Fig. 1c).
Overall Survival
Overall Survival: Line 1
Overall survival from the start of first-line therapy was significantly worse among patients with COPD compared with patients without COPD (38.8 vs. 67.9 months; adjusted HR 1.30; 95% CI 1.12–1.51; p < 0.005; Fig. 2). No significant differences in overall survival from first-line therapy were observed in patients with/without asthma (73.3 vs. 60.9 months; adjusted HR 0.90; 95% CI 0.75–1.10), or with/without asthma or COPD (45.03 vs. 66.86 months; adjusted HR 1.11; 95% CI 0.98–1.27).Fig. 2 Overall survival. Kaplan–Meier analyses were used to estimate overall survival. Patients were observed from the line of therapy initiation to death (event), or the observation period of patients without a subsequent line of therapy was censored at the end of follow-up (censoring; i.e., first event end of data availability, and end of continuous medical activity). Patients at risk were defined as the total number of patients who were still observed (no prior event and no censoring) at the specific time period (i.e., patients without the study event prior to that time point and who were still followed)
Overall Survival: Line 2
MM patients with COPD had worse overall survival from the start of second-line therapy compared with patients without COPD (35.70 vs. 49.86 months); however, this difference was not statistically significant in multivariable adjusted models (adjusted HR 1.26; 95% CI 0.98–1.61). No significant differences in overall survival were observed for MM patients with/without asthma (63.66 vs. 48.13 months; adjusted HR 1.01; 95% CI 0.76–1.35), or with/without asthma or COPD (39.56 vs. 48.96 months; adjusted HR 1.15; 95% CI 0.94–1.41). Similarly, numerically worse overall survival was observed from the start of third- and fourth-line therapy among MM patients with COPD (data not shown).
Discussion
In this study of patients with MM from the Optum EHR database, approximately 15% had a previous asthma or COPD diagnosis. Time from first- to second-line treatment was significantly longer for patients with a diagnosis of COPD or a diagnosis of asthma or COPD. Overall survival from start of first-line therapy was significantly worse among MM patients with COPD; numerically worse overall survival was observed from the start of lines 2–4.
In the current study of 5186 patients with MM, 15% of patients had an asthma or COPD diagnosis. This is similar to the proportion of patients in the ICARIA-MM study who had asthma or COPD (~ 10%) [10]. In ICARIA-MM, asthma and COPD were not used as exclusion criteria. Previous MM studies have used COPD/pulmonary disease as an exclusion criterion (e.g., POLLUX; ELOQUENT-2 [if uncontrolled]; CASTOR; CANDOR; MAIA; CASSIOPEIA) [11–16]. Asthma and COPD were used as exclusion criteria in these studies due to concern for bronchial hyperreactivity, infusion reactions, and need for additional pre- and post-medications [19]. Because of this, there are limited data in patients with MM and COPD who have been treated with monoclonal antibodies to date.
Based on the assessment of MM treatments in the current study, real-world monoclonal antibody use is not reported frequently to date, lagging behind treatment guidelines [20]. Within the small number of patients who received monoclonal antibody treatment, there was a trend towards more use in patients without asthma/COPD (2.28%) than with asthma/COPD (1.38%), suggesting that there may be some reluctance to treat due to concern for bronchial hyperreactivity, infusion reactions, and to paucity of data due to exclusion of patients from clinical trials [11–16, 19].
Extending time to next treatment can frequently be a main objective of MM therapy and can also be interpreted as a measure of delayed progression [21]. Based on the lack of significant differences in time to next treatment between patients with and without COPD or asthma, the comorbidity of COPD or asthma does not automatically portend a worse prognosis, and these patients should be considered for inclusion in future clinical trials. In fact, patients with COPD exhibited a significantly longer time from first- to second-line therapy compared with patients without COPD. These results provide real-world data that may help inform clinical decisions related to therapies for MM patients with asthma and COPD.
In the current study, overall survival from first-line therapy was significantly worse among patients with COPD, and numerical differences were observed in the second through fourth line; however, we had limited power to detect significant differences in later treatment lines due to the fact that the number of patients with COPD decreased from 524 patients in line 1 to 28 patients in line 4. Results from a recent study also demonstrated significantly worse overall survival among patients with obstructive pulmonary defects [18]. The presence of peak expiratory flow and/or carbon monoxide diffusion capacity < 65% of predicted were independent prognostic factors of survival in the study. These pulmonary function parameters were not explored in the current study, however, providing areas of interest for additional real-world studies.
In the current study, higher proportions of patients with asthma/COPD had diabetes and cardiovascular and renal comorbidities compared with patients without asthma/COPD. Therefore, the discrepancy between the observed prolonged time to next treatment in early treatment lines and decreased overall survival for patients with COPD may be linked to decreased receipt of later-line treatment and more associated comorbidities.
Previous studies have reported preexisting moderate or severe pulmonary disease to be a negative predictor of survival among patients with MM in a Swedish registry-based population [22], and an association between higher all-cause and myeloma-specific mortality and previous chronic pulmonary disease, independent of age [17].
Interestingly, numerically longer survival was observed in patients with asthma in lines 2 and 3 and in patients with COPD/asthma in line 3 of the current study. It is possible that a proportion of patients in the groups without a history of asthma or COPD had abnormal lung function, which may only be identified during spirometry testing [23, 24]. Additional studies are needed to better understand the relationship between preexisting pulmonary comorbidities and survival among patients with MM.
This study has some limitations. Patients were classified as having asthma and/or COPD based on the presence of at least one medical record with a diagnosis of asthma/COPD in the 12-month period prior to the index date, which may have resulted in some misclassification. As with all observational studies, there is the potential for unmeasured or residual confounding, though we adjusted for several potential confounders, including age and QCCI. However, other factors, such as smoking status, were not accounted for, which may explain some of the differences in overall survival between subgroups. Additionally, the lower number of patients included in each subsequent line of therapy resulted in reduced power, limiting our ability to detect differences in outcomes between subgroups. Strengths of the study include the inclusion of real-world data on MM patients with asthma or COPD, which increases the available information on this patient subgroup. These data provide longer-term treatment and outcomes information that may be used to inform future studies on MM patients with pulmonary comorbidities.
Conclusions
Among 5186 patients with MM, approximately 15% had an asthma or COPD diagnosis at baseline. The most commonly observed comorbidities among all patients were cardiovascular disease, diabetes, and renal impairment, which were even higher among those with asthma or COPD. Time from first- to second-line treatment was significantly longer for patients with a diagnosis of COPD. Overall survival from start of first-line therapy was significantly worse among patients with COPD, with numerically worse overall survival in subsequent lines. These data suggest that patients with COPD do not experience a shorter time interval to next treatment, but they may exhibit worse overall survival from the start of first-line therapy. Future investigations with larger datasets may improve the understanding of the influence of individual treatments on outcomes in these patients with multiple myeloma and pulmonary comorbidities.
Acknowledgements
Funding
Sponsorship for this study and Rapid Service Fee were funded by Sanofi (Cambridge, MA, USA).
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published
Authorship Contributions
All authors contributed to the interpretation of the data and were involved in the process of writing and reviewing this manuscript. All authors take complete responsibility for the integrity of the data and accuracy of the data analysis. The authors acknowledge medical writing assistance from Erin Burns-Tidmore, PhD, of Elevate Medical Affairs, contracted by Sanofi Genzyme for publication support services. The authors acknowledge programming support from Meriem Garsaa, of Quinten, contracted by Sanofi Genzyme for analytic support services.
Disclosures
Megan S. Rice is employed by Sanofi and may hold stock and/or stock options in the company. Sarah Naeger is employed by Sanofi and may hold stock and/or stock options in the company. Erin Singh is employed by Sanofi and may hold stock and/or stock options in the company.
Compliance with Ethics Guidelines
This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.
Data Availability
The datasets generated during and/or analyzed during the current study are from the US Optum® de-identified electronic health record database housed in DARWIN, https://www.optum.com/business/solutions/government/federal/data-analytics-federal/clinical-data.html#. | CARFILZOMIB | DrugsGivenReaction | CC BY-NC | 33728584 | 19,735,371 | 2021-06 |
What was the outcome of reaction 'Death'? | Real-World Treatment Patterns and Outcomes Among Multiple Myeloma Patients with Asthma and COPD in the United States.
BACKGROUND
Multiple myeloma (MM) is the second most frequent hematologic malignancy after lymphoma, contributing to approximately 10% of all hematologic malignancies. The prognosis of patients with MM is impacted by the heterogeneity of the disease, with worse outcomes reported in patients classified as International Staging System stage III, those with high-risk cytogenetics and elevated serum lactate dehydrogenase, and among patients who are elderly and have comorbidities. Previous studies have demonstrated an association between the presence of lung disease and worse outcomes; however, this impact in a real-world setting is not well understood.
METHODS
This retrospective, observational, cohort study included data from the nationwide US Optum® de-identified electronic health record (EHR) database from January 1, 2006, to December 31, 2019. MM patients with asthma or chronic obstructive pulmonary disease (COPD) were compared with MM patients without asthma or COPD for time to next treatment and overall survival using one-sided log-rank tests stratified by age and multivariable Cox proportional hazard models.
RESULTS
Among 5186 patients with MM, approximately 15% had an asthma or COPD diagnosis (asthma/COPD) at baseline. The most commonly observed comorbidities among all MM patients and among those MM patients with asthma/COPD were cardiovascular disease, diabetes, and renal impairment. Time from first- to second-line treatment was significantly longer for patients with a diagnosis of COPD. Overall survival from first-line therapy was significantly worse among patients with COPD, with numerically worse overall survival from second-line therapy.
CONCLUSIONS
These real-world data suggest that patients with asthma or COPD do not experience a shorter time interval to next treatment, but have significantly worse overall survival from start of first-line therapy and numerically worse survival from the start of later lines. Future investigations with larger datasets may improve the understanding of the influence of individual treatments on outcomes in these patients.
Key Summary Points
Why carry out this study?
Comorbidities are known to impact outcomes in patients with multiple myeloma, but many patients with pulmonary disease are excluded from clinical trials; therefore, not much is known about this subgroup of patients.
Previous results have demonstrated an association between the presence of lung disease and worse outcomes; however, this impact in a real-world setting is not well understood.
The objective of the current study was to assess the prevalence of asthma and chronic obstructive pulmonary disease (COPD) in a real-world patient population with multiple myeloma, and to describe treatment patterns in patients with/without asthma/COPD, and time to next treatment and overall survival in patients with asthma/COPD.
What was learned from the study?
These real-world data suggest that patients with asthma or COPD experience prolonged time to next treatment from first to second line, but have significantly worse overall survival from start of first-line therapy and numerically worse survival from the start of later lines of therapy.
Future investigations with larger datasets may improve the understanding of the influence of individual treatments on outcomes in these patients.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article, go to https://doi.org/10.6084/m9.figshare.14113682.
Introduction
Multiple myeloma (MM) is the second most frequent hematologic malignancy after lymphoma, contributing to 1% of all cancers and approximately 10% of all hematologic malignancies [1, 2]. Despite the introduction of targeted therapies and combination regimens, patients with MM continue to experience multiple relapses and/or become refractory to treatment [3].
The prognosis of patients with MM has been shown to be impacted by the heterogeneity of the disease, with prognostic factors categorized by burden of disease, tumor biology, host factors, and depth of response to therapy [4]. Worse outcomes have been reported in patients classified as International Staging System stage III, those with high-risk cytogenetics and elevated serum lactate dehydrogenase, and among patients who are elderly and have comorbidities. Treatment decision-making may require consideration of preexisting comorbidities and organ dysfunction, which have been associated with an increased risk of treatment- and disease-related complications that contribute to high levels of mortality earlier in the treatment continuum.
In ICARIA-MM, a recent phase 3 study of isatuximab, an anti-CD38 monoclonal antibody that has been approved in combination with pomalidomide and dexamethasone in the United States, the European Union, Japan, and other countries for the treatment of adult patients with relapsed/refractory MM who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor (PI) [5–9], approximately 10% of patients had a previous history of asthma or chronic obstructive pulmonary disorder (COPD) [10]. However, previous MM studies investigating other molecules have used COPD/pulmonary disease as an exclusion criterion (e.g., POLLUX; ELOQUENT-2 [if uncontrolled]; CASTOR; CANDOR; MAIA; CASSIOPEIA) [11–16]. As a result, little is known from randomized controlled trials about treatment patterns and outcomes in MM patients with respiratory comorbidities. Although some retrospective studies have demonstrated an association between the presence of lung disease and worse outcome [17], and an independent association has been reported between pulmonary function abnormalities and worse outcome in patients with MM [18], the real-world impact of preexisting lung disease is not well understood.
Therefore, the objective of the current study was to assess the prevalence of asthma and COPD in a real-world patient population with MM, and to describe treatment patterns, time to next treatment, and overall survival in MM patients by asthma/COPD status.
Methods
This retrospective, observational, cohort study included data from the nationwide US Optum® de-identified electronic health record (EHR) database. The dataset includes all data collected from January 1, 2006, to December 31, 2019. The dataset is statistically deidentified under the Expert Determination method consistent with the Health Insurance Portability and Accountability Act and managed according to Optum’s customer data use agreements. This article is based on previously collected data and does not contain any studies with human participants or animals performed by any of the authors.
Inclusion Criteria
Inclusion and exclusion criteria are described in Table 1. In this study, patients were included if they had ≥ 2 medical records with a diagnosis of MM at least 30 days apart but no more than 365 days apart. The first of these two medical records was considered the diagnosis date. Patients were aged ≥ 18 years as of the first observed treatment for MM. Patients had ≥ 1 medical record for a medical service with a procedure code or a prescription for an MM treatment, including immunomodulatory drugs (i.e., thalidomide, lenalidomide, pomalidomide), proteasome inhibitors (PIs; i.e., bortezomib, carfilzomib, ixazomib), histone deacetylase inhibitors (i.e., panobinostat), monoclonal antibodies (i.e., daratumumab, elotuzumab, isatuximab), chemotherapy (i.e., bendamustine, cisplatin, cyclophosphamide, doxorubicin, etoposide, liposomal doxorubicin, melphalan), or other treatments (i.e., selinexor, an inhibitor of nuclear export). Patients were included if they initiated the first MM treatment ≤ 1 month prior to or any time after the MM diagnosis date, and if they initiated first-line therapy for first observed treatment for MM on or after January 1, 2012. Patients were enrolled in an integrated delivery network and must have had at least one medical activity within 12 months prior to the index date (date of initiation of the line of therapy) and at least one medical activity within 2 months after the index date.Table 1 Analysis population
n % Remaining
Inclusion criteria
Patients with ≥ 2 medical records with a diagnosis for MM at least 30 days apart but no more than 365 days apart 45,663 –
Patients with ≥ 1 medical record with a procedure code or a prescription fill for an MM treatment at anytime 21,324 47%
Patients who were initiated on the first MM treatment within 1 month prior to or any time after the first observed diagnosis for MM 20,177 95%
Patients with their first observed MM treatment (defined as the index date) on or after 2012 16,784 83%
Patients aged ≥ 18 years as of the first observed MM treatment 16,779 100%
Patient enrolled in an integrated delivery network (IDN) 10,939 65%
Exclusion criteria
Patients with an indicator of enrollment in a clinical trial on or after first observed treatment for MM 10,244 94%
Patients with ≥ 2 medical records on different days with a diagnosis for a blood cancer other than MM anytime 9354 91%
Patients with a diagnosis for neoplasms of unspecified behavior (ICD-9-CM: 239; ICD-10-CM: D49) on or after the first observed MM diagnosis 8732 93%
Patients with ≥ 2 medical records with a diagnosis for malignant neoplasm within 2 years prior to the index date 6468 74%
Patient with an indicator of SCT any time prior to the index date 5997 93%
Patients with ≥ 1 medical record with a diagnosis for relapse/remission MM (ICD-9-CM: 203.01 or 203.02; ICD-10-CM: C90.01 or C90.02) any time prior to the index date 5186 86%
MM multiple myeloma, SCT stem cell transplant
Exclusion Criteria
Patients were excluded if any of the following criteria were met: an indicator of enrollment in a clinical trial on or after the first observed treatment for MM, ≥ 2 medical records on different days with a diagnosis for a blood cancer other than MM at any time, ≥ 1 medical record with a diagnosis for neoplasm of unspecified nature on or after the first observed treatment for MM, ≥ 2 medical records with a diagnosis for malignant neoplasm ≤ 2 years prior to the first observed treatment for MM, an indicator of stem cell transplant (SCT) prior to the first observed treatment for MM, ≥ 1 medical record with a diagnosis for relapsed MM or MM in remission prior to the first observed treatment for MM, or first-line treatment with melphalan or doxorubicin (with or without corticosteroids) before an indicator of SCT.
Outcome Definitions
For time to next treatment, an event was defined as the start of the subsequent line of therapy, which was the date of the first occurrence of (a) treatment switch, (b) treatment add-on, (c) resumption of MM treatment (old or new regimen) after a treatment discontinuation (a drop of all therapeutic agents of the treatment regimen for > 90 days), or (d) death. For overall survival, an event was defined as death.
Subgroups
To be included in the asthma group, patients had ≥ 1 medical record with a diagnosis for asthma during the 12-month baseline period prior to initiating treatment. To be included in the COPD group, patients had ≥ 1 medical record with a diagnosis for COPD during the 12-month baseline period prior to initiating treatment. To be included in the asthma or COPD group, patients had ≥ 1 medical record with a diagnosis for asthma or COPD during the 12-month baseline period prior to initiating treatment.
Statistical Analysis
Patient characteristics were summarized by line of therapy for the first four lines of therapy and replicated separately among the following subgroups: (a) patients with COPD, (b) patients without COPD, (c) patients with asthma, (d) patients without asthma, (e) patients with either asthma or COPD (asthma/COPD), and (f) patients with neither asthma nor COPD. Mean, standard deviation, and median are presented for continuous variables, and the frequency and percentage are presented for categorical variables.
For time-to-next-treatment analyses, patients were observed from the line of therapy initiation to start of the subsequent line of therapy. Patients without a subsequent line of therapy were censored at the earliest of death, the date of their last medical activity, or the end of the study period. For overall survival analyses, patients were observed from the line of therapy initiation to date of death, or patients without an observed date of death were censored at the end of the study period or the date of last medical activity.
Patients with asthma, COPD, or asthma/COPD were compared with patients without asthma, COPD, or asthma/COPD for time to next treatment and overall survival using a one-sided log-rank test stratified by age. Cox proportional hazard models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for time to next treatment and overall survival, adjusted for age, sex, race, geographic region, insurance type, and Quan–Charlson comorbidity index (QCCI).
Results
Patient Characteristics
A total of 5186 patients with MM were included in the analysis (Table 2). Of these patients, 10.1% (n = 524) had a COPD diagnosis at baseline, 7.2% (n = 373) had an asthma diagnosis at baseline, and 15.4% (n = 799) had a diagnosis of asthma or COPD at baseline. The most commonly observed comorbidities among all MM patients and among those MM patients with asthma/COPD included cardiovascular disease, diabetes, and renal impairment. Both patients with asthma or COPD and patients without asthma or COPD had a median age of 69 years, and similar proportions were observed across the age categories.Table 2 Patient characteristics
First line
All
(N = 5186) COPD
(n = 524) No COPD
(n = 4662) Asthma
(n = 373) No asthma
(n = 4813) COPD or asthma
(n = 799) Neither COPD nor asthma
(n = 4387)
At the index datea
Age (years)
Mean (SD) 68.4 (11.0) 70.2 (9.8) 68.2 (11.1) 67.6 (10.2) 68.5 (11.0) 69.2 (10.0) 68.2 (11.1)
Median 69 70 69 68 69 69 69
Age categories, n (%)
< 50 267 (5) 7 (1) 260 (6) 17 (5) 250 (5) 21 (3) 246 (6)
50–54 258 (5) 18 (3) 240 (5) 19 (5) 239 (5) 34 (4) 224 (5)
55–59 488 (9) 49 (9) 439 (9) 40 (11) 448 (9) 75 (9) 413 (9)
60–64 814 (16) 78 (15) 736 (16) 62 (17) 752 (16) 122 (15) 692 (16)
65–69 833 (16) 92 (18) 741 (16) 75 (20) 758 (16) 150 (19) 683 (16)
70–74 814 (16) 88 (17) 726 (16) 57 (15) 757 (16) 133 (17) 681 (16)
75–79 775 (15) 86 (16) 689 (15) 57 (15) 718 (15) 127 (16) 648 (15)
80–84 709 (14) 74 (14) 635 (14) 31 (8) 678 (14) 95 (12) 614 (14)
≥ 85 228 (4) 32 (6) 196 (4) 15 (4) 213 (4) 42 (5) 186 (4)
Race, n (%)
Caucasian 3953 (76) 399 (76) 3554 (76) 258 (69) 3695 (77) 590 (74) 3363 (77)
African American 903 (17) 105 (20) 798 (17) 90 (24) 813 (17) 167 (21) 736 (17)
Asian 55 (1) 1 (0) 54 (1) 5 (1) 50 (1) 6 (1) 49 (1)
Other/unknown 275 (5) 19 (4) 256 (5) 20 (5) 255 (5) 36 (5) 239 (5)
Ethnicity, n (%)
Hispanic 201 (4) 15 (3) 186 (4) 18 (5) 183 (4) 33 (4) 168 (4)
Non-Hispanic 4725 (91) 486 (93) 4239 (91) 337 (90) 4388 (91) 730 (91) 3995 (91)
Unknown 260 (5) 23 (4) 237 (5) 18 (5) 242 (5) 36 (5) 224 (5)
Sex, n (%)
Female 2456 (47) 239 (46) 2217 (48) 206 (55) 2250 (47) 396 (50) 2060 (47)
Male 2724 (53) 285 (54) 2439 (52) 166 (45) 2558 (53) 402 (50) 2322 (53)
Unknown 6 (0) 6 (0) 1 (0) 5 (0) 1 (0) 5 (0)
Region of residence, n (%)
Northeast 708 (14) 63 (12) 645 (14) 49 (13) 659 (14) 96 (12) 612 (14)
Midwest 2808 (54) 310 (59) 2498 (54) 229 (61) 2579 (54) 472 (59) 2336 (53)
South 1147 (22) 99 (19) 1048 (22) 64 (17) 1083 (23) 152 (19) 995 (23)
West 414 (8) 41 (8) 373 (8) 23 (6) 391 (8) 61 (8) 353 (8)
Other/unknown 109 (2) 11 (2) 98 (2) 8 (2) 101 (2) 18 (2) 91 (2)
Calendar year, n (%)
2012 453 (8.74) 37 (7.06) 416 (8.92) 19 (5.09) 434 (9.02) 52 (6.51) 401 (9.14)
2013 570 (10.99) 52 (9.92) 518 (11.11) 34 (9.12) 536 (11.14) 79 (9.89) 491 (11.19)
2014 658 (12.69) 67 (12.79) 591 (12.68) 49 (13.14) 609 (12.65) 107 (13.39) 551 (12.56)
2015 707 (13.63) 68 (12.98) 639 (13.71) 41 (10.99) 666 (13.84) 99 (12.39) 608 (13.86)
2016 772 (14.89) 72 (13.74) 700 (15.02) 70 (18.77) 702 (14.59) 118 (14.77) 654 (14.91)
2017 768 (14.81) 94 (17.94) 674 (14.46) 67 (17.96) 701 (14.56) 141 (17.65) 627 (14.29)
2018 646 (12.46) 72 (13.74) 574 (12.31) 50 (13.40) 596 (12.38) 108 (13.52) 538 (12.26)
2019 612 (11.80) 62 (11.83) 550 (11.80) 43 (11.53) 569 (11.82) 95 (11.89) 517 (11.78)
Time from MM diagnosis to treatment line initiation (months)
Mean (SD) 9.1 (17.2) 6.9 (13.8) 9.4 (16.5) 7.3 (14.8) 9.3 (17.4) 7.2 (14.7) 9.5 (17.6)
Insurance type, n (%)
Commercial 1630 (31) 117 (22) 1513 (32) 128 (34) 1502 (31) 223 (28) 1407 (32)
Medicare 2755 (53) 314 (60) 2441 (52) 186 (50) 2569 (53) 449 (56) 2306 (53)
Medicaid 220 (4) 38 (7) 182 (4) 27 (7) 193 (4) 51 (6) 169 (4)
Other payor type 83 (2) 8 (2) 75 (2) 2 (1) 81 (2) 10 (1) 73 (2)
Uninsured 64 (1) 8 (2) 56 (1) 7 (2) 57 (1) 12 (2) 52 (1)
Unknown 275 (5) 32 (6) 243 (5) 19 (5) 256 (5) 45 (6) 230 (5)
Missing 159 (3) 7 (1) 152 (3) 4 (1) 155 (3) 9 (1) 150 (3)
Integrated patient, n (%)
Yes 1320 (25) 125 (24) 1195 (26) 119 (32) 1201 (25) 215 (27) 1105 (25)
No 3866 (75) 399 (76) 3467 (74) 254 (68) 3612 (75) 584 (73) 3282 (75)
During the baseline periodb
Quan–Charlson comorbidity index (excluding MM)
Mean (SD) 2.7 (3.1) 5.2 (3.2) 2.4 (3.0) 4.7 (3.2) 2.6 (3.1) 5 (3.2) 2.3 (3.0)
Comorbidities, n (%)
Anemia 751 (14) 115 (22) 636 (14) 79 (21) 672 (14) 166 (21) 585 (13)
Cardiovascular disease 2659 (51) 386 (74) 2273 (49) 279 (75) 2380 (49) 582 (73) 2077 (47)
Diabetes 1094 (21) 175 (33) 919 (20) 136 (36) 958 (20) 271 (34) 823 (19)
Hypercalcemia 648 (12) 74 (14) 574 (12) 55 (15) 593 (12) 123 (15) 525 (12)
Peripheral neuropathy 357 (7) 58 (11) 299 (6) 29 (8) 328 (7) 81 (10) 276 (6)
Renal impairment 1363 (26) 215 (41) 1148 (25) 134 (36) 1229 (26) 303 (38) 1060 (24)
Skeletal-related events 878 (17) 130 (25) 748 (16) 75 (20) 803 (17) 185 (23) 693 (16)
Thrombocytopenia 546 (11) 87 (17) 459 (10) 54 (14) 492 (10) 122 (15) 424 (10)
MM multiple myeloma, SD standard deviation
aIndex date was defined as the start for the treatment line
bBaseline period was defined as the 12-month period prior to each treatment start date, excluding the index date
The second-line analysis included 2386 patients (161 [6.7%] with asthma and 184 [7.7%] with COPD). The third-line analysis included 1064 patients (68 [6.4%] with asthma and 78 [7.3%] with COPD). The fourth-line analysis included 474 patients (33 [7.0%] with asthma and 28 [5.9%] with COPD).
A description of asthma/COPD and MM treatments are shown in Tables 3 and 4, respectively. The most common treatments for patients with asthma/COPD were systemic corticosteroids (76.7%, asthma; 72.7%, COPD), oral corticosteroids (70.5%, asthma; 70.0%, COPD), and short-acting beta agonists (56.6%, asthma; 55.7%, COPD) (Table 3).Table 3 Description of asthma and COPD treatments
First line
Asthma COPD
n = 373 n = 524
Asthma + COPD treatments, n (%)
SABA (Y/N) 211 (56.6) 292 (55.7)
LABA (Y/N) 18 (4.8) 32 (6.1)
ICS (Y/N) 31 (8.3) 33 (6.3)
ICS dose low 0 2 (0.4)
ICS dose medium 26 (7.0) 27 (5.2)
ICS dose high 7 (1.9) 8 (1.5)
Leukotriene modifiers (Y/N) 53 (14.2) 31 (5.9)
Theophylline (Y/N) 3 (0.8) 6 (1.1)
Tiotropium (Y/N) 26 (7.0) 69 (13.2)
OCS use (Y/N) 263 (70.5) 367 (70.0)
Systemic corticosteroids (Y/N) 286 (76.7) 381 (72.7)
Controller medication 131 (35.1) 171 (32.6)
1 type of controller mediation (Y/N) 91 (24.4) 119 (22.7)
2 types of controller medications (Y/N) 32 (8.6) 44 (8.4)
≥ 3 types of controller medications (Y/N) 8 (2.1) 8 (1.5)
ICS only 3 (0.8) 1 (0.2)
ICS + SABA 10 (2.7) 14 (2.7)
ICS + LABA 98 (26.3) 126 (24.0)
Triple or more therapy 13 (3.5) 16 (3.1)
COPD specific
LAMA (Y/N) 61 (16.4) 129 (24.6)
LAMA + LABA (Y/N) 5 (1.3) 9 (1.7)
Long-term oxygen use (Y/N) 1 (0.3) 8 (1.5)
Systematic antibiotics (Y/N) 217 (58.2) 303 (57.8)
ICS inhaled corticosteroid, LABA long-acting beta agonist, LAMA long-acting muscarinic antagonist, OCS oral corticosteroid, SABA short-acting beta agonist, Y/N yes or no response
Table 4 Description of multiple myeloma treatments
First line
All
(N = 5186) COPD
(n = 524) Asthma
(n = 373) COPD or asthma
(n = 799) Neither COPD nor asthma (n = 4387)
Type of treatment, n (%)
IMiDs 3071 (59.22) 288 (54.96) 223 (59.79) 460 (57.57) 2611 (59.52)
Thalidomide 173 (3.34) 18 (3.44) 16 (4.29) 28 (3.50) 145 (3.31)
Lenalidomide 2803 (54.05) 258 (49.24) 204 (54.69) 417 (52.19) 2386 (54.39)
Pomalidomide 126 (2.43) 17 (3.24) 5 (1.34) 21 (2.63) 105 (2.39)
PIs 2871 (55.36) 305 (58.21) 213 (57.10) 457 (57.20) 2414 (55.03)
Bortezomib 2684 (51.75) 299 (57.06) 205 (54.96) 445 (55.69) 2239 (51.04)
Carfilzomib 164 (3.16) 4 (0.76) 10 (2.68) 13 (1.63) 151 (3.44)
Ixazomib 61 (1.18) 3 (0.57) 2 (0.54) 4 (0.50) 57 (1.30)
HDAC inhibitors 1 (0.02) 1 (0.19) 0 (0) 1 (0.13) 0 (0)
Panobinostat 1 (0.02) 1 (0.19) 0 (0) 1 (0.13) 0 (0)
Monoclonal antibodies 111 (2.14) 9 (1.72) 4 (1.07) 11 (1.38) 100 (2.28)
Daratumumab 101 (1.95) 9 (1.72) 4 (1.07) 11 (1.38) 90 (2.05)
Elotuzumab 11 (0.21) 0 (0) 0 (0) 0 (0) 11 (0.25)
Isatuximab
Chemotherapy 1188 (22.91) 114 (21.76) 101 (27.08) 184 (23.03) 1004 (22.89)
Bendamustine 10 (0.19) 1 (0.19) 1 (0.27) 1 (0.13) 9 (0.21)
Cisplatin 63 (1.21) 6 (1.15) 4 (1.07) 8 (1.00) 55 (1.25)
Cyclophosphamide 1051 (20.27) 107 (20.42) 90 (24.13) 169 (21.15) 882 (20.10)
Doxorubicin 126 (2.43) 8 (1.53) 9 (2.41) 16 (2.00) 110 (2.51)
Etoposide 74 (1.43) 5 (0.95) 5 (1.34) 9 (1.13) 65 (1.48)
Liposomal doxorubicin 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Melphalan 129 (2.49) 7 (1.34) 9 (2.41) 13 (1.63) 116 (2.64)
Top 10 treatment regimens (mono or combination therapy), n (%)
1 Lenalidomide, 1657 (32.0) Lenalidomide, 160 (30.5) Lenalidomide, 116 (31.1) Lenalidomide, 250 (31.3) Lenalidomide, 1407 (32.1)
2 Bortezomib, 1041 (20.1) Bortezomib, 136 (26.0) Lenalidomide, bortezomib, 67 (18.0) Bortezomib, 180 (22.5) Bortezomib, 861 (19.6)
3 Lenalidomide, bortezomib, 831 (16.0) Lenalidomide, bortezomib, 77 (14.7) Bortezomib, 65 (17.4) Lenalidomide, bortezomib, 131 (16.4) Lenalidomide, bortezomib, 700 (16.0)
4 Bortezomib, cyclophosphamide, 516 (9.9) Bortezomib, cyclophosphamide, 61 (11.6) Bortezomib, cyclophosphamide, 48 (12.9) Bortezomib, cyclophosphamide, 92 (11.5) Bortezomib, cyclophosphamide, 424 (9.7)
5 Cyclophosphamide, 243 (4.7) Cyclophosphamide, 19 (3.6) Cyclophosphamide, 19 (5.1) Cyclophosphamide, 35 (4.4) Cyclophosphamide, 208 (4.7)
6 Pomalidomide, 81 (1.6) Pomalidomide, 12 (2.3) Thalidomide, 6 (1.6) Pomalidomide, 15 (1.9) Pomalidomide, 66 (1.5)
7 Thalidomide, 65 (1.3) Thalidomide, 8 (1.5) Bortezomib, cyclophosphamide, lenalidomide, 6 (1.6) Thalidomide, 11 (1.4) Carfilzomib, 57 (1.3)
8 Lenalidomide, bortezomib, cyclophosphamide, 65 (1.3) Bortezomib, cyclophosphamide, lenalidomide, 8 (1.5) Lenalidomide, bortezomib, cyclophosphamide, 5 (1.3) Bortezomib, cyclophosphamide, lenalidomide, 11 (1.4) Lenalidomide, bortezomib, cyclophosphamide, 56 (1.3)
9 Melphalan, 62 (1.2) Lenalidomide, bortezomib, cyclophosphamide, 5 (1.0) Melphalan, 5 (1.3) Lenalidomide, bortezomib, cyclophosphamide, 9 (1.1) Melphalan, 55 (1.3)
10 Carfilzomib, 60 (1.2) Melphalan, 4 (0.8) Lenalidomide, carfilzomib, 3 (0.8) Melphalan, 7 (0.9) Thalidomide, 54 (1.2)
Stem cell transplant (SCT)
Yes 319 (6.2) 14 (2.7) 18 (4.8) 30 (3.8) 289 (6.6)
No 4867 (93.8) 510 (97.3) 355 (95.2) 769 (96.2) 4098 (93.4)
Maintenance therapy, n (%) 186 (3.59) 13 (2.48) 14 (3.75) 24 (3.00) 162 (3.69)
Bortezomib 23 (0.44) 1 (0.19) 3 (0.80) 4 (0.50) 19 (0.43)
Lenalidomide 156 (3.01) 12 (2.29) 10 (2.68) 19 (2.38) 137 (3.12)
Thalidomide 7 (0.13) 0 (0) 1 (0.27) 1 (0.13) 6 (0.14)
Combination therapy, n (%)
2-agent combination 1614 (31.12) 151 (28.82) 127 (34.05) 245 (30.66) 1369 (31.21)
3-agent combination 189 (3.64) 20 (3.82) 21 (5.63) 34 (4.26) 155 (3.53)
4-agent combination 27 (0.52) 2 (0.38) 1 (0.27) 3 (0.38) 24 (0.55)
≥ 5-agent combination 63 (1.21) 4 (0.76) 4 (1.07) 7 (0.88) 56 (1.28)
Top 10 therapies by agent, n (%)
1 Lenalidomide, 2803 (54.05) Bortezomib, 299 (57.06) Bortezomib, 205 (54.96) Bortezomib, 445 (55.69) Lenalidomide, 2386 (54.39)
2 Bortezomib, 2684 (51.75) Lenalidomide, 258 (49.24) Lenalidomide, 204 (54.69) Lenalidomide, 417 (52.19) Bortezomib, 2239 (51.04)
3 Cyclophosphamide, 1051 (20.27) Cyclophosphamide, 107 (20.42) Cyclophosphamide, 90 (24.13) Cyclophosphamide, 169 (21.15) Cyclophosphamide, 882 (20.10)
4 Thalidomide, 173 (3.34) Thalidomide, 18 (3.44) Thalidomide, 16 (4.29) Thalidomide, 28 (3.50) Carfilzomib, 151 (3.44)
5 Carfilzomib, 164 (3.16) Pomalidomide, 17 (3.24) Carfilzomib, 10 (2.68) Pomalidomide, 21 (2.63) Thalidomide, 145 (3.31)
6 Melphalan, 129 (2.49) Daratumumab, 9 (1.72) Doxorubicin, 9 (2.41) Doxorubicin, 16 (2.00) Melphalan, 116 (2.64)
7 Pomalidomide, 126 (2.43) Doxorubicin, 8 (1.53) Melphalan, 9 (2.41) Carfilzomib, 13 (1.63) Doxorubicin, 110 (2.51)
8 Doxorubicin, 126 (2.43) Melphalan, 7 (1.34) Pomalidomide, 5 (1.34) Melphalan, 13 (1.63) Pomalidomide, 105 (2.39)
9 Daratumumab, 101 (1.95) Cisplatin, 6 (1.15) Etoposide, 5 (1.34) Daratumumab, 11 (1.38) Daratumumab, 90 (2.05)
10 Etoposide, 74 (1.43) Etoposide, 5 (0.95) Cisplatin, 4 (1.07) Etoposide, 9 (1.13) Etoposide, 65 (1.48)
Top 5 therapies by type, n (%)
1 IMiDs, 3102 (59.81) PIs, 306 (58.40) IMiDs, 225 (60.32) IMiDs, 466 (58.32) IMiDs, 2636 (60.09)
2 PIs, 2909 (56.09) IMiDs, 293 (55.92) PIs, 217 (58.18) PIs, 462 (57.82) PIs, 2447 (55.78)
3 Chemotherapy, 1453 (28.02) Chemotherapy, 134 (25.57) Chemotherapy, 118 (31.64) Chemotherapy, 216 (27.03) Chemotherapy, 1237 (28.20)
4 Monoclonal antibodies, 112 (2.16) Monoclonal antibodies, 9 (1.72) Monoclonal antibodies, 4 (1.07) Monoclonal antibodies, 11 (1.38) Monoclonal antibodies, 101 (2.30)
5 HDAC inhibitors, 1 (0.02) HDAC inhibitors, 1 (0.19) HDAC inhibitors, 1 (0.13)
Characteristics at the end of line of therapy, n (%)
Treatment augmentation (add-on) 300 (5.78) 25 (4.77) 24 (6.43) 44 (5.51) 256 (5.84)
Treatment switch 813 (15.68) 60 (11.45) 51 (13.67) 103 (12.89) 710 (16.18)
Treatment discontinuation 1214 (23.41) 96 (18.32) 84 (22.52) 166 (20.78) 1048 (23.89)
SCT 59 (1.14) 3 (0.57) 2 (0.54) 5 (0.63) 54 (1.23)
Death 120 (2.31) 22 (4.20) 15 (4.02) 30 (3.75) 90 (2.05)
Censored
Last date of medical activity 720 (13.88) 69 (13.17) 52 (13.94) 105 (13.14) 615 (14.02)
End of data availability 1960 (37.79) 249 (47.52) 145 (38.87) 346 (43.30) 1614 (36.79)
COPD chronic obstructive pulmonary disease, HDAC histone deacetylase, IMiDs immunomodulatory drugs, PI proteasome inhibitor
Approximately half of patients received first-line anti-myeloma treatment with bortezomib or lenalidomide (Table 4). Overall, 31.1% of patients received a two-agent combination. Evidence for receipt of SCT was low across the groups, particularly for patients with COPD. Steroids were assumed to be present in treatment lines due to concerns about adequate capture of steroid use.
Time to Next Treatment
First to Second Line
The median time to next treatment for patients with COPD was significantly longer compared with patients with no COPD (27.56 vs. 22.10 months; adjusted HR 0.71; 95% CI 0.61–0.83; p = 0.04; Fig. 1a). There was no significant difference in time to next treatment between patients with asthma and patients without asthma (25.83 vs. 22.56 months; adjusted HR 0.88; 95% CI 0.74–1.04). The median time to next treatment for patients with asthma or COPD was significantly longer compared with patients with no asthma nor COPD (25.83 vs. 22.38 months; adjusted HR 0.80; 95% CI 0.70–0.90).Fig. 1 Time to next treatment. Kaplan–Meier analyses were used to estimate time to next treatment from first to second line (a), second to third line (b), and third to fourth line (c). Patients were observed from the line of therapy initiation (index date) to the subsequent line of therapy initiation (event; earliest of second-line index date or date of death), or the observation period of patients without a subsequent line of therapy was censored at the end of follow-up (censoring; i.e., first event end of data availability, and end of continuous medical activity). Patients at risk were defined as the total number of patients who were still observed (no prior event and no censoring) at the specific time period (i.e., patients without the study event prior to that time point and who were still followed)
Second to Third Line
No significant differences in time to third-line treatment were observed in patients with/without COPD (18.93 vs. 18.66 months; HR 1.07; 95% CI 0.85–1.35), with/without asthma (19.03 vs. 18.66 months; HR 0.93; 95% CI 0.73–1.20), or with/without asthma or COPD (18.66 vs. 18.70 months; HR 1.02; 95% CI 0.85–1.22; Fig. 1b).
Third to Fourth Line
No significant differences in time to fourth-line treatment were observed in patients with/without asthma (15.90 vs. 14.46 months; HR 1.02; 95% CI 0.71–1.46), with/without COPD (15.73 vs. 14.46 months; HR 0.96; 95% CI 0.65–1.42), or with/without asthma or COPD (15.90 vs. 14.26 months; HR 0.98; 95% CI 0.74–1.30; Fig. 1c).
Overall Survival
Overall Survival: Line 1
Overall survival from the start of first-line therapy was significantly worse among patients with COPD compared with patients without COPD (38.8 vs. 67.9 months; adjusted HR 1.30; 95% CI 1.12–1.51; p < 0.005; Fig. 2). No significant differences in overall survival from first-line therapy were observed in patients with/without asthma (73.3 vs. 60.9 months; adjusted HR 0.90; 95% CI 0.75–1.10), or with/without asthma or COPD (45.03 vs. 66.86 months; adjusted HR 1.11; 95% CI 0.98–1.27).Fig. 2 Overall survival. Kaplan–Meier analyses were used to estimate overall survival. Patients were observed from the line of therapy initiation to death (event), or the observation period of patients without a subsequent line of therapy was censored at the end of follow-up (censoring; i.e., first event end of data availability, and end of continuous medical activity). Patients at risk were defined as the total number of patients who were still observed (no prior event and no censoring) at the specific time period (i.e., patients without the study event prior to that time point and who were still followed)
Overall Survival: Line 2
MM patients with COPD had worse overall survival from the start of second-line therapy compared with patients without COPD (35.70 vs. 49.86 months); however, this difference was not statistically significant in multivariable adjusted models (adjusted HR 1.26; 95% CI 0.98–1.61). No significant differences in overall survival were observed for MM patients with/without asthma (63.66 vs. 48.13 months; adjusted HR 1.01; 95% CI 0.76–1.35), or with/without asthma or COPD (39.56 vs. 48.96 months; adjusted HR 1.15; 95% CI 0.94–1.41). Similarly, numerically worse overall survival was observed from the start of third- and fourth-line therapy among MM patients with COPD (data not shown).
Discussion
In this study of patients with MM from the Optum EHR database, approximately 15% had a previous asthma or COPD diagnosis. Time from first- to second-line treatment was significantly longer for patients with a diagnosis of COPD or a diagnosis of asthma or COPD. Overall survival from start of first-line therapy was significantly worse among MM patients with COPD; numerically worse overall survival was observed from the start of lines 2–4.
In the current study of 5186 patients with MM, 15% of patients had an asthma or COPD diagnosis. This is similar to the proportion of patients in the ICARIA-MM study who had asthma or COPD (~ 10%) [10]. In ICARIA-MM, asthma and COPD were not used as exclusion criteria. Previous MM studies have used COPD/pulmonary disease as an exclusion criterion (e.g., POLLUX; ELOQUENT-2 [if uncontrolled]; CASTOR; CANDOR; MAIA; CASSIOPEIA) [11–16]. Asthma and COPD were used as exclusion criteria in these studies due to concern for bronchial hyperreactivity, infusion reactions, and need for additional pre- and post-medications [19]. Because of this, there are limited data in patients with MM and COPD who have been treated with monoclonal antibodies to date.
Based on the assessment of MM treatments in the current study, real-world monoclonal antibody use is not reported frequently to date, lagging behind treatment guidelines [20]. Within the small number of patients who received monoclonal antibody treatment, there was a trend towards more use in patients without asthma/COPD (2.28%) than with asthma/COPD (1.38%), suggesting that there may be some reluctance to treat due to concern for bronchial hyperreactivity, infusion reactions, and to paucity of data due to exclusion of patients from clinical trials [11–16, 19].
Extending time to next treatment can frequently be a main objective of MM therapy and can also be interpreted as a measure of delayed progression [21]. Based on the lack of significant differences in time to next treatment between patients with and without COPD or asthma, the comorbidity of COPD or asthma does not automatically portend a worse prognosis, and these patients should be considered for inclusion in future clinical trials. In fact, patients with COPD exhibited a significantly longer time from first- to second-line therapy compared with patients without COPD. These results provide real-world data that may help inform clinical decisions related to therapies for MM patients with asthma and COPD.
In the current study, overall survival from first-line therapy was significantly worse among patients with COPD, and numerical differences were observed in the second through fourth line; however, we had limited power to detect significant differences in later treatment lines due to the fact that the number of patients with COPD decreased from 524 patients in line 1 to 28 patients in line 4. Results from a recent study also demonstrated significantly worse overall survival among patients with obstructive pulmonary defects [18]. The presence of peak expiratory flow and/or carbon monoxide diffusion capacity < 65% of predicted were independent prognostic factors of survival in the study. These pulmonary function parameters were not explored in the current study, however, providing areas of interest for additional real-world studies.
In the current study, higher proportions of patients with asthma/COPD had diabetes and cardiovascular and renal comorbidities compared with patients without asthma/COPD. Therefore, the discrepancy between the observed prolonged time to next treatment in early treatment lines and decreased overall survival for patients with COPD may be linked to decreased receipt of later-line treatment and more associated comorbidities.
Previous studies have reported preexisting moderate or severe pulmonary disease to be a negative predictor of survival among patients with MM in a Swedish registry-based population [22], and an association between higher all-cause and myeloma-specific mortality and previous chronic pulmonary disease, independent of age [17].
Interestingly, numerically longer survival was observed in patients with asthma in lines 2 and 3 and in patients with COPD/asthma in line 3 of the current study. It is possible that a proportion of patients in the groups without a history of asthma or COPD had abnormal lung function, which may only be identified during spirometry testing [23, 24]. Additional studies are needed to better understand the relationship between preexisting pulmonary comorbidities and survival among patients with MM.
This study has some limitations. Patients were classified as having asthma and/or COPD based on the presence of at least one medical record with a diagnosis of asthma/COPD in the 12-month period prior to the index date, which may have resulted in some misclassification. As with all observational studies, there is the potential for unmeasured or residual confounding, though we adjusted for several potential confounders, including age and QCCI. However, other factors, such as smoking status, were not accounted for, which may explain some of the differences in overall survival between subgroups. Additionally, the lower number of patients included in each subsequent line of therapy resulted in reduced power, limiting our ability to detect differences in outcomes between subgroups. Strengths of the study include the inclusion of real-world data on MM patients with asthma or COPD, which increases the available information on this patient subgroup. These data provide longer-term treatment and outcomes information that may be used to inform future studies on MM patients with pulmonary comorbidities.
Conclusions
Among 5186 patients with MM, approximately 15% had an asthma or COPD diagnosis at baseline. The most commonly observed comorbidities among all patients were cardiovascular disease, diabetes, and renal impairment, which were even higher among those with asthma or COPD. Time from first- to second-line treatment was significantly longer for patients with a diagnosis of COPD. Overall survival from start of first-line therapy was significantly worse among patients with COPD, with numerically worse overall survival in subsequent lines. These data suggest that patients with COPD do not experience a shorter time interval to next treatment, but they may exhibit worse overall survival from the start of first-line therapy. Future investigations with larger datasets may improve the understanding of the influence of individual treatments on outcomes in these patients with multiple myeloma and pulmonary comorbidities.
Acknowledgements
Funding
Sponsorship for this study and Rapid Service Fee were funded by Sanofi (Cambridge, MA, USA).
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published
Authorship Contributions
All authors contributed to the interpretation of the data and were involved in the process of writing and reviewing this manuscript. All authors take complete responsibility for the integrity of the data and accuracy of the data analysis. The authors acknowledge medical writing assistance from Erin Burns-Tidmore, PhD, of Elevate Medical Affairs, contracted by Sanofi Genzyme for publication support services. The authors acknowledge programming support from Meriem Garsaa, of Quinten, contracted by Sanofi Genzyme for analytic support services.
Disclosures
Megan S. Rice is employed by Sanofi and may hold stock and/or stock options in the company. Sarah Naeger is employed by Sanofi and may hold stock and/or stock options in the company. Erin Singh is employed by Sanofi and may hold stock and/or stock options in the company.
Compliance with Ethics Guidelines
This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.
Data Availability
The datasets generated during and/or analyzed during the current study are from the US Optum® de-identified electronic health record database housed in DARWIN, https://www.optum.com/business/solutions/government/federal/data-analytics-federal/clinical-data.html#. | Fatal | ReactionOutcome | CC BY-NC | 33728584 | 19,735,371 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute pulmonary oedema'. | Naloxone-Induced Acute Pulmonary Edema is Dose-Dependent: A Case Series.
BACKGROUND Naloxone remains the mainstay for the treatment of opioids overdose both in the clinical and public settings. Naloxone has been showing relative safety, leading to trivial adverdse effects which are mostly due to acute withdrawal effects, but when used in patients with known long-term addiction, it usually requires additional dosing or rapid infusion to achieve detoxification effects in a timely manner or to sustain the effects after they fade away. In some patients this has resulted in fatal adverse effects, including non-cardiogenic pulmonary edema (NCPE), which may require intensive care for those patients. Whether the higher dose is the cause has been debatable and not enough studies have looked into this subject. CASE REPORT Here, we report a series of 2 cases where 2 young patients were given naloxone following opioid overdose. Both our patients required frequent dosing due to insufficient response or owing to the washout of the naloxone effect shortly after, given its short half-life. Although the administered doses were different, both patients developed the adverse effect of NCPE and required ventilator support. CONCLUSIONS Evidence suggests that such a catastrophic adverse effect following the administration of such a critical medication, which is known to be relatively safe and is being publicized for saving lives, might limit its use and would require more attention and further studies to standardize a safe dose, limiting these life-threatening events and decreasing the need for unnecessary invasive respiratory support as well as admissions to intensive care units, which might create an additional burden on the health care system.
Background
Naloxone remains the main opiate antagonist used to reverse the effects of opioid overdose, both in clinical settings and illicit drug use [1]. It was developed in the 1960s and is a relatively safe medication with minimal adverse effects, which include acute withdrawal symptoms (eg, vomiting); however, it is reported that rapid infusion or using higher doses of naloxone induces a catecholamines surge that has fatal adverse effects in rare situations, such as acute pulmonary edema, ventricular arrythmias, and cardiac arrest [2,3]. We report a series of 2 cases of young patients who tolerated a low dose of naloxone well but developed acute pulmonary edema after administration of higher-dose naloxone [4].
Case Reports
Case Presentation #1
A 29-year-old man with a history of heroin abuse was found unresponsive at home secondary to a reported heroin overdose. He responded well to 2 milligrams (mg) of naloxone in the field, and was brought to the hospital alert, awake, and oriented to person, place, and time. The patient was monitored for several hours in the Emergency Department (ED) and then was discharged home the same day after an uneventful hospital course. A few hours after discharge, he was brought back to the hospital unresponsive after another overdose of heroin. He received repeated doses of naloxone to a total of 8 mg until he became responsive. Two hours later, the patient developed severe shortness of breath, hypoxemia, and altered mental status, necessitating endotracheal intubation. The patient’s vital signs were within normal limits (blood pressure of 132/89 mmHg, heart rate of 98 beats per minute, respiratory rate of 16/min, and body temperature 37°C). A chest examination was significant for bilateral basal crepitations only. Arterial blood gas (ABG) showed pH: 7.452 [7.350–7450], pCO2: 34.6 mmHg [35–50] mmHg, and pO2: 405 mmHg [85–106] mmHg. Troponin was 0.00 NG/ML (reference range <0.08 NG/ML) and lactate was 1.0 mmol/L (reference range 0.5–2.0 mmol/L). A chest radiograph showed bilateral infiltrates consistent with pulmonary edema (Figure 1). The patient was treated with IV 40 mg Lasix and was successfully extubated 7 h later. A repeat chest radiograph showed resolution of pulmonary infiltrates. The patient was saturating well at 94–96% on 3-L nasal cannula and transferred to the medical floors, where he was weaned off oxygen and observed for the following 24 h, where he was hemodynamically and clinically stable, then discharged home.
Case Presentation #2
A 37-year-old man with a medical history of intravenous heroin use and cocaine use presented to the ED due to a suspected heroin overdose. In the field the patient was given 2 mg of naloxone, but remained obtunded in the ED and was given 0.4 mg naloxone. A urine drug screen on admission was positive for cocaine and heroin but negative for other illicit substances. Alcohol level was 0.00, troponin level was <0.02 NG/ML (reference range <0.08 NG/ML), B-Type natriuretic peptide (BNP) was 18 pg/mL (reference range 0–100 pg/mL) on admission. Vitals on admission were blood pressure of 120/57 mmHg, heart rate of 84 beats per minute, respiratory rate 19/ min, and temperature 36.8°C, and oxygen saturation 96% on room air. His mental status improved after being given naloxone in the ED, but he became hypoxic and in respiratory distress eventually requiring bilevel positive airway pressure (BiPAP). Cardiac electrocardiography showed sinus tachycardia and an emergent chest X-ray showed interval development of diffuse reticulonodular opacities (Figure 2). Repeat vitals were blood pressure 104/55 mmHg, heart rate 130 beats per minute, respiratory rate 30/min, temperature of 37.3°C, and oxygen saturation 84%. Arterial blood gas was measured, showing pH 7.359, pCO2 43.5 mm Hg (reference: 35–50 mm Hg), pO2 83.6 mm Hg (reference: 85.0–106.0 mm Hg), oxygen saturation 96.2%, and bicarbonate level 23.9 mmol/L (reference: 22–26 mmol/L). He was transferred to the Intensive Care Unit (ICU) on bilevel positive airway pressure (BiPAP) due being at a low threshold for endotracheal intubation. While in the ICU, he was given IV 40 mg Lasix daily, with significant improvement of symptoms. After a short uneventful ICU course, he was weaned off the BiPAP and transitioned to 4-L nasal cannula and transferred to the medical floors and remained vitally stable with an unremarkable physical exam.
Discussion
Naloxone hydrochloride (Narcan) is a competitive opioid antagonist that was initially approved by the FDA in 1971 for the emergency treatment of opioid overdose as witnessed by respiratory and central nervous system depression [5]. Opioids used by addicts usually have a long half-life, while naloxone’s half-life is relatively short, so the respiratory symptoms recur shortly after its effect has subsided [3]. Due to this short half-life, patients may require higher doses or faster rates of infusion for the reversal of the opioid overdose, which causes a surge in the catecholamines release, leading to manifestation of adverse effects, including non-cardiogenic pulmonary edema and/or cardiac arrythmias [2].
The fluid balance in the lung and risk for development of pulmonary edema are critically determined by a multitude of factors, including pulmonary capillary and arterial pressures. Catecholamines were shown to contribute to the formation of pulmonary edema in patients with neurogenic as well as high-altitude pulmonary edema (HAPE) by a non-human experiment conducted by Rassler et al 2003 [6]. The responsible mechanisms for the increase in epinephrine in plasma following the administration of naloxone include its direct antagonizing effects on µ-opioid receptors in the adrenal medulla, and neutrally mediated changes of central sympathetic out-flow has been proposed as an explanation for the naloxone-induced non-cardiogenic acute pulmonary edema [7]. Whether this is a dose-dependent adverse effect remains unclear, as it has been reported with low doses of naloxone as well as shown by Partridge et al in 1986 [8]. However, the fact that our patient developed acute pulmonary edema after administration of 8 mg, but not 2 mg, of naloxone suggests a dose-dependent relationship. This finding reinforces the current recommendation of the American Heart Association to gradually titrate up naloxone to the least effective dose to prevent these serious adverse effects [9]. Our 2 patients had no known significant past medical history to otherwise explain the acute pulmonary edema. We excluded cardiac etiologies due to negative troponin level, BNP, and normal echocardiography studies. Furthermore, because of the chronological occurrence of pulmonary edema after naloxone administration and because no other medications known to cause such adverse effect were administered at the time, we believe that naloxone was the causative agent.
Conclusions
Naloxone remains the drug of choice in managing opioid overdose but can rarely cause non-cardiogenic acute pulmonary edema. This adverse effect is apparently dose-dependent. Therefore, healthcare providers should aim to use the least effective dose.
Figure 1. Blue arrows showed bilateral infiltrates consistent with pulmonary edema.
Figure 2. Blue arrows showed diffuse reticulonodular opacities.
Conflict of Interests
None. | NALOXONE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33730013 | 19,165,260 | 2021-03-17 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dyspnoea'. | Naloxone-Induced Acute Pulmonary Edema is Dose-Dependent: A Case Series.
BACKGROUND Naloxone remains the mainstay for the treatment of opioids overdose both in the clinical and public settings. Naloxone has been showing relative safety, leading to trivial adverdse effects which are mostly due to acute withdrawal effects, but when used in patients with known long-term addiction, it usually requires additional dosing or rapid infusion to achieve detoxification effects in a timely manner or to sustain the effects after they fade away. In some patients this has resulted in fatal adverse effects, including non-cardiogenic pulmonary edema (NCPE), which may require intensive care for those patients. Whether the higher dose is the cause has been debatable and not enough studies have looked into this subject. CASE REPORT Here, we report a series of 2 cases where 2 young patients were given naloxone following opioid overdose. Both our patients required frequent dosing due to insufficient response or owing to the washout of the naloxone effect shortly after, given its short half-life. Although the administered doses were different, both patients developed the adverse effect of NCPE and required ventilator support. CONCLUSIONS Evidence suggests that such a catastrophic adverse effect following the administration of such a critical medication, which is known to be relatively safe and is being publicized for saving lives, might limit its use and would require more attention and further studies to standardize a safe dose, limiting these life-threatening events and decreasing the need for unnecessary invasive respiratory support as well as admissions to intensive care units, which might create an additional burden on the health care system.
Background
Naloxone remains the main opiate antagonist used to reverse the effects of opioid overdose, both in clinical settings and illicit drug use [1]. It was developed in the 1960s and is a relatively safe medication with minimal adverse effects, which include acute withdrawal symptoms (eg, vomiting); however, it is reported that rapid infusion or using higher doses of naloxone induces a catecholamines surge that has fatal adverse effects in rare situations, such as acute pulmonary edema, ventricular arrythmias, and cardiac arrest [2,3]. We report a series of 2 cases of young patients who tolerated a low dose of naloxone well but developed acute pulmonary edema after administration of higher-dose naloxone [4].
Case Reports
Case Presentation #1
A 29-year-old man with a history of heroin abuse was found unresponsive at home secondary to a reported heroin overdose. He responded well to 2 milligrams (mg) of naloxone in the field, and was brought to the hospital alert, awake, and oriented to person, place, and time. The patient was monitored for several hours in the Emergency Department (ED) and then was discharged home the same day after an uneventful hospital course. A few hours after discharge, he was brought back to the hospital unresponsive after another overdose of heroin. He received repeated doses of naloxone to a total of 8 mg until he became responsive. Two hours later, the patient developed severe shortness of breath, hypoxemia, and altered mental status, necessitating endotracheal intubation. The patient’s vital signs were within normal limits (blood pressure of 132/89 mmHg, heart rate of 98 beats per minute, respiratory rate of 16/min, and body temperature 37°C). A chest examination was significant for bilateral basal crepitations only. Arterial blood gas (ABG) showed pH: 7.452 [7.350–7450], pCO2: 34.6 mmHg [35–50] mmHg, and pO2: 405 mmHg [85–106] mmHg. Troponin was 0.00 NG/ML (reference range <0.08 NG/ML) and lactate was 1.0 mmol/L (reference range 0.5–2.0 mmol/L). A chest radiograph showed bilateral infiltrates consistent with pulmonary edema (Figure 1). The patient was treated with IV 40 mg Lasix and was successfully extubated 7 h later. A repeat chest radiograph showed resolution of pulmonary infiltrates. The patient was saturating well at 94–96% on 3-L nasal cannula and transferred to the medical floors, where he was weaned off oxygen and observed for the following 24 h, where he was hemodynamically and clinically stable, then discharged home.
Case Presentation #2
A 37-year-old man with a medical history of intravenous heroin use and cocaine use presented to the ED due to a suspected heroin overdose. In the field the patient was given 2 mg of naloxone, but remained obtunded in the ED and was given 0.4 mg naloxone. A urine drug screen on admission was positive for cocaine and heroin but negative for other illicit substances. Alcohol level was 0.00, troponin level was <0.02 NG/ML (reference range <0.08 NG/ML), B-Type natriuretic peptide (BNP) was 18 pg/mL (reference range 0–100 pg/mL) on admission. Vitals on admission were blood pressure of 120/57 mmHg, heart rate of 84 beats per minute, respiratory rate 19/ min, and temperature 36.8°C, and oxygen saturation 96% on room air. His mental status improved after being given naloxone in the ED, but he became hypoxic and in respiratory distress eventually requiring bilevel positive airway pressure (BiPAP). Cardiac electrocardiography showed sinus tachycardia and an emergent chest X-ray showed interval development of diffuse reticulonodular opacities (Figure 2). Repeat vitals were blood pressure 104/55 mmHg, heart rate 130 beats per minute, respiratory rate 30/min, temperature of 37.3°C, and oxygen saturation 84%. Arterial blood gas was measured, showing pH 7.359, pCO2 43.5 mm Hg (reference: 35–50 mm Hg), pO2 83.6 mm Hg (reference: 85.0–106.0 mm Hg), oxygen saturation 96.2%, and bicarbonate level 23.9 mmol/L (reference: 22–26 mmol/L). He was transferred to the Intensive Care Unit (ICU) on bilevel positive airway pressure (BiPAP) due being at a low threshold for endotracheal intubation. While in the ICU, he was given IV 40 mg Lasix daily, with significant improvement of symptoms. After a short uneventful ICU course, he was weaned off the BiPAP and transitioned to 4-L nasal cannula and transferred to the medical floors and remained vitally stable with an unremarkable physical exam.
Discussion
Naloxone hydrochloride (Narcan) is a competitive opioid antagonist that was initially approved by the FDA in 1971 for the emergency treatment of opioid overdose as witnessed by respiratory and central nervous system depression [5]. Opioids used by addicts usually have a long half-life, while naloxone’s half-life is relatively short, so the respiratory symptoms recur shortly after its effect has subsided [3]. Due to this short half-life, patients may require higher doses or faster rates of infusion for the reversal of the opioid overdose, which causes a surge in the catecholamines release, leading to manifestation of adverse effects, including non-cardiogenic pulmonary edema and/or cardiac arrythmias [2].
The fluid balance in the lung and risk for development of pulmonary edema are critically determined by a multitude of factors, including pulmonary capillary and arterial pressures. Catecholamines were shown to contribute to the formation of pulmonary edema in patients with neurogenic as well as high-altitude pulmonary edema (HAPE) by a non-human experiment conducted by Rassler et al 2003 [6]. The responsible mechanisms for the increase in epinephrine in plasma following the administration of naloxone include its direct antagonizing effects on µ-opioid receptors in the adrenal medulla, and neutrally mediated changes of central sympathetic out-flow has been proposed as an explanation for the naloxone-induced non-cardiogenic acute pulmonary edema [7]. Whether this is a dose-dependent adverse effect remains unclear, as it has been reported with low doses of naloxone as well as shown by Partridge et al in 1986 [8]. However, the fact that our patient developed acute pulmonary edema after administration of 8 mg, but not 2 mg, of naloxone suggests a dose-dependent relationship. This finding reinforces the current recommendation of the American Heart Association to gradually titrate up naloxone to the least effective dose to prevent these serious adverse effects [9]. Our 2 patients had no known significant past medical history to otherwise explain the acute pulmonary edema. We excluded cardiac etiologies due to negative troponin level, BNP, and normal echocardiography studies. Furthermore, because of the chronological occurrence of pulmonary edema after naloxone administration and because no other medications known to cause such adverse effect were administered at the time, we believe that naloxone was the causative agent.
Conclusions
Naloxone remains the drug of choice in managing opioid overdose but can rarely cause non-cardiogenic acute pulmonary edema. This adverse effect is apparently dose-dependent. Therefore, healthcare providers should aim to use the least effective dose.
Figure 1. Blue arrows showed bilateral infiltrates consistent with pulmonary edema.
Figure 2. Blue arrows showed diffuse reticulonodular opacities.
Conflict of Interests
None. | NALOXONE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33730013 | 19,165,260 | 2021-03-17 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Mental disorder'. | Naloxone-Induced Acute Pulmonary Edema is Dose-Dependent: A Case Series.
BACKGROUND Naloxone remains the mainstay for the treatment of opioids overdose both in the clinical and public settings. Naloxone has been showing relative safety, leading to trivial adverdse effects which are mostly due to acute withdrawal effects, but when used in patients with known long-term addiction, it usually requires additional dosing or rapid infusion to achieve detoxification effects in a timely manner or to sustain the effects after they fade away. In some patients this has resulted in fatal adverse effects, including non-cardiogenic pulmonary edema (NCPE), which may require intensive care for those patients. Whether the higher dose is the cause has been debatable and not enough studies have looked into this subject. CASE REPORT Here, we report a series of 2 cases where 2 young patients were given naloxone following opioid overdose. Both our patients required frequent dosing due to insufficient response or owing to the washout of the naloxone effect shortly after, given its short half-life. Although the administered doses were different, both patients developed the adverse effect of NCPE and required ventilator support. CONCLUSIONS Evidence suggests that such a catastrophic adverse effect following the administration of such a critical medication, which is known to be relatively safe and is being publicized for saving lives, might limit its use and would require more attention and further studies to standardize a safe dose, limiting these life-threatening events and decreasing the need for unnecessary invasive respiratory support as well as admissions to intensive care units, which might create an additional burden on the health care system.
Background
Naloxone remains the main opiate antagonist used to reverse the effects of opioid overdose, both in clinical settings and illicit drug use [1]. It was developed in the 1960s and is a relatively safe medication with minimal adverse effects, which include acute withdrawal symptoms (eg, vomiting); however, it is reported that rapid infusion or using higher doses of naloxone induces a catecholamines surge that has fatal adverse effects in rare situations, such as acute pulmonary edema, ventricular arrythmias, and cardiac arrest [2,3]. We report a series of 2 cases of young patients who tolerated a low dose of naloxone well but developed acute pulmonary edema after administration of higher-dose naloxone [4].
Case Reports
Case Presentation #1
A 29-year-old man with a history of heroin abuse was found unresponsive at home secondary to a reported heroin overdose. He responded well to 2 milligrams (mg) of naloxone in the field, and was brought to the hospital alert, awake, and oriented to person, place, and time. The patient was monitored for several hours in the Emergency Department (ED) and then was discharged home the same day after an uneventful hospital course. A few hours after discharge, he was brought back to the hospital unresponsive after another overdose of heroin. He received repeated doses of naloxone to a total of 8 mg until he became responsive. Two hours later, the patient developed severe shortness of breath, hypoxemia, and altered mental status, necessitating endotracheal intubation. The patient’s vital signs were within normal limits (blood pressure of 132/89 mmHg, heart rate of 98 beats per minute, respiratory rate of 16/min, and body temperature 37°C). A chest examination was significant for bilateral basal crepitations only. Arterial blood gas (ABG) showed pH: 7.452 [7.350–7450], pCO2: 34.6 mmHg [35–50] mmHg, and pO2: 405 mmHg [85–106] mmHg. Troponin was 0.00 NG/ML (reference range <0.08 NG/ML) and lactate was 1.0 mmol/L (reference range 0.5–2.0 mmol/L). A chest radiograph showed bilateral infiltrates consistent with pulmonary edema (Figure 1). The patient was treated with IV 40 mg Lasix and was successfully extubated 7 h later. A repeat chest radiograph showed resolution of pulmonary infiltrates. The patient was saturating well at 94–96% on 3-L nasal cannula and transferred to the medical floors, where he was weaned off oxygen and observed for the following 24 h, where he was hemodynamically and clinically stable, then discharged home.
Case Presentation #2
A 37-year-old man with a medical history of intravenous heroin use and cocaine use presented to the ED due to a suspected heroin overdose. In the field the patient was given 2 mg of naloxone, but remained obtunded in the ED and was given 0.4 mg naloxone. A urine drug screen on admission was positive for cocaine and heroin but negative for other illicit substances. Alcohol level was 0.00, troponin level was <0.02 NG/ML (reference range <0.08 NG/ML), B-Type natriuretic peptide (BNP) was 18 pg/mL (reference range 0–100 pg/mL) on admission. Vitals on admission were blood pressure of 120/57 mmHg, heart rate of 84 beats per minute, respiratory rate 19/ min, and temperature 36.8°C, and oxygen saturation 96% on room air. His mental status improved after being given naloxone in the ED, but he became hypoxic and in respiratory distress eventually requiring bilevel positive airway pressure (BiPAP). Cardiac electrocardiography showed sinus tachycardia and an emergent chest X-ray showed interval development of diffuse reticulonodular opacities (Figure 2). Repeat vitals were blood pressure 104/55 mmHg, heart rate 130 beats per minute, respiratory rate 30/min, temperature of 37.3°C, and oxygen saturation 84%. Arterial blood gas was measured, showing pH 7.359, pCO2 43.5 mm Hg (reference: 35–50 mm Hg), pO2 83.6 mm Hg (reference: 85.0–106.0 mm Hg), oxygen saturation 96.2%, and bicarbonate level 23.9 mmol/L (reference: 22–26 mmol/L). He was transferred to the Intensive Care Unit (ICU) on bilevel positive airway pressure (BiPAP) due being at a low threshold for endotracheal intubation. While in the ICU, he was given IV 40 mg Lasix daily, with significant improvement of symptoms. After a short uneventful ICU course, he was weaned off the BiPAP and transitioned to 4-L nasal cannula and transferred to the medical floors and remained vitally stable with an unremarkable physical exam.
Discussion
Naloxone hydrochloride (Narcan) is a competitive opioid antagonist that was initially approved by the FDA in 1971 for the emergency treatment of opioid overdose as witnessed by respiratory and central nervous system depression [5]. Opioids used by addicts usually have a long half-life, while naloxone’s half-life is relatively short, so the respiratory symptoms recur shortly after its effect has subsided [3]. Due to this short half-life, patients may require higher doses or faster rates of infusion for the reversal of the opioid overdose, which causes a surge in the catecholamines release, leading to manifestation of adverse effects, including non-cardiogenic pulmonary edema and/or cardiac arrythmias [2].
The fluid balance in the lung and risk for development of pulmonary edema are critically determined by a multitude of factors, including pulmonary capillary and arterial pressures. Catecholamines were shown to contribute to the formation of pulmonary edema in patients with neurogenic as well as high-altitude pulmonary edema (HAPE) by a non-human experiment conducted by Rassler et al 2003 [6]. The responsible mechanisms for the increase in epinephrine in plasma following the administration of naloxone include its direct antagonizing effects on µ-opioid receptors in the adrenal medulla, and neutrally mediated changes of central sympathetic out-flow has been proposed as an explanation for the naloxone-induced non-cardiogenic acute pulmonary edema [7]. Whether this is a dose-dependent adverse effect remains unclear, as it has been reported with low doses of naloxone as well as shown by Partridge et al in 1986 [8]. However, the fact that our patient developed acute pulmonary edema after administration of 8 mg, but not 2 mg, of naloxone suggests a dose-dependent relationship. This finding reinforces the current recommendation of the American Heart Association to gradually titrate up naloxone to the least effective dose to prevent these serious adverse effects [9]. Our 2 patients had no known significant past medical history to otherwise explain the acute pulmonary edema. We excluded cardiac etiologies due to negative troponin level, BNP, and normal echocardiography studies. Furthermore, because of the chronological occurrence of pulmonary edema after naloxone administration and because no other medications known to cause such adverse effect were administered at the time, we believe that naloxone was the causative agent.
Conclusions
Naloxone remains the drug of choice in managing opioid overdose but can rarely cause non-cardiogenic acute pulmonary edema. This adverse effect is apparently dose-dependent. Therefore, healthcare providers should aim to use the least effective dose.
Figure 1. Blue arrows showed bilateral infiltrates consistent with pulmonary edema.
Figure 2. Blue arrows showed diffuse reticulonodular opacities.
Conflict of Interests
None. | NALOXONE | DrugsGivenReaction | CC BY-NC-ND | 33730013 | 19,082,994 | 2021-03-17 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Respiratory distress'. | Naloxone-Induced Acute Pulmonary Edema is Dose-Dependent: A Case Series.
BACKGROUND Naloxone remains the mainstay for the treatment of opioids overdose both in the clinical and public settings. Naloxone has been showing relative safety, leading to trivial adverdse effects which are mostly due to acute withdrawal effects, but when used in patients with known long-term addiction, it usually requires additional dosing or rapid infusion to achieve detoxification effects in a timely manner or to sustain the effects after they fade away. In some patients this has resulted in fatal adverse effects, including non-cardiogenic pulmonary edema (NCPE), which may require intensive care for those patients. Whether the higher dose is the cause has been debatable and not enough studies have looked into this subject. CASE REPORT Here, we report a series of 2 cases where 2 young patients were given naloxone following opioid overdose. Both our patients required frequent dosing due to insufficient response or owing to the washout of the naloxone effect shortly after, given its short half-life. Although the administered doses were different, both patients developed the adverse effect of NCPE and required ventilator support. CONCLUSIONS Evidence suggests that such a catastrophic adverse effect following the administration of such a critical medication, which is known to be relatively safe and is being publicized for saving lives, might limit its use and would require more attention and further studies to standardize a safe dose, limiting these life-threatening events and decreasing the need for unnecessary invasive respiratory support as well as admissions to intensive care units, which might create an additional burden on the health care system.
Background
Naloxone remains the main opiate antagonist used to reverse the effects of opioid overdose, both in clinical settings and illicit drug use [1]. It was developed in the 1960s and is a relatively safe medication with minimal adverse effects, which include acute withdrawal symptoms (eg, vomiting); however, it is reported that rapid infusion or using higher doses of naloxone induces a catecholamines surge that has fatal adverse effects in rare situations, such as acute pulmonary edema, ventricular arrythmias, and cardiac arrest [2,3]. We report a series of 2 cases of young patients who tolerated a low dose of naloxone well but developed acute pulmonary edema after administration of higher-dose naloxone [4].
Case Reports
Case Presentation #1
A 29-year-old man with a history of heroin abuse was found unresponsive at home secondary to a reported heroin overdose. He responded well to 2 milligrams (mg) of naloxone in the field, and was brought to the hospital alert, awake, and oriented to person, place, and time. The patient was monitored for several hours in the Emergency Department (ED) and then was discharged home the same day after an uneventful hospital course. A few hours after discharge, he was brought back to the hospital unresponsive after another overdose of heroin. He received repeated doses of naloxone to a total of 8 mg until he became responsive. Two hours later, the patient developed severe shortness of breath, hypoxemia, and altered mental status, necessitating endotracheal intubation. The patient’s vital signs were within normal limits (blood pressure of 132/89 mmHg, heart rate of 98 beats per minute, respiratory rate of 16/min, and body temperature 37°C). A chest examination was significant for bilateral basal crepitations only. Arterial blood gas (ABG) showed pH: 7.452 [7.350–7450], pCO2: 34.6 mmHg [35–50] mmHg, and pO2: 405 mmHg [85–106] mmHg. Troponin was 0.00 NG/ML (reference range <0.08 NG/ML) and lactate was 1.0 mmol/L (reference range 0.5–2.0 mmol/L). A chest radiograph showed bilateral infiltrates consistent with pulmonary edema (Figure 1). The patient was treated with IV 40 mg Lasix and was successfully extubated 7 h later. A repeat chest radiograph showed resolution of pulmonary infiltrates. The patient was saturating well at 94–96% on 3-L nasal cannula and transferred to the medical floors, where he was weaned off oxygen and observed for the following 24 h, where he was hemodynamically and clinically stable, then discharged home.
Case Presentation #2
A 37-year-old man with a medical history of intravenous heroin use and cocaine use presented to the ED due to a suspected heroin overdose. In the field the patient was given 2 mg of naloxone, but remained obtunded in the ED and was given 0.4 mg naloxone. A urine drug screen on admission was positive for cocaine and heroin but negative for other illicit substances. Alcohol level was 0.00, troponin level was <0.02 NG/ML (reference range <0.08 NG/ML), B-Type natriuretic peptide (BNP) was 18 pg/mL (reference range 0–100 pg/mL) on admission. Vitals on admission were blood pressure of 120/57 mmHg, heart rate of 84 beats per minute, respiratory rate 19/ min, and temperature 36.8°C, and oxygen saturation 96% on room air. His mental status improved after being given naloxone in the ED, but he became hypoxic and in respiratory distress eventually requiring bilevel positive airway pressure (BiPAP). Cardiac electrocardiography showed sinus tachycardia and an emergent chest X-ray showed interval development of diffuse reticulonodular opacities (Figure 2). Repeat vitals were blood pressure 104/55 mmHg, heart rate 130 beats per minute, respiratory rate 30/min, temperature of 37.3°C, and oxygen saturation 84%. Arterial blood gas was measured, showing pH 7.359, pCO2 43.5 mm Hg (reference: 35–50 mm Hg), pO2 83.6 mm Hg (reference: 85.0–106.0 mm Hg), oxygen saturation 96.2%, and bicarbonate level 23.9 mmol/L (reference: 22–26 mmol/L). He was transferred to the Intensive Care Unit (ICU) on bilevel positive airway pressure (BiPAP) due being at a low threshold for endotracheal intubation. While in the ICU, he was given IV 40 mg Lasix daily, with significant improvement of symptoms. After a short uneventful ICU course, he was weaned off the BiPAP and transitioned to 4-L nasal cannula and transferred to the medical floors and remained vitally stable with an unremarkable physical exam.
Discussion
Naloxone hydrochloride (Narcan) is a competitive opioid antagonist that was initially approved by the FDA in 1971 for the emergency treatment of opioid overdose as witnessed by respiratory and central nervous system depression [5]. Opioids used by addicts usually have a long half-life, while naloxone’s half-life is relatively short, so the respiratory symptoms recur shortly after its effect has subsided [3]. Due to this short half-life, patients may require higher doses or faster rates of infusion for the reversal of the opioid overdose, which causes a surge in the catecholamines release, leading to manifestation of adverse effects, including non-cardiogenic pulmonary edema and/or cardiac arrythmias [2].
The fluid balance in the lung and risk for development of pulmonary edema are critically determined by a multitude of factors, including pulmonary capillary and arterial pressures. Catecholamines were shown to contribute to the formation of pulmonary edema in patients with neurogenic as well as high-altitude pulmonary edema (HAPE) by a non-human experiment conducted by Rassler et al 2003 [6]. The responsible mechanisms for the increase in epinephrine in plasma following the administration of naloxone include its direct antagonizing effects on µ-opioid receptors in the adrenal medulla, and neutrally mediated changes of central sympathetic out-flow has been proposed as an explanation for the naloxone-induced non-cardiogenic acute pulmonary edema [7]. Whether this is a dose-dependent adverse effect remains unclear, as it has been reported with low doses of naloxone as well as shown by Partridge et al in 1986 [8]. However, the fact that our patient developed acute pulmonary edema after administration of 8 mg, but not 2 mg, of naloxone suggests a dose-dependent relationship. This finding reinforces the current recommendation of the American Heart Association to gradually titrate up naloxone to the least effective dose to prevent these serious adverse effects [9]. Our 2 patients had no known significant past medical history to otherwise explain the acute pulmonary edema. We excluded cardiac etiologies due to negative troponin level, BNP, and normal echocardiography studies. Furthermore, because of the chronological occurrence of pulmonary edema after naloxone administration and because no other medications known to cause such adverse effect were administered at the time, we believe that naloxone was the causative agent.
Conclusions
Naloxone remains the drug of choice in managing opioid overdose but can rarely cause non-cardiogenic acute pulmonary edema. This adverse effect is apparently dose-dependent. Therefore, healthcare providers should aim to use the least effective dose.
Figure 1. Blue arrows showed bilateral infiltrates consistent with pulmonary edema.
Figure 2. Blue arrows showed diffuse reticulonodular opacities.
Conflict of Interests
None. | NALOXONE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33730013 | 19,165,251 | 2021-03-17 |
What was the outcome of reaction 'Dyspnoea'? | Naloxone-Induced Acute Pulmonary Edema is Dose-Dependent: A Case Series.
BACKGROUND Naloxone remains the mainstay for the treatment of opioids overdose both in the clinical and public settings. Naloxone has been showing relative safety, leading to trivial adverdse effects which are mostly due to acute withdrawal effects, but when used in patients with known long-term addiction, it usually requires additional dosing or rapid infusion to achieve detoxification effects in a timely manner or to sustain the effects after they fade away. In some patients this has resulted in fatal adverse effects, including non-cardiogenic pulmonary edema (NCPE), which may require intensive care for those patients. Whether the higher dose is the cause has been debatable and not enough studies have looked into this subject. CASE REPORT Here, we report a series of 2 cases where 2 young patients were given naloxone following opioid overdose. Both our patients required frequent dosing due to insufficient response or owing to the washout of the naloxone effect shortly after, given its short half-life. Although the administered doses were different, both patients developed the adverse effect of NCPE and required ventilator support. CONCLUSIONS Evidence suggests that such a catastrophic adverse effect following the administration of such a critical medication, which is known to be relatively safe and is being publicized for saving lives, might limit its use and would require more attention and further studies to standardize a safe dose, limiting these life-threatening events and decreasing the need for unnecessary invasive respiratory support as well as admissions to intensive care units, which might create an additional burden on the health care system.
Background
Naloxone remains the main opiate antagonist used to reverse the effects of opioid overdose, both in clinical settings and illicit drug use [1]. It was developed in the 1960s and is a relatively safe medication with minimal adverse effects, which include acute withdrawal symptoms (eg, vomiting); however, it is reported that rapid infusion or using higher doses of naloxone induces a catecholamines surge that has fatal adverse effects in rare situations, such as acute pulmonary edema, ventricular arrythmias, and cardiac arrest [2,3]. We report a series of 2 cases of young patients who tolerated a low dose of naloxone well but developed acute pulmonary edema after administration of higher-dose naloxone [4].
Case Reports
Case Presentation #1
A 29-year-old man with a history of heroin abuse was found unresponsive at home secondary to a reported heroin overdose. He responded well to 2 milligrams (mg) of naloxone in the field, and was brought to the hospital alert, awake, and oriented to person, place, and time. The patient was monitored for several hours in the Emergency Department (ED) and then was discharged home the same day after an uneventful hospital course. A few hours after discharge, he was brought back to the hospital unresponsive after another overdose of heroin. He received repeated doses of naloxone to a total of 8 mg until he became responsive. Two hours later, the patient developed severe shortness of breath, hypoxemia, and altered mental status, necessitating endotracheal intubation. The patient’s vital signs were within normal limits (blood pressure of 132/89 mmHg, heart rate of 98 beats per minute, respiratory rate of 16/min, and body temperature 37°C). A chest examination was significant for bilateral basal crepitations only. Arterial blood gas (ABG) showed pH: 7.452 [7.350–7450], pCO2: 34.6 mmHg [35–50] mmHg, and pO2: 405 mmHg [85–106] mmHg. Troponin was 0.00 NG/ML (reference range <0.08 NG/ML) and lactate was 1.0 mmol/L (reference range 0.5–2.0 mmol/L). A chest radiograph showed bilateral infiltrates consistent with pulmonary edema (Figure 1). The patient was treated with IV 40 mg Lasix and was successfully extubated 7 h later. A repeat chest radiograph showed resolution of pulmonary infiltrates. The patient was saturating well at 94–96% on 3-L nasal cannula and transferred to the medical floors, where he was weaned off oxygen and observed for the following 24 h, where he was hemodynamically and clinically stable, then discharged home.
Case Presentation #2
A 37-year-old man with a medical history of intravenous heroin use and cocaine use presented to the ED due to a suspected heroin overdose. In the field the patient was given 2 mg of naloxone, but remained obtunded in the ED and was given 0.4 mg naloxone. A urine drug screen on admission was positive for cocaine and heroin but negative for other illicit substances. Alcohol level was 0.00, troponin level was <0.02 NG/ML (reference range <0.08 NG/ML), B-Type natriuretic peptide (BNP) was 18 pg/mL (reference range 0–100 pg/mL) on admission. Vitals on admission were blood pressure of 120/57 mmHg, heart rate of 84 beats per minute, respiratory rate 19/ min, and temperature 36.8°C, and oxygen saturation 96% on room air. His mental status improved after being given naloxone in the ED, but he became hypoxic and in respiratory distress eventually requiring bilevel positive airway pressure (BiPAP). Cardiac electrocardiography showed sinus tachycardia and an emergent chest X-ray showed interval development of diffuse reticulonodular opacities (Figure 2). Repeat vitals were blood pressure 104/55 mmHg, heart rate 130 beats per minute, respiratory rate 30/min, temperature of 37.3°C, and oxygen saturation 84%. Arterial blood gas was measured, showing pH 7.359, pCO2 43.5 mm Hg (reference: 35–50 mm Hg), pO2 83.6 mm Hg (reference: 85.0–106.0 mm Hg), oxygen saturation 96.2%, and bicarbonate level 23.9 mmol/L (reference: 22–26 mmol/L). He was transferred to the Intensive Care Unit (ICU) on bilevel positive airway pressure (BiPAP) due being at a low threshold for endotracheal intubation. While in the ICU, he was given IV 40 mg Lasix daily, with significant improvement of symptoms. After a short uneventful ICU course, he was weaned off the BiPAP and transitioned to 4-L nasal cannula and transferred to the medical floors and remained vitally stable with an unremarkable physical exam.
Discussion
Naloxone hydrochloride (Narcan) is a competitive opioid antagonist that was initially approved by the FDA in 1971 for the emergency treatment of opioid overdose as witnessed by respiratory and central nervous system depression [5]. Opioids used by addicts usually have a long half-life, while naloxone’s half-life is relatively short, so the respiratory symptoms recur shortly after its effect has subsided [3]. Due to this short half-life, patients may require higher doses or faster rates of infusion for the reversal of the opioid overdose, which causes a surge in the catecholamines release, leading to manifestation of adverse effects, including non-cardiogenic pulmonary edema and/or cardiac arrythmias [2].
The fluid balance in the lung and risk for development of pulmonary edema are critically determined by a multitude of factors, including pulmonary capillary and arterial pressures. Catecholamines were shown to contribute to the formation of pulmonary edema in patients with neurogenic as well as high-altitude pulmonary edema (HAPE) by a non-human experiment conducted by Rassler et al 2003 [6]. The responsible mechanisms for the increase in epinephrine in plasma following the administration of naloxone include its direct antagonizing effects on µ-opioid receptors in the adrenal medulla, and neutrally mediated changes of central sympathetic out-flow has been proposed as an explanation for the naloxone-induced non-cardiogenic acute pulmonary edema [7]. Whether this is a dose-dependent adverse effect remains unclear, as it has been reported with low doses of naloxone as well as shown by Partridge et al in 1986 [8]. However, the fact that our patient developed acute pulmonary edema after administration of 8 mg, but not 2 mg, of naloxone suggests a dose-dependent relationship. This finding reinforces the current recommendation of the American Heart Association to gradually titrate up naloxone to the least effective dose to prevent these serious adverse effects [9]. Our 2 patients had no known significant past medical history to otherwise explain the acute pulmonary edema. We excluded cardiac etiologies due to negative troponin level, BNP, and normal echocardiography studies. Furthermore, because of the chronological occurrence of pulmonary edema after naloxone administration and because no other medications known to cause such adverse effect were administered at the time, we believe that naloxone was the causative agent.
Conclusions
Naloxone remains the drug of choice in managing opioid overdose but can rarely cause non-cardiogenic acute pulmonary edema. This adverse effect is apparently dose-dependent. Therefore, healthcare providers should aim to use the least effective dose.
Figure 1. Blue arrows showed bilateral infiltrates consistent with pulmonary edema.
Figure 2. Blue arrows showed diffuse reticulonodular opacities.
Conflict of Interests
None. | Recovered | ReactionOutcome | CC BY-NC-ND | 33730013 | 19,165,260 | 2021-03-17 |
What was the outcome of reaction 'Mental disorder'? | Naloxone-Induced Acute Pulmonary Edema is Dose-Dependent: A Case Series.
BACKGROUND Naloxone remains the mainstay for the treatment of opioids overdose both in the clinical and public settings. Naloxone has been showing relative safety, leading to trivial adverdse effects which are mostly due to acute withdrawal effects, but when used in patients with known long-term addiction, it usually requires additional dosing or rapid infusion to achieve detoxification effects in a timely manner or to sustain the effects after they fade away. In some patients this has resulted in fatal adverse effects, including non-cardiogenic pulmonary edema (NCPE), which may require intensive care for those patients. Whether the higher dose is the cause has been debatable and not enough studies have looked into this subject. CASE REPORT Here, we report a series of 2 cases where 2 young patients were given naloxone following opioid overdose. Both our patients required frequent dosing due to insufficient response or owing to the washout of the naloxone effect shortly after, given its short half-life. Although the administered doses were different, both patients developed the adverse effect of NCPE and required ventilator support. CONCLUSIONS Evidence suggests that such a catastrophic adverse effect following the administration of such a critical medication, which is known to be relatively safe and is being publicized for saving lives, might limit its use and would require more attention and further studies to standardize a safe dose, limiting these life-threatening events and decreasing the need for unnecessary invasive respiratory support as well as admissions to intensive care units, which might create an additional burden on the health care system.
Background
Naloxone remains the main opiate antagonist used to reverse the effects of opioid overdose, both in clinical settings and illicit drug use [1]. It was developed in the 1960s and is a relatively safe medication with minimal adverse effects, which include acute withdrawal symptoms (eg, vomiting); however, it is reported that rapid infusion or using higher doses of naloxone induces a catecholamines surge that has fatal adverse effects in rare situations, such as acute pulmonary edema, ventricular arrythmias, and cardiac arrest [2,3]. We report a series of 2 cases of young patients who tolerated a low dose of naloxone well but developed acute pulmonary edema after administration of higher-dose naloxone [4].
Case Reports
Case Presentation #1
A 29-year-old man with a history of heroin abuse was found unresponsive at home secondary to a reported heroin overdose. He responded well to 2 milligrams (mg) of naloxone in the field, and was brought to the hospital alert, awake, and oriented to person, place, and time. The patient was monitored for several hours in the Emergency Department (ED) and then was discharged home the same day after an uneventful hospital course. A few hours after discharge, he was brought back to the hospital unresponsive after another overdose of heroin. He received repeated doses of naloxone to a total of 8 mg until he became responsive. Two hours later, the patient developed severe shortness of breath, hypoxemia, and altered mental status, necessitating endotracheal intubation. The patient’s vital signs were within normal limits (blood pressure of 132/89 mmHg, heart rate of 98 beats per minute, respiratory rate of 16/min, and body temperature 37°C). A chest examination was significant for bilateral basal crepitations only. Arterial blood gas (ABG) showed pH: 7.452 [7.350–7450], pCO2: 34.6 mmHg [35–50] mmHg, and pO2: 405 mmHg [85–106] mmHg. Troponin was 0.00 NG/ML (reference range <0.08 NG/ML) and lactate was 1.0 mmol/L (reference range 0.5–2.0 mmol/L). A chest radiograph showed bilateral infiltrates consistent with pulmonary edema (Figure 1). The patient was treated with IV 40 mg Lasix and was successfully extubated 7 h later. A repeat chest radiograph showed resolution of pulmonary infiltrates. The patient was saturating well at 94–96% on 3-L nasal cannula and transferred to the medical floors, where he was weaned off oxygen and observed for the following 24 h, where he was hemodynamically and clinically stable, then discharged home.
Case Presentation #2
A 37-year-old man with a medical history of intravenous heroin use and cocaine use presented to the ED due to a suspected heroin overdose. In the field the patient was given 2 mg of naloxone, but remained obtunded in the ED and was given 0.4 mg naloxone. A urine drug screen on admission was positive for cocaine and heroin but negative for other illicit substances. Alcohol level was 0.00, troponin level was <0.02 NG/ML (reference range <0.08 NG/ML), B-Type natriuretic peptide (BNP) was 18 pg/mL (reference range 0–100 pg/mL) on admission. Vitals on admission were blood pressure of 120/57 mmHg, heart rate of 84 beats per minute, respiratory rate 19/ min, and temperature 36.8°C, and oxygen saturation 96% on room air. His mental status improved after being given naloxone in the ED, but he became hypoxic and in respiratory distress eventually requiring bilevel positive airway pressure (BiPAP). Cardiac electrocardiography showed sinus tachycardia and an emergent chest X-ray showed interval development of diffuse reticulonodular opacities (Figure 2). Repeat vitals were blood pressure 104/55 mmHg, heart rate 130 beats per minute, respiratory rate 30/min, temperature of 37.3°C, and oxygen saturation 84%. Arterial blood gas was measured, showing pH 7.359, pCO2 43.5 mm Hg (reference: 35–50 mm Hg), pO2 83.6 mm Hg (reference: 85.0–106.0 mm Hg), oxygen saturation 96.2%, and bicarbonate level 23.9 mmol/L (reference: 22–26 mmol/L). He was transferred to the Intensive Care Unit (ICU) on bilevel positive airway pressure (BiPAP) due being at a low threshold for endotracheal intubation. While in the ICU, he was given IV 40 mg Lasix daily, with significant improvement of symptoms. After a short uneventful ICU course, he was weaned off the BiPAP and transitioned to 4-L nasal cannula and transferred to the medical floors and remained vitally stable with an unremarkable physical exam.
Discussion
Naloxone hydrochloride (Narcan) is a competitive opioid antagonist that was initially approved by the FDA in 1971 for the emergency treatment of opioid overdose as witnessed by respiratory and central nervous system depression [5]. Opioids used by addicts usually have a long half-life, while naloxone’s half-life is relatively short, so the respiratory symptoms recur shortly after its effect has subsided [3]. Due to this short half-life, patients may require higher doses or faster rates of infusion for the reversal of the opioid overdose, which causes a surge in the catecholamines release, leading to manifestation of adverse effects, including non-cardiogenic pulmonary edema and/or cardiac arrythmias [2].
The fluid balance in the lung and risk for development of pulmonary edema are critically determined by a multitude of factors, including pulmonary capillary and arterial pressures. Catecholamines were shown to contribute to the formation of pulmonary edema in patients with neurogenic as well as high-altitude pulmonary edema (HAPE) by a non-human experiment conducted by Rassler et al 2003 [6]. The responsible mechanisms for the increase in epinephrine in plasma following the administration of naloxone include its direct antagonizing effects on µ-opioid receptors in the adrenal medulla, and neutrally mediated changes of central sympathetic out-flow has been proposed as an explanation for the naloxone-induced non-cardiogenic acute pulmonary edema [7]. Whether this is a dose-dependent adverse effect remains unclear, as it has been reported with low doses of naloxone as well as shown by Partridge et al in 1986 [8]. However, the fact that our patient developed acute pulmonary edema after administration of 8 mg, but not 2 mg, of naloxone suggests a dose-dependent relationship. This finding reinforces the current recommendation of the American Heart Association to gradually titrate up naloxone to the least effective dose to prevent these serious adverse effects [9]. Our 2 patients had no known significant past medical history to otherwise explain the acute pulmonary edema. We excluded cardiac etiologies due to negative troponin level, BNP, and normal echocardiography studies. Furthermore, because of the chronological occurrence of pulmonary edema after naloxone administration and because no other medications known to cause such adverse effect were administered at the time, we believe that naloxone was the causative agent.
Conclusions
Naloxone remains the drug of choice in managing opioid overdose but can rarely cause non-cardiogenic acute pulmonary edema. This adverse effect is apparently dose-dependent. Therefore, healthcare providers should aim to use the least effective dose.
Figure 1. Blue arrows showed bilateral infiltrates consistent with pulmonary edema.
Figure 2. Blue arrows showed diffuse reticulonodular opacities.
Conflict of Interests
None. | Recovering | ReactionOutcome | CC BY-NC-ND | 33730013 | 19,082,994 | 2021-03-17 |
What was the outcome of reaction 'Respiratory distress'? | Naloxone-Induced Acute Pulmonary Edema is Dose-Dependent: A Case Series.
BACKGROUND Naloxone remains the mainstay for the treatment of opioids overdose both in the clinical and public settings. Naloxone has been showing relative safety, leading to trivial adverdse effects which are mostly due to acute withdrawal effects, but when used in patients with known long-term addiction, it usually requires additional dosing or rapid infusion to achieve detoxification effects in a timely manner or to sustain the effects after they fade away. In some patients this has resulted in fatal adverse effects, including non-cardiogenic pulmonary edema (NCPE), which may require intensive care for those patients. Whether the higher dose is the cause has been debatable and not enough studies have looked into this subject. CASE REPORT Here, we report a series of 2 cases where 2 young patients were given naloxone following opioid overdose. Both our patients required frequent dosing due to insufficient response or owing to the washout of the naloxone effect shortly after, given its short half-life. Although the administered doses were different, both patients developed the adverse effect of NCPE and required ventilator support. CONCLUSIONS Evidence suggests that such a catastrophic adverse effect following the administration of such a critical medication, which is known to be relatively safe and is being publicized for saving lives, might limit its use and would require more attention and further studies to standardize a safe dose, limiting these life-threatening events and decreasing the need for unnecessary invasive respiratory support as well as admissions to intensive care units, which might create an additional burden on the health care system.
Background
Naloxone remains the main opiate antagonist used to reverse the effects of opioid overdose, both in clinical settings and illicit drug use [1]. It was developed in the 1960s and is a relatively safe medication with minimal adverse effects, which include acute withdrawal symptoms (eg, vomiting); however, it is reported that rapid infusion or using higher doses of naloxone induces a catecholamines surge that has fatal adverse effects in rare situations, such as acute pulmonary edema, ventricular arrythmias, and cardiac arrest [2,3]. We report a series of 2 cases of young patients who tolerated a low dose of naloxone well but developed acute pulmonary edema after administration of higher-dose naloxone [4].
Case Reports
Case Presentation #1
A 29-year-old man with a history of heroin abuse was found unresponsive at home secondary to a reported heroin overdose. He responded well to 2 milligrams (mg) of naloxone in the field, and was brought to the hospital alert, awake, and oriented to person, place, and time. The patient was monitored for several hours in the Emergency Department (ED) and then was discharged home the same day after an uneventful hospital course. A few hours after discharge, he was brought back to the hospital unresponsive after another overdose of heroin. He received repeated doses of naloxone to a total of 8 mg until he became responsive. Two hours later, the patient developed severe shortness of breath, hypoxemia, and altered mental status, necessitating endotracheal intubation. The patient’s vital signs were within normal limits (blood pressure of 132/89 mmHg, heart rate of 98 beats per minute, respiratory rate of 16/min, and body temperature 37°C). A chest examination was significant for bilateral basal crepitations only. Arterial blood gas (ABG) showed pH: 7.452 [7.350–7450], pCO2: 34.6 mmHg [35–50] mmHg, and pO2: 405 mmHg [85–106] mmHg. Troponin was 0.00 NG/ML (reference range <0.08 NG/ML) and lactate was 1.0 mmol/L (reference range 0.5–2.0 mmol/L). A chest radiograph showed bilateral infiltrates consistent with pulmonary edema (Figure 1). The patient was treated with IV 40 mg Lasix and was successfully extubated 7 h later. A repeat chest radiograph showed resolution of pulmonary infiltrates. The patient was saturating well at 94–96% on 3-L nasal cannula and transferred to the medical floors, where he was weaned off oxygen and observed for the following 24 h, where he was hemodynamically and clinically stable, then discharged home.
Case Presentation #2
A 37-year-old man with a medical history of intravenous heroin use and cocaine use presented to the ED due to a suspected heroin overdose. In the field the patient was given 2 mg of naloxone, but remained obtunded in the ED and was given 0.4 mg naloxone. A urine drug screen on admission was positive for cocaine and heroin but negative for other illicit substances. Alcohol level was 0.00, troponin level was <0.02 NG/ML (reference range <0.08 NG/ML), B-Type natriuretic peptide (BNP) was 18 pg/mL (reference range 0–100 pg/mL) on admission. Vitals on admission were blood pressure of 120/57 mmHg, heart rate of 84 beats per minute, respiratory rate 19/ min, and temperature 36.8°C, and oxygen saturation 96% on room air. His mental status improved after being given naloxone in the ED, but he became hypoxic and in respiratory distress eventually requiring bilevel positive airway pressure (BiPAP). Cardiac electrocardiography showed sinus tachycardia and an emergent chest X-ray showed interval development of diffuse reticulonodular opacities (Figure 2). Repeat vitals were blood pressure 104/55 mmHg, heart rate 130 beats per minute, respiratory rate 30/min, temperature of 37.3°C, and oxygen saturation 84%. Arterial blood gas was measured, showing pH 7.359, pCO2 43.5 mm Hg (reference: 35–50 mm Hg), pO2 83.6 mm Hg (reference: 85.0–106.0 mm Hg), oxygen saturation 96.2%, and bicarbonate level 23.9 mmol/L (reference: 22–26 mmol/L). He was transferred to the Intensive Care Unit (ICU) on bilevel positive airway pressure (BiPAP) due being at a low threshold for endotracheal intubation. While in the ICU, he was given IV 40 mg Lasix daily, with significant improvement of symptoms. After a short uneventful ICU course, he was weaned off the BiPAP and transitioned to 4-L nasal cannula and transferred to the medical floors and remained vitally stable with an unremarkable physical exam.
Discussion
Naloxone hydrochloride (Narcan) is a competitive opioid antagonist that was initially approved by the FDA in 1971 for the emergency treatment of opioid overdose as witnessed by respiratory and central nervous system depression [5]. Opioids used by addicts usually have a long half-life, while naloxone’s half-life is relatively short, so the respiratory symptoms recur shortly after its effect has subsided [3]. Due to this short half-life, patients may require higher doses or faster rates of infusion for the reversal of the opioid overdose, which causes a surge in the catecholamines release, leading to manifestation of adverse effects, including non-cardiogenic pulmonary edema and/or cardiac arrythmias [2].
The fluid balance in the lung and risk for development of pulmonary edema are critically determined by a multitude of factors, including pulmonary capillary and arterial pressures. Catecholamines were shown to contribute to the formation of pulmonary edema in patients with neurogenic as well as high-altitude pulmonary edema (HAPE) by a non-human experiment conducted by Rassler et al 2003 [6]. The responsible mechanisms for the increase in epinephrine in plasma following the administration of naloxone include its direct antagonizing effects on µ-opioid receptors in the adrenal medulla, and neutrally mediated changes of central sympathetic out-flow has been proposed as an explanation for the naloxone-induced non-cardiogenic acute pulmonary edema [7]. Whether this is a dose-dependent adverse effect remains unclear, as it has been reported with low doses of naloxone as well as shown by Partridge et al in 1986 [8]. However, the fact that our patient developed acute pulmonary edema after administration of 8 mg, but not 2 mg, of naloxone suggests a dose-dependent relationship. This finding reinforces the current recommendation of the American Heart Association to gradually titrate up naloxone to the least effective dose to prevent these serious adverse effects [9]. Our 2 patients had no known significant past medical history to otherwise explain the acute pulmonary edema. We excluded cardiac etiologies due to negative troponin level, BNP, and normal echocardiography studies. Furthermore, because of the chronological occurrence of pulmonary edema after naloxone administration and because no other medications known to cause such adverse effect were administered at the time, we believe that naloxone was the causative agent.
Conclusions
Naloxone remains the drug of choice in managing opioid overdose but can rarely cause non-cardiogenic acute pulmonary edema. This adverse effect is apparently dose-dependent. Therefore, healthcare providers should aim to use the least effective dose.
Figure 1. Blue arrows showed bilateral infiltrates consistent with pulmonary edema.
Figure 2. Blue arrows showed diffuse reticulonodular opacities.
Conflict of Interests
None. | Recovering | ReactionOutcome | CC BY-NC-ND | 33730013 | 19,165,251 | 2021-03-17 |
What was the outcome of reaction 'Sinus tachycardia'? | Naloxone-Induced Acute Pulmonary Edema is Dose-Dependent: A Case Series.
BACKGROUND Naloxone remains the mainstay for the treatment of opioids overdose both in the clinical and public settings. Naloxone has been showing relative safety, leading to trivial adverdse effects which are mostly due to acute withdrawal effects, but when used in patients with known long-term addiction, it usually requires additional dosing or rapid infusion to achieve detoxification effects in a timely manner or to sustain the effects after they fade away. In some patients this has resulted in fatal adverse effects, including non-cardiogenic pulmonary edema (NCPE), which may require intensive care for those patients. Whether the higher dose is the cause has been debatable and not enough studies have looked into this subject. CASE REPORT Here, we report a series of 2 cases where 2 young patients were given naloxone following opioid overdose. Both our patients required frequent dosing due to insufficient response or owing to the washout of the naloxone effect shortly after, given its short half-life. Although the administered doses were different, both patients developed the adverse effect of NCPE and required ventilator support. CONCLUSIONS Evidence suggests that such a catastrophic adverse effect following the administration of such a critical medication, which is known to be relatively safe and is being publicized for saving lives, might limit its use and would require more attention and further studies to standardize a safe dose, limiting these life-threatening events and decreasing the need for unnecessary invasive respiratory support as well as admissions to intensive care units, which might create an additional burden on the health care system.
Background
Naloxone remains the main opiate antagonist used to reverse the effects of opioid overdose, both in clinical settings and illicit drug use [1]. It was developed in the 1960s and is a relatively safe medication with minimal adverse effects, which include acute withdrawal symptoms (eg, vomiting); however, it is reported that rapid infusion or using higher doses of naloxone induces a catecholamines surge that has fatal adverse effects in rare situations, such as acute pulmonary edema, ventricular arrythmias, and cardiac arrest [2,3]. We report a series of 2 cases of young patients who tolerated a low dose of naloxone well but developed acute pulmonary edema after administration of higher-dose naloxone [4].
Case Reports
Case Presentation #1
A 29-year-old man with a history of heroin abuse was found unresponsive at home secondary to a reported heroin overdose. He responded well to 2 milligrams (mg) of naloxone in the field, and was brought to the hospital alert, awake, and oriented to person, place, and time. The patient was monitored for several hours in the Emergency Department (ED) and then was discharged home the same day after an uneventful hospital course. A few hours after discharge, he was brought back to the hospital unresponsive after another overdose of heroin. He received repeated doses of naloxone to a total of 8 mg until he became responsive. Two hours later, the patient developed severe shortness of breath, hypoxemia, and altered mental status, necessitating endotracheal intubation. The patient’s vital signs were within normal limits (blood pressure of 132/89 mmHg, heart rate of 98 beats per minute, respiratory rate of 16/min, and body temperature 37°C). A chest examination was significant for bilateral basal crepitations only. Arterial blood gas (ABG) showed pH: 7.452 [7.350–7450], pCO2: 34.6 mmHg [35–50] mmHg, and pO2: 405 mmHg [85–106] mmHg. Troponin was 0.00 NG/ML (reference range <0.08 NG/ML) and lactate was 1.0 mmol/L (reference range 0.5–2.0 mmol/L). A chest radiograph showed bilateral infiltrates consistent with pulmonary edema (Figure 1). The patient was treated with IV 40 mg Lasix and was successfully extubated 7 h later. A repeat chest radiograph showed resolution of pulmonary infiltrates. The patient was saturating well at 94–96% on 3-L nasal cannula and transferred to the medical floors, where he was weaned off oxygen and observed for the following 24 h, where he was hemodynamically and clinically stable, then discharged home.
Case Presentation #2
A 37-year-old man with a medical history of intravenous heroin use and cocaine use presented to the ED due to a suspected heroin overdose. In the field the patient was given 2 mg of naloxone, but remained obtunded in the ED and was given 0.4 mg naloxone. A urine drug screen on admission was positive for cocaine and heroin but negative for other illicit substances. Alcohol level was 0.00, troponin level was <0.02 NG/ML (reference range <0.08 NG/ML), B-Type natriuretic peptide (BNP) was 18 pg/mL (reference range 0–100 pg/mL) on admission. Vitals on admission were blood pressure of 120/57 mmHg, heart rate of 84 beats per minute, respiratory rate 19/ min, and temperature 36.8°C, and oxygen saturation 96% on room air. His mental status improved after being given naloxone in the ED, but he became hypoxic and in respiratory distress eventually requiring bilevel positive airway pressure (BiPAP). Cardiac electrocardiography showed sinus tachycardia and an emergent chest X-ray showed interval development of diffuse reticulonodular opacities (Figure 2). Repeat vitals were blood pressure 104/55 mmHg, heart rate 130 beats per minute, respiratory rate 30/min, temperature of 37.3°C, and oxygen saturation 84%. Arterial blood gas was measured, showing pH 7.359, pCO2 43.5 mm Hg (reference: 35–50 mm Hg), pO2 83.6 mm Hg (reference: 85.0–106.0 mm Hg), oxygen saturation 96.2%, and bicarbonate level 23.9 mmol/L (reference: 22–26 mmol/L). He was transferred to the Intensive Care Unit (ICU) on bilevel positive airway pressure (BiPAP) due being at a low threshold for endotracheal intubation. While in the ICU, he was given IV 40 mg Lasix daily, with significant improvement of symptoms. After a short uneventful ICU course, he was weaned off the BiPAP and transitioned to 4-L nasal cannula and transferred to the medical floors and remained vitally stable with an unremarkable physical exam.
Discussion
Naloxone hydrochloride (Narcan) is a competitive opioid antagonist that was initially approved by the FDA in 1971 for the emergency treatment of opioid overdose as witnessed by respiratory and central nervous system depression [5]. Opioids used by addicts usually have a long half-life, while naloxone’s half-life is relatively short, so the respiratory symptoms recur shortly after its effect has subsided [3]. Due to this short half-life, patients may require higher doses or faster rates of infusion for the reversal of the opioid overdose, which causes a surge in the catecholamines release, leading to manifestation of adverse effects, including non-cardiogenic pulmonary edema and/or cardiac arrythmias [2].
The fluid balance in the lung and risk for development of pulmonary edema are critically determined by a multitude of factors, including pulmonary capillary and arterial pressures. Catecholamines were shown to contribute to the formation of pulmonary edema in patients with neurogenic as well as high-altitude pulmonary edema (HAPE) by a non-human experiment conducted by Rassler et al 2003 [6]. The responsible mechanisms for the increase in epinephrine in plasma following the administration of naloxone include its direct antagonizing effects on µ-opioid receptors in the adrenal medulla, and neutrally mediated changes of central sympathetic out-flow has been proposed as an explanation for the naloxone-induced non-cardiogenic acute pulmonary edema [7]. Whether this is a dose-dependent adverse effect remains unclear, as it has been reported with low doses of naloxone as well as shown by Partridge et al in 1986 [8]. However, the fact that our patient developed acute pulmonary edema after administration of 8 mg, but not 2 mg, of naloxone suggests a dose-dependent relationship. This finding reinforces the current recommendation of the American Heart Association to gradually titrate up naloxone to the least effective dose to prevent these serious adverse effects [9]. Our 2 patients had no known significant past medical history to otherwise explain the acute pulmonary edema. We excluded cardiac etiologies due to negative troponin level, BNP, and normal echocardiography studies. Furthermore, because of the chronological occurrence of pulmonary edema after naloxone administration and because no other medications known to cause such adverse effect were administered at the time, we believe that naloxone was the causative agent.
Conclusions
Naloxone remains the drug of choice in managing opioid overdose but can rarely cause non-cardiogenic acute pulmonary edema. This adverse effect is apparently dose-dependent. Therefore, healthcare providers should aim to use the least effective dose.
Figure 1. Blue arrows showed bilateral infiltrates consistent with pulmonary edema.
Figure 2. Blue arrows showed diffuse reticulonodular opacities.
Conflict of Interests
None. | Recovering | ReactionOutcome | CC BY-NC-ND | 33730013 | 19,082,994 | 2021-03-17 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Fall'. | Zoledronic Acid after Treatment with Denosumab is Associated with Bone Loss within 1 Year.
BACKGROUND
Bone mineral density (BMD) declines when zoledronic acid (ZA) is administered. This case series describes the patterns of change in BMD when 1 or 2 doses of ZA are administered after denosumab.
METHODS
Twelve patients who received at least 2 doses of denosumab followed by at least 1 dose of ZA and who had a dual energy X-ray absorptiometry (DXA) scan at the end of denosumab and 1 year after the first dose of ZA were included. We excluded patients with bone cancer or conditions affecting bone metabolism, including hyperparathyroidism, rickets, osteogenesis imperfecta, rheumatologic disorders, fibrous dysplasia, Paget's disease of bone, untreated hyperthyroidism, chronic kidney disease, liver cirrhosis, malabsorption, ongoing corticosteroid therapy, and aromatase inhibitor use.
RESULTS
There was a significant decline in BMD at the femoral neck within 1 year of the first ZA dose and a non-significant downward trend in the hip and lumbar spine. This trend was more severe in patients with osteoporosis at the time of drug transition. No increase in clinical vertebral fractures was observed. BMD seemed to stabilize in a smaller number of patients who received a second dose of ZA and had a DXA scan 1 year later.
CONCLUSIONS
A single dose of ZA administered approximately 6 months after denosumab leads to some BMD loss, mostly within 1 year of ZA administration, particularly in patients with osteoporosis at the time of denosumab discontinuation.
INTRODUCTION
Denosumab is a monoclonal antibody that mimics the action of endogenous osteoprotegerin by binding to and preventing the action of the: receptor activator of nuclear factor-κB ligand (RANKL), thereby inhibiting osteoclasts and preventing bone resorption.[1,2] Denosumab is a potent antiresorptive agent, leading to significant increases in bone mineral density (BMD) and fracture prevention.[3] However, acute discontinuation of denosumab leads to a rebound rapid increase in bone turnover with a large bone loss [4–6] and in some cases is associated with an increase in the risk of vertebral compression fractures.[7–13] This phenomenon is believed to be due to a compensatory upregulation of the RANK receptors on osteoclast precursors while in the presence of denosumab.[4] To avoid this rebound increase in bone resorption and the associated bone loss, “consolidation therapy” has been recommended. This approach entails transitioning patients from denosumab to a bisphosphonate prior to complete discontinuation of antiresorptive therapy,[13,14] and zoledronic acid (ZA) became one of the drugs commonly used in this setting. However, the use of ZA after denosumab does not seem to fully prevent the bone loss that follows discontinuation of denosumab. In a recent retrospective study by Everts-Graber et al. [15], patients previously treated with denosumab for 2 to 5 years followed by a single infusion of ZA experienced some loss of BMD on a dual energy X-ray absorptiometry (DXA) scan 12 to 42 months later. However, only patients who had achieved osteopenia while on denosumab were transitioned to ZA in this study, limiting those findings to a select group of patients with a rather robust response to denosumab.
In our clinical practice, we follow a protocol that attempts to limit total antiresorptive therapy (denosumab+consolidation with ZA) to no more than 5 to 6 years. To transition to ZA, patients should have had stable or improved BMD on denosumab for at least 1 year, but we do not aim to achieve osteopenia prior to initiating consolidation therapy. We routinely evaluate patient response on DXA around 12 months after ZA administration. In this case series, we describe changes in BMD and prevalence of clinical fractures 1 year after transitioning from denosumab to ZA in patients with both osteopenia and osteoporosis at the end of denosumab therapy. We also report observations on BMD changes after a second dose of ZA was given a year later to a smaller subgroup of patients.
METHODS
1. Data sources and patients
This is a retrospective case series of patients with osteoporosis treated with denosumab followed by ZA in the Endocrinology Clinic at an academic medical center. We used the electronic medical records (EMR; Epic 2018 version UI 2; Epic Systems Corp., Verona, WI, USA) to identify patients treated with denosumab followed by ZA between January 1, 2012 (the year denosumab was approved for clinical use in the USA) and June 30, 2020. Eligible patients met the following inclusion criteria: (1) received at least 2 doses of denosumab; (2) followed by at least 1 dose of ZA; (3) underwent DXA at the end of their treatment course with denosumab and approximately 1 year after the first dose of ZA. Patients were excluded if they had bone cancer or other conditions affecting bone metabolism including hyperparathyroidism, rickets, osteogenesis imperfecta, rheumatologic disorders, fibrous dysplasia of the bone, Paget’s disease of the bone, untreated hyperthyroidism, chronic kidney disease, liver cirrhosis, malabsorptive conditions (such as inflammatory bowel disease or celiac disease), and ongoing glucocorticoid or aromatase inhibitor use.
The EMR contains complete demographic, clinical, laboratory, and medication data for all patients seen at our medical center.
2. Data elements
Key data elements included patient demographics, height, weight, body mass index (BMI), medical comorbidities, smoking status, alcohol consumption history, DXA measurements and date of each measurement, number of denosumab doses and date of each dose, and number of post-denosumab ZA doses and date of each dose. All doses of denosumab and ZA were administered at our center and dates of administration were extracted from the patients’ EMR.
We also recorded basic laboratory results at the initiation of denosumab, including serum concentrations of calcium, creatinine, parathyroid hormone (PTH), and 25-hydroxy-vitamin D (25[OH]D). Only laboratory values obtained at the core laboratory at our medical center were recorded and used in this analysis to eliminate the bias that could be introduced by the variability between different assays. Calcium and creatinine were determined using Roche Modular P analyzers (Hoffmann-La Roche, Basel, Switzerland). Serum calcium was determined by colorimetric assay (lower detection limit, 0.2 mg/dL; intra-assay coefficient of variation [CV], 0.9%; inter-assay CV, 1.6%; Roche Diagnostics, Mannheim, Germany) and serum creatinine was determined by enzymatic colorimetric assay (lower detection limit, 0.03 mg/dL; intra-assay CV, 0.9%; inter-assay CV, 1.1%; Roche Diagnostics). The 25(OH)D was determined by ARUP Laboratories using the DiaSorin Liaison CIA technology that measured both 25(OH)D2 and 25(OH)D3 (lower detection limit, 0.8 ng/mL; intra-assay CV, 6.7%; inter-assay CV, 6.3%). The laboratory participated in regular Vitamin D External Quality Assessment Scheme performance assessments and passed quality assurance minimal standards. PTH was determined using Roche Modular E170 analyzer using an electrochemiluminescence immunoassay (lower detection limit, 1.2 pg/mL; intra-assay CV, 1.9 %; inter-assay CV, 4.5%; Roche Diagnostics). There were no changes to any of the tests used during the duration of time covered by the study. DXA scans were performed using a Hologic Discovery v12.6.2 instrument (Hologic Inc., Bedford, MA, USA; Center-specific hip and spine least significant change [LSC]=0.020 g/cm2). Areal BMD was measured at the total hip, femoral neck, and lumbar spine (L1-4) and expressed in grams/cm2.
All data were extracted from the patients’ EMR by 1 investigator (TK) and cross-checked by another investigator (ASR).
3. Statistical analyses
Statistical analyses were conducted using SAS for Windows, version 9.3 (SAS Institute Inc., Cary, NC, USA) and statistical significance was defined as a P-value less than 0.05 without correction for multiple testing. Due to the small sample size, data are presented as median (interquartile range) or percentage.
We began by examining patient characteristics and baseline DXA and laboratory results. We also calculated the number of doses of denosumab that each patient received and the duration of time between the last dose of denosumab and the first dose of ZA.
We then examined the change in BMD from baseline (before initiation of denosumab) to the end of the denosumab treatment course and between the end of the denosumab treatment course and the first DXA scan following ZA. We used nonparametric methods (Wilcoxon signed-rank test) to compare these data points. Finally, we used univariable logistic regression to examine the association between changes in BMD and total number of denosumab doses received and between changes in BMD and the duration of time between the last dose of denosumab and the first dose of ZA. Multivariable analyses were not performed due to the small sample size. The institutional review board approved this study.
RESULTS
1. Baseline evaluation
We identified 12 patients who met the study inclusion and exclusion criteria. A description of our study cohort is presented in Table 1. Three of the patients had their initial DXA scan prior to initiation of denosumab performed outside our medical center, and those measurements were excluded from the analysis. All other DXA scans were performed in our laboratory. At the time of transitioning to consolidation therapy, 6 of the patients still had osteoporosis (defined by a T-score ≤-2.5 at the lumbar spine, hip or femoral neck), and 6 had osteopenia. The reasons for transition to ZA in patients who still had osteoporosis was plateauing of BMD after 5 to 6 doses of denosumab in 4 patients, and patient request due to frequent traveling in 2 patients. The average t-scores in all 12 patients at the lumbar spine, total hip, and femoral neck were −1.23, −1.66, and −1.93, respectively.
2. Treatment and follow-up
Patients received a median of 5.3 doses of denosumab 6 months apart (range, 3–7 doses). All patients subsequently received at least one dose of ZA (median, 2; range, 1–3 doses). The median duration of time between the last dose of denosumab and the first dose of ZA was 201.5 days (~ 6.7 months).
All patients underwent a DXA measurement in our lab at the end of their denosumab treatment course and another DXA after the first dose of ZA. The median duration of time between the first dose of ZA and the corresponding follow-up DXA scan was 12.0 (1.0) months.
Five patients received a second yearly dose of ZA and had another DXA measurement following the second dose. In these patients, the median duration of time between the first and second doses of ZA was 12.7 (0.4) months. The median duration of time between the second dose of ZA and the corresponding DXA was 12.3 (0.3) months.
None of the patients suffered a clinical fracture while on denosumab. After transition to ZA, 1 patient sustained a distal radial fracture upon a fall. The fracture happened when she lost her balance while trying to sit on a stool and fell down on her extended wrist. She had received 3 doses of denosumab and 1 dose of ZA, the latter being about 6 months prior to the fracture. Her DXA scan about 6 months after the fracture showed a T score of −1.9 at the lumbar spine, −1.0 at the total hip, and −1.6 at the femoral neck. While spine X-rays were not routinely obtained on all patients, 3 patients underwent spine imaging after switching from denosumab to ZA (2 patients underwent thoracic and lumbar spine imaging, and 1 patient underwent lumbar spine imaging only), and no vertebral fractures were identified.
3. Changes in BMD over time
Table 2 shows the mean BMD for all patients with available DXA scans prior to initiation of denosumab (pre-Dmab, N=9), after completion of treatment with denosumab (post-Dmab, N=12) and after the first dose of ZA (post-ZA, N=12). As mentioned previously, the analyses excluded 3 pre-denosumab DXA scans that were performed outside our medical center.
When comparing the changes in measurements between the pre-Dmab and that obtained at the time of completion of denosumab, a statistically significant increase in BMD (P=0.008) was seen at the femoral neck. A non-significant increase was noted at the lumbar spine and total hip.
When comparing the DXA scan obtained at the end of denosumab treatment and that obtained after the first dose of ZA, we noted a significant decline in BMD (P=0.04) at the femoral neck. A non-significant downward trend was seen at the lumbar spine and total hip. The BMD at all 3 sites however remained higher than the BMD measured prior to initiation of denosumab. Patients who experienced a decline in BMD with ZA underwent a limited evaluation for secondary causes of bone loss (including abnormal renal function, vitamin D deficiency, hyperthyroidism, and hyperparathyroidism), and none was found.
On average, within approximately 1 year of switching from denosumab to ZA, patients lost 23% of the BMD gain they had accrued at the lumbar spine while on denosumab, 47% of the BMD gain accrued at the total hip and 54% of the BMD gain accrued at the femoral neck (Table 3). Of the patients who had osteopenia at the end of denosumab, 4 (67%) experienced some loss in BMD in at least one site. Of the patients with osteoporosis at the end of denosumab 5 (83%) experienced some loss of BMD in at least one site. Table 3 shows the proportion of BMD gain lost upon switching to ZA in each of these subgroups.
In a univariable logistic regression, the decline in BMD between the DXA scan obtained at the end of denosumab and the one obtained after the first dose of ZA was independent of the number of denosumab doses (for change in BMD at the lumbar spine OR=0.48 and P=0.22; at the total hip OR=0.70 and P=0.55; and at the femoral neck OR=0.70 and P=0.55) It was also independent of the time between the last dose of denosumab and the first dose of ZA (for change in BMD at the lumbar spine OR=1.0 and P=0.54; at the total hip OR=1.0 and P=0.54; and at the femoral neck OR=1.0 and P=0.3)
Five individuals received a second dose of ZA and had another DXA scan ~1 year later. We examined the changes in BMD between the DXA that followed the first ZA dose and the one following the second dose. Fig. 1 shows these changes for the individual patients with available data (N=5). The graphs suggest general stabilization of BMD at the lumbar spine, total hip, and femoral neck a year after the second annual consolidation dose of ZA. Due to the small number of patients in this subgroup, no statistical analyses on the trends were performed.
DISCUSSION
This case series suggests that patients who receive 1 dose of ZA after treatment with denosumab lose some of the BMD accrued while on denosumab. These results are consistent with previous studies where BMD loss was observed after a single consolidation dose of ZA.[15–17] The studies by Lehmann and Aeberli [16] and Reid et al. [17] measured BMD 2 to 2.5 years after ZA and could not determine the exact timeline of bone loss. However, our observations confirm what the work of Everts-Graber et al. [15] suggests, in that much of the observed bone loss happens during the first 12 months that follow the ZA infusion. In addition, our observations suggest that the bone loss might slow down when another yearly dose of ZA is given, but caution should be applied in interpreting these findings given the small sample size.
Our findings also suggest that the bone loss at the total hip and spine is much larger in patients who remained osteoporotic while on denosumab. This finding might present an argument in favor of ensuring patients’ BMD is in the osteopenia range on denosumab before switching them to ZA. It is worth making a note here of a recent study by Anastasilakis that randomized 57 women previously treated with denosumab for osteoporosis to another 2 doses of denosumab versus a single dose of ZA. Twelve months after randomization, an equal but non-significant increase in the lumbar spine and femoral neck BMD was seen in both groups, despite higher levels of bone turnover markers (BTMs) in the group randomized to ZA.[18] While these results contradict the decline in BMD with the transition from denosumab to ZA observed by other studies, it should be noted that all patients had osteopenia at the time of transition, which might again argue in favor of attaining osteopenia with denosumab before initiation of consolidation therapy.
One possible explanation for the observed bone loss when switching from denosumab to ZA lies in the fact that bisphosphonates need “open bone surfaces” to adhere to in order to exert their antiresorptive action.[3] Since bone turnover is still profoundly suppressed 6 months after a dose of denosumab, it is likely that ZA adherence to bone surfaces is reduced when given at that time. Thus, a single dose of ZA given after completion of denosumab treatment may be partially “wasted” and not fully taken up to the bone surfaces. One would then expect a more frequently dosed bisphosphonate to have more opportunities for adherence as the bone turnover is gradually restored after denosumab, thus allowing more antiresorptive action. This was indeed shown by Freemantle et al. in the DAPS study where 1 year of alendronate following 1 year of denosumab prevented post-denosumab bone loss.[19]
Alternatively, it may be attractive to delay ZA by more than 6 months after the last dose of denosumab to allow for some recovery of bone turnover and for the drug to adhere better to bone surfaces. Horne et al. [20] tested this hypothesis in a group of postmenopausal women treated with 1 year of romosozumab followed by 2 years of denosumab. Following denosumab, the subjects received a single dose of ZA, but the administration of ZA was delayed by an average of 65 days (i.e., it was administered about 8 months rather than 6 months after the last dose of denosumab). The bone loss 1 year after ZA was milder with this regimen.[20] While this may suggest that a delay in the timing of ZA after denosumab could enhance the antiresorptive efficacy of the drug, this approach might be associated with an increased risk of vertebral fractures, as such fractures have been observed as early as 2 months after discontinuation of denosumab.[11] Additionally, this study added the new variable of romosozumab treatment prior to denosumab, and it is not clear to what degree a change in bone quality from romosozumab may have contributed to the milder bone loss observed after ZA.
It is important to acknowledge potential limitations of this work. First, our sample size was small and this may explain the lack of statistical significance in some of our analyses. Notably however, while our analyses of BMD changes at the lumbar spine and hip did not reach statistical significance, the trends were comparable to previous studies that did achieve statistical significance.[15,16] Measurement of BTMs is also missing from our study, somewhat limiting our interpretation of the results. Finally, while our study focuses on the changes in BMD over time, it is important to acknowledge that fractures are the clinically-relevant outcome of low BMD. Although all clinical fractures were documented in our patients’ records, routine x-rays to assess for subclinical fractures were not obtained. Nonetheless, there was no evidence of an increased risk of clinical vertebral fractures in our patients despite the observed decline in BMD.
In conclusion, a single dose of ZA given approximately 6 months after long-term denosumab therapy leads to a loss of a portion of the BMD gained with denosumab, and much of this loss seems to occur within 1 year of ZA, particularly in patients who are osteoporotic at the time of transition. Furthermore, limited data suggest that the loss in BMD may plateau after a second dose of ZA. However, larger and longer-term studies with careful evaluation of fracture risk are needed to provide a definitive answer on the safety and best approach to post-denosumab consolidation therapy with ZA.
Fig. 1 Bone mineral density (BMD) and T-score measurements in 5 patients who received 2 doses of zoledronic acid. Each line represents an individual patient. DXA, dual energy X-ray absorptiometry; Pre-Dmab, DXA scans prior to initiation of denosumab; Post-Dmab, DXA scans after completion of treatment with denosumab; Post-ZA1, DXA scans after the first dose of zoledronic acid; Post-ZA2, DXA scans after the second dose of zoledronic acid.
Table 1 Patient characteristics
Characteristics Value (N=12)
Age (yr), median (IQR) 76.8 (8.8)
Sex (female) 12 (100.0)
Race (white) 12 (100.0)
BMI (kg/m2), median (IQR) 21.9 (4.5)
25(OH)D (ng/mL), median (IQR) 37.5 (13.0)
Calcium (mg/dL), median (IQR) 9.8 (0.7)
PTH (pg/mL), median (IQR)a) 40.1 (3.9)
Creatinine (mg/dL), median (IQR) 0.7 (0.2)
Smoking
Current smoker 1 (8.3)
Previous smoker 4 (33.3)
Alcoholic drinks per week, median (IQR) 1 (1.5)
Trauma
Presence of low-trauma fracture before Dmab 2 (16.7)
Presence of low-trauma vertebral fracture before Dmab 1 (8.3)
BMD (gm/cm2), median (IQR)b)
Lumbar spine 0.82 (0.03)
Total hip 0.69 (0.05)
Femoral neck 0.59 (0.02)
Treatment received
Received bisphosphonate before Dmab 7 (58.3)
Bisphosphonate washout before Dmab (yr), median (IQR)c) 4 (2.5)
No. of Dmab doses, median (IQR) 5.3 (1.2)
No. of ZA doses, median (IQR) 2 (0.3)
Patients with osteoporosis at time of transition to ZA 6 (50.0)
Lag time between last dose of Dmab and first dose of ZA (days), median (IQR) 201.5 (31.3)
The data is presented as median (IQR) or number (%).
a) PTH available in 5 patients.
b) Baseline BMD in 9.
c) Bisphosphonate washout applies to 7 patients who received bisphosphonate before Dmab.
IQR, interquartile range; BMI, body mass index; 25(OH)D, 25-hydroxy-vitamin D; PTH, parathyroid hormone; BMD, bone mineral density; Dmab, denosumab; ZA, zoledronic aid.
Table 2 Changes in bone density measurements over time
DXA measurement site DXA time
Pre-Dmab (N=9) Post-Dmab (N=12) Post-ZA (N=12)
BMD (g/cm2)
Lumbar spine 0.82 (0.03) 0.90 (0.15)a) 0.87 (0.08)a)
Total hip 0.69 (0.05) 0.75 (0.04) 0.72 (0.08)
Femoral neck 0.59 (0.02) 0.63 (0.06)b) 0.62 (0.05)c)
The data is presented as median (interquartile range).
a) Lumbar spine measurement excluded in 1 patient due to severe degenerative changes.
b) Statistically significant increase from pre-Dmab, P=0.008.
c) Statistically significant decrease from post-Dmab, P=0.040.
DXA, dual energy X-ray absorptiometry; Pre-Dmab, DXA scans prior to initiation of denosumab; Post-Dmab, DXA scans after completion of treatment with denosumab; Post-ZA, DXA scans after the first dose of zoledronic acid; BMD, bone mineral density.
Table 3 Relative changes in BMD upon switching from Dmab to ZA
Site All patients Patients with osteopenia at end of Dmab Patients with osteoporosis at end of Dmab
Median BMD gain on Dmab (g/cm2) Median BMD loss after switching to ZA (g/cm2) Percent of median BMD gain that is lost with ZA Percent of median BMD gain that is lost with ZA Percent of median BMD gain that is lost with ZA
Lumbar spine 0.048 0.011 23% 7% 61%
Total hip 0.034 0.016 47% 43% 220%
Femoral neck 0.048 0.026 54% 49% 37%
BMD, bone mineral density; Dmab, denosumab; ZA, zoledronic aid.
Funding
The authors received no financial support for this article.
Ethics approval and consent to participate
The study was reviewed and approved by the Institutional Review Board for human subjects’ research.
Conflict of interest
No potential conflict of interest relevant to this article was reported. | DENOSUMAB | DrugsGivenReaction | CC BY-NC | 33730783 | 19,075,920 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Radius fracture'. | Zoledronic Acid after Treatment with Denosumab is Associated with Bone Loss within 1 Year.
BACKGROUND
Bone mineral density (BMD) declines when zoledronic acid (ZA) is administered. This case series describes the patterns of change in BMD when 1 or 2 doses of ZA are administered after denosumab.
METHODS
Twelve patients who received at least 2 doses of denosumab followed by at least 1 dose of ZA and who had a dual energy X-ray absorptiometry (DXA) scan at the end of denosumab and 1 year after the first dose of ZA were included. We excluded patients with bone cancer or conditions affecting bone metabolism, including hyperparathyroidism, rickets, osteogenesis imperfecta, rheumatologic disorders, fibrous dysplasia, Paget's disease of bone, untreated hyperthyroidism, chronic kidney disease, liver cirrhosis, malabsorption, ongoing corticosteroid therapy, and aromatase inhibitor use.
RESULTS
There was a significant decline in BMD at the femoral neck within 1 year of the first ZA dose and a non-significant downward trend in the hip and lumbar spine. This trend was more severe in patients with osteoporosis at the time of drug transition. No increase in clinical vertebral fractures was observed. BMD seemed to stabilize in a smaller number of patients who received a second dose of ZA and had a DXA scan 1 year later.
CONCLUSIONS
A single dose of ZA administered approximately 6 months after denosumab leads to some BMD loss, mostly within 1 year of ZA administration, particularly in patients with osteoporosis at the time of denosumab discontinuation.
INTRODUCTION
Denosumab is a monoclonal antibody that mimics the action of endogenous osteoprotegerin by binding to and preventing the action of the: receptor activator of nuclear factor-κB ligand (RANKL), thereby inhibiting osteoclasts and preventing bone resorption.[1,2] Denosumab is a potent antiresorptive agent, leading to significant increases in bone mineral density (BMD) and fracture prevention.[3] However, acute discontinuation of denosumab leads to a rebound rapid increase in bone turnover with a large bone loss [4–6] and in some cases is associated with an increase in the risk of vertebral compression fractures.[7–13] This phenomenon is believed to be due to a compensatory upregulation of the RANK receptors on osteoclast precursors while in the presence of denosumab.[4] To avoid this rebound increase in bone resorption and the associated bone loss, “consolidation therapy” has been recommended. This approach entails transitioning patients from denosumab to a bisphosphonate prior to complete discontinuation of antiresorptive therapy,[13,14] and zoledronic acid (ZA) became one of the drugs commonly used in this setting. However, the use of ZA after denosumab does not seem to fully prevent the bone loss that follows discontinuation of denosumab. In a recent retrospective study by Everts-Graber et al. [15], patients previously treated with denosumab for 2 to 5 years followed by a single infusion of ZA experienced some loss of BMD on a dual energy X-ray absorptiometry (DXA) scan 12 to 42 months later. However, only patients who had achieved osteopenia while on denosumab were transitioned to ZA in this study, limiting those findings to a select group of patients with a rather robust response to denosumab.
In our clinical practice, we follow a protocol that attempts to limit total antiresorptive therapy (denosumab+consolidation with ZA) to no more than 5 to 6 years. To transition to ZA, patients should have had stable or improved BMD on denosumab for at least 1 year, but we do not aim to achieve osteopenia prior to initiating consolidation therapy. We routinely evaluate patient response on DXA around 12 months after ZA administration. In this case series, we describe changes in BMD and prevalence of clinical fractures 1 year after transitioning from denosumab to ZA in patients with both osteopenia and osteoporosis at the end of denosumab therapy. We also report observations on BMD changes after a second dose of ZA was given a year later to a smaller subgroup of patients.
METHODS
1. Data sources and patients
This is a retrospective case series of patients with osteoporosis treated with denosumab followed by ZA in the Endocrinology Clinic at an academic medical center. We used the electronic medical records (EMR; Epic 2018 version UI 2; Epic Systems Corp., Verona, WI, USA) to identify patients treated with denosumab followed by ZA between January 1, 2012 (the year denosumab was approved for clinical use in the USA) and June 30, 2020. Eligible patients met the following inclusion criteria: (1) received at least 2 doses of denosumab; (2) followed by at least 1 dose of ZA; (3) underwent DXA at the end of their treatment course with denosumab and approximately 1 year after the first dose of ZA. Patients were excluded if they had bone cancer or other conditions affecting bone metabolism including hyperparathyroidism, rickets, osteogenesis imperfecta, rheumatologic disorders, fibrous dysplasia of the bone, Paget’s disease of the bone, untreated hyperthyroidism, chronic kidney disease, liver cirrhosis, malabsorptive conditions (such as inflammatory bowel disease or celiac disease), and ongoing glucocorticoid or aromatase inhibitor use.
The EMR contains complete demographic, clinical, laboratory, and medication data for all patients seen at our medical center.
2. Data elements
Key data elements included patient demographics, height, weight, body mass index (BMI), medical comorbidities, smoking status, alcohol consumption history, DXA measurements and date of each measurement, number of denosumab doses and date of each dose, and number of post-denosumab ZA doses and date of each dose. All doses of denosumab and ZA were administered at our center and dates of administration were extracted from the patients’ EMR.
We also recorded basic laboratory results at the initiation of denosumab, including serum concentrations of calcium, creatinine, parathyroid hormone (PTH), and 25-hydroxy-vitamin D (25[OH]D). Only laboratory values obtained at the core laboratory at our medical center were recorded and used in this analysis to eliminate the bias that could be introduced by the variability between different assays. Calcium and creatinine were determined using Roche Modular P analyzers (Hoffmann-La Roche, Basel, Switzerland). Serum calcium was determined by colorimetric assay (lower detection limit, 0.2 mg/dL; intra-assay coefficient of variation [CV], 0.9%; inter-assay CV, 1.6%; Roche Diagnostics, Mannheim, Germany) and serum creatinine was determined by enzymatic colorimetric assay (lower detection limit, 0.03 mg/dL; intra-assay CV, 0.9%; inter-assay CV, 1.1%; Roche Diagnostics). The 25(OH)D was determined by ARUP Laboratories using the DiaSorin Liaison CIA technology that measured both 25(OH)D2 and 25(OH)D3 (lower detection limit, 0.8 ng/mL; intra-assay CV, 6.7%; inter-assay CV, 6.3%). The laboratory participated in regular Vitamin D External Quality Assessment Scheme performance assessments and passed quality assurance minimal standards. PTH was determined using Roche Modular E170 analyzer using an electrochemiluminescence immunoassay (lower detection limit, 1.2 pg/mL; intra-assay CV, 1.9 %; inter-assay CV, 4.5%; Roche Diagnostics). There were no changes to any of the tests used during the duration of time covered by the study. DXA scans were performed using a Hologic Discovery v12.6.2 instrument (Hologic Inc., Bedford, MA, USA; Center-specific hip and spine least significant change [LSC]=0.020 g/cm2). Areal BMD was measured at the total hip, femoral neck, and lumbar spine (L1-4) and expressed in grams/cm2.
All data were extracted from the patients’ EMR by 1 investigator (TK) and cross-checked by another investigator (ASR).
3. Statistical analyses
Statistical analyses were conducted using SAS for Windows, version 9.3 (SAS Institute Inc., Cary, NC, USA) and statistical significance was defined as a P-value less than 0.05 without correction for multiple testing. Due to the small sample size, data are presented as median (interquartile range) or percentage.
We began by examining patient characteristics and baseline DXA and laboratory results. We also calculated the number of doses of denosumab that each patient received and the duration of time between the last dose of denosumab and the first dose of ZA.
We then examined the change in BMD from baseline (before initiation of denosumab) to the end of the denosumab treatment course and between the end of the denosumab treatment course and the first DXA scan following ZA. We used nonparametric methods (Wilcoxon signed-rank test) to compare these data points. Finally, we used univariable logistic regression to examine the association between changes in BMD and total number of denosumab doses received and between changes in BMD and the duration of time between the last dose of denosumab and the first dose of ZA. Multivariable analyses were not performed due to the small sample size. The institutional review board approved this study.
RESULTS
1. Baseline evaluation
We identified 12 patients who met the study inclusion and exclusion criteria. A description of our study cohort is presented in Table 1. Three of the patients had their initial DXA scan prior to initiation of denosumab performed outside our medical center, and those measurements were excluded from the analysis. All other DXA scans were performed in our laboratory. At the time of transitioning to consolidation therapy, 6 of the patients still had osteoporosis (defined by a T-score ≤-2.5 at the lumbar spine, hip or femoral neck), and 6 had osteopenia. The reasons for transition to ZA in patients who still had osteoporosis was plateauing of BMD after 5 to 6 doses of denosumab in 4 patients, and patient request due to frequent traveling in 2 patients. The average t-scores in all 12 patients at the lumbar spine, total hip, and femoral neck were −1.23, −1.66, and −1.93, respectively.
2. Treatment and follow-up
Patients received a median of 5.3 doses of denosumab 6 months apart (range, 3–7 doses). All patients subsequently received at least one dose of ZA (median, 2; range, 1–3 doses). The median duration of time between the last dose of denosumab and the first dose of ZA was 201.5 days (~ 6.7 months).
All patients underwent a DXA measurement in our lab at the end of their denosumab treatment course and another DXA after the first dose of ZA. The median duration of time between the first dose of ZA and the corresponding follow-up DXA scan was 12.0 (1.0) months.
Five patients received a second yearly dose of ZA and had another DXA measurement following the second dose. In these patients, the median duration of time between the first and second doses of ZA was 12.7 (0.4) months. The median duration of time between the second dose of ZA and the corresponding DXA was 12.3 (0.3) months.
None of the patients suffered a clinical fracture while on denosumab. After transition to ZA, 1 patient sustained a distal radial fracture upon a fall. The fracture happened when she lost her balance while trying to sit on a stool and fell down on her extended wrist. She had received 3 doses of denosumab and 1 dose of ZA, the latter being about 6 months prior to the fracture. Her DXA scan about 6 months after the fracture showed a T score of −1.9 at the lumbar spine, −1.0 at the total hip, and −1.6 at the femoral neck. While spine X-rays were not routinely obtained on all patients, 3 patients underwent spine imaging after switching from denosumab to ZA (2 patients underwent thoracic and lumbar spine imaging, and 1 patient underwent lumbar spine imaging only), and no vertebral fractures were identified.
3. Changes in BMD over time
Table 2 shows the mean BMD for all patients with available DXA scans prior to initiation of denosumab (pre-Dmab, N=9), after completion of treatment with denosumab (post-Dmab, N=12) and after the first dose of ZA (post-ZA, N=12). As mentioned previously, the analyses excluded 3 pre-denosumab DXA scans that were performed outside our medical center.
When comparing the changes in measurements between the pre-Dmab and that obtained at the time of completion of denosumab, a statistically significant increase in BMD (P=0.008) was seen at the femoral neck. A non-significant increase was noted at the lumbar spine and total hip.
When comparing the DXA scan obtained at the end of denosumab treatment and that obtained after the first dose of ZA, we noted a significant decline in BMD (P=0.04) at the femoral neck. A non-significant downward trend was seen at the lumbar spine and total hip. The BMD at all 3 sites however remained higher than the BMD measured prior to initiation of denosumab. Patients who experienced a decline in BMD with ZA underwent a limited evaluation for secondary causes of bone loss (including abnormal renal function, vitamin D deficiency, hyperthyroidism, and hyperparathyroidism), and none was found.
On average, within approximately 1 year of switching from denosumab to ZA, patients lost 23% of the BMD gain they had accrued at the lumbar spine while on denosumab, 47% of the BMD gain accrued at the total hip and 54% of the BMD gain accrued at the femoral neck (Table 3). Of the patients who had osteopenia at the end of denosumab, 4 (67%) experienced some loss in BMD in at least one site. Of the patients with osteoporosis at the end of denosumab 5 (83%) experienced some loss of BMD in at least one site. Table 3 shows the proportion of BMD gain lost upon switching to ZA in each of these subgroups.
In a univariable logistic regression, the decline in BMD between the DXA scan obtained at the end of denosumab and the one obtained after the first dose of ZA was independent of the number of denosumab doses (for change in BMD at the lumbar spine OR=0.48 and P=0.22; at the total hip OR=0.70 and P=0.55; and at the femoral neck OR=0.70 and P=0.55) It was also independent of the time between the last dose of denosumab and the first dose of ZA (for change in BMD at the lumbar spine OR=1.0 and P=0.54; at the total hip OR=1.0 and P=0.54; and at the femoral neck OR=1.0 and P=0.3)
Five individuals received a second dose of ZA and had another DXA scan ~1 year later. We examined the changes in BMD between the DXA that followed the first ZA dose and the one following the second dose. Fig. 1 shows these changes for the individual patients with available data (N=5). The graphs suggest general stabilization of BMD at the lumbar spine, total hip, and femoral neck a year after the second annual consolidation dose of ZA. Due to the small number of patients in this subgroup, no statistical analyses on the trends were performed.
DISCUSSION
This case series suggests that patients who receive 1 dose of ZA after treatment with denosumab lose some of the BMD accrued while on denosumab. These results are consistent with previous studies where BMD loss was observed after a single consolidation dose of ZA.[15–17] The studies by Lehmann and Aeberli [16] and Reid et al. [17] measured BMD 2 to 2.5 years after ZA and could not determine the exact timeline of bone loss. However, our observations confirm what the work of Everts-Graber et al. [15] suggests, in that much of the observed bone loss happens during the first 12 months that follow the ZA infusion. In addition, our observations suggest that the bone loss might slow down when another yearly dose of ZA is given, but caution should be applied in interpreting these findings given the small sample size.
Our findings also suggest that the bone loss at the total hip and spine is much larger in patients who remained osteoporotic while on denosumab. This finding might present an argument in favor of ensuring patients’ BMD is in the osteopenia range on denosumab before switching them to ZA. It is worth making a note here of a recent study by Anastasilakis that randomized 57 women previously treated with denosumab for osteoporosis to another 2 doses of denosumab versus a single dose of ZA. Twelve months after randomization, an equal but non-significant increase in the lumbar spine and femoral neck BMD was seen in both groups, despite higher levels of bone turnover markers (BTMs) in the group randomized to ZA.[18] While these results contradict the decline in BMD with the transition from denosumab to ZA observed by other studies, it should be noted that all patients had osteopenia at the time of transition, which might again argue in favor of attaining osteopenia with denosumab before initiation of consolidation therapy.
One possible explanation for the observed bone loss when switching from denosumab to ZA lies in the fact that bisphosphonates need “open bone surfaces” to adhere to in order to exert their antiresorptive action.[3] Since bone turnover is still profoundly suppressed 6 months after a dose of denosumab, it is likely that ZA adherence to bone surfaces is reduced when given at that time. Thus, a single dose of ZA given after completion of denosumab treatment may be partially “wasted” and not fully taken up to the bone surfaces. One would then expect a more frequently dosed bisphosphonate to have more opportunities for adherence as the bone turnover is gradually restored after denosumab, thus allowing more antiresorptive action. This was indeed shown by Freemantle et al. in the DAPS study where 1 year of alendronate following 1 year of denosumab prevented post-denosumab bone loss.[19]
Alternatively, it may be attractive to delay ZA by more than 6 months after the last dose of denosumab to allow for some recovery of bone turnover and for the drug to adhere better to bone surfaces. Horne et al. [20] tested this hypothesis in a group of postmenopausal women treated with 1 year of romosozumab followed by 2 years of denosumab. Following denosumab, the subjects received a single dose of ZA, but the administration of ZA was delayed by an average of 65 days (i.e., it was administered about 8 months rather than 6 months after the last dose of denosumab). The bone loss 1 year after ZA was milder with this regimen.[20] While this may suggest that a delay in the timing of ZA after denosumab could enhance the antiresorptive efficacy of the drug, this approach might be associated with an increased risk of vertebral fractures, as such fractures have been observed as early as 2 months after discontinuation of denosumab.[11] Additionally, this study added the new variable of romosozumab treatment prior to denosumab, and it is not clear to what degree a change in bone quality from romosozumab may have contributed to the milder bone loss observed after ZA.
It is important to acknowledge potential limitations of this work. First, our sample size was small and this may explain the lack of statistical significance in some of our analyses. Notably however, while our analyses of BMD changes at the lumbar spine and hip did not reach statistical significance, the trends were comparable to previous studies that did achieve statistical significance.[15,16] Measurement of BTMs is also missing from our study, somewhat limiting our interpretation of the results. Finally, while our study focuses on the changes in BMD over time, it is important to acknowledge that fractures are the clinically-relevant outcome of low BMD. Although all clinical fractures were documented in our patients’ records, routine x-rays to assess for subclinical fractures were not obtained. Nonetheless, there was no evidence of an increased risk of clinical vertebral fractures in our patients despite the observed decline in BMD.
In conclusion, a single dose of ZA given approximately 6 months after long-term denosumab therapy leads to a loss of a portion of the BMD gained with denosumab, and much of this loss seems to occur within 1 year of ZA, particularly in patients who are osteoporotic at the time of transition. Furthermore, limited data suggest that the loss in BMD may plateau after a second dose of ZA. However, larger and longer-term studies with careful evaluation of fracture risk are needed to provide a definitive answer on the safety and best approach to post-denosumab consolidation therapy with ZA.
Fig. 1 Bone mineral density (BMD) and T-score measurements in 5 patients who received 2 doses of zoledronic acid. Each line represents an individual patient. DXA, dual energy X-ray absorptiometry; Pre-Dmab, DXA scans prior to initiation of denosumab; Post-Dmab, DXA scans after completion of treatment with denosumab; Post-ZA1, DXA scans after the first dose of zoledronic acid; Post-ZA2, DXA scans after the second dose of zoledronic acid.
Table 1 Patient characteristics
Characteristics Value (N=12)
Age (yr), median (IQR) 76.8 (8.8)
Sex (female) 12 (100.0)
Race (white) 12 (100.0)
BMI (kg/m2), median (IQR) 21.9 (4.5)
25(OH)D (ng/mL), median (IQR) 37.5 (13.0)
Calcium (mg/dL), median (IQR) 9.8 (0.7)
PTH (pg/mL), median (IQR)a) 40.1 (3.9)
Creatinine (mg/dL), median (IQR) 0.7 (0.2)
Smoking
Current smoker 1 (8.3)
Previous smoker 4 (33.3)
Alcoholic drinks per week, median (IQR) 1 (1.5)
Trauma
Presence of low-trauma fracture before Dmab 2 (16.7)
Presence of low-trauma vertebral fracture before Dmab 1 (8.3)
BMD (gm/cm2), median (IQR)b)
Lumbar spine 0.82 (0.03)
Total hip 0.69 (0.05)
Femoral neck 0.59 (0.02)
Treatment received
Received bisphosphonate before Dmab 7 (58.3)
Bisphosphonate washout before Dmab (yr), median (IQR)c) 4 (2.5)
No. of Dmab doses, median (IQR) 5.3 (1.2)
No. of ZA doses, median (IQR) 2 (0.3)
Patients with osteoporosis at time of transition to ZA 6 (50.0)
Lag time between last dose of Dmab and first dose of ZA (days), median (IQR) 201.5 (31.3)
The data is presented as median (IQR) or number (%).
a) PTH available in 5 patients.
b) Baseline BMD in 9.
c) Bisphosphonate washout applies to 7 patients who received bisphosphonate before Dmab.
IQR, interquartile range; BMI, body mass index; 25(OH)D, 25-hydroxy-vitamin D; PTH, parathyroid hormone; BMD, bone mineral density; Dmab, denosumab; ZA, zoledronic aid.
Table 2 Changes in bone density measurements over time
DXA measurement site DXA time
Pre-Dmab (N=9) Post-Dmab (N=12) Post-ZA (N=12)
BMD (g/cm2)
Lumbar spine 0.82 (0.03) 0.90 (0.15)a) 0.87 (0.08)a)
Total hip 0.69 (0.05) 0.75 (0.04) 0.72 (0.08)
Femoral neck 0.59 (0.02) 0.63 (0.06)b) 0.62 (0.05)c)
The data is presented as median (interquartile range).
a) Lumbar spine measurement excluded in 1 patient due to severe degenerative changes.
b) Statistically significant increase from pre-Dmab, P=0.008.
c) Statistically significant decrease from post-Dmab, P=0.040.
DXA, dual energy X-ray absorptiometry; Pre-Dmab, DXA scans prior to initiation of denosumab; Post-Dmab, DXA scans after completion of treatment with denosumab; Post-ZA, DXA scans after the first dose of zoledronic acid; BMD, bone mineral density.
Table 3 Relative changes in BMD upon switching from Dmab to ZA
Site All patients Patients with osteopenia at end of Dmab Patients with osteoporosis at end of Dmab
Median BMD gain on Dmab (g/cm2) Median BMD loss after switching to ZA (g/cm2) Percent of median BMD gain that is lost with ZA Percent of median BMD gain that is lost with ZA Percent of median BMD gain that is lost with ZA
Lumbar spine 0.048 0.011 23% 7% 61%
Total hip 0.034 0.016 47% 43% 220%
Femoral neck 0.048 0.026 54% 49% 37%
BMD, bone mineral density; Dmab, denosumab; ZA, zoledronic aid.
Funding
The authors received no financial support for this article.
Ethics approval and consent to participate
The study was reviewed and approved by the Institutional Review Board for human subjects’ research.
Conflict of interest
No potential conflict of interest relevant to this article was reported. | DENOSUMAB | DrugsGivenReaction | CC BY-NC | 33730783 | 19,075,920 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapeutic product effect incomplete'. | Zoledronic Acid after Treatment with Denosumab is Associated with Bone Loss within 1 Year.
BACKGROUND
Bone mineral density (BMD) declines when zoledronic acid (ZA) is administered. This case series describes the patterns of change in BMD when 1 or 2 doses of ZA are administered after denosumab.
METHODS
Twelve patients who received at least 2 doses of denosumab followed by at least 1 dose of ZA and who had a dual energy X-ray absorptiometry (DXA) scan at the end of denosumab and 1 year after the first dose of ZA were included. We excluded patients with bone cancer or conditions affecting bone metabolism, including hyperparathyroidism, rickets, osteogenesis imperfecta, rheumatologic disorders, fibrous dysplasia, Paget's disease of bone, untreated hyperthyroidism, chronic kidney disease, liver cirrhosis, malabsorption, ongoing corticosteroid therapy, and aromatase inhibitor use.
RESULTS
There was a significant decline in BMD at the femoral neck within 1 year of the first ZA dose and a non-significant downward trend in the hip and lumbar spine. This trend was more severe in patients with osteoporosis at the time of drug transition. No increase in clinical vertebral fractures was observed. BMD seemed to stabilize in a smaller number of patients who received a second dose of ZA and had a DXA scan 1 year later.
CONCLUSIONS
A single dose of ZA administered approximately 6 months after denosumab leads to some BMD loss, mostly within 1 year of ZA administration, particularly in patients with osteoporosis at the time of denosumab discontinuation.
INTRODUCTION
Denosumab is a monoclonal antibody that mimics the action of endogenous osteoprotegerin by binding to and preventing the action of the: receptor activator of nuclear factor-κB ligand (RANKL), thereby inhibiting osteoclasts and preventing bone resorption.[1,2] Denosumab is a potent antiresorptive agent, leading to significant increases in bone mineral density (BMD) and fracture prevention.[3] However, acute discontinuation of denosumab leads to a rebound rapid increase in bone turnover with a large bone loss [4–6] and in some cases is associated with an increase in the risk of vertebral compression fractures.[7–13] This phenomenon is believed to be due to a compensatory upregulation of the RANK receptors on osteoclast precursors while in the presence of denosumab.[4] To avoid this rebound increase in bone resorption and the associated bone loss, “consolidation therapy” has been recommended. This approach entails transitioning patients from denosumab to a bisphosphonate prior to complete discontinuation of antiresorptive therapy,[13,14] and zoledronic acid (ZA) became one of the drugs commonly used in this setting. However, the use of ZA after denosumab does not seem to fully prevent the bone loss that follows discontinuation of denosumab. In a recent retrospective study by Everts-Graber et al. [15], patients previously treated with denosumab for 2 to 5 years followed by a single infusion of ZA experienced some loss of BMD on a dual energy X-ray absorptiometry (DXA) scan 12 to 42 months later. However, only patients who had achieved osteopenia while on denosumab were transitioned to ZA in this study, limiting those findings to a select group of patients with a rather robust response to denosumab.
In our clinical practice, we follow a protocol that attempts to limit total antiresorptive therapy (denosumab+consolidation with ZA) to no more than 5 to 6 years. To transition to ZA, patients should have had stable or improved BMD on denosumab for at least 1 year, but we do not aim to achieve osteopenia prior to initiating consolidation therapy. We routinely evaluate patient response on DXA around 12 months after ZA administration. In this case series, we describe changes in BMD and prevalence of clinical fractures 1 year after transitioning from denosumab to ZA in patients with both osteopenia and osteoporosis at the end of denosumab therapy. We also report observations on BMD changes after a second dose of ZA was given a year later to a smaller subgroup of patients.
METHODS
1. Data sources and patients
This is a retrospective case series of patients with osteoporosis treated with denosumab followed by ZA in the Endocrinology Clinic at an academic medical center. We used the electronic medical records (EMR; Epic 2018 version UI 2; Epic Systems Corp., Verona, WI, USA) to identify patients treated with denosumab followed by ZA between January 1, 2012 (the year denosumab was approved for clinical use in the USA) and June 30, 2020. Eligible patients met the following inclusion criteria: (1) received at least 2 doses of denosumab; (2) followed by at least 1 dose of ZA; (3) underwent DXA at the end of their treatment course with denosumab and approximately 1 year after the first dose of ZA. Patients were excluded if they had bone cancer or other conditions affecting bone metabolism including hyperparathyroidism, rickets, osteogenesis imperfecta, rheumatologic disorders, fibrous dysplasia of the bone, Paget’s disease of the bone, untreated hyperthyroidism, chronic kidney disease, liver cirrhosis, malabsorptive conditions (such as inflammatory bowel disease or celiac disease), and ongoing glucocorticoid or aromatase inhibitor use.
The EMR contains complete demographic, clinical, laboratory, and medication data for all patients seen at our medical center.
2. Data elements
Key data elements included patient demographics, height, weight, body mass index (BMI), medical comorbidities, smoking status, alcohol consumption history, DXA measurements and date of each measurement, number of denosumab doses and date of each dose, and number of post-denosumab ZA doses and date of each dose. All doses of denosumab and ZA were administered at our center and dates of administration were extracted from the patients’ EMR.
We also recorded basic laboratory results at the initiation of denosumab, including serum concentrations of calcium, creatinine, parathyroid hormone (PTH), and 25-hydroxy-vitamin D (25[OH]D). Only laboratory values obtained at the core laboratory at our medical center were recorded and used in this analysis to eliminate the bias that could be introduced by the variability between different assays. Calcium and creatinine were determined using Roche Modular P analyzers (Hoffmann-La Roche, Basel, Switzerland). Serum calcium was determined by colorimetric assay (lower detection limit, 0.2 mg/dL; intra-assay coefficient of variation [CV], 0.9%; inter-assay CV, 1.6%; Roche Diagnostics, Mannheim, Germany) and serum creatinine was determined by enzymatic colorimetric assay (lower detection limit, 0.03 mg/dL; intra-assay CV, 0.9%; inter-assay CV, 1.1%; Roche Diagnostics). The 25(OH)D was determined by ARUP Laboratories using the DiaSorin Liaison CIA technology that measured both 25(OH)D2 and 25(OH)D3 (lower detection limit, 0.8 ng/mL; intra-assay CV, 6.7%; inter-assay CV, 6.3%). The laboratory participated in regular Vitamin D External Quality Assessment Scheme performance assessments and passed quality assurance minimal standards. PTH was determined using Roche Modular E170 analyzer using an electrochemiluminescence immunoassay (lower detection limit, 1.2 pg/mL; intra-assay CV, 1.9 %; inter-assay CV, 4.5%; Roche Diagnostics). There were no changes to any of the tests used during the duration of time covered by the study. DXA scans were performed using a Hologic Discovery v12.6.2 instrument (Hologic Inc., Bedford, MA, USA; Center-specific hip and spine least significant change [LSC]=0.020 g/cm2). Areal BMD was measured at the total hip, femoral neck, and lumbar spine (L1-4) and expressed in grams/cm2.
All data were extracted from the patients’ EMR by 1 investigator (TK) and cross-checked by another investigator (ASR).
3. Statistical analyses
Statistical analyses were conducted using SAS for Windows, version 9.3 (SAS Institute Inc., Cary, NC, USA) and statistical significance was defined as a P-value less than 0.05 without correction for multiple testing. Due to the small sample size, data are presented as median (interquartile range) or percentage.
We began by examining patient characteristics and baseline DXA and laboratory results. We also calculated the number of doses of denosumab that each patient received and the duration of time between the last dose of denosumab and the first dose of ZA.
We then examined the change in BMD from baseline (before initiation of denosumab) to the end of the denosumab treatment course and between the end of the denosumab treatment course and the first DXA scan following ZA. We used nonparametric methods (Wilcoxon signed-rank test) to compare these data points. Finally, we used univariable logistic regression to examine the association between changes in BMD and total number of denosumab doses received and between changes in BMD and the duration of time between the last dose of denosumab and the first dose of ZA. Multivariable analyses were not performed due to the small sample size. The institutional review board approved this study.
RESULTS
1. Baseline evaluation
We identified 12 patients who met the study inclusion and exclusion criteria. A description of our study cohort is presented in Table 1. Three of the patients had their initial DXA scan prior to initiation of denosumab performed outside our medical center, and those measurements were excluded from the analysis. All other DXA scans were performed in our laboratory. At the time of transitioning to consolidation therapy, 6 of the patients still had osteoporosis (defined by a T-score ≤-2.5 at the lumbar spine, hip or femoral neck), and 6 had osteopenia. The reasons for transition to ZA in patients who still had osteoporosis was plateauing of BMD after 5 to 6 doses of denosumab in 4 patients, and patient request due to frequent traveling in 2 patients. The average t-scores in all 12 patients at the lumbar spine, total hip, and femoral neck were −1.23, −1.66, and −1.93, respectively.
2. Treatment and follow-up
Patients received a median of 5.3 doses of denosumab 6 months apart (range, 3–7 doses). All patients subsequently received at least one dose of ZA (median, 2; range, 1–3 doses). The median duration of time between the last dose of denosumab and the first dose of ZA was 201.5 days (~ 6.7 months).
All patients underwent a DXA measurement in our lab at the end of their denosumab treatment course and another DXA after the first dose of ZA. The median duration of time between the first dose of ZA and the corresponding follow-up DXA scan was 12.0 (1.0) months.
Five patients received a second yearly dose of ZA and had another DXA measurement following the second dose. In these patients, the median duration of time between the first and second doses of ZA was 12.7 (0.4) months. The median duration of time between the second dose of ZA and the corresponding DXA was 12.3 (0.3) months.
None of the patients suffered a clinical fracture while on denosumab. After transition to ZA, 1 patient sustained a distal radial fracture upon a fall. The fracture happened when she lost her balance while trying to sit on a stool and fell down on her extended wrist. She had received 3 doses of denosumab and 1 dose of ZA, the latter being about 6 months prior to the fracture. Her DXA scan about 6 months after the fracture showed a T score of −1.9 at the lumbar spine, −1.0 at the total hip, and −1.6 at the femoral neck. While spine X-rays were not routinely obtained on all patients, 3 patients underwent spine imaging after switching from denosumab to ZA (2 patients underwent thoracic and lumbar spine imaging, and 1 patient underwent lumbar spine imaging only), and no vertebral fractures were identified.
3. Changes in BMD over time
Table 2 shows the mean BMD for all patients with available DXA scans prior to initiation of denosumab (pre-Dmab, N=9), after completion of treatment with denosumab (post-Dmab, N=12) and after the first dose of ZA (post-ZA, N=12). As mentioned previously, the analyses excluded 3 pre-denosumab DXA scans that were performed outside our medical center.
When comparing the changes in measurements between the pre-Dmab and that obtained at the time of completion of denosumab, a statistically significant increase in BMD (P=0.008) was seen at the femoral neck. A non-significant increase was noted at the lumbar spine and total hip.
When comparing the DXA scan obtained at the end of denosumab treatment and that obtained after the first dose of ZA, we noted a significant decline in BMD (P=0.04) at the femoral neck. A non-significant downward trend was seen at the lumbar spine and total hip. The BMD at all 3 sites however remained higher than the BMD measured prior to initiation of denosumab. Patients who experienced a decline in BMD with ZA underwent a limited evaluation for secondary causes of bone loss (including abnormal renal function, vitamin D deficiency, hyperthyroidism, and hyperparathyroidism), and none was found.
On average, within approximately 1 year of switching from denosumab to ZA, patients lost 23% of the BMD gain they had accrued at the lumbar spine while on denosumab, 47% of the BMD gain accrued at the total hip and 54% of the BMD gain accrued at the femoral neck (Table 3). Of the patients who had osteopenia at the end of denosumab, 4 (67%) experienced some loss in BMD in at least one site. Of the patients with osteoporosis at the end of denosumab 5 (83%) experienced some loss of BMD in at least one site. Table 3 shows the proportion of BMD gain lost upon switching to ZA in each of these subgroups.
In a univariable logistic regression, the decline in BMD between the DXA scan obtained at the end of denosumab and the one obtained after the first dose of ZA was independent of the number of denosumab doses (for change in BMD at the lumbar spine OR=0.48 and P=0.22; at the total hip OR=0.70 and P=0.55; and at the femoral neck OR=0.70 and P=0.55) It was also independent of the time between the last dose of denosumab and the first dose of ZA (for change in BMD at the lumbar spine OR=1.0 and P=0.54; at the total hip OR=1.0 and P=0.54; and at the femoral neck OR=1.0 and P=0.3)
Five individuals received a second dose of ZA and had another DXA scan ~1 year later. We examined the changes in BMD between the DXA that followed the first ZA dose and the one following the second dose. Fig. 1 shows these changes for the individual patients with available data (N=5). The graphs suggest general stabilization of BMD at the lumbar spine, total hip, and femoral neck a year after the second annual consolidation dose of ZA. Due to the small number of patients in this subgroup, no statistical analyses on the trends were performed.
DISCUSSION
This case series suggests that patients who receive 1 dose of ZA after treatment with denosumab lose some of the BMD accrued while on denosumab. These results are consistent with previous studies where BMD loss was observed after a single consolidation dose of ZA.[15–17] The studies by Lehmann and Aeberli [16] and Reid et al. [17] measured BMD 2 to 2.5 years after ZA and could not determine the exact timeline of bone loss. However, our observations confirm what the work of Everts-Graber et al. [15] suggests, in that much of the observed bone loss happens during the first 12 months that follow the ZA infusion. In addition, our observations suggest that the bone loss might slow down when another yearly dose of ZA is given, but caution should be applied in interpreting these findings given the small sample size.
Our findings also suggest that the bone loss at the total hip and spine is much larger in patients who remained osteoporotic while on denosumab. This finding might present an argument in favor of ensuring patients’ BMD is in the osteopenia range on denosumab before switching them to ZA. It is worth making a note here of a recent study by Anastasilakis that randomized 57 women previously treated with denosumab for osteoporosis to another 2 doses of denosumab versus a single dose of ZA. Twelve months after randomization, an equal but non-significant increase in the lumbar spine and femoral neck BMD was seen in both groups, despite higher levels of bone turnover markers (BTMs) in the group randomized to ZA.[18] While these results contradict the decline in BMD with the transition from denosumab to ZA observed by other studies, it should be noted that all patients had osteopenia at the time of transition, which might again argue in favor of attaining osteopenia with denosumab before initiation of consolidation therapy.
One possible explanation for the observed bone loss when switching from denosumab to ZA lies in the fact that bisphosphonates need “open bone surfaces” to adhere to in order to exert their antiresorptive action.[3] Since bone turnover is still profoundly suppressed 6 months after a dose of denosumab, it is likely that ZA adherence to bone surfaces is reduced when given at that time. Thus, a single dose of ZA given after completion of denosumab treatment may be partially “wasted” and not fully taken up to the bone surfaces. One would then expect a more frequently dosed bisphosphonate to have more opportunities for adherence as the bone turnover is gradually restored after denosumab, thus allowing more antiresorptive action. This was indeed shown by Freemantle et al. in the DAPS study where 1 year of alendronate following 1 year of denosumab prevented post-denosumab bone loss.[19]
Alternatively, it may be attractive to delay ZA by more than 6 months after the last dose of denosumab to allow for some recovery of bone turnover and for the drug to adhere better to bone surfaces. Horne et al. [20] tested this hypothesis in a group of postmenopausal women treated with 1 year of romosozumab followed by 2 years of denosumab. Following denosumab, the subjects received a single dose of ZA, but the administration of ZA was delayed by an average of 65 days (i.e., it was administered about 8 months rather than 6 months after the last dose of denosumab). The bone loss 1 year after ZA was milder with this regimen.[20] While this may suggest that a delay in the timing of ZA after denosumab could enhance the antiresorptive efficacy of the drug, this approach might be associated with an increased risk of vertebral fractures, as such fractures have been observed as early as 2 months after discontinuation of denosumab.[11] Additionally, this study added the new variable of romosozumab treatment prior to denosumab, and it is not clear to what degree a change in bone quality from romosozumab may have contributed to the milder bone loss observed after ZA.
It is important to acknowledge potential limitations of this work. First, our sample size was small and this may explain the lack of statistical significance in some of our analyses. Notably however, while our analyses of BMD changes at the lumbar spine and hip did not reach statistical significance, the trends were comparable to previous studies that did achieve statistical significance.[15,16] Measurement of BTMs is also missing from our study, somewhat limiting our interpretation of the results. Finally, while our study focuses on the changes in BMD over time, it is important to acknowledge that fractures are the clinically-relevant outcome of low BMD. Although all clinical fractures were documented in our patients’ records, routine x-rays to assess for subclinical fractures were not obtained. Nonetheless, there was no evidence of an increased risk of clinical vertebral fractures in our patients despite the observed decline in BMD.
In conclusion, a single dose of ZA given approximately 6 months after long-term denosumab therapy leads to a loss of a portion of the BMD gained with denosumab, and much of this loss seems to occur within 1 year of ZA, particularly in patients who are osteoporotic at the time of transition. Furthermore, limited data suggest that the loss in BMD may plateau after a second dose of ZA. However, larger and longer-term studies with careful evaluation of fracture risk are needed to provide a definitive answer on the safety and best approach to post-denosumab consolidation therapy with ZA.
Fig. 1 Bone mineral density (BMD) and T-score measurements in 5 patients who received 2 doses of zoledronic acid. Each line represents an individual patient. DXA, dual energy X-ray absorptiometry; Pre-Dmab, DXA scans prior to initiation of denosumab; Post-Dmab, DXA scans after completion of treatment with denosumab; Post-ZA1, DXA scans after the first dose of zoledronic acid; Post-ZA2, DXA scans after the second dose of zoledronic acid.
Table 1 Patient characteristics
Characteristics Value (N=12)
Age (yr), median (IQR) 76.8 (8.8)
Sex (female) 12 (100.0)
Race (white) 12 (100.0)
BMI (kg/m2), median (IQR) 21.9 (4.5)
25(OH)D (ng/mL), median (IQR) 37.5 (13.0)
Calcium (mg/dL), median (IQR) 9.8 (0.7)
PTH (pg/mL), median (IQR)a) 40.1 (3.9)
Creatinine (mg/dL), median (IQR) 0.7 (0.2)
Smoking
Current smoker 1 (8.3)
Previous smoker 4 (33.3)
Alcoholic drinks per week, median (IQR) 1 (1.5)
Trauma
Presence of low-trauma fracture before Dmab 2 (16.7)
Presence of low-trauma vertebral fracture before Dmab 1 (8.3)
BMD (gm/cm2), median (IQR)b)
Lumbar spine 0.82 (0.03)
Total hip 0.69 (0.05)
Femoral neck 0.59 (0.02)
Treatment received
Received bisphosphonate before Dmab 7 (58.3)
Bisphosphonate washout before Dmab (yr), median (IQR)c) 4 (2.5)
No. of Dmab doses, median (IQR) 5.3 (1.2)
No. of ZA doses, median (IQR) 2 (0.3)
Patients with osteoporosis at time of transition to ZA 6 (50.0)
Lag time between last dose of Dmab and first dose of ZA (days), median (IQR) 201.5 (31.3)
The data is presented as median (IQR) or number (%).
a) PTH available in 5 patients.
b) Baseline BMD in 9.
c) Bisphosphonate washout applies to 7 patients who received bisphosphonate before Dmab.
IQR, interquartile range; BMI, body mass index; 25(OH)D, 25-hydroxy-vitamin D; PTH, parathyroid hormone; BMD, bone mineral density; Dmab, denosumab; ZA, zoledronic aid.
Table 2 Changes in bone density measurements over time
DXA measurement site DXA time
Pre-Dmab (N=9) Post-Dmab (N=12) Post-ZA (N=12)
BMD (g/cm2)
Lumbar spine 0.82 (0.03) 0.90 (0.15)a) 0.87 (0.08)a)
Total hip 0.69 (0.05) 0.75 (0.04) 0.72 (0.08)
Femoral neck 0.59 (0.02) 0.63 (0.06)b) 0.62 (0.05)c)
The data is presented as median (interquartile range).
a) Lumbar spine measurement excluded in 1 patient due to severe degenerative changes.
b) Statistically significant increase from pre-Dmab, P=0.008.
c) Statistically significant decrease from post-Dmab, P=0.040.
DXA, dual energy X-ray absorptiometry; Pre-Dmab, DXA scans prior to initiation of denosumab; Post-Dmab, DXA scans after completion of treatment with denosumab; Post-ZA, DXA scans after the first dose of zoledronic acid; BMD, bone mineral density.
Table 3 Relative changes in BMD upon switching from Dmab to ZA
Site All patients Patients with osteopenia at end of Dmab Patients with osteoporosis at end of Dmab
Median BMD gain on Dmab (g/cm2) Median BMD loss after switching to ZA (g/cm2) Percent of median BMD gain that is lost with ZA Percent of median BMD gain that is lost with ZA Percent of median BMD gain that is lost with ZA
Lumbar spine 0.048 0.011 23% 7% 61%
Total hip 0.034 0.016 47% 43% 220%
Femoral neck 0.048 0.026 54% 49% 37%
BMD, bone mineral density; Dmab, denosumab; ZA, zoledronic aid.
Funding
The authors received no financial support for this article.
Ethics approval and consent to participate
The study was reviewed and approved by the Institutional Review Board for human subjects’ research.
Conflict of interest
No potential conflict of interest relevant to this article was reported. | DENOSUMAB | DrugsGivenReaction | CC BY-NC | 33730783 | 19,075,920 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Wrist fracture'. | Zoledronic Acid after Treatment with Denosumab is Associated with Bone Loss within 1 Year.
BACKGROUND
Bone mineral density (BMD) declines when zoledronic acid (ZA) is administered. This case series describes the patterns of change in BMD when 1 or 2 doses of ZA are administered after denosumab.
METHODS
Twelve patients who received at least 2 doses of denosumab followed by at least 1 dose of ZA and who had a dual energy X-ray absorptiometry (DXA) scan at the end of denosumab and 1 year after the first dose of ZA were included. We excluded patients with bone cancer or conditions affecting bone metabolism, including hyperparathyroidism, rickets, osteogenesis imperfecta, rheumatologic disorders, fibrous dysplasia, Paget's disease of bone, untreated hyperthyroidism, chronic kidney disease, liver cirrhosis, malabsorption, ongoing corticosteroid therapy, and aromatase inhibitor use.
RESULTS
There was a significant decline in BMD at the femoral neck within 1 year of the first ZA dose and a non-significant downward trend in the hip and lumbar spine. This trend was more severe in patients with osteoporosis at the time of drug transition. No increase in clinical vertebral fractures was observed. BMD seemed to stabilize in a smaller number of patients who received a second dose of ZA and had a DXA scan 1 year later.
CONCLUSIONS
A single dose of ZA administered approximately 6 months after denosumab leads to some BMD loss, mostly within 1 year of ZA administration, particularly in patients with osteoporosis at the time of denosumab discontinuation.
INTRODUCTION
Denosumab is a monoclonal antibody that mimics the action of endogenous osteoprotegerin by binding to and preventing the action of the: receptor activator of nuclear factor-κB ligand (RANKL), thereby inhibiting osteoclasts and preventing bone resorption.[1,2] Denosumab is a potent antiresorptive agent, leading to significant increases in bone mineral density (BMD) and fracture prevention.[3] However, acute discontinuation of denosumab leads to a rebound rapid increase in bone turnover with a large bone loss [4–6] and in some cases is associated with an increase in the risk of vertebral compression fractures.[7–13] This phenomenon is believed to be due to a compensatory upregulation of the RANK receptors on osteoclast precursors while in the presence of denosumab.[4] To avoid this rebound increase in bone resorption and the associated bone loss, “consolidation therapy” has been recommended. This approach entails transitioning patients from denosumab to a bisphosphonate prior to complete discontinuation of antiresorptive therapy,[13,14] and zoledronic acid (ZA) became one of the drugs commonly used in this setting. However, the use of ZA after denosumab does not seem to fully prevent the bone loss that follows discontinuation of denosumab. In a recent retrospective study by Everts-Graber et al. [15], patients previously treated with denosumab for 2 to 5 years followed by a single infusion of ZA experienced some loss of BMD on a dual energy X-ray absorptiometry (DXA) scan 12 to 42 months later. However, only patients who had achieved osteopenia while on denosumab were transitioned to ZA in this study, limiting those findings to a select group of patients with a rather robust response to denosumab.
In our clinical practice, we follow a protocol that attempts to limit total antiresorptive therapy (denosumab+consolidation with ZA) to no more than 5 to 6 years. To transition to ZA, patients should have had stable or improved BMD on denosumab for at least 1 year, but we do not aim to achieve osteopenia prior to initiating consolidation therapy. We routinely evaluate patient response on DXA around 12 months after ZA administration. In this case series, we describe changes in BMD and prevalence of clinical fractures 1 year after transitioning from denosumab to ZA in patients with both osteopenia and osteoporosis at the end of denosumab therapy. We also report observations on BMD changes after a second dose of ZA was given a year later to a smaller subgroup of patients.
METHODS
1. Data sources and patients
This is a retrospective case series of patients with osteoporosis treated with denosumab followed by ZA in the Endocrinology Clinic at an academic medical center. We used the electronic medical records (EMR; Epic 2018 version UI 2; Epic Systems Corp., Verona, WI, USA) to identify patients treated with denosumab followed by ZA between January 1, 2012 (the year denosumab was approved for clinical use in the USA) and June 30, 2020. Eligible patients met the following inclusion criteria: (1) received at least 2 doses of denosumab; (2) followed by at least 1 dose of ZA; (3) underwent DXA at the end of their treatment course with denosumab and approximately 1 year after the first dose of ZA. Patients were excluded if they had bone cancer or other conditions affecting bone metabolism including hyperparathyroidism, rickets, osteogenesis imperfecta, rheumatologic disorders, fibrous dysplasia of the bone, Paget’s disease of the bone, untreated hyperthyroidism, chronic kidney disease, liver cirrhosis, malabsorptive conditions (such as inflammatory bowel disease or celiac disease), and ongoing glucocorticoid or aromatase inhibitor use.
The EMR contains complete demographic, clinical, laboratory, and medication data for all patients seen at our medical center.
2. Data elements
Key data elements included patient demographics, height, weight, body mass index (BMI), medical comorbidities, smoking status, alcohol consumption history, DXA measurements and date of each measurement, number of denosumab doses and date of each dose, and number of post-denosumab ZA doses and date of each dose. All doses of denosumab and ZA were administered at our center and dates of administration were extracted from the patients’ EMR.
We also recorded basic laboratory results at the initiation of denosumab, including serum concentrations of calcium, creatinine, parathyroid hormone (PTH), and 25-hydroxy-vitamin D (25[OH]D). Only laboratory values obtained at the core laboratory at our medical center were recorded and used in this analysis to eliminate the bias that could be introduced by the variability between different assays. Calcium and creatinine were determined using Roche Modular P analyzers (Hoffmann-La Roche, Basel, Switzerland). Serum calcium was determined by colorimetric assay (lower detection limit, 0.2 mg/dL; intra-assay coefficient of variation [CV], 0.9%; inter-assay CV, 1.6%; Roche Diagnostics, Mannheim, Germany) and serum creatinine was determined by enzymatic colorimetric assay (lower detection limit, 0.03 mg/dL; intra-assay CV, 0.9%; inter-assay CV, 1.1%; Roche Diagnostics). The 25(OH)D was determined by ARUP Laboratories using the DiaSorin Liaison CIA technology that measured both 25(OH)D2 and 25(OH)D3 (lower detection limit, 0.8 ng/mL; intra-assay CV, 6.7%; inter-assay CV, 6.3%). The laboratory participated in regular Vitamin D External Quality Assessment Scheme performance assessments and passed quality assurance minimal standards. PTH was determined using Roche Modular E170 analyzer using an electrochemiluminescence immunoassay (lower detection limit, 1.2 pg/mL; intra-assay CV, 1.9 %; inter-assay CV, 4.5%; Roche Diagnostics). There were no changes to any of the tests used during the duration of time covered by the study. DXA scans were performed using a Hologic Discovery v12.6.2 instrument (Hologic Inc., Bedford, MA, USA; Center-specific hip and spine least significant change [LSC]=0.020 g/cm2). Areal BMD was measured at the total hip, femoral neck, and lumbar spine (L1-4) and expressed in grams/cm2.
All data were extracted from the patients’ EMR by 1 investigator (TK) and cross-checked by another investigator (ASR).
3. Statistical analyses
Statistical analyses were conducted using SAS for Windows, version 9.3 (SAS Institute Inc., Cary, NC, USA) and statistical significance was defined as a P-value less than 0.05 without correction for multiple testing. Due to the small sample size, data are presented as median (interquartile range) or percentage.
We began by examining patient characteristics and baseline DXA and laboratory results. We also calculated the number of doses of denosumab that each patient received and the duration of time between the last dose of denosumab and the first dose of ZA.
We then examined the change in BMD from baseline (before initiation of denosumab) to the end of the denosumab treatment course and between the end of the denosumab treatment course and the first DXA scan following ZA. We used nonparametric methods (Wilcoxon signed-rank test) to compare these data points. Finally, we used univariable logistic regression to examine the association between changes in BMD and total number of denosumab doses received and between changes in BMD and the duration of time between the last dose of denosumab and the first dose of ZA. Multivariable analyses were not performed due to the small sample size. The institutional review board approved this study.
RESULTS
1. Baseline evaluation
We identified 12 patients who met the study inclusion and exclusion criteria. A description of our study cohort is presented in Table 1. Three of the patients had their initial DXA scan prior to initiation of denosumab performed outside our medical center, and those measurements were excluded from the analysis. All other DXA scans were performed in our laboratory. At the time of transitioning to consolidation therapy, 6 of the patients still had osteoporosis (defined by a T-score ≤-2.5 at the lumbar spine, hip or femoral neck), and 6 had osteopenia. The reasons for transition to ZA in patients who still had osteoporosis was plateauing of BMD after 5 to 6 doses of denosumab in 4 patients, and patient request due to frequent traveling in 2 patients. The average t-scores in all 12 patients at the lumbar spine, total hip, and femoral neck were −1.23, −1.66, and −1.93, respectively.
2. Treatment and follow-up
Patients received a median of 5.3 doses of denosumab 6 months apart (range, 3–7 doses). All patients subsequently received at least one dose of ZA (median, 2; range, 1–3 doses). The median duration of time between the last dose of denosumab and the first dose of ZA was 201.5 days (~ 6.7 months).
All patients underwent a DXA measurement in our lab at the end of their denosumab treatment course and another DXA after the first dose of ZA. The median duration of time between the first dose of ZA and the corresponding follow-up DXA scan was 12.0 (1.0) months.
Five patients received a second yearly dose of ZA and had another DXA measurement following the second dose. In these patients, the median duration of time between the first and second doses of ZA was 12.7 (0.4) months. The median duration of time between the second dose of ZA and the corresponding DXA was 12.3 (0.3) months.
None of the patients suffered a clinical fracture while on denosumab. After transition to ZA, 1 patient sustained a distal radial fracture upon a fall. The fracture happened when she lost her balance while trying to sit on a stool and fell down on her extended wrist. She had received 3 doses of denosumab and 1 dose of ZA, the latter being about 6 months prior to the fracture. Her DXA scan about 6 months after the fracture showed a T score of −1.9 at the lumbar spine, −1.0 at the total hip, and −1.6 at the femoral neck. While spine X-rays were not routinely obtained on all patients, 3 patients underwent spine imaging after switching from denosumab to ZA (2 patients underwent thoracic and lumbar spine imaging, and 1 patient underwent lumbar spine imaging only), and no vertebral fractures were identified.
3. Changes in BMD over time
Table 2 shows the mean BMD for all patients with available DXA scans prior to initiation of denosumab (pre-Dmab, N=9), after completion of treatment with denosumab (post-Dmab, N=12) and after the first dose of ZA (post-ZA, N=12). As mentioned previously, the analyses excluded 3 pre-denosumab DXA scans that were performed outside our medical center.
When comparing the changes in measurements between the pre-Dmab and that obtained at the time of completion of denosumab, a statistically significant increase in BMD (P=0.008) was seen at the femoral neck. A non-significant increase was noted at the lumbar spine and total hip.
When comparing the DXA scan obtained at the end of denosumab treatment and that obtained after the first dose of ZA, we noted a significant decline in BMD (P=0.04) at the femoral neck. A non-significant downward trend was seen at the lumbar spine and total hip. The BMD at all 3 sites however remained higher than the BMD measured prior to initiation of denosumab. Patients who experienced a decline in BMD with ZA underwent a limited evaluation for secondary causes of bone loss (including abnormal renal function, vitamin D deficiency, hyperthyroidism, and hyperparathyroidism), and none was found.
On average, within approximately 1 year of switching from denosumab to ZA, patients lost 23% of the BMD gain they had accrued at the lumbar spine while on denosumab, 47% of the BMD gain accrued at the total hip and 54% of the BMD gain accrued at the femoral neck (Table 3). Of the patients who had osteopenia at the end of denosumab, 4 (67%) experienced some loss in BMD in at least one site. Of the patients with osteoporosis at the end of denosumab 5 (83%) experienced some loss of BMD in at least one site. Table 3 shows the proportion of BMD gain lost upon switching to ZA in each of these subgroups.
In a univariable logistic regression, the decline in BMD between the DXA scan obtained at the end of denosumab and the one obtained after the first dose of ZA was independent of the number of denosumab doses (for change in BMD at the lumbar spine OR=0.48 and P=0.22; at the total hip OR=0.70 and P=0.55; and at the femoral neck OR=0.70 and P=0.55) It was also independent of the time between the last dose of denosumab and the first dose of ZA (for change in BMD at the lumbar spine OR=1.0 and P=0.54; at the total hip OR=1.0 and P=0.54; and at the femoral neck OR=1.0 and P=0.3)
Five individuals received a second dose of ZA and had another DXA scan ~1 year later. We examined the changes in BMD between the DXA that followed the first ZA dose and the one following the second dose. Fig. 1 shows these changes for the individual patients with available data (N=5). The graphs suggest general stabilization of BMD at the lumbar spine, total hip, and femoral neck a year after the second annual consolidation dose of ZA. Due to the small number of patients in this subgroup, no statistical analyses on the trends were performed.
DISCUSSION
This case series suggests that patients who receive 1 dose of ZA after treatment with denosumab lose some of the BMD accrued while on denosumab. These results are consistent with previous studies where BMD loss was observed after a single consolidation dose of ZA.[15–17] The studies by Lehmann and Aeberli [16] and Reid et al. [17] measured BMD 2 to 2.5 years after ZA and could not determine the exact timeline of bone loss. However, our observations confirm what the work of Everts-Graber et al. [15] suggests, in that much of the observed bone loss happens during the first 12 months that follow the ZA infusion. In addition, our observations suggest that the bone loss might slow down when another yearly dose of ZA is given, but caution should be applied in interpreting these findings given the small sample size.
Our findings also suggest that the bone loss at the total hip and spine is much larger in patients who remained osteoporotic while on denosumab. This finding might present an argument in favor of ensuring patients’ BMD is in the osteopenia range on denosumab before switching them to ZA. It is worth making a note here of a recent study by Anastasilakis that randomized 57 women previously treated with denosumab for osteoporosis to another 2 doses of denosumab versus a single dose of ZA. Twelve months after randomization, an equal but non-significant increase in the lumbar spine and femoral neck BMD was seen in both groups, despite higher levels of bone turnover markers (BTMs) in the group randomized to ZA.[18] While these results contradict the decline in BMD with the transition from denosumab to ZA observed by other studies, it should be noted that all patients had osteopenia at the time of transition, which might again argue in favor of attaining osteopenia with denosumab before initiation of consolidation therapy.
One possible explanation for the observed bone loss when switching from denosumab to ZA lies in the fact that bisphosphonates need “open bone surfaces” to adhere to in order to exert their antiresorptive action.[3] Since bone turnover is still profoundly suppressed 6 months after a dose of denosumab, it is likely that ZA adherence to bone surfaces is reduced when given at that time. Thus, a single dose of ZA given after completion of denosumab treatment may be partially “wasted” and not fully taken up to the bone surfaces. One would then expect a more frequently dosed bisphosphonate to have more opportunities for adherence as the bone turnover is gradually restored after denosumab, thus allowing more antiresorptive action. This was indeed shown by Freemantle et al. in the DAPS study where 1 year of alendronate following 1 year of denosumab prevented post-denosumab bone loss.[19]
Alternatively, it may be attractive to delay ZA by more than 6 months after the last dose of denosumab to allow for some recovery of bone turnover and for the drug to adhere better to bone surfaces. Horne et al. [20] tested this hypothesis in a group of postmenopausal women treated with 1 year of romosozumab followed by 2 years of denosumab. Following denosumab, the subjects received a single dose of ZA, but the administration of ZA was delayed by an average of 65 days (i.e., it was administered about 8 months rather than 6 months after the last dose of denosumab). The bone loss 1 year after ZA was milder with this regimen.[20] While this may suggest that a delay in the timing of ZA after denosumab could enhance the antiresorptive efficacy of the drug, this approach might be associated with an increased risk of vertebral fractures, as such fractures have been observed as early as 2 months after discontinuation of denosumab.[11] Additionally, this study added the new variable of romosozumab treatment prior to denosumab, and it is not clear to what degree a change in bone quality from romosozumab may have contributed to the milder bone loss observed after ZA.
It is important to acknowledge potential limitations of this work. First, our sample size was small and this may explain the lack of statistical significance in some of our analyses. Notably however, while our analyses of BMD changes at the lumbar spine and hip did not reach statistical significance, the trends were comparable to previous studies that did achieve statistical significance.[15,16] Measurement of BTMs is also missing from our study, somewhat limiting our interpretation of the results. Finally, while our study focuses on the changes in BMD over time, it is important to acknowledge that fractures are the clinically-relevant outcome of low BMD. Although all clinical fractures were documented in our patients’ records, routine x-rays to assess for subclinical fractures were not obtained. Nonetheless, there was no evidence of an increased risk of clinical vertebral fractures in our patients despite the observed decline in BMD.
In conclusion, a single dose of ZA given approximately 6 months after long-term denosumab therapy leads to a loss of a portion of the BMD gained with denosumab, and much of this loss seems to occur within 1 year of ZA, particularly in patients who are osteoporotic at the time of transition. Furthermore, limited data suggest that the loss in BMD may plateau after a second dose of ZA. However, larger and longer-term studies with careful evaluation of fracture risk are needed to provide a definitive answer on the safety and best approach to post-denosumab consolidation therapy with ZA.
Fig. 1 Bone mineral density (BMD) and T-score measurements in 5 patients who received 2 doses of zoledronic acid. Each line represents an individual patient. DXA, dual energy X-ray absorptiometry; Pre-Dmab, DXA scans prior to initiation of denosumab; Post-Dmab, DXA scans after completion of treatment with denosumab; Post-ZA1, DXA scans after the first dose of zoledronic acid; Post-ZA2, DXA scans after the second dose of zoledronic acid.
Table 1 Patient characteristics
Characteristics Value (N=12)
Age (yr), median (IQR) 76.8 (8.8)
Sex (female) 12 (100.0)
Race (white) 12 (100.0)
BMI (kg/m2), median (IQR) 21.9 (4.5)
25(OH)D (ng/mL), median (IQR) 37.5 (13.0)
Calcium (mg/dL), median (IQR) 9.8 (0.7)
PTH (pg/mL), median (IQR)a) 40.1 (3.9)
Creatinine (mg/dL), median (IQR) 0.7 (0.2)
Smoking
Current smoker 1 (8.3)
Previous smoker 4 (33.3)
Alcoholic drinks per week, median (IQR) 1 (1.5)
Trauma
Presence of low-trauma fracture before Dmab 2 (16.7)
Presence of low-trauma vertebral fracture before Dmab 1 (8.3)
BMD (gm/cm2), median (IQR)b)
Lumbar spine 0.82 (0.03)
Total hip 0.69 (0.05)
Femoral neck 0.59 (0.02)
Treatment received
Received bisphosphonate before Dmab 7 (58.3)
Bisphosphonate washout before Dmab (yr), median (IQR)c) 4 (2.5)
No. of Dmab doses, median (IQR) 5.3 (1.2)
No. of ZA doses, median (IQR) 2 (0.3)
Patients with osteoporosis at time of transition to ZA 6 (50.0)
Lag time between last dose of Dmab and first dose of ZA (days), median (IQR) 201.5 (31.3)
The data is presented as median (IQR) or number (%).
a) PTH available in 5 patients.
b) Baseline BMD in 9.
c) Bisphosphonate washout applies to 7 patients who received bisphosphonate before Dmab.
IQR, interquartile range; BMI, body mass index; 25(OH)D, 25-hydroxy-vitamin D; PTH, parathyroid hormone; BMD, bone mineral density; Dmab, denosumab; ZA, zoledronic aid.
Table 2 Changes in bone density measurements over time
DXA measurement site DXA time
Pre-Dmab (N=9) Post-Dmab (N=12) Post-ZA (N=12)
BMD (g/cm2)
Lumbar spine 0.82 (0.03) 0.90 (0.15)a) 0.87 (0.08)a)
Total hip 0.69 (0.05) 0.75 (0.04) 0.72 (0.08)
Femoral neck 0.59 (0.02) 0.63 (0.06)b) 0.62 (0.05)c)
The data is presented as median (interquartile range).
a) Lumbar spine measurement excluded in 1 patient due to severe degenerative changes.
b) Statistically significant increase from pre-Dmab, P=0.008.
c) Statistically significant decrease from post-Dmab, P=0.040.
DXA, dual energy X-ray absorptiometry; Pre-Dmab, DXA scans prior to initiation of denosumab; Post-Dmab, DXA scans after completion of treatment with denosumab; Post-ZA, DXA scans after the first dose of zoledronic acid; BMD, bone mineral density.
Table 3 Relative changes in BMD upon switching from Dmab to ZA
Site All patients Patients with osteopenia at end of Dmab Patients with osteoporosis at end of Dmab
Median BMD gain on Dmab (g/cm2) Median BMD loss after switching to ZA (g/cm2) Percent of median BMD gain that is lost with ZA Percent of median BMD gain that is lost with ZA Percent of median BMD gain that is lost with ZA
Lumbar spine 0.048 0.011 23% 7% 61%
Total hip 0.034 0.016 47% 43% 220%
Femoral neck 0.048 0.026 54% 49% 37%
BMD, bone mineral density; Dmab, denosumab; ZA, zoledronic aid.
Funding
The authors received no financial support for this article.
Ethics approval and consent to participate
The study was reviewed and approved by the Institutional Review Board for human subjects’ research.
Conflict of interest
No potential conflict of interest relevant to this article was reported. | DENOSUMAB, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC | 33730783 | 19,281,652 | 2021-02 |
What was the dosage of drug 'DENOSUMAB'? | Zoledronic Acid after Treatment with Denosumab is Associated with Bone Loss within 1 Year.
BACKGROUND
Bone mineral density (BMD) declines when zoledronic acid (ZA) is administered. This case series describes the patterns of change in BMD when 1 or 2 doses of ZA are administered after denosumab.
METHODS
Twelve patients who received at least 2 doses of denosumab followed by at least 1 dose of ZA and who had a dual energy X-ray absorptiometry (DXA) scan at the end of denosumab and 1 year after the first dose of ZA were included. We excluded patients with bone cancer or conditions affecting bone metabolism, including hyperparathyroidism, rickets, osteogenesis imperfecta, rheumatologic disorders, fibrous dysplasia, Paget's disease of bone, untreated hyperthyroidism, chronic kidney disease, liver cirrhosis, malabsorption, ongoing corticosteroid therapy, and aromatase inhibitor use.
RESULTS
There was a significant decline in BMD at the femoral neck within 1 year of the first ZA dose and a non-significant downward trend in the hip and lumbar spine. This trend was more severe in patients with osteoporosis at the time of drug transition. No increase in clinical vertebral fractures was observed. BMD seemed to stabilize in a smaller number of patients who received a second dose of ZA and had a DXA scan 1 year later.
CONCLUSIONS
A single dose of ZA administered approximately 6 months after denosumab leads to some BMD loss, mostly within 1 year of ZA administration, particularly in patients with osteoporosis at the time of denosumab discontinuation.
INTRODUCTION
Denosumab is a monoclonal antibody that mimics the action of endogenous osteoprotegerin by binding to and preventing the action of the: receptor activator of nuclear factor-κB ligand (RANKL), thereby inhibiting osteoclasts and preventing bone resorption.[1,2] Denosumab is a potent antiresorptive agent, leading to significant increases in bone mineral density (BMD) and fracture prevention.[3] However, acute discontinuation of denosumab leads to a rebound rapid increase in bone turnover with a large bone loss [4–6] and in some cases is associated with an increase in the risk of vertebral compression fractures.[7–13] This phenomenon is believed to be due to a compensatory upregulation of the RANK receptors on osteoclast precursors while in the presence of denosumab.[4] To avoid this rebound increase in bone resorption and the associated bone loss, “consolidation therapy” has been recommended. This approach entails transitioning patients from denosumab to a bisphosphonate prior to complete discontinuation of antiresorptive therapy,[13,14] and zoledronic acid (ZA) became one of the drugs commonly used in this setting. However, the use of ZA after denosumab does not seem to fully prevent the bone loss that follows discontinuation of denosumab. In a recent retrospective study by Everts-Graber et al. [15], patients previously treated with denosumab for 2 to 5 years followed by a single infusion of ZA experienced some loss of BMD on a dual energy X-ray absorptiometry (DXA) scan 12 to 42 months later. However, only patients who had achieved osteopenia while on denosumab were transitioned to ZA in this study, limiting those findings to a select group of patients with a rather robust response to denosumab.
In our clinical practice, we follow a protocol that attempts to limit total antiresorptive therapy (denosumab+consolidation with ZA) to no more than 5 to 6 years. To transition to ZA, patients should have had stable or improved BMD on denosumab for at least 1 year, but we do not aim to achieve osteopenia prior to initiating consolidation therapy. We routinely evaluate patient response on DXA around 12 months after ZA administration. In this case series, we describe changes in BMD and prevalence of clinical fractures 1 year after transitioning from denosumab to ZA in patients with both osteopenia and osteoporosis at the end of denosumab therapy. We also report observations on BMD changes after a second dose of ZA was given a year later to a smaller subgroup of patients.
METHODS
1. Data sources and patients
This is a retrospective case series of patients with osteoporosis treated with denosumab followed by ZA in the Endocrinology Clinic at an academic medical center. We used the electronic medical records (EMR; Epic 2018 version UI 2; Epic Systems Corp., Verona, WI, USA) to identify patients treated with denosumab followed by ZA between January 1, 2012 (the year denosumab was approved for clinical use in the USA) and June 30, 2020. Eligible patients met the following inclusion criteria: (1) received at least 2 doses of denosumab; (2) followed by at least 1 dose of ZA; (3) underwent DXA at the end of their treatment course with denosumab and approximately 1 year after the first dose of ZA. Patients were excluded if they had bone cancer or other conditions affecting bone metabolism including hyperparathyroidism, rickets, osteogenesis imperfecta, rheumatologic disorders, fibrous dysplasia of the bone, Paget’s disease of the bone, untreated hyperthyroidism, chronic kidney disease, liver cirrhosis, malabsorptive conditions (such as inflammatory bowel disease or celiac disease), and ongoing glucocorticoid or aromatase inhibitor use.
The EMR contains complete demographic, clinical, laboratory, and medication data for all patients seen at our medical center.
2. Data elements
Key data elements included patient demographics, height, weight, body mass index (BMI), medical comorbidities, smoking status, alcohol consumption history, DXA measurements and date of each measurement, number of denosumab doses and date of each dose, and number of post-denosumab ZA doses and date of each dose. All doses of denosumab and ZA were administered at our center and dates of administration were extracted from the patients’ EMR.
We also recorded basic laboratory results at the initiation of denosumab, including serum concentrations of calcium, creatinine, parathyroid hormone (PTH), and 25-hydroxy-vitamin D (25[OH]D). Only laboratory values obtained at the core laboratory at our medical center were recorded and used in this analysis to eliminate the bias that could be introduced by the variability between different assays. Calcium and creatinine were determined using Roche Modular P analyzers (Hoffmann-La Roche, Basel, Switzerland). Serum calcium was determined by colorimetric assay (lower detection limit, 0.2 mg/dL; intra-assay coefficient of variation [CV], 0.9%; inter-assay CV, 1.6%; Roche Diagnostics, Mannheim, Germany) and serum creatinine was determined by enzymatic colorimetric assay (lower detection limit, 0.03 mg/dL; intra-assay CV, 0.9%; inter-assay CV, 1.1%; Roche Diagnostics). The 25(OH)D was determined by ARUP Laboratories using the DiaSorin Liaison CIA technology that measured both 25(OH)D2 and 25(OH)D3 (lower detection limit, 0.8 ng/mL; intra-assay CV, 6.7%; inter-assay CV, 6.3%). The laboratory participated in regular Vitamin D External Quality Assessment Scheme performance assessments and passed quality assurance minimal standards. PTH was determined using Roche Modular E170 analyzer using an electrochemiluminescence immunoassay (lower detection limit, 1.2 pg/mL; intra-assay CV, 1.9 %; inter-assay CV, 4.5%; Roche Diagnostics). There were no changes to any of the tests used during the duration of time covered by the study. DXA scans were performed using a Hologic Discovery v12.6.2 instrument (Hologic Inc., Bedford, MA, USA; Center-specific hip and spine least significant change [LSC]=0.020 g/cm2). Areal BMD was measured at the total hip, femoral neck, and lumbar spine (L1-4) and expressed in grams/cm2.
All data were extracted from the patients’ EMR by 1 investigator (TK) and cross-checked by another investigator (ASR).
3. Statistical analyses
Statistical analyses were conducted using SAS for Windows, version 9.3 (SAS Institute Inc., Cary, NC, USA) and statistical significance was defined as a P-value less than 0.05 without correction for multiple testing. Due to the small sample size, data are presented as median (interquartile range) or percentage.
We began by examining patient characteristics and baseline DXA and laboratory results. We also calculated the number of doses of denosumab that each patient received and the duration of time between the last dose of denosumab and the first dose of ZA.
We then examined the change in BMD from baseline (before initiation of denosumab) to the end of the denosumab treatment course and between the end of the denosumab treatment course and the first DXA scan following ZA. We used nonparametric methods (Wilcoxon signed-rank test) to compare these data points. Finally, we used univariable logistic regression to examine the association between changes in BMD and total number of denosumab doses received and between changes in BMD and the duration of time between the last dose of denosumab and the first dose of ZA. Multivariable analyses were not performed due to the small sample size. The institutional review board approved this study.
RESULTS
1. Baseline evaluation
We identified 12 patients who met the study inclusion and exclusion criteria. A description of our study cohort is presented in Table 1. Three of the patients had their initial DXA scan prior to initiation of denosumab performed outside our medical center, and those measurements were excluded from the analysis. All other DXA scans were performed in our laboratory. At the time of transitioning to consolidation therapy, 6 of the patients still had osteoporosis (defined by a T-score ≤-2.5 at the lumbar spine, hip or femoral neck), and 6 had osteopenia. The reasons for transition to ZA in patients who still had osteoporosis was plateauing of BMD after 5 to 6 doses of denosumab in 4 patients, and patient request due to frequent traveling in 2 patients. The average t-scores in all 12 patients at the lumbar spine, total hip, and femoral neck were −1.23, −1.66, and −1.93, respectively.
2. Treatment and follow-up
Patients received a median of 5.3 doses of denosumab 6 months apart (range, 3–7 doses). All patients subsequently received at least one dose of ZA (median, 2; range, 1–3 doses). The median duration of time between the last dose of denosumab and the first dose of ZA was 201.5 days (~ 6.7 months).
All patients underwent a DXA measurement in our lab at the end of their denosumab treatment course and another DXA after the first dose of ZA. The median duration of time between the first dose of ZA and the corresponding follow-up DXA scan was 12.0 (1.0) months.
Five patients received a second yearly dose of ZA and had another DXA measurement following the second dose. In these patients, the median duration of time between the first and second doses of ZA was 12.7 (0.4) months. The median duration of time between the second dose of ZA and the corresponding DXA was 12.3 (0.3) months.
None of the patients suffered a clinical fracture while on denosumab. After transition to ZA, 1 patient sustained a distal radial fracture upon a fall. The fracture happened when she lost her balance while trying to sit on a stool and fell down on her extended wrist. She had received 3 doses of denosumab and 1 dose of ZA, the latter being about 6 months prior to the fracture. Her DXA scan about 6 months after the fracture showed a T score of −1.9 at the lumbar spine, −1.0 at the total hip, and −1.6 at the femoral neck. While spine X-rays were not routinely obtained on all patients, 3 patients underwent spine imaging after switching from denosumab to ZA (2 patients underwent thoracic and lumbar spine imaging, and 1 patient underwent lumbar spine imaging only), and no vertebral fractures were identified.
3. Changes in BMD over time
Table 2 shows the mean BMD for all patients with available DXA scans prior to initiation of denosumab (pre-Dmab, N=9), after completion of treatment with denosumab (post-Dmab, N=12) and after the first dose of ZA (post-ZA, N=12). As mentioned previously, the analyses excluded 3 pre-denosumab DXA scans that were performed outside our medical center.
When comparing the changes in measurements between the pre-Dmab and that obtained at the time of completion of denosumab, a statistically significant increase in BMD (P=0.008) was seen at the femoral neck. A non-significant increase was noted at the lumbar spine and total hip.
When comparing the DXA scan obtained at the end of denosumab treatment and that obtained after the first dose of ZA, we noted a significant decline in BMD (P=0.04) at the femoral neck. A non-significant downward trend was seen at the lumbar spine and total hip. The BMD at all 3 sites however remained higher than the BMD measured prior to initiation of denosumab. Patients who experienced a decline in BMD with ZA underwent a limited evaluation for secondary causes of bone loss (including abnormal renal function, vitamin D deficiency, hyperthyroidism, and hyperparathyroidism), and none was found.
On average, within approximately 1 year of switching from denosumab to ZA, patients lost 23% of the BMD gain they had accrued at the lumbar spine while on denosumab, 47% of the BMD gain accrued at the total hip and 54% of the BMD gain accrued at the femoral neck (Table 3). Of the patients who had osteopenia at the end of denosumab, 4 (67%) experienced some loss in BMD in at least one site. Of the patients with osteoporosis at the end of denosumab 5 (83%) experienced some loss of BMD in at least one site. Table 3 shows the proportion of BMD gain lost upon switching to ZA in each of these subgroups.
In a univariable logistic regression, the decline in BMD between the DXA scan obtained at the end of denosumab and the one obtained after the first dose of ZA was independent of the number of denosumab doses (for change in BMD at the lumbar spine OR=0.48 and P=0.22; at the total hip OR=0.70 and P=0.55; and at the femoral neck OR=0.70 and P=0.55) It was also independent of the time between the last dose of denosumab and the first dose of ZA (for change in BMD at the lumbar spine OR=1.0 and P=0.54; at the total hip OR=1.0 and P=0.54; and at the femoral neck OR=1.0 and P=0.3)
Five individuals received a second dose of ZA and had another DXA scan ~1 year later. We examined the changes in BMD between the DXA that followed the first ZA dose and the one following the second dose. Fig. 1 shows these changes for the individual patients with available data (N=5). The graphs suggest general stabilization of BMD at the lumbar spine, total hip, and femoral neck a year after the second annual consolidation dose of ZA. Due to the small number of patients in this subgroup, no statistical analyses on the trends were performed.
DISCUSSION
This case series suggests that patients who receive 1 dose of ZA after treatment with denosumab lose some of the BMD accrued while on denosumab. These results are consistent with previous studies where BMD loss was observed after a single consolidation dose of ZA.[15–17] The studies by Lehmann and Aeberli [16] and Reid et al. [17] measured BMD 2 to 2.5 years after ZA and could not determine the exact timeline of bone loss. However, our observations confirm what the work of Everts-Graber et al. [15] suggests, in that much of the observed bone loss happens during the first 12 months that follow the ZA infusion. In addition, our observations suggest that the bone loss might slow down when another yearly dose of ZA is given, but caution should be applied in interpreting these findings given the small sample size.
Our findings also suggest that the bone loss at the total hip and spine is much larger in patients who remained osteoporotic while on denosumab. This finding might present an argument in favor of ensuring patients’ BMD is in the osteopenia range on denosumab before switching them to ZA. It is worth making a note here of a recent study by Anastasilakis that randomized 57 women previously treated with denosumab for osteoporosis to another 2 doses of denosumab versus a single dose of ZA. Twelve months after randomization, an equal but non-significant increase in the lumbar spine and femoral neck BMD was seen in both groups, despite higher levels of bone turnover markers (BTMs) in the group randomized to ZA.[18] While these results contradict the decline in BMD with the transition from denosumab to ZA observed by other studies, it should be noted that all patients had osteopenia at the time of transition, which might again argue in favor of attaining osteopenia with denosumab before initiation of consolidation therapy.
One possible explanation for the observed bone loss when switching from denosumab to ZA lies in the fact that bisphosphonates need “open bone surfaces” to adhere to in order to exert their antiresorptive action.[3] Since bone turnover is still profoundly suppressed 6 months after a dose of denosumab, it is likely that ZA adherence to bone surfaces is reduced when given at that time. Thus, a single dose of ZA given after completion of denosumab treatment may be partially “wasted” and not fully taken up to the bone surfaces. One would then expect a more frequently dosed bisphosphonate to have more opportunities for adherence as the bone turnover is gradually restored after denosumab, thus allowing more antiresorptive action. This was indeed shown by Freemantle et al. in the DAPS study where 1 year of alendronate following 1 year of denosumab prevented post-denosumab bone loss.[19]
Alternatively, it may be attractive to delay ZA by more than 6 months after the last dose of denosumab to allow for some recovery of bone turnover and for the drug to adhere better to bone surfaces. Horne et al. [20] tested this hypothesis in a group of postmenopausal women treated with 1 year of romosozumab followed by 2 years of denosumab. Following denosumab, the subjects received a single dose of ZA, but the administration of ZA was delayed by an average of 65 days (i.e., it was administered about 8 months rather than 6 months after the last dose of denosumab). The bone loss 1 year after ZA was milder with this regimen.[20] While this may suggest that a delay in the timing of ZA after denosumab could enhance the antiresorptive efficacy of the drug, this approach might be associated with an increased risk of vertebral fractures, as such fractures have been observed as early as 2 months after discontinuation of denosumab.[11] Additionally, this study added the new variable of romosozumab treatment prior to denosumab, and it is not clear to what degree a change in bone quality from romosozumab may have contributed to the milder bone loss observed after ZA.
It is important to acknowledge potential limitations of this work. First, our sample size was small and this may explain the lack of statistical significance in some of our analyses. Notably however, while our analyses of BMD changes at the lumbar spine and hip did not reach statistical significance, the trends were comparable to previous studies that did achieve statistical significance.[15,16] Measurement of BTMs is also missing from our study, somewhat limiting our interpretation of the results. Finally, while our study focuses on the changes in BMD over time, it is important to acknowledge that fractures are the clinically-relevant outcome of low BMD. Although all clinical fractures were documented in our patients’ records, routine x-rays to assess for subclinical fractures were not obtained. Nonetheless, there was no evidence of an increased risk of clinical vertebral fractures in our patients despite the observed decline in BMD.
In conclusion, a single dose of ZA given approximately 6 months after long-term denosumab therapy leads to a loss of a portion of the BMD gained with denosumab, and much of this loss seems to occur within 1 year of ZA, particularly in patients who are osteoporotic at the time of transition. Furthermore, limited data suggest that the loss in BMD may plateau after a second dose of ZA. However, larger and longer-term studies with careful evaluation of fracture risk are needed to provide a definitive answer on the safety and best approach to post-denosumab consolidation therapy with ZA.
Fig. 1 Bone mineral density (BMD) and T-score measurements in 5 patients who received 2 doses of zoledronic acid. Each line represents an individual patient. DXA, dual energy X-ray absorptiometry; Pre-Dmab, DXA scans prior to initiation of denosumab; Post-Dmab, DXA scans after completion of treatment with denosumab; Post-ZA1, DXA scans after the first dose of zoledronic acid; Post-ZA2, DXA scans after the second dose of zoledronic acid.
Table 1 Patient characteristics
Characteristics Value (N=12)
Age (yr), median (IQR) 76.8 (8.8)
Sex (female) 12 (100.0)
Race (white) 12 (100.0)
BMI (kg/m2), median (IQR) 21.9 (4.5)
25(OH)D (ng/mL), median (IQR) 37.5 (13.0)
Calcium (mg/dL), median (IQR) 9.8 (0.7)
PTH (pg/mL), median (IQR)a) 40.1 (3.9)
Creatinine (mg/dL), median (IQR) 0.7 (0.2)
Smoking
Current smoker 1 (8.3)
Previous smoker 4 (33.3)
Alcoholic drinks per week, median (IQR) 1 (1.5)
Trauma
Presence of low-trauma fracture before Dmab 2 (16.7)
Presence of low-trauma vertebral fracture before Dmab 1 (8.3)
BMD (gm/cm2), median (IQR)b)
Lumbar spine 0.82 (0.03)
Total hip 0.69 (0.05)
Femoral neck 0.59 (0.02)
Treatment received
Received bisphosphonate before Dmab 7 (58.3)
Bisphosphonate washout before Dmab (yr), median (IQR)c) 4 (2.5)
No. of Dmab doses, median (IQR) 5.3 (1.2)
No. of ZA doses, median (IQR) 2 (0.3)
Patients with osteoporosis at time of transition to ZA 6 (50.0)
Lag time between last dose of Dmab and first dose of ZA (days), median (IQR) 201.5 (31.3)
The data is presented as median (IQR) or number (%).
a) PTH available in 5 patients.
b) Baseline BMD in 9.
c) Bisphosphonate washout applies to 7 patients who received bisphosphonate before Dmab.
IQR, interquartile range; BMI, body mass index; 25(OH)D, 25-hydroxy-vitamin D; PTH, parathyroid hormone; BMD, bone mineral density; Dmab, denosumab; ZA, zoledronic aid.
Table 2 Changes in bone density measurements over time
DXA measurement site DXA time
Pre-Dmab (N=9) Post-Dmab (N=12) Post-ZA (N=12)
BMD (g/cm2)
Lumbar spine 0.82 (0.03) 0.90 (0.15)a) 0.87 (0.08)a)
Total hip 0.69 (0.05) 0.75 (0.04) 0.72 (0.08)
Femoral neck 0.59 (0.02) 0.63 (0.06)b) 0.62 (0.05)c)
The data is presented as median (interquartile range).
a) Lumbar spine measurement excluded in 1 patient due to severe degenerative changes.
b) Statistically significant increase from pre-Dmab, P=0.008.
c) Statistically significant decrease from post-Dmab, P=0.040.
DXA, dual energy X-ray absorptiometry; Pre-Dmab, DXA scans prior to initiation of denosumab; Post-Dmab, DXA scans after completion of treatment with denosumab; Post-ZA, DXA scans after the first dose of zoledronic acid; BMD, bone mineral density.
Table 3 Relative changes in BMD upon switching from Dmab to ZA
Site All patients Patients with osteopenia at end of Dmab Patients with osteoporosis at end of Dmab
Median BMD gain on Dmab (g/cm2) Median BMD loss after switching to ZA (g/cm2) Percent of median BMD gain that is lost with ZA Percent of median BMD gain that is lost with ZA Percent of median BMD gain that is lost with ZA
Lumbar spine 0.048 0.011 23% 7% 61%
Total hip 0.034 0.016 47% 43% 220%
Femoral neck 0.048 0.026 54% 49% 37%
BMD, bone mineral density; Dmab, denosumab; ZA, zoledronic aid.
Funding
The authors received no financial support for this article.
Ethics approval and consent to participate
The study was reviewed and approved by the Institutional Review Board for human subjects’ research.
Conflict of interest
No potential conflict of interest relevant to this article was reported. | UNKNOWN | DrugDosageText | CC BY-NC | 33730783 | 19,281,652 | 2021-02 |
What was the dosage of drug 'ZOLEDRONIC ACID'? | Zoledronic Acid after Treatment with Denosumab is Associated with Bone Loss within 1 Year.
BACKGROUND
Bone mineral density (BMD) declines when zoledronic acid (ZA) is administered. This case series describes the patterns of change in BMD when 1 or 2 doses of ZA are administered after denosumab.
METHODS
Twelve patients who received at least 2 doses of denosumab followed by at least 1 dose of ZA and who had a dual energy X-ray absorptiometry (DXA) scan at the end of denosumab and 1 year after the first dose of ZA were included. We excluded patients with bone cancer or conditions affecting bone metabolism, including hyperparathyroidism, rickets, osteogenesis imperfecta, rheumatologic disorders, fibrous dysplasia, Paget's disease of bone, untreated hyperthyroidism, chronic kidney disease, liver cirrhosis, malabsorption, ongoing corticosteroid therapy, and aromatase inhibitor use.
RESULTS
There was a significant decline in BMD at the femoral neck within 1 year of the first ZA dose and a non-significant downward trend in the hip and lumbar spine. This trend was more severe in patients with osteoporosis at the time of drug transition. No increase in clinical vertebral fractures was observed. BMD seemed to stabilize in a smaller number of patients who received a second dose of ZA and had a DXA scan 1 year later.
CONCLUSIONS
A single dose of ZA administered approximately 6 months after denosumab leads to some BMD loss, mostly within 1 year of ZA administration, particularly in patients with osteoporosis at the time of denosumab discontinuation.
INTRODUCTION
Denosumab is a monoclonal antibody that mimics the action of endogenous osteoprotegerin by binding to and preventing the action of the: receptor activator of nuclear factor-κB ligand (RANKL), thereby inhibiting osteoclasts and preventing bone resorption.[1,2] Denosumab is a potent antiresorptive agent, leading to significant increases in bone mineral density (BMD) and fracture prevention.[3] However, acute discontinuation of denosumab leads to a rebound rapid increase in bone turnover with a large bone loss [4–6] and in some cases is associated with an increase in the risk of vertebral compression fractures.[7–13] This phenomenon is believed to be due to a compensatory upregulation of the RANK receptors on osteoclast precursors while in the presence of denosumab.[4] To avoid this rebound increase in bone resorption and the associated bone loss, “consolidation therapy” has been recommended. This approach entails transitioning patients from denosumab to a bisphosphonate prior to complete discontinuation of antiresorptive therapy,[13,14] and zoledronic acid (ZA) became one of the drugs commonly used in this setting. However, the use of ZA after denosumab does not seem to fully prevent the bone loss that follows discontinuation of denosumab. In a recent retrospective study by Everts-Graber et al. [15], patients previously treated with denosumab for 2 to 5 years followed by a single infusion of ZA experienced some loss of BMD on a dual energy X-ray absorptiometry (DXA) scan 12 to 42 months later. However, only patients who had achieved osteopenia while on denosumab were transitioned to ZA in this study, limiting those findings to a select group of patients with a rather robust response to denosumab.
In our clinical practice, we follow a protocol that attempts to limit total antiresorptive therapy (denosumab+consolidation with ZA) to no more than 5 to 6 years. To transition to ZA, patients should have had stable or improved BMD on denosumab for at least 1 year, but we do not aim to achieve osteopenia prior to initiating consolidation therapy. We routinely evaluate patient response on DXA around 12 months after ZA administration. In this case series, we describe changes in BMD and prevalence of clinical fractures 1 year after transitioning from denosumab to ZA in patients with both osteopenia and osteoporosis at the end of denosumab therapy. We also report observations on BMD changes after a second dose of ZA was given a year later to a smaller subgroup of patients.
METHODS
1. Data sources and patients
This is a retrospective case series of patients with osteoporosis treated with denosumab followed by ZA in the Endocrinology Clinic at an academic medical center. We used the electronic medical records (EMR; Epic 2018 version UI 2; Epic Systems Corp., Verona, WI, USA) to identify patients treated with denosumab followed by ZA between January 1, 2012 (the year denosumab was approved for clinical use in the USA) and June 30, 2020. Eligible patients met the following inclusion criteria: (1) received at least 2 doses of denosumab; (2) followed by at least 1 dose of ZA; (3) underwent DXA at the end of their treatment course with denosumab and approximately 1 year after the first dose of ZA. Patients were excluded if they had bone cancer or other conditions affecting bone metabolism including hyperparathyroidism, rickets, osteogenesis imperfecta, rheumatologic disorders, fibrous dysplasia of the bone, Paget’s disease of the bone, untreated hyperthyroidism, chronic kidney disease, liver cirrhosis, malabsorptive conditions (such as inflammatory bowel disease or celiac disease), and ongoing glucocorticoid or aromatase inhibitor use.
The EMR contains complete demographic, clinical, laboratory, and medication data for all patients seen at our medical center.
2. Data elements
Key data elements included patient demographics, height, weight, body mass index (BMI), medical comorbidities, smoking status, alcohol consumption history, DXA measurements and date of each measurement, number of denosumab doses and date of each dose, and number of post-denosumab ZA doses and date of each dose. All doses of denosumab and ZA were administered at our center and dates of administration were extracted from the patients’ EMR.
We also recorded basic laboratory results at the initiation of denosumab, including serum concentrations of calcium, creatinine, parathyroid hormone (PTH), and 25-hydroxy-vitamin D (25[OH]D). Only laboratory values obtained at the core laboratory at our medical center were recorded and used in this analysis to eliminate the bias that could be introduced by the variability between different assays. Calcium and creatinine were determined using Roche Modular P analyzers (Hoffmann-La Roche, Basel, Switzerland). Serum calcium was determined by colorimetric assay (lower detection limit, 0.2 mg/dL; intra-assay coefficient of variation [CV], 0.9%; inter-assay CV, 1.6%; Roche Diagnostics, Mannheim, Germany) and serum creatinine was determined by enzymatic colorimetric assay (lower detection limit, 0.03 mg/dL; intra-assay CV, 0.9%; inter-assay CV, 1.1%; Roche Diagnostics). The 25(OH)D was determined by ARUP Laboratories using the DiaSorin Liaison CIA technology that measured both 25(OH)D2 and 25(OH)D3 (lower detection limit, 0.8 ng/mL; intra-assay CV, 6.7%; inter-assay CV, 6.3%). The laboratory participated in regular Vitamin D External Quality Assessment Scheme performance assessments and passed quality assurance minimal standards. PTH was determined using Roche Modular E170 analyzer using an electrochemiluminescence immunoassay (lower detection limit, 1.2 pg/mL; intra-assay CV, 1.9 %; inter-assay CV, 4.5%; Roche Diagnostics). There were no changes to any of the tests used during the duration of time covered by the study. DXA scans were performed using a Hologic Discovery v12.6.2 instrument (Hologic Inc., Bedford, MA, USA; Center-specific hip and spine least significant change [LSC]=0.020 g/cm2). Areal BMD was measured at the total hip, femoral neck, and lumbar spine (L1-4) and expressed in grams/cm2.
All data were extracted from the patients’ EMR by 1 investigator (TK) and cross-checked by another investigator (ASR).
3. Statistical analyses
Statistical analyses were conducted using SAS for Windows, version 9.3 (SAS Institute Inc., Cary, NC, USA) and statistical significance was defined as a P-value less than 0.05 without correction for multiple testing. Due to the small sample size, data are presented as median (interquartile range) or percentage.
We began by examining patient characteristics and baseline DXA and laboratory results. We also calculated the number of doses of denosumab that each patient received and the duration of time between the last dose of denosumab and the first dose of ZA.
We then examined the change in BMD from baseline (before initiation of denosumab) to the end of the denosumab treatment course and between the end of the denosumab treatment course and the first DXA scan following ZA. We used nonparametric methods (Wilcoxon signed-rank test) to compare these data points. Finally, we used univariable logistic regression to examine the association between changes in BMD and total number of denosumab doses received and between changes in BMD and the duration of time between the last dose of denosumab and the first dose of ZA. Multivariable analyses were not performed due to the small sample size. The institutional review board approved this study.
RESULTS
1. Baseline evaluation
We identified 12 patients who met the study inclusion and exclusion criteria. A description of our study cohort is presented in Table 1. Three of the patients had their initial DXA scan prior to initiation of denosumab performed outside our medical center, and those measurements were excluded from the analysis. All other DXA scans were performed in our laboratory. At the time of transitioning to consolidation therapy, 6 of the patients still had osteoporosis (defined by a T-score ≤-2.5 at the lumbar spine, hip or femoral neck), and 6 had osteopenia. The reasons for transition to ZA in patients who still had osteoporosis was plateauing of BMD after 5 to 6 doses of denosumab in 4 patients, and patient request due to frequent traveling in 2 patients. The average t-scores in all 12 patients at the lumbar spine, total hip, and femoral neck were −1.23, −1.66, and −1.93, respectively.
2. Treatment and follow-up
Patients received a median of 5.3 doses of denosumab 6 months apart (range, 3–7 doses). All patients subsequently received at least one dose of ZA (median, 2; range, 1–3 doses). The median duration of time between the last dose of denosumab and the first dose of ZA was 201.5 days (~ 6.7 months).
All patients underwent a DXA measurement in our lab at the end of their denosumab treatment course and another DXA after the first dose of ZA. The median duration of time between the first dose of ZA and the corresponding follow-up DXA scan was 12.0 (1.0) months.
Five patients received a second yearly dose of ZA and had another DXA measurement following the second dose. In these patients, the median duration of time between the first and second doses of ZA was 12.7 (0.4) months. The median duration of time between the second dose of ZA and the corresponding DXA was 12.3 (0.3) months.
None of the patients suffered a clinical fracture while on denosumab. After transition to ZA, 1 patient sustained a distal radial fracture upon a fall. The fracture happened when she lost her balance while trying to sit on a stool and fell down on her extended wrist. She had received 3 doses of denosumab and 1 dose of ZA, the latter being about 6 months prior to the fracture. Her DXA scan about 6 months after the fracture showed a T score of −1.9 at the lumbar spine, −1.0 at the total hip, and −1.6 at the femoral neck. While spine X-rays were not routinely obtained on all patients, 3 patients underwent spine imaging after switching from denosumab to ZA (2 patients underwent thoracic and lumbar spine imaging, and 1 patient underwent lumbar spine imaging only), and no vertebral fractures were identified.
3. Changes in BMD over time
Table 2 shows the mean BMD for all patients with available DXA scans prior to initiation of denosumab (pre-Dmab, N=9), after completion of treatment with denosumab (post-Dmab, N=12) and after the first dose of ZA (post-ZA, N=12). As mentioned previously, the analyses excluded 3 pre-denosumab DXA scans that were performed outside our medical center.
When comparing the changes in measurements between the pre-Dmab and that obtained at the time of completion of denosumab, a statistically significant increase in BMD (P=0.008) was seen at the femoral neck. A non-significant increase was noted at the lumbar spine and total hip.
When comparing the DXA scan obtained at the end of denosumab treatment and that obtained after the first dose of ZA, we noted a significant decline in BMD (P=0.04) at the femoral neck. A non-significant downward trend was seen at the lumbar spine and total hip. The BMD at all 3 sites however remained higher than the BMD measured prior to initiation of denosumab. Patients who experienced a decline in BMD with ZA underwent a limited evaluation for secondary causes of bone loss (including abnormal renal function, vitamin D deficiency, hyperthyroidism, and hyperparathyroidism), and none was found.
On average, within approximately 1 year of switching from denosumab to ZA, patients lost 23% of the BMD gain they had accrued at the lumbar spine while on denosumab, 47% of the BMD gain accrued at the total hip and 54% of the BMD gain accrued at the femoral neck (Table 3). Of the patients who had osteopenia at the end of denosumab, 4 (67%) experienced some loss in BMD in at least one site. Of the patients with osteoporosis at the end of denosumab 5 (83%) experienced some loss of BMD in at least one site. Table 3 shows the proportion of BMD gain lost upon switching to ZA in each of these subgroups.
In a univariable logistic regression, the decline in BMD between the DXA scan obtained at the end of denosumab and the one obtained after the first dose of ZA was independent of the number of denosumab doses (for change in BMD at the lumbar spine OR=0.48 and P=0.22; at the total hip OR=0.70 and P=0.55; and at the femoral neck OR=0.70 and P=0.55) It was also independent of the time between the last dose of denosumab and the first dose of ZA (for change in BMD at the lumbar spine OR=1.0 and P=0.54; at the total hip OR=1.0 and P=0.54; and at the femoral neck OR=1.0 and P=0.3)
Five individuals received a second dose of ZA and had another DXA scan ~1 year later. We examined the changes in BMD between the DXA that followed the first ZA dose and the one following the second dose. Fig. 1 shows these changes for the individual patients with available data (N=5). The graphs suggest general stabilization of BMD at the lumbar spine, total hip, and femoral neck a year after the second annual consolidation dose of ZA. Due to the small number of patients in this subgroup, no statistical analyses on the trends were performed.
DISCUSSION
This case series suggests that patients who receive 1 dose of ZA after treatment with denosumab lose some of the BMD accrued while on denosumab. These results are consistent with previous studies where BMD loss was observed after a single consolidation dose of ZA.[15–17] The studies by Lehmann and Aeberli [16] and Reid et al. [17] measured BMD 2 to 2.5 years after ZA and could not determine the exact timeline of bone loss. However, our observations confirm what the work of Everts-Graber et al. [15] suggests, in that much of the observed bone loss happens during the first 12 months that follow the ZA infusion. In addition, our observations suggest that the bone loss might slow down when another yearly dose of ZA is given, but caution should be applied in interpreting these findings given the small sample size.
Our findings also suggest that the bone loss at the total hip and spine is much larger in patients who remained osteoporotic while on denosumab. This finding might present an argument in favor of ensuring patients’ BMD is in the osteopenia range on denosumab before switching them to ZA. It is worth making a note here of a recent study by Anastasilakis that randomized 57 women previously treated with denosumab for osteoporosis to another 2 doses of denosumab versus a single dose of ZA. Twelve months after randomization, an equal but non-significant increase in the lumbar spine and femoral neck BMD was seen in both groups, despite higher levels of bone turnover markers (BTMs) in the group randomized to ZA.[18] While these results contradict the decline in BMD with the transition from denosumab to ZA observed by other studies, it should be noted that all patients had osteopenia at the time of transition, which might again argue in favor of attaining osteopenia with denosumab before initiation of consolidation therapy.
One possible explanation for the observed bone loss when switching from denosumab to ZA lies in the fact that bisphosphonates need “open bone surfaces” to adhere to in order to exert their antiresorptive action.[3] Since bone turnover is still profoundly suppressed 6 months after a dose of denosumab, it is likely that ZA adherence to bone surfaces is reduced when given at that time. Thus, a single dose of ZA given after completion of denosumab treatment may be partially “wasted” and not fully taken up to the bone surfaces. One would then expect a more frequently dosed bisphosphonate to have more opportunities for adherence as the bone turnover is gradually restored after denosumab, thus allowing more antiresorptive action. This was indeed shown by Freemantle et al. in the DAPS study where 1 year of alendronate following 1 year of denosumab prevented post-denosumab bone loss.[19]
Alternatively, it may be attractive to delay ZA by more than 6 months after the last dose of denosumab to allow for some recovery of bone turnover and for the drug to adhere better to bone surfaces. Horne et al. [20] tested this hypothesis in a group of postmenopausal women treated with 1 year of romosozumab followed by 2 years of denosumab. Following denosumab, the subjects received a single dose of ZA, but the administration of ZA was delayed by an average of 65 days (i.e., it was administered about 8 months rather than 6 months after the last dose of denosumab). The bone loss 1 year after ZA was milder with this regimen.[20] While this may suggest that a delay in the timing of ZA after denosumab could enhance the antiresorptive efficacy of the drug, this approach might be associated with an increased risk of vertebral fractures, as such fractures have been observed as early as 2 months after discontinuation of denosumab.[11] Additionally, this study added the new variable of romosozumab treatment prior to denosumab, and it is not clear to what degree a change in bone quality from romosozumab may have contributed to the milder bone loss observed after ZA.
It is important to acknowledge potential limitations of this work. First, our sample size was small and this may explain the lack of statistical significance in some of our analyses. Notably however, while our analyses of BMD changes at the lumbar spine and hip did not reach statistical significance, the trends were comparable to previous studies that did achieve statistical significance.[15,16] Measurement of BTMs is also missing from our study, somewhat limiting our interpretation of the results. Finally, while our study focuses on the changes in BMD over time, it is important to acknowledge that fractures are the clinically-relevant outcome of low BMD. Although all clinical fractures were documented in our patients’ records, routine x-rays to assess for subclinical fractures were not obtained. Nonetheless, there was no evidence of an increased risk of clinical vertebral fractures in our patients despite the observed decline in BMD.
In conclusion, a single dose of ZA given approximately 6 months after long-term denosumab therapy leads to a loss of a portion of the BMD gained with denosumab, and much of this loss seems to occur within 1 year of ZA, particularly in patients who are osteoporotic at the time of transition. Furthermore, limited data suggest that the loss in BMD may plateau after a second dose of ZA. However, larger and longer-term studies with careful evaluation of fracture risk are needed to provide a definitive answer on the safety and best approach to post-denosumab consolidation therapy with ZA.
Fig. 1 Bone mineral density (BMD) and T-score measurements in 5 patients who received 2 doses of zoledronic acid. Each line represents an individual patient. DXA, dual energy X-ray absorptiometry; Pre-Dmab, DXA scans prior to initiation of denosumab; Post-Dmab, DXA scans after completion of treatment with denosumab; Post-ZA1, DXA scans after the first dose of zoledronic acid; Post-ZA2, DXA scans after the second dose of zoledronic acid.
Table 1 Patient characteristics
Characteristics Value (N=12)
Age (yr), median (IQR) 76.8 (8.8)
Sex (female) 12 (100.0)
Race (white) 12 (100.0)
BMI (kg/m2), median (IQR) 21.9 (4.5)
25(OH)D (ng/mL), median (IQR) 37.5 (13.0)
Calcium (mg/dL), median (IQR) 9.8 (0.7)
PTH (pg/mL), median (IQR)a) 40.1 (3.9)
Creatinine (mg/dL), median (IQR) 0.7 (0.2)
Smoking
Current smoker 1 (8.3)
Previous smoker 4 (33.3)
Alcoholic drinks per week, median (IQR) 1 (1.5)
Trauma
Presence of low-trauma fracture before Dmab 2 (16.7)
Presence of low-trauma vertebral fracture before Dmab 1 (8.3)
BMD (gm/cm2), median (IQR)b)
Lumbar spine 0.82 (0.03)
Total hip 0.69 (0.05)
Femoral neck 0.59 (0.02)
Treatment received
Received bisphosphonate before Dmab 7 (58.3)
Bisphosphonate washout before Dmab (yr), median (IQR)c) 4 (2.5)
No. of Dmab doses, median (IQR) 5.3 (1.2)
No. of ZA doses, median (IQR) 2 (0.3)
Patients with osteoporosis at time of transition to ZA 6 (50.0)
Lag time between last dose of Dmab and first dose of ZA (days), median (IQR) 201.5 (31.3)
The data is presented as median (IQR) or number (%).
a) PTH available in 5 patients.
b) Baseline BMD in 9.
c) Bisphosphonate washout applies to 7 patients who received bisphosphonate before Dmab.
IQR, interquartile range; BMI, body mass index; 25(OH)D, 25-hydroxy-vitamin D; PTH, parathyroid hormone; BMD, bone mineral density; Dmab, denosumab; ZA, zoledronic aid.
Table 2 Changes in bone density measurements over time
DXA measurement site DXA time
Pre-Dmab (N=9) Post-Dmab (N=12) Post-ZA (N=12)
BMD (g/cm2)
Lumbar spine 0.82 (0.03) 0.90 (0.15)a) 0.87 (0.08)a)
Total hip 0.69 (0.05) 0.75 (0.04) 0.72 (0.08)
Femoral neck 0.59 (0.02) 0.63 (0.06)b) 0.62 (0.05)c)
The data is presented as median (interquartile range).
a) Lumbar spine measurement excluded in 1 patient due to severe degenerative changes.
b) Statistically significant increase from pre-Dmab, P=0.008.
c) Statistically significant decrease from post-Dmab, P=0.040.
DXA, dual energy X-ray absorptiometry; Pre-Dmab, DXA scans prior to initiation of denosumab; Post-Dmab, DXA scans after completion of treatment with denosumab; Post-ZA, DXA scans after the first dose of zoledronic acid; BMD, bone mineral density.
Table 3 Relative changes in BMD upon switching from Dmab to ZA
Site All patients Patients with osteopenia at end of Dmab Patients with osteoporosis at end of Dmab
Median BMD gain on Dmab (g/cm2) Median BMD loss after switching to ZA (g/cm2) Percent of median BMD gain that is lost with ZA Percent of median BMD gain that is lost with ZA Percent of median BMD gain that is lost with ZA
Lumbar spine 0.048 0.011 23% 7% 61%
Total hip 0.034 0.016 47% 43% 220%
Femoral neck 0.048 0.026 54% 49% 37%
BMD, bone mineral density; Dmab, denosumab; ZA, zoledronic aid.
Funding
The authors received no financial support for this article.
Ethics approval and consent to participate
The study was reviewed and approved by the Institutional Review Board for human subjects’ research.
Conflict of interest
No potential conflict of interest relevant to this article was reported. | UNKNOWN | DrugDosageText | CC BY-NC | 33730783 | 19,281,652 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Asthenia'. | Efficacy of tocilizumab therapy in a patient with severe pancytopenia associated with a STAT3 gain-of-function mutation.
We aimed to report the clinical characteristics, immunological features, and treatment of one patient with a de novo STAT3 gain-of-function mutation identified by next generation sequencing. We investigated the efficacy of tocilizumab therapy in immune dysregulation diseases caused by STAT3 mutation.
The patient was a 16-year-old girl. She presented with recurrent respiratory infections and chronic diarrhea after birth. She had life-threatening autoimmune pancytopenia at 14 years old. After receiving glucocorticoid therapy, she developed diabetes. However, her pancytopenia relapsed when the glucocorticoid was tapered. Next-generation sequencing showed a de novo heterozygous mutation in the STAT3 gene, c.1261G > A (p. G421R), which was previously described as a gain-of-function mutation. After tocilizumab therapy, her pancytopenia fully resolved, and insulin and glucocorticoid therapies were gradually discontinued within 12 months. She had lymphopenia and an inverted CD4/CD8 ratio before therapy. Lymphocyte subpopulation analysis indicated an expansion of effector memory CD4+, effector memory CD8+ and central memory CD4+ T cells. The proportions of memory B cells and naive CD4+ T cells were decreased, and the proportion of naïve B cells was increased. None of the abnormal lymphocytic changes improved significantly. STAT3 GOF mutations were identified by next gene sequencing in those with early-onset multi-organ autoimmunity. Including our patient, 13 patients with STAT3 GOF mutations received targeted treatment. Twelve of them were treated with tocilizumab alone or combination tocilizumab with JAK inhibitor, and ten patients improved.
Gene sequencing should be performed for patients with early-onset refractory or multiorgan immune dysregulation diseases. Targeted drugs can effectively improve the clinical problems associated with STAT3 gain-of-function mutations, while nontargeted immunosuppressive therapy is usually insufficient.
Background
Signal Transduction and Activator of Transcription 3 (STAT3), one of the seven members of the STAT family of transcription factors, helps transmit key cytokine signals from cell membrane receptors to the nucleus using Janus kinases (JAKs). STATs are involved in multiple processes, including early development, cellular proliferation, survival, and differentiation. Germline STAT3 gene loss-of-function (LOF) mutations cause hyper IgE syndrome, which often manifests as special facial features, recurrent infections, eczema, and joint hyperextension [1]. STAT3 gain-of-function (GOF) mutations were first reported in 2014 [2–8]. In the phenotypical classification of inborn errors in human immunity by the International Union of Immunological Societies (IUIS) in the 2019 update [9], diseases of immune dysregulation were divided into two categories: a) hematopoietic lymphohistiocytosis syndrome (HLH) and Epstein-Barr virus (EBV) susceptibility and b) syndromes with autoimmunity and others. GOF mutation of the germline STAT3 gene is one of the regulatory T cell defects accompanied by autoimmune manifestations. These mutations cause early-onset lymphoproliferation with lymphadenopathy, hepatosplenomegaly and multiorgan autoimmunity, including cytopenia, hepatitis, inflammatory lung disease, enteropathy, and diabetes mellitus.
Patients with STAT3 GOF were treated with regular immunosuppressive treatments before the results of gene sequencing which always couldn’t control all the clinical manifestations [10–14]. Functional analyses of STAT3 GOF mutations demonstrated increased transcriptional activity of STAT3 in unstimulated and/or stimulated cells in vitro [3]. Because IL-6 is one of the primary cytokines that utilizes STAT3 for signal transduction, IL-6 receptor (IL-6R) antagonist therapy currently have been reported to be effective in these patients [4, 5, 10–13]. Here, we reviewed the clinical manifestations and immunological features of one patient with a STAT3 GOF mutation. Moreover, we aimed to investigate the efficacy of tocilizumab therapy.
Results
Case review
A 16-year-old girl born to nonconsanguineous Chinese parents presented with recurrent respiratory infections after birth and suffered at least 1–2 pneumonia events per year. She had chronic diarrhea from 3 months old. When she was 12 years old, she developed cervical adenopathy, alopecia, and bilateral lower limb weakness. She had life-threatening autoimmune pancytopenia with a positive Coomb’s test at the age of 14. She also presented with growth retardation and hepatosplenomegaly. Laboratory data showed that her peripheral blood leukocyte count was (0.90–1.36) × 109/L, her hemoglobin level was 87–106 g/L and her platelet count was (32–51) × 109/L. Her antinuclear antibody (ANA), extractable nuclear antibody (ENA) spectrum and anticardiolipin antibody detection were negative. Complement C3 and C4 were normal. She had lymphopenia and an inverted CD4/CD8 ratio before therapy, and her serum immunoglobulin G concentration was slightly higher than the normal range. Lymphocyte subpopulation analysis indicated expansion of effector memory (EM) CD4+ T, EM CD8+ T and central memory (CM) CD4+ T cells. The proportions of memory B cells and naive CD4+ T cells were decreased, and the proportion of naïve B cells was increased (Fig. 1). Magnetic resonance imaging of the lower limbs revealed abnormal signals in the muscles and fluid accumulation in the intermuscular space, which indicated inflammatory changes. Fig. 1 Lymphocyte subpopulaltions of our patient. A:CD19 + IgD + CD27– naïve B (94.2%), CD19 + IgD–CD27+ memory B (1.9%); B:CD38 + CD24+ transitional B (0%), CD38 + CD24– plasmablast B (1.7%); C: CD3 + CD4+ T (24.4%); CD3 + CD8+ T (66.3%); CD3 + CD4–CD8– double negative T (7.2%); D:subpopulaltions of CD4+ T cells: CD3 + CD4 + CD45RA + CD27+ naïve T (11%), CD3 + CD4 + CD45RO + CD27+ central memory T (49.6%), CD3 + CD4 + CD45RO + CD27– effector memory T (23.8%); E:subpopulaltions of CD8 + T cells: CD3 + CD8 + CD45RA + CD27+ naïve T (48.1%), CD3 + CD8 + CD45RO + CD27+ central memory T (13.7%), CD3 + CD8 + CD45RO + CD27– effect memory T (9.3%), CD3 + CD8 + CD45RA + CD27– TEMRA T (28.9%)
Gene analysis
Next-gene sequencing (NGS) revealed that she had a heterozygous de novo mutation in the STAT3 gene, while her parents were normal (Fig. 2). The missense mutation in the DNA binding domain (c.1261G > A, p. G421R) was described as a gain-of-function mutation in previous studies [2]. Fig. 2 Sanger sequence results of our patient and her parents
Treatment and follow-up
Before the gene sequencing results were available, the patient accepted intravenous methylprednisolone (1.6 mg/kg/day) for autoimmune pancytopenia. She was changed to the same dose of oral glucocorticoid tablet after Coomb’s test turned negative and pancytopenia improved. But the pancytopenia relapsed several times once the glucocorticoid dose was less than 2 mg/kg/day. Meanwhile, she developed diabetes and worse weakness of lower limbs during the glucocorticoid treatment. The fasting plasma glucose was 7.2 mmol/L, the glycated hemoglobin (Hb1c) was 5.8%, and all the insulin autoantibodies were negative. The oral glucose tolerance test showed increased C peptide and plasma glucose after 30 min, 60 min, 120 min, and 180 min of oral glucose, while plasma insulin level didn’t increase (supplement Table 2). So, we diagnosed diabetes and considered it as a side effect of glucocorticoid therapy. The blood biochemistry results were normal before and after treatment, including creatine kinase (CK), serum electrolytes, transaminase, and creatinine. The diagnosis of myositis was based on MRI abnormal signals in muscle and cutting movement assessment score (CMAS) was 15 of 52.
After obtaining informed consent from her parents, we administered IL-6R antagonist treatment (tocilizumab) at a dosage of 8 mg/kg intravenous infusion every 2 weeks. After 2 months of tocilizumab treatment, the patient’s pancytopenia fully resolved. She discontinued insulin injection after 4 months of tocilizumab therapy, and glucocorticoid therapy was gradually discontinued within 12 months. Her serum IL-6 levels increased before glucocorticoid therapy and improved for a while but fluctuated after glucocorticoid tapering and gradually decreased to normal after tocilizumab therapy (Fig. 3). She underwent intravenous immunoglobulin (IVIG) replacement after 6 months because of hypogammaglobulinemia. Beginning in the second year of therapy, she extended the interval of tocilizumab to every 4–6 weeks (240 mg/dose, after her weight was above 30 kg), with a good response evidenced by a normal hemoglobin level and negative Coomb’s test. Lymphadenopathy and hepatosplenomegaly returned to mild enlargement (Table 1). Fig. 3 Serum IL-6 before and after tocilizumab of our patient. She accepted glucocorticoid first from week − 18 to week 0
Table 1 Clinical features and immunotype of our patient with a STAT3 GOF mutation
tocilizumab therapy before after
lymphadenopathy yes no
hepatosplenomegaly yes (severe) mild
autoimmune pancytopenia yes no
myositis worse better
alopecia yes better
WBC
(×109/L)
0.90–1.36#
0.9–6.8##
4.7–8.3###
HB
g/L
87–106#
46–139##
112–139###
PLT
(×109/L)
32–51#
32–123##
107–178###
IgM 1.84 0.62
IgA 1.3 0.25
IgG 14.5 6.6 a
IgE < 2 < 2
CD3 89.13% (607) 82.87% (786)
CD4 32.41% (221) 30.61% (290)
CD8 51.17% (349) 48.70% (462)
CD4/CD8 0.63 0.63
CD19 8.74% (60) 9.08% (31)
NK 1.49% (10) 7.28% (69)
* with monthly IVIG replacement
# before glucocorticoid treatment, ## after glucocorticoid treatment;
### after 1 month of tocilizumab therapy
We regularly followed up for infection indicators during targeted therapy. She had cervical lymphadenitis and Candida albicans vaginitis once during 2 years of therapy. Her EBV-DNA load of whole leukocytes in the peripheral blood was higher than the level at the beginning, changing from 1.29 × 104 copies/ml to 3.58 × 106 copies/ml. In addition to treatment with targeted drugs, she accepted oral itraconazole and acyclovir tablets.
Her immune phenotypes after tocilizumab showed hypogammaglobulinemia after 6 months of therapy. All the abnormal lymphocytic changes (expansion of EM CD4+ T, EM CD8+ T and CM CD4+ T cells; decreased memory B cell and naive CD4+ T cell levels; and an increased naïve B cell level) did not improve significantly (Fig. 4). Fig. 4 Subpopulation of T/B lymphocytes of our patient before and 1 month, 12 months after tocilizumab
Discussion
STAT3 GOF mutations were reported in patients with multiple early-onset autoimmune manifestations by NGS [3]. Fabre et al. summarized the clinical features of 42 patients, and the most common manifestations were autoimmune cytopenia, lymphoproliferation, enteropathy, interstitial lung disease, thyroiditis, diabetes, and growth retardation; some of the patients had recurrent or opportunistic infections [14]. The onset age and major symptoms of our patient were similar to those of other patients reported previously [2, 3]. She developed diabetes during glucocorticoid therapy with normal glycated hemoglobin levels, which is different from the early-onset type 1 diabetes reported in the literature. Her Hb1c, insulin autoantibodies and oral glucose tolerance test indicated her diabetes was a side effect of glucocorticoid therapy. We also found that her bilateral lower limb weakness was related to immune myositis on MRI. The abnormal changes in the muscles improved after tocilizumab treatment (Fig. 5). Fig. 5 Magnetic resonance imaging of left lower limbs of patient 1. a and c revealed abnormal signals in muscle and fluid accumulation in the intermuscular space considering inflammatory changes. b and d revealed abnormal changes recovered after tocilizumab
According the functions of immune system, infection tendency, autoimmunity and extremely abnormal immune reactions are common manifestations of primary immunodeficiencies. So, we did NGS at the beginning of diagnose considering a genetic defect may exist. STAT3 GOF mutations were identified by gene sequencing in those with early-onset multi-organ autoimmunity.
Activation of STAT3 leads to the production of downstream cytokines, including glycoprotein 130 (a component of IL-6 and IL-27), common gamma chain cytokines, IL-10 family cytokines and IL-23. After cytokines bind to their receptors, one of four Janus kinases (JAKs) is activated and phosphorylates the cytokine receptor. STAT molecules are recruited to the phosphorylated receptor and then translocate to the nucleus, altering gene expression [15]. The proportions of regulatory T cells are reduced, while IL-17 levels are increased in patients with STAT3 GOF mutations [3, 8]. In vitro, IL-6R antagonists can reduce IL-17 secretion and improve immune dysregulation by increasing regulatory T cell differentiation [4]. Therefore, IL-6R antagonists and JAK inhibitors can inhibit STAT3 signaling pathway overactivation and be used to treat patients with STAT3 GOF mutations.
Twelve patients with STAT3 GOF mutations received targeted treatment in 5 reports [4, 5, 9–11]. Three (including our patient, P1) of the 13 patients were treated with tocilizumab alone, and all three improved (P1, P2, and P3); 1 patient improved with JAK inhibitor treatment alone (P7); the remaining 9 patients were treated successively or simultaneously with tocilizumab and JAK inhibitors because of disease severity or incomplete remission. Combination treatment could take the following factors into consideration: enteropathy (4/9), interstitial pulmonary disease (4/9), arthritis (2/9), hepatitis (3/9), splenomegaly (1/9), and cytopenia (2/9). Seven of the nine patients who received combined treatment achieved remission (Table 2). STAT3 GOF mutation patients manifesting with multiple clinical symptoms might need combination therapy if the tocilizumab or JAK inhibitors alone couldn’t control the disease. The outcomes of targeted therapy are summarized in Table 3. The symptoms of arthritis, cytopenia, hepatosplenomegaly and hepatitis were all alleviated. Three of the 13 patients died. P10 died of infection after transplant, while recurrent HLH was resolved by targeted treatment. P9 died of sepsis and diffuse intravascular coagulation. P13 died of respiratory failure. Considering cytopenia as the common adverse reaction to JAK inhibitors, two patients with the G421R mutant who recovered with tocilizumab alone have been reported in the literature [2, 4]. Therefore, we chose tocilizumab as the first targeted treatment for our patient. After 1 year of treatment, her whole blood cells stayed in the normal range with no serious infections. However, the EBV-DNA titer of peripheral blood leukocytes was higher than that at the beginning. This means that latency and active infections need to be monitored before and after targeted therapy. Table 2 Summary of targeted therapy in all the reported patients with a STAT3 GOF mutation
Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13
a. sex female male male female female female male female male female male male
b. onset age 3 mo 4 yr 6 mo 5 mo 1 yr 1 yr 1 mo 7 yr 3 yr 7 mo 7 yr
c. age 16 yr 10 yr 38 yr 19 yr 9 yr 21 yr 20 yr 8 yr 14 yr 3 yr 8 yr 13 yr 15 yr
d. infections Y Y Y Y Y
e. cytopenia Y Y Y Y Y Y Y Y
f. enteropathy Y Y Y Y Y Y Y Y Y
g. hepatitis Y Y Y Y Y
h. endocrine disease Y Y Y Y Y
i. arthritis Y Y Y Y Y
j. lymphadenopathy Y Y Y
k. hepatosplenomegaly Y Y Y Y Y Y Y Y Y Y
l. interstitial lung disease Y Y Y Y Y
m. short stature Y Y Y Y Y Y Y Y Y Y Y Y
n. reason of for targeted therapy pancytopenia, arthritis enteropathy, colitis interstitial lung disease arthritis, interstitial lung disease hepatosplenomegaly, hepatotitis, enteropathy, interstitial lung disease arthritis enteropathy,
hepatosplenomegaly dermopathy interstitial lung disease anemia enteropathy
HLH
interstitial lung disease
o. tocilizumab alone ✓ ✓ ✓
p. combination of tocilizumab and a JAK inhibitor ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
q. JAK inhibitor alone ✓
r. efficiency of targeted therapy yes yes yes yes yes yes yes yes no yes yes yes no
s. outcome alive alive alive alive alive alive alive alive dead dead dead alive dead
t. mutantmutation in of STAT3 G421R G421R G421R N401D E415L V393A M329K R152W F174S E286G Q344H G421R P715L
u. reference our report [2] [4] [13] [11] [12] [11] [10] [10] [10] [10] [10] [10]
Y represent YES, and slash indicate the parameter was not mentioned in the reference
p: combination of tocilizumab and JAK inhibitors
Patients 4, 5, 6, 9, 11 and 12 were treated with tocilizumab first, and then a JAK inhibitor was added later. Patients 8 and 10 were treated with two targeted drugs simultaneously. Patient 14 was treated with a JAK inhibitor first and then changed to tocilizumab
Table 3 Effect summary for targeted therapy
Cause of targeted therapy Case number Remission number No response Proportion of remission
enteropathy 5 3 2 60%
ILD 5 4 1 80%
arthritis 3 3 0 100%
cytopenia 3 3 0 100%
hepatosplenomegaly 2 2 0 100%
dermopathy 2 1 1 50%
hepatitis/liver failure 1 0 1 0%
The immunological features of STAT3 GOF mutations included hypogammaglobulinemia, increased Th17 cells and decreased Treg cells, which plays a critical role in the development of autoimmunity. While some case reports showed normal Th17 cells or Treg cells in the symptomatic STAT3 GOF patients [8]. There is no immunological index for starting and evaluating the efficacy of targeted therapy. The 12 patients reported above had no immunophenotypic changes with targeted treatment. One patient showed an improvement in the proportion of regulatory T cells after tocilizumab treatment [4]. We evaluated lymphocyte subpopulations before and after treatment. There were no significant improvements in those abnormal changes in our patient after 1 year of treatment. It cannot be ruled out that the immune phenotype changes later than clinical improvement. The relationship between immunological characteristics and mechanism of disease needs further research. The patient still requires monthly IVIG replacement with targeted therapy. Consistent with other reports [2, 16], she had hypogammaglobulinemia and a low proportion of memory B cells. However, the IgG level was higher than normal during the course of autoimmune pancytopenia due to the presence of autoantibodies. Therefore, her hypogammaglobulinemia was consistent with the reduced proportion of memory B cells regardless of the side effects of tocilizumab. The pathogenesis of the abnormal changes leading to reduced unswitched memory B cells and hypogammaglobulinemia require further study.
It has been reported that 5 patients underwent hematopoietic stem cell transplantation [2, 9, 17, 18], of whom four died due to complications, such as infection. The remaining patient was successfully transplanted and lived well. It is known from the reported cases that targeted therapy can effectively control and alleviate life-threatening autoimmune manifestations and lymphoproliferative disorders. The longest follow-up time for targeted therapy is 3.5 years [9]. Our patient was followed up for 2 years, and she had no obvious serious infections or adverse reactions. Aside from IL-6R antagonists and JAK inhibitors, whether better targeted drugs exist requires more clinical data and pathogenesis studies.
Conclusions
We reported the first case of tocilizumab therapy in immune dysregulation disorders caused by a STAT3 GOF mutation in mainland China. Gene sequencing should be performed for patients with early-onset refractory immune dysregulation diseases since routine immunological examination may be nonspecific. Targeted drugs can effectively improve the clinical problems associated with STAT3 gain-of-function mutations, while nontargeted immunosuppressive therapy is usually insufficient.
Methods
The study was carried out at Children’s hospital of Fudan University (Shanghai, China). The protocol 2020–453 was approved by the Ethics Committee of the Children’s Hospital of Fudan University. Because the patient was under the age of 18 years, her parents gave written informed consent to participate tocilizumab therapy and report data in accordance with the declaration of Helsinki.
Clinical data
We retrospectively summarized the clinical data of the STAT3 GOF patient.
Whole-exome sequencing
WES and analysis protocols were adapted for genetic analysis. After obtaining the informed consent from the parents, genomic DNA samples were extracted from the whole blood of the patient and her parents with the QIAamp® DNA Blood Mini Kit (Qiagen, Hilden, Germany). The concentration and quantity of the DNA samples were measured using a NanoDrop ultraviolet spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA) [19]. Genomic DNA fragments were enriched for the target region of the consensus coding sequence exons and sequenced on an Illumina HiSeq 2000 platform (Illumina, San Diego, CA) [19]. Data analyses were conducted by using ANNOVAR and VEP software in our clinical genetic laboratory by a bioinformatics team. The mutation was confirmed by Sanger sequencing.
Routine evaluation of immunological function
Immunological evaluations were carried out during routine clinical work. As previously reported, IgG, IgA, and IgM were detected by nephelometry; IgE was assessed by UniCAP (Pharmacia, Uppsala, Sweden) [20]. Lymphocyte subsets were analyzed by FACSCalibur flow cytometer (Becton Dickinson, Franklin Lakes, NJ, USA) [21]. Whole blood was used for staining of lymphocyte surface markers and analyzed according to a standard multicolor flow cytometric protocol with following antibodies [21]: anti-CD3 (UCHT1), anti-CD8 (RPA-T8), anti-CD27 (M-T271), anti-CD45RA (HI100), anti-CD4 (RPA-T4), anti-TCRαβ (T10B9.1A-31), anti-TCRγδ (B1), anti-CD19 (HIB19), anti-CD24 (ML5), anti-CD38 (HIT2), anti-IgD (IA6–2), and anti-CD57 (NK-1) (all from BD Biosciences).
Supplementary Information
Additional file 1: Supplement Table 1. Variants identified by WES.
Additional file 2: Supplement Table 2. OGTT results of our case (P1).
Abbreviations
STAT3 Signal transduction and activator of transcription 3
JAK Janus kinases
LOF Loss-of-function
GOF Gain-of-function
NGS Next generation sequencing
IUIS International union of immunological societies
HLH Lymphohistiocytosis syndrome
EBV Epstein-barr virus
EM Effector memory
IL-6CM Central memory
IVIG Intravenous immunoglobulin
Acknowledgements
Many thanks to the patient and her parents.
Authors’ contributions
W.X.C., S.J.Q., W.W.J. designed the study. W.X.C., S.J.Q., W.W.J., Y.W.J., H.J., Z.Q.H. diagnosed, treated, and followed up the patient. W.Y. performed the lymphocyte subpopulation analysis. W.W.J. and H.X.Y. abstracted the information from electronic medical chart and follow-up material. S.B.J .and Y.M. did the telephone interview. W.W.J. wrote the first draft. S.J.Q., W.W.J. and L.L.Y. reviewed and revised the manuscript. S.J.Q. and W.X.C. supervised the whole process of the study. The author(s) read and approved the final manuscript.
Funding
This study was funded by the National Natural Science Foundation of China (81373221).
Availability of data and materials
The datasets used and analyzed during the current study available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
The study was carried out at Children’s hospital of Fudan University (Shanghai, China). The protocol 2020–453 was approved by the Ethics Committee of the Children’s Hospital of Fudan University. Because the patient was under the age of 18 years, her parents gave written informed consent to participate tocilizumab therapy and report data in accordance with the declaration of Helsinki.
Consent for publication
Written informed consent for publication of identifying images and other personal or clinical details was obtained from the patient’s parents.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | METHYLPREDNISOLONE, METHYLPREDNISOLONE SODIUM SUCCINATE | DrugsGivenReaction | CC BY | 33731004 | 19,866,414 | 2021-03-17 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Efficacy of tocilizumab therapy in a patient with severe pancytopenia associated with a STAT3 gain-of-function mutation.
We aimed to report the clinical characteristics, immunological features, and treatment of one patient with a de novo STAT3 gain-of-function mutation identified by next generation sequencing. We investigated the efficacy of tocilizumab therapy in immune dysregulation diseases caused by STAT3 mutation.
The patient was a 16-year-old girl. She presented with recurrent respiratory infections and chronic diarrhea after birth. She had life-threatening autoimmune pancytopenia at 14 years old. After receiving glucocorticoid therapy, she developed diabetes. However, her pancytopenia relapsed when the glucocorticoid was tapered. Next-generation sequencing showed a de novo heterozygous mutation in the STAT3 gene, c.1261G > A (p. G421R), which was previously described as a gain-of-function mutation. After tocilizumab therapy, her pancytopenia fully resolved, and insulin and glucocorticoid therapies were gradually discontinued within 12 months. She had lymphopenia and an inverted CD4/CD8 ratio before therapy. Lymphocyte subpopulation analysis indicated an expansion of effector memory CD4+, effector memory CD8+ and central memory CD4+ T cells. The proportions of memory B cells and naive CD4+ T cells were decreased, and the proportion of naïve B cells was increased. None of the abnormal lymphocytic changes improved significantly. STAT3 GOF mutations were identified by next gene sequencing in those with early-onset multi-organ autoimmunity. Including our patient, 13 patients with STAT3 GOF mutations received targeted treatment. Twelve of them were treated with tocilizumab alone or combination tocilizumab with JAK inhibitor, and ten patients improved.
Gene sequencing should be performed for patients with early-onset refractory or multiorgan immune dysregulation diseases. Targeted drugs can effectively improve the clinical problems associated with STAT3 gain-of-function mutations, while nontargeted immunosuppressive therapy is usually insufficient.
Background
Signal Transduction and Activator of Transcription 3 (STAT3), one of the seven members of the STAT family of transcription factors, helps transmit key cytokine signals from cell membrane receptors to the nucleus using Janus kinases (JAKs). STATs are involved in multiple processes, including early development, cellular proliferation, survival, and differentiation. Germline STAT3 gene loss-of-function (LOF) mutations cause hyper IgE syndrome, which often manifests as special facial features, recurrent infections, eczema, and joint hyperextension [1]. STAT3 gain-of-function (GOF) mutations were first reported in 2014 [2–8]. In the phenotypical classification of inborn errors in human immunity by the International Union of Immunological Societies (IUIS) in the 2019 update [9], diseases of immune dysregulation were divided into two categories: a) hematopoietic lymphohistiocytosis syndrome (HLH) and Epstein-Barr virus (EBV) susceptibility and b) syndromes with autoimmunity and others. GOF mutation of the germline STAT3 gene is one of the regulatory T cell defects accompanied by autoimmune manifestations. These mutations cause early-onset lymphoproliferation with lymphadenopathy, hepatosplenomegaly and multiorgan autoimmunity, including cytopenia, hepatitis, inflammatory lung disease, enteropathy, and diabetes mellitus.
Patients with STAT3 GOF were treated with regular immunosuppressive treatments before the results of gene sequencing which always couldn’t control all the clinical manifestations [10–14]. Functional analyses of STAT3 GOF mutations demonstrated increased transcriptional activity of STAT3 in unstimulated and/or stimulated cells in vitro [3]. Because IL-6 is one of the primary cytokines that utilizes STAT3 for signal transduction, IL-6 receptor (IL-6R) antagonist therapy currently have been reported to be effective in these patients [4, 5, 10–13]. Here, we reviewed the clinical manifestations and immunological features of one patient with a STAT3 GOF mutation. Moreover, we aimed to investigate the efficacy of tocilizumab therapy.
Results
Case review
A 16-year-old girl born to nonconsanguineous Chinese parents presented with recurrent respiratory infections after birth and suffered at least 1–2 pneumonia events per year. She had chronic diarrhea from 3 months old. When she was 12 years old, she developed cervical adenopathy, alopecia, and bilateral lower limb weakness. She had life-threatening autoimmune pancytopenia with a positive Coomb’s test at the age of 14. She also presented with growth retardation and hepatosplenomegaly. Laboratory data showed that her peripheral blood leukocyte count was (0.90–1.36) × 109/L, her hemoglobin level was 87–106 g/L and her platelet count was (32–51) × 109/L. Her antinuclear antibody (ANA), extractable nuclear antibody (ENA) spectrum and anticardiolipin antibody detection were negative. Complement C3 and C4 were normal. She had lymphopenia and an inverted CD4/CD8 ratio before therapy, and her serum immunoglobulin G concentration was slightly higher than the normal range. Lymphocyte subpopulation analysis indicated expansion of effector memory (EM) CD4+ T, EM CD8+ T and central memory (CM) CD4+ T cells. The proportions of memory B cells and naive CD4+ T cells were decreased, and the proportion of naïve B cells was increased (Fig. 1). Magnetic resonance imaging of the lower limbs revealed abnormal signals in the muscles and fluid accumulation in the intermuscular space, which indicated inflammatory changes. Fig. 1 Lymphocyte subpopulaltions of our patient. A:CD19 + IgD + CD27– naïve B (94.2%), CD19 + IgD–CD27+ memory B (1.9%); B:CD38 + CD24+ transitional B (0%), CD38 + CD24– plasmablast B (1.7%); C: CD3 + CD4+ T (24.4%); CD3 + CD8+ T (66.3%); CD3 + CD4–CD8– double negative T (7.2%); D:subpopulaltions of CD4+ T cells: CD3 + CD4 + CD45RA + CD27+ naïve T (11%), CD3 + CD4 + CD45RO + CD27+ central memory T (49.6%), CD3 + CD4 + CD45RO + CD27– effector memory T (23.8%); E:subpopulaltions of CD8 + T cells: CD3 + CD8 + CD45RA + CD27+ naïve T (48.1%), CD3 + CD8 + CD45RO + CD27+ central memory T (13.7%), CD3 + CD8 + CD45RO + CD27– effect memory T (9.3%), CD3 + CD8 + CD45RA + CD27– TEMRA T (28.9%)
Gene analysis
Next-gene sequencing (NGS) revealed that she had a heterozygous de novo mutation in the STAT3 gene, while her parents were normal (Fig. 2). The missense mutation in the DNA binding domain (c.1261G > A, p. G421R) was described as a gain-of-function mutation in previous studies [2]. Fig. 2 Sanger sequence results of our patient and her parents
Treatment and follow-up
Before the gene sequencing results were available, the patient accepted intravenous methylprednisolone (1.6 mg/kg/day) for autoimmune pancytopenia. She was changed to the same dose of oral glucocorticoid tablet after Coomb’s test turned negative and pancytopenia improved. But the pancytopenia relapsed several times once the glucocorticoid dose was less than 2 mg/kg/day. Meanwhile, she developed diabetes and worse weakness of lower limbs during the glucocorticoid treatment. The fasting plasma glucose was 7.2 mmol/L, the glycated hemoglobin (Hb1c) was 5.8%, and all the insulin autoantibodies were negative. The oral glucose tolerance test showed increased C peptide and plasma glucose after 30 min, 60 min, 120 min, and 180 min of oral glucose, while plasma insulin level didn’t increase (supplement Table 2). So, we diagnosed diabetes and considered it as a side effect of glucocorticoid therapy. The blood biochemistry results were normal before and after treatment, including creatine kinase (CK), serum electrolytes, transaminase, and creatinine. The diagnosis of myositis was based on MRI abnormal signals in muscle and cutting movement assessment score (CMAS) was 15 of 52.
After obtaining informed consent from her parents, we administered IL-6R antagonist treatment (tocilizumab) at a dosage of 8 mg/kg intravenous infusion every 2 weeks. After 2 months of tocilizumab treatment, the patient’s pancytopenia fully resolved. She discontinued insulin injection after 4 months of tocilizumab therapy, and glucocorticoid therapy was gradually discontinued within 12 months. Her serum IL-6 levels increased before glucocorticoid therapy and improved for a while but fluctuated after glucocorticoid tapering and gradually decreased to normal after tocilizumab therapy (Fig. 3). She underwent intravenous immunoglobulin (IVIG) replacement after 6 months because of hypogammaglobulinemia. Beginning in the second year of therapy, she extended the interval of tocilizumab to every 4–6 weeks (240 mg/dose, after her weight was above 30 kg), with a good response evidenced by a normal hemoglobin level and negative Coomb’s test. Lymphadenopathy and hepatosplenomegaly returned to mild enlargement (Table 1). Fig. 3 Serum IL-6 before and after tocilizumab of our patient. She accepted glucocorticoid first from week − 18 to week 0
Table 1 Clinical features and immunotype of our patient with a STAT3 GOF mutation
tocilizumab therapy before after
lymphadenopathy yes no
hepatosplenomegaly yes (severe) mild
autoimmune pancytopenia yes no
myositis worse better
alopecia yes better
WBC
(×109/L)
0.90–1.36#
0.9–6.8##
4.7–8.3###
HB
g/L
87–106#
46–139##
112–139###
PLT
(×109/L)
32–51#
32–123##
107–178###
IgM 1.84 0.62
IgA 1.3 0.25
IgG 14.5 6.6 a
IgE < 2 < 2
CD3 89.13% (607) 82.87% (786)
CD4 32.41% (221) 30.61% (290)
CD8 51.17% (349) 48.70% (462)
CD4/CD8 0.63 0.63
CD19 8.74% (60) 9.08% (31)
NK 1.49% (10) 7.28% (69)
* with monthly IVIG replacement
# before glucocorticoid treatment, ## after glucocorticoid treatment;
### after 1 month of tocilizumab therapy
We regularly followed up for infection indicators during targeted therapy. She had cervical lymphadenitis and Candida albicans vaginitis once during 2 years of therapy. Her EBV-DNA load of whole leukocytes in the peripheral blood was higher than the level at the beginning, changing from 1.29 × 104 copies/ml to 3.58 × 106 copies/ml. In addition to treatment with targeted drugs, she accepted oral itraconazole and acyclovir tablets.
Her immune phenotypes after tocilizumab showed hypogammaglobulinemia after 6 months of therapy. All the abnormal lymphocytic changes (expansion of EM CD4+ T, EM CD8+ T and CM CD4+ T cells; decreased memory B cell and naive CD4+ T cell levels; and an increased naïve B cell level) did not improve significantly (Fig. 4). Fig. 4 Subpopulation of T/B lymphocytes of our patient before and 1 month, 12 months after tocilizumab
Discussion
STAT3 GOF mutations were reported in patients with multiple early-onset autoimmune manifestations by NGS [3]. Fabre et al. summarized the clinical features of 42 patients, and the most common manifestations were autoimmune cytopenia, lymphoproliferation, enteropathy, interstitial lung disease, thyroiditis, diabetes, and growth retardation; some of the patients had recurrent or opportunistic infections [14]. The onset age and major symptoms of our patient were similar to those of other patients reported previously [2, 3]. She developed diabetes during glucocorticoid therapy with normal glycated hemoglobin levels, which is different from the early-onset type 1 diabetes reported in the literature. Her Hb1c, insulin autoantibodies and oral glucose tolerance test indicated her diabetes was a side effect of glucocorticoid therapy. We also found that her bilateral lower limb weakness was related to immune myositis on MRI. The abnormal changes in the muscles improved after tocilizumab treatment (Fig. 5). Fig. 5 Magnetic resonance imaging of left lower limbs of patient 1. a and c revealed abnormal signals in muscle and fluid accumulation in the intermuscular space considering inflammatory changes. b and d revealed abnormal changes recovered after tocilizumab
According the functions of immune system, infection tendency, autoimmunity and extremely abnormal immune reactions are common manifestations of primary immunodeficiencies. So, we did NGS at the beginning of diagnose considering a genetic defect may exist. STAT3 GOF mutations were identified by gene sequencing in those with early-onset multi-organ autoimmunity.
Activation of STAT3 leads to the production of downstream cytokines, including glycoprotein 130 (a component of IL-6 and IL-27), common gamma chain cytokines, IL-10 family cytokines and IL-23. After cytokines bind to their receptors, one of four Janus kinases (JAKs) is activated and phosphorylates the cytokine receptor. STAT molecules are recruited to the phosphorylated receptor and then translocate to the nucleus, altering gene expression [15]. The proportions of regulatory T cells are reduced, while IL-17 levels are increased in patients with STAT3 GOF mutations [3, 8]. In vitro, IL-6R antagonists can reduce IL-17 secretion and improve immune dysregulation by increasing regulatory T cell differentiation [4]. Therefore, IL-6R antagonists and JAK inhibitors can inhibit STAT3 signaling pathway overactivation and be used to treat patients with STAT3 GOF mutations.
Twelve patients with STAT3 GOF mutations received targeted treatment in 5 reports [4, 5, 9–11]. Three (including our patient, P1) of the 13 patients were treated with tocilizumab alone, and all three improved (P1, P2, and P3); 1 patient improved with JAK inhibitor treatment alone (P7); the remaining 9 patients were treated successively or simultaneously with tocilizumab and JAK inhibitors because of disease severity or incomplete remission. Combination treatment could take the following factors into consideration: enteropathy (4/9), interstitial pulmonary disease (4/9), arthritis (2/9), hepatitis (3/9), splenomegaly (1/9), and cytopenia (2/9). Seven of the nine patients who received combined treatment achieved remission (Table 2). STAT3 GOF mutation patients manifesting with multiple clinical symptoms might need combination therapy if the tocilizumab or JAK inhibitors alone couldn’t control the disease. The outcomes of targeted therapy are summarized in Table 3. The symptoms of arthritis, cytopenia, hepatosplenomegaly and hepatitis were all alleviated. Three of the 13 patients died. P10 died of infection after transplant, while recurrent HLH was resolved by targeted treatment. P9 died of sepsis and diffuse intravascular coagulation. P13 died of respiratory failure. Considering cytopenia as the common adverse reaction to JAK inhibitors, two patients with the G421R mutant who recovered with tocilizumab alone have been reported in the literature [2, 4]. Therefore, we chose tocilizumab as the first targeted treatment for our patient. After 1 year of treatment, her whole blood cells stayed in the normal range with no serious infections. However, the EBV-DNA titer of peripheral blood leukocytes was higher than that at the beginning. This means that latency and active infections need to be monitored before and after targeted therapy. Table 2 Summary of targeted therapy in all the reported patients with a STAT3 GOF mutation
Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13
a. sex female male male female female female male female male female male male
b. onset age 3 mo 4 yr 6 mo 5 mo 1 yr 1 yr 1 mo 7 yr 3 yr 7 mo 7 yr
c. age 16 yr 10 yr 38 yr 19 yr 9 yr 21 yr 20 yr 8 yr 14 yr 3 yr 8 yr 13 yr 15 yr
d. infections Y Y Y Y Y
e. cytopenia Y Y Y Y Y Y Y Y
f. enteropathy Y Y Y Y Y Y Y Y Y
g. hepatitis Y Y Y Y Y
h. endocrine disease Y Y Y Y Y
i. arthritis Y Y Y Y Y
j. lymphadenopathy Y Y Y
k. hepatosplenomegaly Y Y Y Y Y Y Y Y Y Y
l. interstitial lung disease Y Y Y Y Y
m. short stature Y Y Y Y Y Y Y Y Y Y Y Y
n. reason of for targeted therapy pancytopenia, arthritis enteropathy, colitis interstitial lung disease arthritis, interstitial lung disease hepatosplenomegaly, hepatotitis, enteropathy, interstitial lung disease arthritis enteropathy,
hepatosplenomegaly dermopathy interstitial lung disease anemia enteropathy
HLH
interstitial lung disease
o. tocilizumab alone ✓ ✓ ✓
p. combination of tocilizumab and a JAK inhibitor ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
q. JAK inhibitor alone ✓
r. efficiency of targeted therapy yes yes yes yes yes yes yes yes no yes yes yes no
s. outcome alive alive alive alive alive alive alive alive dead dead dead alive dead
t. mutantmutation in of STAT3 G421R G421R G421R N401D E415L V393A M329K R152W F174S E286G Q344H G421R P715L
u. reference our report [2] [4] [13] [11] [12] [11] [10] [10] [10] [10] [10] [10]
Y represent YES, and slash indicate the parameter was not mentioned in the reference
p: combination of tocilizumab and JAK inhibitors
Patients 4, 5, 6, 9, 11 and 12 were treated with tocilizumab first, and then a JAK inhibitor was added later. Patients 8 and 10 were treated with two targeted drugs simultaneously. Patient 14 was treated with a JAK inhibitor first and then changed to tocilizumab
Table 3 Effect summary for targeted therapy
Cause of targeted therapy Case number Remission number No response Proportion of remission
enteropathy 5 3 2 60%
ILD 5 4 1 80%
arthritis 3 3 0 100%
cytopenia 3 3 0 100%
hepatosplenomegaly 2 2 0 100%
dermopathy 2 1 1 50%
hepatitis/liver failure 1 0 1 0%
The immunological features of STAT3 GOF mutations included hypogammaglobulinemia, increased Th17 cells and decreased Treg cells, which plays a critical role in the development of autoimmunity. While some case reports showed normal Th17 cells or Treg cells in the symptomatic STAT3 GOF patients [8]. There is no immunological index for starting and evaluating the efficacy of targeted therapy. The 12 patients reported above had no immunophenotypic changes with targeted treatment. One patient showed an improvement in the proportion of regulatory T cells after tocilizumab treatment [4]. We evaluated lymphocyte subpopulations before and after treatment. There were no significant improvements in those abnormal changes in our patient after 1 year of treatment. It cannot be ruled out that the immune phenotype changes later than clinical improvement. The relationship between immunological characteristics and mechanism of disease needs further research. The patient still requires monthly IVIG replacement with targeted therapy. Consistent with other reports [2, 16], she had hypogammaglobulinemia and a low proportion of memory B cells. However, the IgG level was higher than normal during the course of autoimmune pancytopenia due to the presence of autoantibodies. Therefore, her hypogammaglobulinemia was consistent with the reduced proportion of memory B cells regardless of the side effects of tocilizumab. The pathogenesis of the abnormal changes leading to reduced unswitched memory B cells and hypogammaglobulinemia require further study.
It has been reported that 5 patients underwent hematopoietic stem cell transplantation [2, 9, 17, 18], of whom four died due to complications, such as infection. The remaining patient was successfully transplanted and lived well. It is known from the reported cases that targeted therapy can effectively control and alleviate life-threatening autoimmune manifestations and lymphoproliferative disorders. The longest follow-up time for targeted therapy is 3.5 years [9]. Our patient was followed up for 2 years, and she had no obvious serious infections or adverse reactions. Aside from IL-6R antagonists and JAK inhibitors, whether better targeted drugs exist requires more clinical data and pathogenesis studies.
Conclusions
We reported the first case of tocilizumab therapy in immune dysregulation disorders caused by a STAT3 GOF mutation in mainland China. Gene sequencing should be performed for patients with early-onset refractory immune dysregulation diseases since routine immunological examination may be nonspecific. Targeted drugs can effectively improve the clinical problems associated with STAT3 gain-of-function mutations, while nontargeted immunosuppressive therapy is usually insufficient.
Methods
The study was carried out at Children’s hospital of Fudan University (Shanghai, China). The protocol 2020–453 was approved by the Ethics Committee of the Children’s Hospital of Fudan University. Because the patient was under the age of 18 years, her parents gave written informed consent to participate tocilizumab therapy and report data in accordance with the declaration of Helsinki.
Clinical data
We retrospectively summarized the clinical data of the STAT3 GOF patient.
Whole-exome sequencing
WES and analysis protocols were adapted for genetic analysis. After obtaining the informed consent from the parents, genomic DNA samples were extracted from the whole blood of the patient and her parents with the QIAamp® DNA Blood Mini Kit (Qiagen, Hilden, Germany). The concentration and quantity of the DNA samples were measured using a NanoDrop ultraviolet spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA) [19]. Genomic DNA fragments were enriched for the target region of the consensus coding sequence exons and sequenced on an Illumina HiSeq 2000 platform (Illumina, San Diego, CA) [19]. Data analyses were conducted by using ANNOVAR and VEP software in our clinical genetic laboratory by a bioinformatics team. The mutation was confirmed by Sanger sequencing.
Routine evaluation of immunological function
Immunological evaluations were carried out during routine clinical work. As previously reported, IgG, IgA, and IgM were detected by nephelometry; IgE was assessed by UniCAP (Pharmacia, Uppsala, Sweden) [20]. Lymphocyte subsets were analyzed by FACSCalibur flow cytometer (Becton Dickinson, Franklin Lakes, NJ, USA) [21]. Whole blood was used for staining of lymphocyte surface markers and analyzed according to a standard multicolor flow cytometric protocol with following antibodies [21]: anti-CD3 (UCHT1), anti-CD8 (RPA-T8), anti-CD27 (M-T271), anti-CD45RA (HI100), anti-CD4 (RPA-T4), anti-TCRαβ (T10B9.1A-31), anti-TCRγδ (B1), anti-CD19 (HIB19), anti-CD24 (ML5), anti-CD38 (HIT2), anti-IgD (IA6–2), and anti-CD57 (NK-1) (all from BD Biosciences).
Supplementary Information
Additional file 1: Supplement Table 1. Variants identified by WES.
Additional file 2: Supplement Table 2. OGTT results of our case (P1).
Abbreviations
STAT3 Signal transduction and activator of transcription 3
JAK Janus kinases
LOF Loss-of-function
GOF Gain-of-function
NGS Next generation sequencing
IUIS International union of immunological societies
HLH Lymphohistiocytosis syndrome
EBV Epstein-barr virus
EM Effector memory
IL-6CM Central memory
IVIG Intravenous immunoglobulin
Acknowledgements
Many thanks to the patient and her parents.
Authors’ contributions
W.X.C., S.J.Q., W.W.J. designed the study. W.X.C., S.J.Q., W.W.J., Y.W.J., H.J., Z.Q.H. diagnosed, treated, and followed up the patient. W.Y. performed the lymphocyte subpopulation analysis. W.W.J. and H.X.Y. abstracted the information from electronic medical chart and follow-up material. S.B.J .and Y.M. did the telephone interview. W.W.J. wrote the first draft. S.J.Q., W.W.J. and L.L.Y. reviewed and revised the manuscript. S.J.Q. and W.X.C. supervised the whole process of the study. The author(s) read and approved the final manuscript.
Funding
This study was funded by the National Natural Science Foundation of China (81373221).
Availability of data and materials
The datasets used and analyzed during the current study available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
The study was carried out at Children’s hospital of Fudan University (Shanghai, China). The protocol 2020–453 was approved by the Ethics Committee of the Children’s Hospital of Fudan University. Because the patient was under the age of 18 years, her parents gave written informed consent to participate tocilizumab therapy and report data in accordance with the declaration of Helsinki.
Consent for publication
Written informed consent for publication of identifying images and other personal or clinical details was obtained from the patient’s parents.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | METHYLPREDNISOLONE, METHYLPREDNISOLONE SODIUM SUCCINATE | DrugsGivenReaction | CC BY | 33731004 | 19,866,414 | 2021-03-17 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Steroid diabetes'. | Efficacy of tocilizumab therapy in a patient with severe pancytopenia associated with a STAT3 gain-of-function mutation.
We aimed to report the clinical characteristics, immunological features, and treatment of one patient with a de novo STAT3 gain-of-function mutation identified by next generation sequencing. We investigated the efficacy of tocilizumab therapy in immune dysregulation diseases caused by STAT3 mutation.
The patient was a 16-year-old girl. She presented with recurrent respiratory infections and chronic diarrhea after birth. She had life-threatening autoimmune pancytopenia at 14 years old. After receiving glucocorticoid therapy, she developed diabetes. However, her pancytopenia relapsed when the glucocorticoid was tapered. Next-generation sequencing showed a de novo heterozygous mutation in the STAT3 gene, c.1261G > A (p. G421R), which was previously described as a gain-of-function mutation. After tocilizumab therapy, her pancytopenia fully resolved, and insulin and glucocorticoid therapies were gradually discontinued within 12 months. She had lymphopenia and an inverted CD4/CD8 ratio before therapy. Lymphocyte subpopulation analysis indicated an expansion of effector memory CD4+, effector memory CD8+ and central memory CD4+ T cells. The proportions of memory B cells and naive CD4+ T cells were decreased, and the proportion of naïve B cells was increased. None of the abnormal lymphocytic changes improved significantly. STAT3 GOF mutations were identified by next gene sequencing in those with early-onset multi-organ autoimmunity. Including our patient, 13 patients with STAT3 GOF mutations received targeted treatment. Twelve of them were treated with tocilizumab alone or combination tocilizumab with JAK inhibitor, and ten patients improved.
Gene sequencing should be performed for patients with early-onset refractory or multiorgan immune dysregulation diseases. Targeted drugs can effectively improve the clinical problems associated with STAT3 gain-of-function mutations, while nontargeted immunosuppressive therapy is usually insufficient.
Background
Signal Transduction and Activator of Transcription 3 (STAT3), one of the seven members of the STAT family of transcription factors, helps transmit key cytokine signals from cell membrane receptors to the nucleus using Janus kinases (JAKs). STATs are involved in multiple processes, including early development, cellular proliferation, survival, and differentiation. Germline STAT3 gene loss-of-function (LOF) mutations cause hyper IgE syndrome, which often manifests as special facial features, recurrent infections, eczema, and joint hyperextension [1]. STAT3 gain-of-function (GOF) mutations were first reported in 2014 [2–8]. In the phenotypical classification of inborn errors in human immunity by the International Union of Immunological Societies (IUIS) in the 2019 update [9], diseases of immune dysregulation were divided into two categories: a) hematopoietic lymphohistiocytosis syndrome (HLH) and Epstein-Barr virus (EBV) susceptibility and b) syndromes with autoimmunity and others. GOF mutation of the germline STAT3 gene is one of the regulatory T cell defects accompanied by autoimmune manifestations. These mutations cause early-onset lymphoproliferation with lymphadenopathy, hepatosplenomegaly and multiorgan autoimmunity, including cytopenia, hepatitis, inflammatory lung disease, enteropathy, and diabetes mellitus.
Patients with STAT3 GOF were treated with regular immunosuppressive treatments before the results of gene sequencing which always couldn’t control all the clinical manifestations [10–14]. Functional analyses of STAT3 GOF mutations demonstrated increased transcriptional activity of STAT3 in unstimulated and/or stimulated cells in vitro [3]. Because IL-6 is one of the primary cytokines that utilizes STAT3 for signal transduction, IL-6 receptor (IL-6R) antagonist therapy currently have been reported to be effective in these patients [4, 5, 10–13]. Here, we reviewed the clinical manifestations and immunological features of one patient with a STAT3 GOF mutation. Moreover, we aimed to investigate the efficacy of tocilizumab therapy.
Results
Case review
A 16-year-old girl born to nonconsanguineous Chinese parents presented with recurrent respiratory infections after birth and suffered at least 1–2 pneumonia events per year. She had chronic diarrhea from 3 months old. When she was 12 years old, she developed cervical adenopathy, alopecia, and bilateral lower limb weakness. She had life-threatening autoimmune pancytopenia with a positive Coomb’s test at the age of 14. She also presented with growth retardation and hepatosplenomegaly. Laboratory data showed that her peripheral blood leukocyte count was (0.90–1.36) × 109/L, her hemoglobin level was 87–106 g/L and her platelet count was (32–51) × 109/L. Her antinuclear antibody (ANA), extractable nuclear antibody (ENA) spectrum and anticardiolipin antibody detection were negative. Complement C3 and C4 were normal. She had lymphopenia and an inverted CD4/CD8 ratio before therapy, and her serum immunoglobulin G concentration was slightly higher than the normal range. Lymphocyte subpopulation analysis indicated expansion of effector memory (EM) CD4+ T, EM CD8+ T and central memory (CM) CD4+ T cells. The proportions of memory B cells and naive CD4+ T cells were decreased, and the proportion of naïve B cells was increased (Fig. 1). Magnetic resonance imaging of the lower limbs revealed abnormal signals in the muscles and fluid accumulation in the intermuscular space, which indicated inflammatory changes. Fig. 1 Lymphocyte subpopulaltions of our patient. A:CD19 + IgD + CD27– naïve B (94.2%), CD19 + IgD–CD27+ memory B (1.9%); B:CD38 + CD24+ transitional B (0%), CD38 + CD24– plasmablast B (1.7%); C: CD3 + CD4+ T (24.4%); CD3 + CD8+ T (66.3%); CD3 + CD4–CD8– double negative T (7.2%); D:subpopulaltions of CD4+ T cells: CD3 + CD4 + CD45RA + CD27+ naïve T (11%), CD3 + CD4 + CD45RO + CD27+ central memory T (49.6%), CD3 + CD4 + CD45RO + CD27– effector memory T (23.8%); E:subpopulaltions of CD8 + T cells: CD3 + CD8 + CD45RA + CD27+ naïve T (48.1%), CD3 + CD8 + CD45RO + CD27+ central memory T (13.7%), CD3 + CD8 + CD45RO + CD27– effect memory T (9.3%), CD3 + CD8 + CD45RA + CD27– TEMRA T (28.9%)
Gene analysis
Next-gene sequencing (NGS) revealed that she had a heterozygous de novo mutation in the STAT3 gene, while her parents were normal (Fig. 2). The missense mutation in the DNA binding domain (c.1261G > A, p. G421R) was described as a gain-of-function mutation in previous studies [2]. Fig. 2 Sanger sequence results of our patient and her parents
Treatment and follow-up
Before the gene sequencing results were available, the patient accepted intravenous methylprednisolone (1.6 mg/kg/day) for autoimmune pancytopenia. She was changed to the same dose of oral glucocorticoid tablet after Coomb’s test turned negative and pancytopenia improved. But the pancytopenia relapsed several times once the glucocorticoid dose was less than 2 mg/kg/day. Meanwhile, she developed diabetes and worse weakness of lower limbs during the glucocorticoid treatment. The fasting plasma glucose was 7.2 mmol/L, the glycated hemoglobin (Hb1c) was 5.8%, and all the insulin autoantibodies were negative. The oral glucose tolerance test showed increased C peptide and plasma glucose after 30 min, 60 min, 120 min, and 180 min of oral glucose, while plasma insulin level didn’t increase (supplement Table 2). So, we diagnosed diabetes and considered it as a side effect of glucocorticoid therapy. The blood biochemistry results were normal before and after treatment, including creatine kinase (CK), serum electrolytes, transaminase, and creatinine. The diagnosis of myositis was based on MRI abnormal signals in muscle and cutting movement assessment score (CMAS) was 15 of 52.
After obtaining informed consent from her parents, we administered IL-6R antagonist treatment (tocilizumab) at a dosage of 8 mg/kg intravenous infusion every 2 weeks. After 2 months of tocilizumab treatment, the patient’s pancytopenia fully resolved. She discontinued insulin injection after 4 months of tocilizumab therapy, and glucocorticoid therapy was gradually discontinued within 12 months. Her serum IL-6 levels increased before glucocorticoid therapy and improved for a while but fluctuated after glucocorticoid tapering and gradually decreased to normal after tocilizumab therapy (Fig. 3). She underwent intravenous immunoglobulin (IVIG) replacement after 6 months because of hypogammaglobulinemia. Beginning in the second year of therapy, she extended the interval of tocilizumab to every 4–6 weeks (240 mg/dose, after her weight was above 30 kg), with a good response evidenced by a normal hemoglobin level and negative Coomb’s test. Lymphadenopathy and hepatosplenomegaly returned to mild enlargement (Table 1). Fig. 3 Serum IL-6 before and after tocilizumab of our patient. She accepted glucocorticoid first from week − 18 to week 0
Table 1 Clinical features and immunotype of our patient with a STAT3 GOF mutation
tocilizumab therapy before after
lymphadenopathy yes no
hepatosplenomegaly yes (severe) mild
autoimmune pancytopenia yes no
myositis worse better
alopecia yes better
WBC
(×109/L)
0.90–1.36#
0.9–6.8##
4.7–8.3###
HB
g/L
87–106#
46–139##
112–139###
PLT
(×109/L)
32–51#
32–123##
107–178###
IgM 1.84 0.62
IgA 1.3 0.25
IgG 14.5 6.6 a
IgE < 2 < 2
CD3 89.13% (607) 82.87% (786)
CD4 32.41% (221) 30.61% (290)
CD8 51.17% (349) 48.70% (462)
CD4/CD8 0.63 0.63
CD19 8.74% (60) 9.08% (31)
NK 1.49% (10) 7.28% (69)
* with monthly IVIG replacement
# before glucocorticoid treatment, ## after glucocorticoid treatment;
### after 1 month of tocilizumab therapy
We regularly followed up for infection indicators during targeted therapy. She had cervical lymphadenitis and Candida albicans vaginitis once during 2 years of therapy. Her EBV-DNA load of whole leukocytes in the peripheral blood was higher than the level at the beginning, changing from 1.29 × 104 copies/ml to 3.58 × 106 copies/ml. In addition to treatment with targeted drugs, she accepted oral itraconazole and acyclovir tablets.
Her immune phenotypes after tocilizumab showed hypogammaglobulinemia after 6 months of therapy. All the abnormal lymphocytic changes (expansion of EM CD4+ T, EM CD8+ T and CM CD4+ T cells; decreased memory B cell and naive CD4+ T cell levels; and an increased naïve B cell level) did not improve significantly (Fig. 4). Fig. 4 Subpopulation of T/B lymphocytes of our patient before and 1 month, 12 months after tocilizumab
Discussion
STAT3 GOF mutations were reported in patients with multiple early-onset autoimmune manifestations by NGS [3]. Fabre et al. summarized the clinical features of 42 patients, and the most common manifestations were autoimmune cytopenia, lymphoproliferation, enteropathy, interstitial lung disease, thyroiditis, diabetes, and growth retardation; some of the patients had recurrent or opportunistic infections [14]. The onset age and major symptoms of our patient were similar to those of other patients reported previously [2, 3]. She developed diabetes during glucocorticoid therapy with normal glycated hemoglobin levels, which is different from the early-onset type 1 diabetes reported in the literature. Her Hb1c, insulin autoantibodies and oral glucose tolerance test indicated her diabetes was a side effect of glucocorticoid therapy. We also found that her bilateral lower limb weakness was related to immune myositis on MRI. The abnormal changes in the muscles improved after tocilizumab treatment (Fig. 5). Fig. 5 Magnetic resonance imaging of left lower limbs of patient 1. a and c revealed abnormal signals in muscle and fluid accumulation in the intermuscular space considering inflammatory changes. b and d revealed abnormal changes recovered after tocilizumab
According the functions of immune system, infection tendency, autoimmunity and extremely abnormal immune reactions are common manifestations of primary immunodeficiencies. So, we did NGS at the beginning of diagnose considering a genetic defect may exist. STAT3 GOF mutations were identified by gene sequencing in those with early-onset multi-organ autoimmunity.
Activation of STAT3 leads to the production of downstream cytokines, including glycoprotein 130 (a component of IL-6 and IL-27), common gamma chain cytokines, IL-10 family cytokines and IL-23. After cytokines bind to their receptors, one of four Janus kinases (JAKs) is activated and phosphorylates the cytokine receptor. STAT molecules are recruited to the phosphorylated receptor and then translocate to the nucleus, altering gene expression [15]. The proportions of regulatory T cells are reduced, while IL-17 levels are increased in patients with STAT3 GOF mutations [3, 8]. In vitro, IL-6R antagonists can reduce IL-17 secretion and improve immune dysregulation by increasing regulatory T cell differentiation [4]. Therefore, IL-6R antagonists and JAK inhibitors can inhibit STAT3 signaling pathway overactivation and be used to treat patients with STAT3 GOF mutations.
Twelve patients with STAT3 GOF mutations received targeted treatment in 5 reports [4, 5, 9–11]. Three (including our patient, P1) of the 13 patients were treated with tocilizumab alone, and all three improved (P1, P2, and P3); 1 patient improved with JAK inhibitor treatment alone (P7); the remaining 9 patients were treated successively or simultaneously with tocilizumab and JAK inhibitors because of disease severity or incomplete remission. Combination treatment could take the following factors into consideration: enteropathy (4/9), interstitial pulmonary disease (4/9), arthritis (2/9), hepatitis (3/9), splenomegaly (1/9), and cytopenia (2/9). Seven of the nine patients who received combined treatment achieved remission (Table 2). STAT3 GOF mutation patients manifesting with multiple clinical symptoms might need combination therapy if the tocilizumab or JAK inhibitors alone couldn’t control the disease. The outcomes of targeted therapy are summarized in Table 3. The symptoms of arthritis, cytopenia, hepatosplenomegaly and hepatitis were all alleviated. Three of the 13 patients died. P10 died of infection after transplant, while recurrent HLH was resolved by targeted treatment. P9 died of sepsis and diffuse intravascular coagulation. P13 died of respiratory failure. Considering cytopenia as the common adverse reaction to JAK inhibitors, two patients with the G421R mutant who recovered with tocilizumab alone have been reported in the literature [2, 4]. Therefore, we chose tocilizumab as the first targeted treatment for our patient. After 1 year of treatment, her whole blood cells stayed in the normal range with no serious infections. However, the EBV-DNA titer of peripheral blood leukocytes was higher than that at the beginning. This means that latency and active infections need to be monitored before and after targeted therapy. Table 2 Summary of targeted therapy in all the reported patients with a STAT3 GOF mutation
Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13
a. sex female male male female female female male female male female male male
b. onset age 3 mo 4 yr 6 mo 5 mo 1 yr 1 yr 1 mo 7 yr 3 yr 7 mo 7 yr
c. age 16 yr 10 yr 38 yr 19 yr 9 yr 21 yr 20 yr 8 yr 14 yr 3 yr 8 yr 13 yr 15 yr
d. infections Y Y Y Y Y
e. cytopenia Y Y Y Y Y Y Y Y
f. enteropathy Y Y Y Y Y Y Y Y Y
g. hepatitis Y Y Y Y Y
h. endocrine disease Y Y Y Y Y
i. arthritis Y Y Y Y Y
j. lymphadenopathy Y Y Y
k. hepatosplenomegaly Y Y Y Y Y Y Y Y Y Y
l. interstitial lung disease Y Y Y Y Y
m. short stature Y Y Y Y Y Y Y Y Y Y Y Y
n. reason of for targeted therapy pancytopenia, arthritis enteropathy, colitis interstitial lung disease arthritis, interstitial lung disease hepatosplenomegaly, hepatotitis, enteropathy, interstitial lung disease arthritis enteropathy,
hepatosplenomegaly dermopathy interstitial lung disease anemia enteropathy
HLH
interstitial lung disease
o. tocilizumab alone ✓ ✓ ✓
p. combination of tocilizumab and a JAK inhibitor ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
q. JAK inhibitor alone ✓
r. efficiency of targeted therapy yes yes yes yes yes yes yes yes no yes yes yes no
s. outcome alive alive alive alive alive alive alive alive dead dead dead alive dead
t. mutantmutation in of STAT3 G421R G421R G421R N401D E415L V393A M329K R152W F174S E286G Q344H G421R P715L
u. reference our report [2] [4] [13] [11] [12] [11] [10] [10] [10] [10] [10] [10]
Y represent YES, and slash indicate the parameter was not mentioned in the reference
p: combination of tocilizumab and JAK inhibitors
Patients 4, 5, 6, 9, 11 and 12 were treated with tocilizumab first, and then a JAK inhibitor was added later. Patients 8 and 10 were treated with two targeted drugs simultaneously. Patient 14 was treated with a JAK inhibitor first and then changed to tocilizumab
Table 3 Effect summary for targeted therapy
Cause of targeted therapy Case number Remission number No response Proportion of remission
enteropathy 5 3 2 60%
ILD 5 4 1 80%
arthritis 3 3 0 100%
cytopenia 3 3 0 100%
hepatosplenomegaly 2 2 0 100%
dermopathy 2 1 1 50%
hepatitis/liver failure 1 0 1 0%
The immunological features of STAT3 GOF mutations included hypogammaglobulinemia, increased Th17 cells and decreased Treg cells, which plays a critical role in the development of autoimmunity. While some case reports showed normal Th17 cells or Treg cells in the symptomatic STAT3 GOF patients [8]. There is no immunological index for starting and evaluating the efficacy of targeted therapy. The 12 patients reported above had no immunophenotypic changes with targeted treatment. One patient showed an improvement in the proportion of regulatory T cells after tocilizumab treatment [4]. We evaluated lymphocyte subpopulations before and after treatment. There were no significant improvements in those abnormal changes in our patient after 1 year of treatment. It cannot be ruled out that the immune phenotype changes later than clinical improvement. The relationship between immunological characteristics and mechanism of disease needs further research. The patient still requires monthly IVIG replacement with targeted therapy. Consistent with other reports [2, 16], she had hypogammaglobulinemia and a low proportion of memory B cells. However, the IgG level was higher than normal during the course of autoimmune pancytopenia due to the presence of autoantibodies. Therefore, her hypogammaglobulinemia was consistent with the reduced proportion of memory B cells regardless of the side effects of tocilizumab. The pathogenesis of the abnormal changes leading to reduced unswitched memory B cells and hypogammaglobulinemia require further study.
It has been reported that 5 patients underwent hematopoietic stem cell transplantation [2, 9, 17, 18], of whom four died due to complications, such as infection. The remaining patient was successfully transplanted and lived well. It is known from the reported cases that targeted therapy can effectively control and alleviate life-threatening autoimmune manifestations and lymphoproliferative disorders. The longest follow-up time for targeted therapy is 3.5 years [9]. Our patient was followed up for 2 years, and she had no obvious serious infections or adverse reactions. Aside from IL-6R antagonists and JAK inhibitors, whether better targeted drugs exist requires more clinical data and pathogenesis studies.
Conclusions
We reported the first case of tocilizumab therapy in immune dysregulation disorders caused by a STAT3 GOF mutation in mainland China. Gene sequencing should be performed for patients with early-onset refractory immune dysregulation diseases since routine immunological examination may be nonspecific. Targeted drugs can effectively improve the clinical problems associated with STAT3 gain-of-function mutations, while nontargeted immunosuppressive therapy is usually insufficient.
Methods
The study was carried out at Children’s hospital of Fudan University (Shanghai, China). The protocol 2020–453 was approved by the Ethics Committee of the Children’s Hospital of Fudan University. Because the patient was under the age of 18 years, her parents gave written informed consent to participate tocilizumab therapy and report data in accordance with the declaration of Helsinki.
Clinical data
We retrospectively summarized the clinical data of the STAT3 GOF patient.
Whole-exome sequencing
WES and analysis protocols were adapted for genetic analysis. After obtaining the informed consent from the parents, genomic DNA samples were extracted from the whole blood of the patient and her parents with the QIAamp® DNA Blood Mini Kit (Qiagen, Hilden, Germany). The concentration and quantity of the DNA samples were measured using a NanoDrop ultraviolet spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA) [19]. Genomic DNA fragments were enriched for the target region of the consensus coding sequence exons and sequenced on an Illumina HiSeq 2000 platform (Illumina, San Diego, CA) [19]. Data analyses were conducted by using ANNOVAR and VEP software in our clinical genetic laboratory by a bioinformatics team. The mutation was confirmed by Sanger sequencing.
Routine evaluation of immunological function
Immunological evaluations were carried out during routine clinical work. As previously reported, IgG, IgA, and IgM were detected by nephelometry; IgE was assessed by UniCAP (Pharmacia, Uppsala, Sweden) [20]. Lymphocyte subsets were analyzed by FACSCalibur flow cytometer (Becton Dickinson, Franklin Lakes, NJ, USA) [21]. Whole blood was used for staining of lymphocyte surface markers and analyzed according to a standard multicolor flow cytometric protocol with following antibodies [21]: anti-CD3 (UCHT1), anti-CD8 (RPA-T8), anti-CD27 (M-T271), anti-CD45RA (HI100), anti-CD4 (RPA-T4), anti-TCRαβ (T10B9.1A-31), anti-TCRγδ (B1), anti-CD19 (HIB19), anti-CD24 (ML5), anti-CD38 (HIT2), anti-IgD (IA6–2), and anti-CD57 (NK-1) (all from BD Biosciences).
Supplementary Information
Additional file 1: Supplement Table 1. Variants identified by WES.
Additional file 2: Supplement Table 2. OGTT results of our case (P1).
Abbreviations
STAT3 Signal transduction and activator of transcription 3
JAK Janus kinases
LOF Loss-of-function
GOF Gain-of-function
NGS Next generation sequencing
IUIS International union of immunological societies
HLH Lymphohistiocytosis syndrome
EBV Epstein-barr virus
EM Effector memory
IL-6CM Central memory
IVIG Intravenous immunoglobulin
Acknowledgements
Many thanks to the patient and her parents.
Authors’ contributions
W.X.C., S.J.Q., W.W.J. designed the study. W.X.C., S.J.Q., W.W.J., Y.W.J., H.J., Z.Q.H. diagnosed, treated, and followed up the patient. W.Y. performed the lymphocyte subpopulation analysis. W.W.J. and H.X.Y. abstracted the information from electronic medical chart and follow-up material. S.B.J .and Y.M. did the telephone interview. W.W.J. wrote the first draft. S.J.Q., W.W.J. and L.L.Y. reviewed and revised the manuscript. S.J.Q. and W.X.C. supervised the whole process of the study. The author(s) read and approved the final manuscript.
Funding
This study was funded by the National Natural Science Foundation of China (81373221).
Availability of data and materials
The datasets used and analyzed during the current study available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
The study was carried out at Children’s hospital of Fudan University (Shanghai, China). The protocol 2020–453 was approved by the Ethics Committee of the Children’s Hospital of Fudan University. Because the patient was under the age of 18 years, her parents gave written informed consent to participate tocilizumab therapy and report data in accordance with the declaration of Helsinki.
Consent for publication
Written informed consent for publication of identifying images and other personal or clinical details was obtained from the patient’s parents.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | METHYLPREDNISOLONE, METHYLPREDNISOLONE SODIUM SUCCINATE | DrugsGivenReaction | CC BY | 33731004 | 19,866,414 | 2021-03-17 |
What was the administration route of drug 'METHYLPREDNISOLONE SODIUM SUCCINATE'? | Efficacy of tocilizumab therapy in a patient with severe pancytopenia associated with a STAT3 gain-of-function mutation.
We aimed to report the clinical characteristics, immunological features, and treatment of one patient with a de novo STAT3 gain-of-function mutation identified by next generation sequencing. We investigated the efficacy of tocilizumab therapy in immune dysregulation diseases caused by STAT3 mutation.
The patient was a 16-year-old girl. She presented with recurrent respiratory infections and chronic diarrhea after birth. She had life-threatening autoimmune pancytopenia at 14 years old. After receiving glucocorticoid therapy, she developed diabetes. However, her pancytopenia relapsed when the glucocorticoid was tapered. Next-generation sequencing showed a de novo heterozygous mutation in the STAT3 gene, c.1261G > A (p. G421R), which was previously described as a gain-of-function mutation. After tocilizumab therapy, her pancytopenia fully resolved, and insulin and glucocorticoid therapies were gradually discontinued within 12 months. She had lymphopenia and an inverted CD4/CD8 ratio before therapy. Lymphocyte subpopulation analysis indicated an expansion of effector memory CD4+, effector memory CD8+ and central memory CD4+ T cells. The proportions of memory B cells and naive CD4+ T cells were decreased, and the proportion of naïve B cells was increased. None of the abnormal lymphocytic changes improved significantly. STAT3 GOF mutations were identified by next gene sequencing in those with early-onset multi-organ autoimmunity. Including our patient, 13 patients with STAT3 GOF mutations received targeted treatment. Twelve of them were treated with tocilizumab alone or combination tocilizumab with JAK inhibitor, and ten patients improved.
Gene sequencing should be performed for patients with early-onset refractory or multiorgan immune dysregulation diseases. Targeted drugs can effectively improve the clinical problems associated with STAT3 gain-of-function mutations, while nontargeted immunosuppressive therapy is usually insufficient.
Background
Signal Transduction and Activator of Transcription 3 (STAT3), one of the seven members of the STAT family of transcription factors, helps transmit key cytokine signals from cell membrane receptors to the nucleus using Janus kinases (JAKs). STATs are involved in multiple processes, including early development, cellular proliferation, survival, and differentiation. Germline STAT3 gene loss-of-function (LOF) mutations cause hyper IgE syndrome, which often manifests as special facial features, recurrent infections, eczema, and joint hyperextension [1]. STAT3 gain-of-function (GOF) mutations were first reported in 2014 [2–8]. In the phenotypical classification of inborn errors in human immunity by the International Union of Immunological Societies (IUIS) in the 2019 update [9], diseases of immune dysregulation were divided into two categories: a) hematopoietic lymphohistiocytosis syndrome (HLH) and Epstein-Barr virus (EBV) susceptibility and b) syndromes with autoimmunity and others. GOF mutation of the germline STAT3 gene is one of the regulatory T cell defects accompanied by autoimmune manifestations. These mutations cause early-onset lymphoproliferation with lymphadenopathy, hepatosplenomegaly and multiorgan autoimmunity, including cytopenia, hepatitis, inflammatory lung disease, enteropathy, and diabetes mellitus.
Patients with STAT3 GOF were treated with regular immunosuppressive treatments before the results of gene sequencing which always couldn’t control all the clinical manifestations [10–14]. Functional analyses of STAT3 GOF mutations demonstrated increased transcriptional activity of STAT3 in unstimulated and/or stimulated cells in vitro [3]. Because IL-6 is one of the primary cytokines that utilizes STAT3 for signal transduction, IL-6 receptor (IL-6R) antagonist therapy currently have been reported to be effective in these patients [4, 5, 10–13]. Here, we reviewed the clinical manifestations and immunological features of one patient with a STAT3 GOF mutation. Moreover, we aimed to investigate the efficacy of tocilizumab therapy.
Results
Case review
A 16-year-old girl born to nonconsanguineous Chinese parents presented with recurrent respiratory infections after birth and suffered at least 1–2 pneumonia events per year. She had chronic diarrhea from 3 months old. When she was 12 years old, she developed cervical adenopathy, alopecia, and bilateral lower limb weakness. She had life-threatening autoimmune pancytopenia with a positive Coomb’s test at the age of 14. She also presented with growth retardation and hepatosplenomegaly. Laboratory data showed that her peripheral blood leukocyte count was (0.90–1.36) × 109/L, her hemoglobin level was 87–106 g/L and her platelet count was (32–51) × 109/L. Her antinuclear antibody (ANA), extractable nuclear antibody (ENA) spectrum and anticardiolipin antibody detection were negative. Complement C3 and C4 were normal. She had lymphopenia and an inverted CD4/CD8 ratio before therapy, and her serum immunoglobulin G concentration was slightly higher than the normal range. Lymphocyte subpopulation analysis indicated expansion of effector memory (EM) CD4+ T, EM CD8+ T and central memory (CM) CD4+ T cells. The proportions of memory B cells and naive CD4+ T cells were decreased, and the proportion of naïve B cells was increased (Fig. 1). Magnetic resonance imaging of the lower limbs revealed abnormal signals in the muscles and fluid accumulation in the intermuscular space, which indicated inflammatory changes. Fig. 1 Lymphocyte subpopulaltions of our patient. A:CD19 + IgD + CD27– naïve B (94.2%), CD19 + IgD–CD27+ memory B (1.9%); B:CD38 + CD24+ transitional B (0%), CD38 + CD24– plasmablast B (1.7%); C: CD3 + CD4+ T (24.4%); CD3 + CD8+ T (66.3%); CD3 + CD4–CD8– double negative T (7.2%); D:subpopulaltions of CD4+ T cells: CD3 + CD4 + CD45RA + CD27+ naïve T (11%), CD3 + CD4 + CD45RO + CD27+ central memory T (49.6%), CD3 + CD4 + CD45RO + CD27– effector memory T (23.8%); E:subpopulaltions of CD8 + T cells: CD3 + CD8 + CD45RA + CD27+ naïve T (48.1%), CD3 + CD8 + CD45RO + CD27+ central memory T (13.7%), CD3 + CD8 + CD45RO + CD27– effect memory T (9.3%), CD3 + CD8 + CD45RA + CD27– TEMRA T (28.9%)
Gene analysis
Next-gene sequencing (NGS) revealed that she had a heterozygous de novo mutation in the STAT3 gene, while her parents were normal (Fig. 2). The missense mutation in the DNA binding domain (c.1261G > A, p. G421R) was described as a gain-of-function mutation in previous studies [2]. Fig. 2 Sanger sequence results of our patient and her parents
Treatment and follow-up
Before the gene sequencing results were available, the patient accepted intravenous methylprednisolone (1.6 mg/kg/day) for autoimmune pancytopenia. She was changed to the same dose of oral glucocorticoid tablet after Coomb’s test turned negative and pancytopenia improved. But the pancytopenia relapsed several times once the glucocorticoid dose was less than 2 mg/kg/day. Meanwhile, she developed diabetes and worse weakness of lower limbs during the glucocorticoid treatment. The fasting plasma glucose was 7.2 mmol/L, the glycated hemoglobin (Hb1c) was 5.8%, and all the insulin autoantibodies were negative. The oral glucose tolerance test showed increased C peptide and plasma glucose after 30 min, 60 min, 120 min, and 180 min of oral glucose, while plasma insulin level didn’t increase (supplement Table 2). So, we diagnosed diabetes and considered it as a side effect of glucocorticoid therapy. The blood biochemistry results were normal before and after treatment, including creatine kinase (CK), serum electrolytes, transaminase, and creatinine. The diagnosis of myositis was based on MRI abnormal signals in muscle and cutting movement assessment score (CMAS) was 15 of 52.
After obtaining informed consent from her parents, we administered IL-6R antagonist treatment (tocilizumab) at a dosage of 8 mg/kg intravenous infusion every 2 weeks. After 2 months of tocilizumab treatment, the patient’s pancytopenia fully resolved. She discontinued insulin injection after 4 months of tocilizumab therapy, and glucocorticoid therapy was gradually discontinued within 12 months. Her serum IL-6 levels increased before glucocorticoid therapy and improved for a while but fluctuated after glucocorticoid tapering and gradually decreased to normal after tocilizumab therapy (Fig. 3). She underwent intravenous immunoglobulin (IVIG) replacement after 6 months because of hypogammaglobulinemia. Beginning in the second year of therapy, she extended the interval of tocilizumab to every 4–6 weeks (240 mg/dose, after her weight was above 30 kg), with a good response evidenced by a normal hemoglobin level and negative Coomb’s test. Lymphadenopathy and hepatosplenomegaly returned to mild enlargement (Table 1). Fig. 3 Serum IL-6 before and after tocilizumab of our patient. She accepted glucocorticoid first from week − 18 to week 0
Table 1 Clinical features and immunotype of our patient with a STAT3 GOF mutation
tocilizumab therapy before after
lymphadenopathy yes no
hepatosplenomegaly yes (severe) mild
autoimmune pancytopenia yes no
myositis worse better
alopecia yes better
WBC
(×109/L)
0.90–1.36#
0.9–6.8##
4.7–8.3###
HB
g/L
87–106#
46–139##
112–139###
PLT
(×109/L)
32–51#
32–123##
107–178###
IgM 1.84 0.62
IgA 1.3 0.25
IgG 14.5 6.6 a
IgE < 2 < 2
CD3 89.13% (607) 82.87% (786)
CD4 32.41% (221) 30.61% (290)
CD8 51.17% (349) 48.70% (462)
CD4/CD8 0.63 0.63
CD19 8.74% (60) 9.08% (31)
NK 1.49% (10) 7.28% (69)
* with monthly IVIG replacement
# before glucocorticoid treatment, ## after glucocorticoid treatment;
### after 1 month of tocilizumab therapy
We regularly followed up for infection indicators during targeted therapy. She had cervical lymphadenitis and Candida albicans vaginitis once during 2 years of therapy. Her EBV-DNA load of whole leukocytes in the peripheral blood was higher than the level at the beginning, changing from 1.29 × 104 copies/ml to 3.58 × 106 copies/ml. In addition to treatment with targeted drugs, she accepted oral itraconazole and acyclovir tablets.
Her immune phenotypes after tocilizumab showed hypogammaglobulinemia after 6 months of therapy. All the abnormal lymphocytic changes (expansion of EM CD4+ T, EM CD8+ T and CM CD4+ T cells; decreased memory B cell and naive CD4+ T cell levels; and an increased naïve B cell level) did not improve significantly (Fig. 4). Fig. 4 Subpopulation of T/B lymphocytes of our patient before and 1 month, 12 months after tocilizumab
Discussion
STAT3 GOF mutations were reported in patients with multiple early-onset autoimmune manifestations by NGS [3]. Fabre et al. summarized the clinical features of 42 patients, and the most common manifestations were autoimmune cytopenia, lymphoproliferation, enteropathy, interstitial lung disease, thyroiditis, diabetes, and growth retardation; some of the patients had recurrent or opportunistic infections [14]. The onset age and major symptoms of our patient were similar to those of other patients reported previously [2, 3]. She developed diabetes during glucocorticoid therapy with normal glycated hemoglobin levels, which is different from the early-onset type 1 diabetes reported in the literature. Her Hb1c, insulin autoantibodies and oral glucose tolerance test indicated her diabetes was a side effect of glucocorticoid therapy. We also found that her bilateral lower limb weakness was related to immune myositis on MRI. The abnormal changes in the muscles improved after tocilizumab treatment (Fig. 5). Fig. 5 Magnetic resonance imaging of left lower limbs of patient 1. a and c revealed abnormal signals in muscle and fluid accumulation in the intermuscular space considering inflammatory changes. b and d revealed abnormal changes recovered after tocilizumab
According the functions of immune system, infection tendency, autoimmunity and extremely abnormal immune reactions are common manifestations of primary immunodeficiencies. So, we did NGS at the beginning of diagnose considering a genetic defect may exist. STAT3 GOF mutations were identified by gene sequencing in those with early-onset multi-organ autoimmunity.
Activation of STAT3 leads to the production of downstream cytokines, including glycoprotein 130 (a component of IL-6 and IL-27), common gamma chain cytokines, IL-10 family cytokines and IL-23. After cytokines bind to their receptors, one of four Janus kinases (JAKs) is activated and phosphorylates the cytokine receptor. STAT molecules are recruited to the phosphorylated receptor and then translocate to the nucleus, altering gene expression [15]. The proportions of regulatory T cells are reduced, while IL-17 levels are increased in patients with STAT3 GOF mutations [3, 8]. In vitro, IL-6R antagonists can reduce IL-17 secretion and improve immune dysregulation by increasing regulatory T cell differentiation [4]. Therefore, IL-6R antagonists and JAK inhibitors can inhibit STAT3 signaling pathway overactivation and be used to treat patients with STAT3 GOF mutations.
Twelve patients with STAT3 GOF mutations received targeted treatment in 5 reports [4, 5, 9–11]. Three (including our patient, P1) of the 13 patients were treated with tocilizumab alone, and all three improved (P1, P2, and P3); 1 patient improved with JAK inhibitor treatment alone (P7); the remaining 9 patients were treated successively or simultaneously with tocilizumab and JAK inhibitors because of disease severity or incomplete remission. Combination treatment could take the following factors into consideration: enteropathy (4/9), interstitial pulmonary disease (4/9), arthritis (2/9), hepatitis (3/9), splenomegaly (1/9), and cytopenia (2/9). Seven of the nine patients who received combined treatment achieved remission (Table 2). STAT3 GOF mutation patients manifesting with multiple clinical symptoms might need combination therapy if the tocilizumab or JAK inhibitors alone couldn’t control the disease. The outcomes of targeted therapy are summarized in Table 3. The symptoms of arthritis, cytopenia, hepatosplenomegaly and hepatitis were all alleviated. Three of the 13 patients died. P10 died of infection after transplant, while recurrent HLH was resolved by targeted treatment. P9 died of sepsis and diffuse intravascular coagulation. P13 died of respiratory failure. Considering cytopenia as the common adverse reaction to JAK inhibitors, two patients with the G421R mutant who recovered with tocilizumab alone have been reported in the literature [2, 4]. Therefore, we chose tocilizumab as the first targeted treatment for our patient. After 1 year of treatment, her whole blood cells stayed in the normal range with no serious infections. However, the EBV-DNA titer of peripheral blood leukocytes was higher than that at the beginning. This means that latency and active infections need to be monitored before and after targeted therapy. Table 2 Summary of targeted therapy in all the reported patients with a STAT3 GOF mutation
Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13
a. sex female male male female female female male female male female male male
b. onset age 3 mo 4 yr 6 mo 5 mo 1 yr 1 yr 1 mo 7 yr 3 yr 7 mo 7 yr
c. age 16 yr 10 yr 38 yr 19 yr 9 yr 21 yr 20 yr 8 yr 14 yr 3 yr 8 yr 13 yr 15 yr
d. infections Y Y Y Y Y
e. cytopenia Y Y Y Y Y Y Y Y
f. enteropathy Y Y Y Y Y Y Y Y Y
g. hepatitis Y Y Y Y Y
h. endocrine disease Y Y Y Y Y
i. arthritis Y Y Y Y Y
j. lymphadenopathy Y Y Y
k. hepatosplenomegaly Y Y Y Y Y Y Y Y Y Y
l. interstitial lung disease Y Y Y Y Y
m. short stature Y Y Y Y Y Y Y Y Y Y Y Y
n. reason of for targeted therapy pancytopenia, arthritis enteropathy, colitis interstitial lung disease arthritis, interstitial lung disease hepatosplenomegaly, hepatotitis, enteropathy, interstitial lung disease arthritis enteropathy,
hepatosplenomegaly dermopathy interstitial lung disease anemia enteropathy
HLH
interstitial lung disease
o. tocilizumab alone ✓ ✓ ✓
p. combination of tocilizumab and a JAK inhibitor ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
q. JAK inhibitor alone ✓
r. efficiency of targeted therapy yes yes yes yes yes yes yes yes no yes yes yes no
s. outcome alive alive alive alive alive alive alive alive dead dead dead alive dead
t. mutantmutation in of STAT3 G421R G421R G421R N401D E415L V393A M329K R152W F174S E286G Q344H G421R P715L
u. reference our report [2] [4] [13] [11] [12] [11] [10] [10] [10] [10] [10] [10]
Y represent YES, and slash indicate the parameter was not mentioned in the reference
p: combination of tocilizumab and JAK inhibitors
Patients 4, 5, 6, 9, 11 and 12 were treated with tocilizumab first, and then a JAK inhibitor was added later. Patients 8 and 10 were treated with two targeted drugs simultaneously. Patient 14 was treated with a JAK inhibitor first and then changed to tocilizumab
Table 3 Effect summary for targeted therapy
Cause of targeted therapy Case number Remission number No response Proportion of remission
enteropathy 5 3 2 60%
ILD 5 4 1 80%
arthritis 3 3 0 100%
cytopenia 3 3 0 100%
hepatosplenomegaly 2 2 0 100%
dermopathy 2 1 1 50%
hepatitis/liver failure 1 0 1 0%
The immunological features of STAT3 GOF mutations included hypogammaglobulinemia, increased Th17 cells and decreased Treg cells, which plays a critical role in the development of autoimmunity. While some case reports showed normal Th17 cells or Treg cells in the symptomatic STAT3 GOF patients [8]. There is no immunological index for starting and evaluating the efficacy of targeted therapy. The 12 patients reported above had no immunophenotypic changes with targeted treatment. One patient showed an improvement in the proportion of regulatory T cells after tocilizumab treatment [4]. We evaluated lymphocyte subpopulations before and after treatment. There were no significant improvements in those abnormal changes in our patient after 1 year of treatment. It cannot be ruled out that the immune phenotype changes later than clinical improvement. The relationship between immunological characteristics and mechanism of disease needs further research. The patient still requires monthly IVIG replacement with targeted therapy. Consistent with other reports [2, 16], she had hypogammaglobulinemia and a low proportion of memory B cells. However, the IgG level was higher than normal during the course of autoimmune pancytopenia due to the presence of autoantibodies. Therefore, her hypogammaglobulinemia was consistent with the reduced proportion of memory B cells regardless of the side effects of tocilizumab. The pathogenesis of the abnormal changes leading to reduced unswitched memory B cells and hypogammaglobulinemia require further study.
It has been reported that 5 patients underwent hematopoietic stem cell transplantation [2, 9, 17, 18], of whom four died due to complications, such as infection. The remaining patient was successfully transplanted and lived well. It is known from the reported cases that targeted therapy can effectively control and alleviate life-threatening autoimmune manifestations and lymphoproliferative disorders. The longest follow-up time for targeted therapy is 3.5 years [9]. Our patient was followed up for 2 years, and she had no obvious serious infections or adverse reactions. Aside from IL-6R antagonists and JAK inhibitors, whether better targeted drugs exist requires more clinical data and pathogenesis studies.
Conclusions
We reported the first case of tocilizumab therapy in immune dysregulation disorders caused by a STAT3 GOF mutation in mainland China. Gene sequencing should be performed for patients with early-onset refractory immune dysregulation diseases since routine immunological examination may be nonspecific. Targeted drugs can effectively improve the clinical problems associated with STAT3 gain-of-function mutations, while nontargeted immunosuppressive therapy is usually insufficient.
Methods
The study was carried out at Children’s hospital of Fudan University (Shanghai, China). The protocol 2020–453 was approved by the Ethics Committee of the Children’s Hospital of Fudan University. Because the patient was under the age of 18 years, her parents gave written informed consent to participate tocilizumab therapy and report data in accordance with the declaration of Helsinki.
Clinical data
We retrospectively summarized the clinical data of the STAT3 GOF patient.
Whole-exome sequencing
WES and analysis protocols were adapted for genetic analysis. After obtaining the informed consent from the parents, genomic DNA samples were extracted from the whole blood of the patient and her parents with the QIAamp® DNA Blood Mini Kit (Qiagen, Hilden, Germany). The concentration and quantity of the DNA samples were measured using a NanoDrop ultraviolet spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA) [19]. Genomic DNA fragments were enriched for the target region of the consensus coding sequence exons and sequenced on an Illumina HiSeq 2000 platform (Illumina, San Diego, CA) [19]. Data analyses were conducted by using ANNOVAR and VEP software in our clinical genetic laboratory by a bioinformatics team. The mutation was confirmed by Sanger sequencing.
Routine evaluation of immunological function
Immunological evaluations were carried out during routine clinical work. As previously reported, IgG, IgA, and IgM were detected by nephelometry; IgE was assessed by UniCAP (Pharmacia, Uppsala, Sweden) [20]. Lymphocyte subsets were analyzed by FACSCalibur flow cytometer (Becton Dickinson, Franklin Lakes, NJ, USA) [21]. Whole blood was used for staining of lymphocyte surface markers and analyzed according to a standard multicolor flow cytometric protocol with following antibodies [21]: anti-CD3 (UCHT1), anti-CD8 (RPA-T8), anti-CD27 (M-T271), anti-CD45RA (HI100), anti-CD4 (RPA-T4), anti-TCRαβ (T10B9.1A-31), anti-TCRγδ (B1), anti-CD19 (HIB19), anti-CD24 (ML5), anti-CD38 (HIT2), anti-IgD (IA6–2), and anti-CD57 (NK-1) (all from BD Biosciences).
Supplementary Information
Additional file 1: Supplement Table 1. Variants identified by WES.
Additional file 2: Supplement Table 2. OGTT results of our case (P1).
Abbreviations
STAT3 Signal transduction and activator of transcription 3
JAK Janus kinases
LOF Loss-of-function
GOF Gain-of-function
NGS Next generation sequencing
IUIS International union of immunological societies
HLH Lymphohistiocytosis syndrome
EBV Epstein-barr virus
EM Effector memory
IL-6CM Central memory
IVIG Intravenous immunoglobulin
Acknowledgements
Many thanks to the patient and her parents.
Authors’ contributions
W.X.C., S.J.Q., W.W.J. designed the study. W.X.C., S.J.Q., W.W.J., Y.W.J., H.J., Z.Q.H. diagnosed, treated, and followed up the patient. W.Y. performed the lymphocyte subpopulation analysis. W.W.J. and H.X.Y. abstracted the information from electronic medical chart and follow-up material. S.B.J .and Y.M. did the telephone interview. W.W.J. wrote the first draft. S.J.Q., W.W.J. and L.L.Y. reviewed and revised the manuscript. S.J.Q. and W.X.C. supervised the whole process of the study. The author(s) read and approved the final manuscript.
Funding
This study was funded by the National Natural Science Foundation of China (81373221).
Availability of data and materials
The datasets used and analyzed during the current study available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
The study was carried out at Children’s hospital of Fudan University (Shanghai, China). The protocol 2020–453 was approved by the Ethics Committee of the Children’s Hospital of Fudan University. Because the patient was under the age of 18 years, her parents gave written informed consent to participate tocilizumab therapy and report data in accordance with the declaration of Helsinki.
Consent for publication
Written informed consent for publication of identifying images and other personal or clinical details was obtained from the patient’s parents.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33731004 | 19,866,414 | 2021-03-17 |
What was the administration route of drug 'METHYLPREDNISOLONE'? | Efficacy of tocilizumab therapy in a patient with severe pancytopenia associated with a STAT3 gain-of-function mutation.
We aimed to report the clinical characteristics, immunological features, and treatment of one patient with a de novo STAT3 gain-of-function mutation identified by next generation sequencing. We investigated the efficacy of tocilizumab therapy in immune dysregulation diseases caused by STAT3 mutation.
The patient was a 16-year-old girl. She presented with recurrent respiratory infections and chronic diarrhea after birth. She had life-threatening autoimmune pancytopenia at 14 years old. After receiving glucocorticoid therapy, she developed diabetes. However, her pancytopenia relapsed when the glucocorticoid was tapered. Next-generation sequencing showed a de novo heterozygous mutation in the STAT3 gene, c.1261G > A (p. G421R), which was previously described as a gain-of-function mutation. After tocilizumab therapy, her pancytopenia fully resolved, and insulin and glucocorticoid therapies were gradually discontinued within 12 months. She had lymphopenia and an inverted CD4/CD8 ratio before therapy. Lymphocyte subpopulation analysis indicated an expansion of effector memory CD4+, effector memory CD8+ and central memory CD4+ T cells. The proportions of memory B cells and naive CD4+ T cells were decreased, and the proportion of naïve B cells was increased. None of the abnormal lymphocytic changes improved significantly. STAT3 GOF mutations were identified by next gene sequencing in those with early-onset multi-organ autoimmunity. Including our patient, 13 patients with STAT3 GOF mutations received targeted treatment. Twelve of them were treated with tocilizumab alone or combination tocilizumab with JAK inhibitor, and ten patients improved.
Gene sequencing should be performed for patients with early-onset refractory or multiorgan immune dysregulation diseases. Targeted drugs can effectively improve the clinical problems associated with STAT3 gain-of-function mutations, while nontargeted immunosuppressive therapy is usually insufficient.
Background
Signal Transduction and Activator of Transcription 3 (STAT3), one of the seven members of the STAT family of transcription factors, helps transmit key cytokine signals from cell membrane receptors to the nucleus using Janus kinases (JAKs). STATs are involved in multiple processes, including early development, cellular proliferation, survival, and differentiation. Germline STAT3 gene loss-of-function (LOF) mutations cause hyper IgE syndrome, which often manifests as special facial features, recurrent infections, eczema, and joint hyperextension [1]. STAT3 gain-of-function (GOF) mutations were first reported in 2014 [2–8]. In the phenotypical classification of inborn errors in human immunity by the International Union of Immunological Societies (IUIS) in the 2019 update [9], diseases of immune dysregulation were divided into two categories: a) hematopoietic lymphohistiocytosis syndrome (HLH) and Epstein-Barr virus (EBV) susceptibility and b) syndromes with autoimmunity and others. GOF mutation of the germline STAT3 gene is one of the regulatory T cell defects accompanied by autoimmune manifestations. These mutations cause early-onset lymphoproliferation with lymphadenopathy, hepatosplenomegaly and multiorgan autoimmunity, including cytopenia, hepatitis, inflammatory lung disease, enteropathy, and diabetes mellitus.
Patients with STAT3 GOF were treated with regular immunosuppressive treatments before the results of gene sequencing which always couldn’t control all the clinical manifestations [10–14]. Functional analyses of STAT3 GOF mutations demonstrated increased transcriptional activity of STAT3 in unstimulated and/or stimulated cells in vitro [3]. Because IL-6 is one of the primary cytokines that utilizes STAT3 for signal transduction, IL-6 receptor (IL-6R) antagonist therapy currently have been reported to be effective in these patients [4, 5, 10–13]. Here, we reviewed the clinical manifestations and immunological features of one patient with a STAT3 GOF mutation. Moreover, we aimed to investigate the efficacy of tocilizumab therapy.
Results
Case review
A 16-year-old girl born to nonconsanguineous Chinese parents presented with recurrent respiratory infections after birth and suffered at least 1–2 pneumonia events per year. She had chronic diarrhea from 3 months old. When she was 12 years old, she developed cervical adenopathy, alopecia, and bilateral lower limb weakness. She had life-threatening autoimmune pancytopenia with a positive Coomb’s test at the age of 14. She also presented with growth retardation and hepatosplenomegaly. Laboratory data showed that her peripheral blood leukocyte count was (0.90–1.36) × 109/L, her hemoglobin level was 87–106 g/L and her platelet count was (32–51) × 109/L. Her antinuclear antibody (ANA), extractable nuclear antibody (ENA) spectrum and anticardiolipin antibody detection were negative. Complement C3 and C4 were normal. She had lymphopenia and an inverted CD4/CD8 ratio before therapy, and her serum immunoglobulin G concentration was slightly higher than the normal range. Lymphocyte subpopulation analysis indicated expansion of effector memory (EM) CD4+ T, EM CD8+ T and central memory (CM) CD4+ T cells. The proportions of memory B cells and naive CD4+ T cells were decreased, and the proportion of naïve B cells was increased (Fig. 1). Magnetic resonance imaging of the lower limbs revealed abnormal signals in the muscles and fluid accumulation in the intermuscular space, which indicated inflammatory changes. Fig. 1 Lymphocyte subpopulaltions of our patient. A:CD19 + IgD + CD27– naïve B (94.2%), CD19 + IgD–CD27+ memory B (1.9%); B:CD38 + CD24+ transitional B (0%), CD38 + CD24– plasmablast B (1.7%); C: CD3 + CD4+ T (24.4%); CD3 + CD8+ T (66.3%); CD3 + CD4–CD8– double negative T (7.2%); D:subpopulaltions of CD4+ T cells: CD3 + CD4 + CD45RA + CD27+ naïve T (11%), CD3 + CD4 + CD45RO + CD27+ central memory T (49.6%), CD3 + CD4 + CD45RO + CD27– effector memory T (23.8%); E:subpopulaltions of CD8 + T cells: CD3 + CD8 + CD45RA + CD27+ naïve T (48.1%), CD3 + CD8 + CD45RO + CD27+ central memory T (13.7%), CD3 + CD8 + CD45RO + CD27– effect memory T (9.3%), CD3 + CD8 + CD45RA + CD27– TEMRA T (28.9%)
Gene analysis
Next-gene sequencing (NGS) revealed that she had a heterozygous de novo mutation in the STAT3 gene, while her parents were normal (Fig. 2). The missense mutation in the DNA binding domain (c.1261G > A, p. G421R) was described as a gain-of-function mutation in previous studies [2]. Fig. 2 Sanger sequence results of our patient and her parents
Treatment and follow-up
Before the gene sequencing results were available, the patient accepted intravenous methylprednisolone (1.6 mg/kg/day) for autoimmune pancytopenia. She was changed to the same dose of oral glucocorticoid tablet after Coomb’s test turned negative and pancytopenia improved. But the pancytopenia relapsed several times once the glucocorticoid dose was less than 2 mg/kg/day. Meanwhile, she developed diabetes and worse weakness of lower limbs during the glucocorticoid treatment. The fasting plasma glucose was 7.2 mmol/L, the glycated hemoglobin (Hb1c) was 5.8%, and all the insulin autoantibodies were negative. The oral glucose tolerance test showed increased C peptide and plasma glucose after 30 min, 60 min, 120 min, and 180 min of oral glucose, while plasma insulin level didn’t increase (supplement Table 2). So, we diagnosed diabetes and considered it as a side effect of glucocorticoid therapy. The blood biochemistry results were normal before and after treatment, including creatine kinase (CK), serum electrolytes, transaminase, and creatinine. The diagnosis of myositis was based on MRI abnormal signals in muscle and cutting movement assessment score (CMAS) was 15 of 52.
After obtaining informed consent from her parents, we administered IL-6R antagonist treatment (tocilizumab) at a dosage of 8 mg/kg intravenous infusion every 2 weeks. After 2 months of tocilizumab treatment, the patient’s pancytopenia fully resolved. She discontinued insulin injection after 4 months of tocilizumab therapy, and glucocorticoid therapy was gradually discontinued within 12 months. Her serum IL-6 levels increased before glucocorticoid therapy and improved for a while but fluctuated after glucocorticoid tapering and gradually decreased to normal after tocilizumab therapy (Fig. 3). She underwent intravenous immunoglobulin (IVIG) replacement after 6 months because of hypogammaglobulinemia. Beginning in the second year of therapy, she extended the interval of tocilizumab to every 4–6 weeks (240 mg/dose, after her weight was above 30 kg), with a good response evidenced by a normal hemoglobin level and negative Coomb’s test. Lymphadenopathy and hepatosplenomegaly returned to mild enlargement (Table 1). Fig. 3 Serum IL-6 before and after tocilizumab of our patient. She accepted glucocorticoid first from week − 18 to week 0
Table 1 Clinical features and immunotype of our patient with a STAT3 GOF mutation
tocilizumab therapy before after
lymphadenopathy yes no
hepatosplenomegaly yes (severe) mild
autoimmune pancytopenia yes no
myositis worse better
alopecia yes better
WBC
(×109/L)
0.90–1.36#
0.9–6.8##
4.7–8.3###
HB
g/L
87–106#
46–139##
112–139###
PLT
(×109/L)
32–51#
32–123##
107–178###
IgM 1.84 0.62
IgA 1.3 0.25
IgG 14.5 6.6 a
IgE < 2 < 2
CD3 89.13% (607) 82.87% (786)
CD4 32.41% (221) 30.61% (290)
CD8 51.17% (349) 48.70% (462)
CD4/CD8 0.63 0.63
CD19 8.74% (60) 9.08% (31)
NK 1.49% (10) 7.28% (69)
* with monthly IVIG replacement
# before glucocorticoid treatment, ## after glucocorticoid treatment;
### after 1 month of tocilizumab therapy
We regularly followed up for infection indicators during targeted therapy. She had cervical lymphadenitis and Candida albicans vaginitis once during 2 years of therapy. Her EBV-DNA load of whole leukocytes in the peripheral blood was higher than the level at the beginning, changing from 1.29 × 104 copies/ml to 3.58 × 106 copies/ml. In addition to treatment with targeted drugs, she accepted oral itraconazole and acyclovir tablets.
Her immune phenotypes after tocilizumab showed hypogammaglobulinemia after 6 months of therapy. All the abnormal lymphocytic changes (expansion of EM CD4+ T, EM CD8+ T and CM CD4+ T cells; decreased memory B cell and naive CD4+ T cell levels; and an increased naïve B cell level) did not improve significantly (Fig. 4). Fig. 4 Subpopulation of T/B lymphocytes of our patient before and 1 month, 12 months after tocilizumab
Discussion
STAT3 GOF mutations were reported in patients with multiple early-onset autoimmune manifestations by NGS [3]. Fabre et al. summarized the clinical features of 42 patients, and the most common manifestations were autoimmune cytopenia, lymphoproliferation, enteropathy, interstitial lung disease, thyroiditis, diabetes, and growth retardation; some of the patients had recurrent or opportunistic infections [14]. The onset age and major symptoms of our patient were similar to those of other patients reported previously [2, 3]. She developed diabetes during glucocorticoid therapy with normal glycated hemoglobin levels, which is different from the early-onset type 1 diabetes reported in the literature. Her Hb1c, insulin autoantibodies and oral glucose tolerance test indicated her diabetes was a side effect of glucocorticoid therapy. We also found that her bilateral lower limb weakness was related to immune myositis on MRI. The abnormal changes in the muscles improved after tocilizumab treatment (Fig. 5). Fig. 5 Magnetic resonance imaging of left lower limbs of patient 1. a and c revealed abnormal signals in muscle and fluid accumulation in the intermuscular space considering inflammatory changes. b and d revealed abnormal changes recovered after tocilizumab
According the functions of immune system, infection tendency, autoimmunity and extremely abnormal immune reactions are common manifestations of primary immunodeficiencies. So, we did NGS at the beginning of diagnose considering a genetic defect may exist. STAT3 GOF mutations were identified by gene sequencing in those with early-onset multi-organ autoimmunity.
Activation of STAT3 leads to the production of downstream cytokines, including glycoprotein 130 (a component of IL-6 and IL-27), common gamma chain cytokines, IL-10 family cytokines and IL-23. After cytokines bind to their receptors, one of four Janus kinases (JAKs) is activated and phosphorylates the cytokine receptor. STAT molecules are recruited to the phosphorylated receptor and then translocate to the nucleus, altering gene expression [15]. The proportions of regulatory T cells are reduced, while IL-17 levels are increased in patients with STAT3 GOF mutations [3, 8]. In vitro, IL-6R antagonists can reduce IL-17 secretion and improve immune dysregulation by increasing regulatory T cell differentiation [4]. Therefore, IL-6R antagonists and JAK inhibitors can inhibit STAT3 signaling pathway overactivation and be used to treat patients with STAT3 GOF mutations.
Twelve patients with STAT3 GOF mutations received targeted treatment in 5 reports [4, 5, 9–11]. Three (including our patient, P1) of the 13 patients were treated with tocilizumab alone, and all three improved (P1, P2, and P3); 1 patient improved with JAK inhibitor treatment alone (P7); the remaining 9 patients were treated successively or simultaneously with tocilizumab and JAK inhibitors because of disease severity or incomplete remission. Combination treatment could take the following factors into consideration: enteropathy (4/9), interstitial pulmonary disease (4/9), arthritis (2/9), hepatitis (3/9), splenomegaly (1/9), and cytopenia (2/9). Seven of the nine patients who received combined treatment achieved remission (Table 2). STAT3 GOF mutation patients manifesting with multiple clinical symptoms might need combination therapy if the tocilizumab or JAK inhibitors alone couldn’t control the disease. The outcomes of targeted therapy are summarized in Table 3. The symptoms of arthritis, cytopenia, hepatosplenomegaly and hepatitis were all alleviated. Three of the 13 patients died. P10 died of infection after transplant, while recurrent HLH was resolved by targeted treatment. P9 died of sepsis and diffuse intravascular coagulation. P13 died of respiratory failure. Considering cytopenia as the common adverse reaction to JAK inhibitors, two patients with the G421R mutant who recovered with tocilizumab alone have been reported in the literature [2, 4]. Therefore, we chose tocilizumab as the first targeted treatment for our patient. After 1 year of treatment, her whole blood cells stayed in the normal range with no serious infections. However, the EBV-DNA titer of peripheral blood leukocytes was higher than that at the beginning. This means that latency and active infections need to be monitored before and after targeted therapy. Table 2 Summary of targeted therapy in all the reported patients with a STAT3 GOF mutation
Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13
a. sex female male male female female female male female male female male male
b. onset age 3 mo 4 yr 6 mo 5 mo 1 yr 1 yr 1 mo 7 yr 3 yr 7 mo 7 yr
c. age 16 yr 10 yr 38 yr 19 yr 9 yr 21 yr 20 yr 8 yr 14 yr 3 yr 8 yr 13 yr 15 yr
d. infections Y Y Y Y Y
e. cytopenia Y Y Y Y Y Y Y Y
f. enteropathy Y Y Y Y Y Y Y Y Y
g. hepatitis Y Y Y Y Y
h. endocrine disease Y Y Y Y Y
i. arthritis Y Y Y Y Y
j. lymphadenopathy Y Y Y
k. hepatosplenomegaly Y Y Y Y Y Y Y Y Y Y
l. interstitial lung disease Y Y Y Y Y
m. short stature Y Y Y Y Y Y Y Y Y Y Y Y
n. reason of for targeted therapy pancytopenia, arthritis enteropathy, colitis interstitial lung disease arthritis, interstitial lung disease hepatosplenomegaly, hepatotitis, enteropathy, interstitial lung disease arthritis enteropathy,
hepatosplenomegaly dermopathy interstitial lung disease anemia enteropathy
HLH
interstitial lung disease
o. tocilizumab alone ✓ ✓ ✓
p. combination of tocilizumab and a JAK inhibitor ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
q. JAK inhibitor alone ✓
r. efficiency of targeted therapy yes yes yes yes yes yes yes yes no yes yes yes no
s. outcome alive alive alive alive alive alive alive alive dead dead dead alive dead
t. mutantmutation in of STAT3 G421R G421R G421R N401D E415L V393A M329K R152W F174S E286G Q344H G421R P715L
u. reference our report [2] [4] [13] [11] [12] [11] [10] [10] [10] [10] [10] [10]
Y represent YES, and slash indicate the parameter was not mentioned in the reference
p: combination of tocilizumab and JAK inhibitors
Patients 4, 5, 6, 9, 11 and 12 were treated with tocilizumab first, and then a JAK inhibitor was added later. Patients 8 and 10 were treated with two targeted drugs simultaneously. Patient 14 was treated with a JAK inhibitor first and then changed to tocilizumab
Table 3 Effect summary for targeted therapy
Cause of targeted therapy Case number Remission number No response Proportion of remission
enteropathy 5 3 2 60%
ILD 5 4 1 80%
arthritis 3 3 0 100%
cytopenia 3 3 0 100%
hepatosplenomegaly 2 2 0 100%
dermopathy 2 1 1 50%
hepatitis/liver failure 1 0 1 0%
The immunological features of STAT3 GOF mutations included hypogammaglobulinemia, increased Th17 cells and decreased Treg cells, which plays a critical role in the development of autoimmunity. While some case reports showed normal Th17 cells or Treg cells in the symptomatic STAT3 GOF patients [8]. There is no immunological index for starting and evaluating the efficacy of targeted therapy. The 12 patients reported above had no immunophenotypic changes with targeted treatment. One patient showed an improvement in the proportion of regulatory T cells after tocilizumab treatment [4]. We evaluated lymphocyte subpopulations before and after treatment. There were no significant improvements in those abnormal changes in our patient after 1 year of treatment. It cannot be ruled out that the immune phenotype changes later than clinical improvement. The relationship between immunological characteristics and mechanism of disease needs further research. The patient still requires monthly IVIG replacement with targeted therapy. Consistent with other reports [2, 16], she had hypogammaglobulinemia and a low proportion of memory B cells. However, the IgG level was higher than normal during the course of autoimmune pancytopenia due to the presence of autoantibodies. Therefore, her hypogammaglobulinemia was consistent with the reduced proportion of memory B cells regardless of the side effects of tocilizumab. The pathogenesis of the abnormal changes leading to reduced unswitched memory B cells and hypogammaglobulinemia require further study.
It has been reported that 5 patients underwent hematopoietic stem cell transplantation [2, 9, 17, 18], of whom four died due to complications, such as infection. The remaining patient was successfully transplanted and lived well. It is known from the reported cases that targeted therapy can effectively control and alleviate life-threatening autoimmune manifestations and lymphoproliferative disorders. The longest follow-up time for targeted therapy is 3.5 years [9]. Our patient was followed up for 2 years, and she had no obvious serious infections or adverse reactions. Aside from IL-6R antagonists and JAK inhibitors, whether better targeted drugs exist requires more clinical data and pathogenesis studies.
Conclusions
We reported the first case of tocilizumab therapy in immune dysregulation disorders caused by a STAT3 GOF mutation in mainland China. Gene sequencing should be performed for patients with early-onset refractory immune dysregulation diseases since routine immunological examination may be nonspecific. Targeted drugs can effectively improve the clinical problems associated with STAT3 gain-of-function mutations, while nontargeted immunosuppressive therapy is usually insufficient.
Methods
The study was carried out at Children’s hospital of Fudan University (Shanghai, China). The protocol 2020–453 was approved by the Ethics Committee of the Children’s Hospital of Fudan University. Because the patient was under the age of 18 years, her parents gave written informed consent to participate tocilizumab therapy and report data in accordance with the declaration of Helsinki.
Clinical data
We retrospectively summarized the clinical data of the STAT3 GOF patient.
Whole-exome sequencing
WES and analysis protocols were adapted for genetic analysis. After obtaining the informed consent from the parents, genomic DNA samples were extracted from the whole blood of the patient and her parents with the QIAamp® DNA Blood Mini Kit (Qiagen, Hilden, Germany). The concentration and quantity of the DNA samples were measured using a NanoDrop ultraviolet spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA) [19]. Genomic DNA fragments were enriched for the target region of the consensus coding sequence exons and sequenced on an Illumina HiSeq 2000 platform (Illumina, San Diego, CA) [19]. Data analyses were conducted by using ANNOVAR and VEP software in our clinical genetic laboratory by a bioinformatics team. The mutation was confirmed by Sanger sequencing.
Routine evaluation of immunological function
Immunological evaluations were carried out during routine clinical work. As previously reported, IgG, IgA, and IgM were detected by nephelometry; IgE was assessed by UniCAP (Pharmacia, Uppsala, Sweden) [20]. Lymphocyte subsets were analyzed by FACSCalibur flow cytometer (Becton Dickinson, Franklin Lakes, NJ, USA) [21]. Whole blood was used for staining of lymphocyte surface markers and analyzed according to a standard multicolor flow cytometric protocol with following antibodies [21]: anti-CD3 (UCHT1), anti-CD8 (RPA-T8), anti-CD27 (M-T271), anti-CD45RA (HI100), anti-CD4 (RPA-T4), anti-TCRαβ (T10B9.1A-31), anti-TCRγδ (B1), anti-CD19 (HIB19), anti-CD24 (ML5), anti-CD38 (HIT2), anti-IgD (IA6–2), and anti-CD57 (NK-1) (all from BD Biosciences).
Supplementary Information
Additional file 1: Supplement Table 1. Variants identified by WES.
Additional file 2: Supplement Table 2. OGTT results of our case (P1).
Abbreviations
STAT3 Signal transduction and activator of transcription 3
JAK Janus kinases
LOF Loss-of-function
GOF Gain-of-function
NGS Next generation sequencing
IUIS International union of immunological societies
HLH Lymphohistiocytosis syndrome
EBV Epstein-barr virus
EM Effector memory
IL-6CM Central memory
IVIG Intravenous immunoglobulin
Acknowledgements
Many thanks to the patient and her parents.
Authors’ contributions
W.X.C., S.J.Q., W.W.J. designed the study. W.X.C., S.J.Q., W.W.J., Y.W.J., H.J., Z.Q.H. diagnosed, treated, and followed up the patient. W.Y. performed the lymphocyte subpopulation analysis. W.W.J. and H.X.Y. abstracted the information from electronic medical chart and follow-up material. S.B.J .and Y.M. did the telephone interview. W.W.J. wrote the first draft. S.J.Q., W.W.J. and L.L.Y. reviewed and revised the manuscript. S.J.Q. and W.X.C. supervised the whole process of the study. The author(s) read and approved the final manuscript.
Funding
This study was funded by the National Natural Science Foundation of China (81373221).
Availability of data and materials
The datasets used and analyzed during the current study available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
The study was carried out at Children’s hospital of Fudan University (Shanghai, China). The protocol 2020–453 was approved by the Ethics Committee of the Children’s Hospital of Fudan University. Because the patient was under the age of 18 years, her parents gave written informed consent to participate tocilizumab therapy and report data in accordance with the declaration of Helsinki.
Consent for publication
Written informed consent for publication of identifying images and other personal or clinical details was obtained from the patient’s parents.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Oral | DrugAdministrationRoute | CC BY | 33731004 | 19,866,414 | 2021-03-17 |
What was the dosage of drug 'METHYLPREDNISOLONE SODIUM SUCCINATE'? | Efficacy of tocilizumab therapy in a patient with severe pancytopenia associated with a STAT3 gain-of-function mutation.
We aimed to report the clinical characteristics, immunological features, and treatment of one patient with a de novo STAT3 gain-of-function mutation identified by next generation sequencing. We investigated the efficacy of tocilizumab therapy in immune dysregulation diseases caused by STAT3 mutation.
The patient was a 16-year-old girl. She presented with recurrent respiratory infections and chronic diarrhea after birth. She had life-threatening autoimmune pancytopenia at 14 years old. After receiving glucocorticoid therapy, she developed diabetes. However, her pancytopenia relapsed when the glucocorticoid was tapered. Next-generation sequencing showed a de novo heterozygous mutation in the STAT3 gene, c.1261G > A (p. G421R), which was previously described as a gain-of-function mutation. After tocilizumab therapy, her pancytopenia fully resolved, and insulin and glucocorticoid therapies were gradually discontinued within 12 months. She had lymphopenia and an inverted CD4/CD8 ratio before therapy. Lymphocyte subpopulation analysis indicated an expansion of effector memory CD4+, effector memory CD8+ and central memory CD4+ T cells. The proportions of memory B cells and naive CD4+ T cells were decreased, and the proportion of naïve B cells was increased. None of the abnormal lymphocytic changes improved significantly. STAT3 GOF mutations were identified by next gene sequencing in those with early-onset multi-organ autoimmunity. Including our patient, 13 patients with STAT3 GOF mutations received targeted treatment. Twelve of them were treated with tocilizumab alone or combination tocilizumab with JAK inhibitor, and ten patients improved.
Gene sequencing should be performed for patients with early-onset refractory or multiorgan immune dysregulation diseases. Targeted drugs can effectively improve the clinical problems associated with STAT3 gain-of-function mutations, while nontargeted immunosuppressive therapy is usually insufficient.
Background
Signal Transduction and Activator of Transcription 3 (STAT3), one of the seven members of the STAT family of transcription factors, helps transmit key cytokine signals from cell membrane receptors to the nucleus using Janus kinases (JAKs). STATs are involved in multiple processes, including early development, cellular proliferation, survival, and differentiation. Germline STAT3 gene loss-of-function (LOF) mutations cause hyper IgE syndrome, which often manifests as special facial features, recurrent infections, eczema, and joint hyperextension [1]. STAT3 gain-of-function (GOF) mutations were first reported in 2014 [2–8]. In the phenotypical classification of inborn errors in human immunity by the International Union of Immunological Societies (IUIS) in the 2019 update [9], diseases of immune dysregulation were divided into two categories: a) hematopoietic lymphohistiocytosis syndrome (HLH) and Epstein-Barr virus (EBV) susceptibility and b) syndromes with autoimmunity and others. GOF mutation of the germline STAT3 gene is one of the regulatory T cell defects accompanied by autoimmune manifestations. These mutations cause early-onset lymphoproliferation with lymphadenopathy, hepatosplenomegaly and multiorgan autoimmunity, including cytopenia, hepatitis, inflammatory lung disease, enteropathy, and diabetes mellitus.
Patients with STAT3 GOF were treated with regular immunosuppressive treatments before the results of gene sequencing which always couldn’t control all the clinical manifestations [10–14]. Functional analyses of STAT3 GOF mutations demonstrated increased transcriptional activity of STAT3 in unstimulated and/or stimulated cells in vitro [3]. Because IL-6 is one of the primary cytokines that utilizes STAT3 for signal transduction, IL-6 receptor (IL-6R) antagonist therapy currently have been reported to be effective in these patients [4, 5, 10–13]. Here, we reviewed the clinical manifestations and immunological features of one patient with a STAT3 GOF mutation. Moreover, we aimed to investigate the efficacy of tocilizumab therapy.
Results
Case review
A 16-year-old girl born to nonconsanguineous Chinese parents presented with recurrent respiratory infections after birth and suffered at least 1–2 pneumonia events per year. She had chronic diarrhea from 3 months old. When she was 12 years old, she developed cervical adenopathy, alopecia, and bilateral lower limb weakness. She had life-threatening autoimmune pancytopenia with a positive Coomb’s test at the age of 14. She also presented with growth retardation and hepatosplenomegaly. Laboratory data showed that her peripheral blood leukocyte count was (0.90–1.36) × 109/L, her hemoglobin level was 87–106 g/L and her platelet count was (32–51) × 109/L. Her antinuclear antibody (ANA), extractable nuclear antibody (ENA) spectrum and anticardiolipin antibody detection were negative. Complement C3 and C4 were normal. She had lymphopenia and an inverted CD4/CD8 ratio before therapy, and her serum immunoglobulin G concentration was slightly higher than the normal range. Lymphocyte subpopulation analysis indicated expansion of effector memory (EM) CD4+ T, EM CD8+ T and central memory (CM) CD4+ T cells. The proportions of memory B cells and naive CD4+ T cells were decreased, and the proportion of naïve B cells was increased (Fig. 1). Magnetic resonance imaging of the lower limbs revealed abnormal signals in the muscles and fluid accumulation in the intermuscular space, which indicated inflammatory changes. Fig. 1 Lymphocyte subpopulaltions of our patient. A:CD19 + IgD + CD27– naïve B (94.2%), CD19 + IgD–CD27+ memory B (1.9%); B:CD38 + CD24+ transitional B (0%), CD38 + CD24– plasmablast B (1.7%); C: CD3 + CD4+ T (24.4%); CD3 + CD8+ T (66.3%); CD3 + CD4–CD8– double negative T (7.2%); D:subpopulaltions of CD4+ T cells: CD3 + CD4 + CD45RA + CD27+ naïve T (11%), CD3 + CD4 + CD45RO + CD27+ central memory T (49.6%), CD3 + CD4 + CD45RO + CD27– effector memory T (23.8%); E:subpopulaltions of CD8 + T cells: CD3 + CD8 + CD45RA + CD27+ naïve T (48.1%), CD3 + CD8 + CD45RO + CD27+ central memory T (13.7%), CD3 + CD8 + CD45RO + CD27– effect memory T (9.3%), CD3 + CD8 + CD45RA + CD27– TEMRA T (28.9%)
Gene analysis
Next-gene sequencing (NGS) revealed that she had a heterozygous de novo mutation in the STAT3 gene, while her parents were normal (Fig. 2). The missense mutation in the DNA binding domain (c.1261G > A, p. G421R) was described as a gain-of-function mutation in previous studies [2]. Fig. 2 Sanger sequence results of our patient and her parents
Treatment and follow-up
Before the gene sequencing results were available, the patient accepted intravenous methylprednisolone (1.6 mg/kg/day) for autoimmune pancytopenia. She was changed to the same dose of oral glucocorticoid tablet after Coomb’s test turned negative and pancytopenia improved. But the pancytopenia relapsed several times once the glucocorticoid dose was less than 2 mg/kg/day. Meanwhile, she developed diabetes and worse weakness of lower limbs during the glucocorticoid treatment. The fasting plasma glucose was 7.2 mmol/L, the glycated hemoglobin (Hb1c) was 5.8%, and all the insulin autoantibodies were negative. The oral glucose tolerance test showed increased C peptide and plasma glucose after 30 min, 60 min, 120 min, and 180 min of oral glucose, while plasma insulin level didn’t increase (supplement Table 2). So, we diagnosed diabetes and considered it as a side effect of glucocorticoid therapy. The blood biochemistry results were normal before and after treatment, including creatine kinase (CK), serum electrolytes, transaminase, and creatinine. The diagnosis of myositis was based on MRI abnormal signals in muscle and cutting movement assessment score (CMAS) was 15 of 52.
After obtaining informed consent from her parents, we administered IL-6R antagonist treatment (tocilizumab) at a dosage of 8 mg/kg intravenous infusion every 2 weeks. After 2 months of tocilizumab treatment, the patient’s pancytopenia fully resolved. She discontinued insulin injection after 4 months of tocilizumab therapy, and glucocorticoid therapy was gradually discontinued within 12 months. Her serum IL-6 levels increased before glucocorticoid therapy and improved for a while but fluctuated after glucocorticoid tapering and gradually decreased to normal after tocilizumab therapy (Fig. 3). She underwent intravenous immunoglobulin (IVIG) replacement after 6 months because of hypogammaglobulinemia. Beginning in the second year of therapy, she extended the interval of tocilizumab to every 4–6 weeks (240 mg/dose, after her weight was above 30 kg), with a good response evidenced by a normal hemoglobin level and negative Coomb’s test. Lymphadenopathy and hepatosplenomegaly returned to mild enlargement (Table 1). Fig. 3 Serum IL-6 before and after tocilizumab of our patient. She accepted glucocorticoid first from week − 18 to week 0
Table 1 Clinical features and immunotype of our patient with a STAT3 GOF mutation
tocilizumab therapy before after
lymphadenopathy yes no
hepatosplenomegaly yes (severe) mild
autoimmune pancytopenia yes no
myositis worse better
alopecia yes better
WBC
(×109/L)
0.90–1.36#
0.9–6.8##
4.7–8.3###
HB
g/L
87–106#
46–139##
112–139###
PLT
(×109/L)
32–51#
32–123##
107–178###
IgM 1.84 0.62
IgA 1.3 0.25
IgG 14.5 6.6 a
IgE < 2 < 2
CD3 89.13% (607) 82.87% (786)
CD4 32.41% (221) 30.61% (290)
CD8 51.17% (349) 48.70% (462)
CD4/CD8 0.63 0.63
CD19 8.74% (60) 9.08% (31)
NK 1.49% (10) 7.28% (69)
* with monthly IVIG replacement
# before glucocorticoid treatment, ## after glucocorticoid treatment;
### after 1 month of tocilizumab therapy
We regularly followed up for infection indicators during targeted therapy. She had cervical lymphadenitis and Candida albicans vaginitis once during 2 years of therapy. Her EBV-DNA load of whole leukocytes in the peripheral blood was higher than the level at the beginning, changing from 1.29 × 104 copies/ml to 3.58 × 106 copies/ml. In addition to treatment with targeted drugs, she accepted oral itraconazole and acyclovir tablets.
Her immune phenotypes after tocilizumab showed hypogammaglobulinemia after 6 months of therapy. All the abnormal lymphocytic changes (expansion of EM CD4+ T, EM CD8+ T and CM CD4+ T cells; decreased memory B cell and naive CD4+ T cell levels; and an increased naïve B cell level) did not improve significantly (Fig. 4). Fig. 4 Subpopulation of T/B lymphocytes of our patient before and 1 month, 12 months after tocilizumab
Discussion
STAT3 GOF mutations were reported in patients with multiple early-onset autoimmune manifestations by NGS [3]. Fabre et al. summarized the clinical features of 42 patients, and the most common manifestations were autoimmune cytopenia, lymphoproliferation, enteropathy, interstitial lung disease, thyroiditis, diabetes, and growth retardation; some of the patients had recurrent or opportunistic infections [14]. The onset age and major symptoms of our patient were similar to those of other patients reported previously [2, 3]. She developed diabetes during glucocorticoid therapy with normal glycated hemoglobin levels, which is different from the early-onset type 1 diabetes reported in the literature. Her Hb1c, insulin autoantibodies and oral glucose tolerance test indicated her diabetes was a side effect of glucocorticoid therapy. We also found that her bilateral lower limb weakness was related to immune myositis on MRI. The abnormal changes in the muscles improved after tocilizumab treatment (Fig. 5). Fig. 5 Magnetic resonance imaging of left lower limbs of patient 1. a and c revealed abnormal signals in muscle and fluid accumulation in the intermuscular space considering inflammatory changes. b and d revealed abnormal changes recovered after tocilizumab
According the functions of immune system, infection tendency, autoimmunity and extremely abnormal immune reactions are common manifestations of primary immunodeficiencies. So, we did NGS at the beginning of diagnose considering a genetic defect may exist. STAT3 GOF mutations were identified by gene sequencing in those with early-onset multi-organ autoimmunity.
Activation of STAT3 leads to the production of downstream cytokines, including glycoprotein 130 (a component of IL-6 and IL-27), common gamma chain cytokines, IL-10 family cytokines and IL-23. After cytokines bind to their receptors, one of four Janus kinases (JAKs) is activated and phosphorylates the cytokine receptor. STAT molecules are recruited to the phosphorylated receptor and then translocate to the nucleus, altering gene expression [15]. The proportions of regulatory T cells are reduced, while IL-17 levels are increased in patients with STAT3 GOF mutations [3, 8]. In vitro, IL-6R antagonists can reduce IL-17 secretion and improve immune dysregulation by increasing regulatory T cell differentiation [4]. Therefore, IL-6R antagonists and JAK inhibitors can inhibit STAT3 signaling pathway overactivation and be used to treat patients with STAT3 GOF mutations.
Twelve patients with STAT3 GOF mutations received targeted treatment in 5 reports [4, 5, 9–11]. Three (including our patient, P1) of the 13 patients were treated with tocilizumab alone, and all three improved (P1, P2, and P3); 1 patient improved with JAK inhibitor treatment alone (P7); the remaining 9 patients were treated successively or simultaneously with tocilizumab and JAK inhibitors because of disease severity or incomplete remission. Combination treatment could take the following factors into consideration: enteropathy (4/9), interstitial pulmonary disease (4/9), arthritis (2/9), hepatitis (3/9), splenomegaly (1/9), and cytopenia (2/9). Seven of the nine patients who received combined treatment achieved remission (Table 2). STAT3 GOF mutation patients manifesting with multiple clinical symptoms might need combination therapy if the tocilizumab or JAK inhibitors alone couldn’t control the disease. The outcomes of targeted therapy are summarized in Table 3. The symptoms of arthritis, cytopenia, hepatosplenomegaly and hepatitis were all alleviated. Three of the 13 patients died. P10 died of infection after transplant, while recurrent HLH was resolved by targeted treatment. P9 died of sepsis and diffuse intravascular coagulation. P13 died of respiratory failure. Considering cytopenia as the common adverse reaction to JAK inhibitors, two patients with the G421R mutant who recovered with tocilizumab alone have been reported in the literature [2, 4]. Therefore, we chose tocilizumab as the first targeted treatment for our patient. After 1 year of treatment, her whole blood cells stayed in the normal range with no serious infections. However, the EBV-DNA titer of peripheral blood leukocytes was higher than that at the beginning. This means that latency and active infections need to be monitored before and after targeted therapy. Table 2 Summary of targeted therapy in all the reported patients with a STAT3 GOF mutation
Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13
a. sex female male male female female female male female male female male male
b. onset age 3 mo 4 yr 6 mo 5 mo 1 yr 1 yr 1 mo 7 yr 3 yr 7 mo 7 yr
c. age 16 yr 10 yr 38 yr 19 yr 9 yr 21 yr 20 yr 8 yr 14 yr 3 yr 8 yr 13 yr 15 yr
d. infections Y Y Y Y Y
e. cytopenia Y Y Y Y Y Y Y Y
f. enteropathy Y Y Y Y Y Y Y Y Y
g. hepatitis Y Y Y Y Y
h. endocrine disease Y Y Y Y Y
i. arthritis Y Y Y Y Y
j. lymphadenopathy Y Y Y
k. hepatosplenomegaly Y Y Y Y Y Y Y Y Y Y
l. interstitial lung disease Y Y Y Y Y
m. short stature Y Y Y Y Y Y Y Y Y Y Y Y
n. reason of for targeted therapy pancytopenia, arthritis enteropathy, colitis interstitial lung disease arthritis, interstitial lung disease hepatosplenomegaly, hepatotitis, enteropathy, interstitial lung disease arthritis enteropathy,
hepatosplenomegaly dermopathy interstitial lung disease anemia enteropathy
HLH
interstitial lung disease
o. tocilizumab alone ✓ ✓ ✓
p. combination of tocilizumab and a JAK inhibitor ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
q. JAK inhibitor alone ✓
r. efficiency of targeted therapy yes yes yes yes yes yes yes yes no yes yes yes no
s. outcome alive alive alive alive alive alive alive alive dead dead dead alive dead
t. mutantmutation in of STAT3 G421R G421R G421R N401D E415L V393A M329K R152W F174S E286G Q344H G421R P715L
u. reference our report [2] [4] [13] [11] [12] [11] [10] [10] [10] [10] [10] [10]
Y represent YES, and slash indicate the parameter was not mentioned in the reference
p: combination of tocilizumab and JAK inhibitors
Patients 4, 5, 6, 9, 11 and 12 were treated with tocilizumab first, and then a JAK inhibitor was added later. Patients 8 and 10 were treated with two targeted drugs simultaneously. Patient 14 was treated with a JAK inhibitor first and then changed to tocilizumab
Table 3 Effect summary for targeted therapy
Cause of targeted therapy Case number Remission number No response Proportion of remission
enteropathy 5 3 2 60%
ILD 5 4 1 80%
arthritis 3 3 0 100%
cytopenia 3 3 0 100%
hepatosplenomegaly 2 2 0 100%
dermopathy 2 1 1 50%
hepatitis/liver failure 1 0 1 0%
The immunological features of STAT3 GOF mutations included hypogammaglobulinemia, increased Th17 cells and decreased Treg cells, which plays a critical role in the development of autoimmunity. While some case reports showed normal Th17 cells or Treg cells in the symptomatic STAT3 GOF patients [8]. There is no immunological index for starting and evaluating the efficacy of targeted therapy. The 12 patients reported above had no immunophenotypic changes with targeted treatment. One patient showed an improvement in the proportion of regulatory T cells after tocilizumab treatment [4]. We evaluated lymphocyte subpopulations before and after treatment. There were no significant improvements in those abnormal changes in our patient after 1 year of treatment. It cannot be ruled out that the immune phenotype changes later than clinical improvement. The relationship between immunological characteristics and mechanism of disease needs further research. The patient still requires monthly IVIG replacement with targeted therapy. Consistent with other reports [2, 16], she had hypogammaglobulinemia and a low proportion of memory B cells. However, the IgG level was higher than normal during the course of autoimmune pancytopenia due to the presence of autoantibodies. Therefore, her hypogammaglobulinemia was consistent with the reduced proportion of memory B cells regardless of the side effects of tocilizumab. The pathogenesis of the abnormal changes leading to reduced unswitched memory B cells and hypogammaglobulinemia require further study.
It has been reported that 5 patients underwent hematopoietic stem cell transplantation [2, 9, 17, 18], of whom four died due to complications, such as infection. The remaining patient was successfully transplanted and lived well. It is known from the reported cases that targeted therapy can effectively control and alleviate life-threatening autoimmune manifestations and lymphoproliferative disorders. The longest follow-up time for targeted therapy is 3.5 years [9]. Our patient was followed up for 2 years, and she had no obvious serious infections or adverse reactions. Aside from IL-6R antagonists and JAK inhibitors, whether better targeted drugs exist requires more clinical data and pathogenesis studies.
Conclusions
We reported the first case of tocilizumab therapy in immune dysregulation disorders caused by a STAT3 GOF mutation in mainland China. Gene sequencing should be performed for patients with early-onset refractory immune dysregulation diseases since routine immunological examination may be nonspecific. Targeted drugs can effectively improve the clinical problems associated with STAT3 gain-of-function mutations, while nontargeted immunosuppressive therapy is usually insufficient.
Methods
The study was carried out at Children’s hospital of Fudan University (Shanghai, China). The protocol 2020–453 was approved by the Ethics Committee of the Children’s Hospital of Fudan University. Because the patient was under the age of 18 years, her parents gave written informed consent to participate tocilizumab therapy and report data in accordance with the declaration of Helsinki.
Clinical data
We retrospectively summarized the clinical data of the STAT3 GOF patient.
Whole-exome sequencing
WES and analysis protocols were adapted for genetic analysis. After obtaining the informed consent from the parents, genomic DNA samples were extracted from the whole blood of the patient and her parents with the QIAamp® DNA Blood Mini Kit (Qiagen, Hilden, Germany). The concentration and quantity of the DNA samples were measured using a NanoDrop ultraviolet spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA) [19]. Genomic DNA fragments were enriched for the target region of the consensus coding sequence exons and sequenced on an Illumina HiSeq 2000 platform (Illumina, San Diego, CA) [19]. Data analyses were conducted by using ANNOVAR and VEP software in our clinical genetic laboratory by a bioinformatics team. The mutation was confirmed by Sanger sequencing.
Routine evaluation of immunological function
Immunological evaluations were carried out during routine clinical work. As previously reported, IgG, IgA, and IgM were detected by nephelometry; IgE was assessed by UniCAP (Pharmacia, Uppsala, Sweden) [20]. Lymphocyte subsets were analyzed by FACSCalibur flow cytometer (Becton Dickinson, Franklin Lakes, NJ, USA) [21]. Whole blood was used for staining of lymphocyte surface markers and analyzed according to a standard multicolor flow cytometric protocol with following antibodies [21]: anti-CD3 (UCHT1), anti-CD8 (RPA-T8), anti-CD27 (M-T271), anti-CD45RA (HI100), anti-CD4 (RPA-T4), anti-TCRαβ (T10B9.1A-31), anti-TCRγδ (B1), anti-CD19 (HIB19), anti-CD24 (ML5), anti-CD38 (HIT2), anti-IgD (IA6–2), and anti-CD57 (NK-1) (all from BD Biosciences).
Supplementary Information
Additional file 1: Supplement Table 1. Variants identified by WES.
Additional file 2: Supplement Table 2. OGTT results of our case (P1).
Abbreviations
STAT3 Signal transduction and activator of transcription 3
JAK Janus kinases
LOF Loss-of-function
GOF Gain-of-function
NGS Next generation sequencing
IUIS International union of immunological societies
HLH Lymphohistiocytosis syndrome
EBV Epstein-barr virus
EM Effector memory
IL-6CM Central memory
IVIG Intravenous immunoglobulin
Acknowledgements
Many thanks to the patient and her parents.
Authors’ contributions
W.X.C., S.J.Q., W.W.J. designed the study. W.X.C., S.J.Q., W.W.J., Y.W.J., H.J., Z.Q.H. diagnosed, treated, and followed up the patient. W.Y. performed the lymphocyte subpopulation analysis. W.W.J. and H.X.Y. abstracted the information from electronic medical chart and follow-up material. S.B.J .and Y.M. did the telephone interview. W.W.J. wrote the first draft. S.J.Q., W.W.J. and L.L.Y. reviewed and revised the manuscript. S.J.Q. and W.X.C. supervised the whole process of the study. The author(s) read and approved the final manuscript.
Funding
This study was funded by the National Natural Science Foundation of China (81373221).
Availability of data and materials
The datasets used and analyzed during the current study available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
The study was carried out at Children’s hospital of Fudan University (Shanghai, China). The protocol 2020–453 was approved by the Ethics Committee of the Children’s Hospital of Fudan University. Because the patient was under the age of 18 years, her parents gave written informed consent to participate tocilizumab therapy and report data in accordance with the declaration of Helsinki.
Consent for publication
Written informed consent for publication of identifying images and other personal or clinical details was obtained from the patient’s parents.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 1.6 MG/KG, DAILY | DrugDosageText | CC BY | 33731004 | 19,866,414 | 2021-03-17 |
What was the dosage of drug 'METHYLPREDNISOLONE'? | Efficacy of tocilizumab therapy in a patient with severe pancytopenia associated with a STAT3 gain-of-function mutation.
We aimed to report the clinical characteristics, immunological features, and treatment of one patient with a de novo STAT3 gain-of-function mutation identified by next generation sequencing. We investigated the efficacy of tocilizumab therapy in immune dysregulation diseases caused by STAT3 mutation.
The patient was a 16-year-old girl. She presented with recurrent respiratory infections and chronic diarrhea after birth. She had life-threatening autoimmune pancytopenia at 14 years old. After receiving glucocorticoid therapy, she developed diabetes. However, her pancytopenia relapsed when the glucocorticoid was tapered. Next-generation sequencing showed a de novo heterozygous mutation in the STAT3 gene, c.1261G > A (p. G421R), which was previously described as a gain-of-function mutation. After tocilizumab therapy, her pancytopenia fully resolved, and insulin and glucocorticoid therapies were gradually discontinued within 12 months. She had lymphopenia and an inverted CD4/CD8 ratio before therapy. Lymphocyte subpopulation analysis indicated an expansion of effector memory CD4+, effector memory CD8+ and central memory CD4+ T cells. The proportions of memory B cells and naive CD4+ T cells were decreased, and the proportion of naïve B cells was increased. None of the abnormal lymphocytic changes improved significantly. STAT3 GOF mutations were identified by next gene sequencing in those with early-onset multi-organ autoimmunity. Including our patient, 13 patients with STAT3 GOF mutations received targeted treatment. Twelve of them were treated with tocilizumab alone or combination tocilizumab with JAK inhibitor, and ten patients improved.
Gene sequencing should be performed for patients with early-onset refractory or multiorgan immune dysregulation diseases. Targeted drugs can effectively improve the clinical problems associated with STAT3 gain-of-function mutations, while nontargeted immunosuppressive therapy is usually insufficient.
Background
Signal Transduction and Activator of Transcription 3 (STAT3), one of the seven members of the STAT family of transcription factors, helps transmit key cytokine signals from cell membrane receptors to the nucleus using Janus kinases (JAKs). STATs are involved in multiple processes, including early development, cellular proliferation, survival, and differentiation. Germline STAT3 gene loss-of-function (LOF) mutations cause hyper IgE syndrome, which often manifests as special facial features, recurrent infections, eczema, and joint hyperextension [1]. STAT3 gain-of-function (GOF) mutations were first reported in 2014 [2–8]. In the phenotypical classification of inborn errors in human immunity by the International Union of Immunological Societies (IUIS) in the 2019 update [9], diseases of immune dysregulation were divided into two categories: a) hematopoietic lymphohistiocytosis syndrome (HLH) and Epstein-Barr virus (EBV) susceptibility and b) syndromes with autoimmunity and others. GOF mutation of the germline STAT3 gene is one of the regulatory T cell defects accompanied by autoimmune manifestations. These mutations cause early-onset lymphoproliferation with lymphadenopathy, hepatosplenomegaly and multiorgan autoimmunity, including cytopenia, hepatitis, inflammatory lung disease, enteropathy, and diabetes mellitus.
Patients with STAT3 GOF were treated with regular immunosuppressive treatments before the results of gene sequencing which always couldn’t control all the clinical manifestations [10–14]. Functional analyses of STAT3 GOF mutations demonstrated increased transcriptional activity of STAT3 in unstimulated and/or stimulated cells in vitro [3]. Because IL-6 is one of the primary cytokines that utilizes STAT3 for signal transduction, IL-6 receptor (IL-6R) antagonist therapy currently have been reported to be effective in these patients [4, 5, 10–13]. Here, we reviewed the clinical manifestations and immunological features of one patient with a STAT3 GOF mutation. Moreover, we aimed to investigate the efficacy of tocilizumab therapy.
Results
Case review
A 16-year-old girl born to nonconsanguineous Chinese parents presented with recurrent respiratory infections after birth and suffered at least 1–2 pneumonia events per year. She had chronic diarrhea from 3 months old. When she was 12 years old, she developed cervical adenopathy, alopecia, and bilateral lower limb weakness. She had life-threatening autoimmune pancytopenia with a positive Coomb’s test at the age of 14. She also presented with growth retardation and hepatosplenomegaly. Laboratory data showed that her peripheral blood leukocyte count was (0.90–1.36) × 109/L, her hemoglobin level was 87–106 g/L and her platelet count was (32–51) × 109/L. Her antinuclear antibody (ANA), extractable nuclear antibody (ENA) spectrum and anticardiolipin antibody detection were negative. Complement C3 and C4 were normal. She had lymphopenia and an inverted CD4/CD8 ratio before therapy, and her serum immunoglobulin G concentration was slightly higher than the normal range. Lymphocyte subpopulation analysis indicated expansion of effector memory (EM) CD4+ T, EM CD8+ T and central memory (CM) CD4+ T cells. The proportions of memory B cells and naive CD4+ T cells were decreased, and the proportion of naïve B cells was increased (Fig. 1). Magnetic resonance imaging of the lower limbs revealed abnormal signals in the muscles and fluid accumulation in the intermuscular space, which indicated inflammatory changes. Fig. 1 Lymphocyte subpopulaltions of our patient. A:CD19 + IgD + CD27– naïve B (94.2%), CD19 + IgD–CD27+ memory B (1.9%); B:CD38 + CD24+ transitional B (0%), CD38 + CD24– plasmablast B (1.7%); C: CD3 + CD4+ T (24.4%); CD3 + CD8+ T (66.3%); CD3 + CD4–CD8– double negative T (7.2%); D:subpopulaltions of CD4+ T cells: CD3 + CD4 + CD45RA + CD27+ naïve T (11%), CD3 + CD4 + CD45RO + CD27+ central memory T (49.6%), CD3 + CD4 + CD45RO + CD27– effector memory T (23.8%); E:subpopulaltions of CD8 + T cells: CD3 + CD8 + CD45RA + CD27+ naïve T (48.1%), CD3 + CD8 + CD45RO + CD27+ central memory T (13.7%), CD3 + CD8 + CD45RO + CD27– effect memory T (9.3%), CD3 + CD8 + CD45RA + CD27– TEMRA T (28.9%)
Gene analysis
Next-gene sequencing (NGS) revealed that she had a heterozygous de novo mutation in the STAT3 gene, while her parents were normal (Fig. 2). The missense mutation in the DNA binding domain (c.1261G > A, p. G421R) was described as a gain-of-function mutation in previous studies [2]. Fig. 2 Sanger sequence results of our patient and her parents
Treatment and follow-up
Before the gene sequencing results were available, the patient accepted intravenous methylprednisolone (1.6 mg/kg/day) for autoimmune pancytopenia. She was changed to the same dose of oral glucocorticoid tablet after Coomb’s test turned negative and pancytopenia improved. But the pancytopenia relapsed several times once the glucocorticoid dose was less than 2 mg/kg/day. Meanwhile, she developed diabetes and worse weakness of lower limbs during the glucocorticoid treatment. The fasting plasma glucose was 7.2 mmol/L, the glycated hemoglobin (Hb1c) was 5.8%, and all the insulin autoantibodies were negative. The oral glucose tolerance test showed increased C peptide and plasma glucose after 30 min, 60 min, 120 min, and 180 min of oral glucose, while plasma insulin level didn’t increase (supplement Table 2). So, we diagnosed diabetes and considered it as a side effect of glucocorticoid therapy. The blood biochemistry results were normal before and after treatment, including creatine kinase (CK), serum electrolytes, transaminase, and creatinine. The diagnosis of myositis was based on MRI abnormal signals in muscle and cutting movement assessment score (CMAS) was 15 of 52.
After obtaining informed consent from her parents, we administered IL-6R antagonist treatment (tocilizumab) at a dosage of 8 mg/kg intravenous infusion every 2 weeks. After 2 months of tocilizumab treatment, the patient’s pancytopenia fully resolved. She discontinued insulin injection after 4 months of tocilizumab therapy, and glucocorticoid therapy was gradually discontinued within 12 months. Her serum IL-6 levels increased before glucocorticoid therapy and improved for a while but fluctuated after glucocorticoid tapering and gradually decreased to normal after tocilizumab therapy (Fig. 3). She underwent intravenous immunoglobulin (IVIG) replacement after 6 months because of hypogammaglobulinemia. Beginning in the second year of therapy, she extended the interval of tocilizumab to every 4–6 weeks (240 mg/dose, after her weight was above 30 kg), with a good response evidenced by a normal hemoglobin level and negative Coomb’s test. Lymphadenopathy and hepatosplenomegaly returned to mild enlargement (Table 1). Fig. 3 Serum IL-6 before and after tocilizumab of our patient. She accepted glucocorticoid first from week − 18 to week 0
Table 1 Clinical features and immunotype of our patient with a STAT3 GOF mutation
tocilizumab therapy before after
lymphadenopathy yes no
hepatosplenomegaly yes (severe) mild
autoimmune pancytopenia yes no
myositis worse better
alopecia yes better
WBC
(×109/L)
0.90–1.36#
0.9–6.8##
4.7–8.3###
HB
g/L
87–106#
46–139##
112–139###
PLT
(×109/L)
32–51#
32–123##
107–178###
IgM 1.84 0.62
IgA 1.3 0.25
IgG 14.5 6.6 a
IgE < 2 < 2
CD3 89.13% (607) 82.87% (786)
CD4 32.41% (221) 30.61% (290)
CD8 51.17% (349) 48.70% (462)
CD4/CD8 0.63 0.63
CD19 8.74% (60) 9.08% (31)
NK 1.49% (10) 7.28% (69)
* with monthly IVIG replacement
# before glucocorticoid treatment, ## after glucocorticoid treatment;
### after 1 month of tocilizumab therapy
We regularly followed up for infection indicators during targeted therapy. She had cervical lymphadenitis and Candida albicans vaginitis once during 2 years of therapy. Her EBV-DNA load of whole leukocytes in the peripheral blood was higher than the level at the beginning, changing from 1.29 × 104 copies/ml to 3.58 × 106 copies/ml. In addition to treatment with targeted drugs, she accepted oral itraconazole and acyclovir tablets.
Her immune phenotypes after tocilizumab showed hypogammaglobulinemia after 6 months of therapy. All the abnormal lymphocytic changes (expansion of EM CD4+ T, EM CD8+ T and CM CD4+ T cells; decreased memory B cell and naive CD4+ T cell levels; and an increased naïve B cell level) did not improve significantly (Fig. 4). Fig. 4 Subpopulation of T/B lymphocytes of our patient before and 1 month, 12 months after tocilizumab
Discussion
STAT3 GOF mutations were reported in patients with multiple early-onset autoimmune manifestations by NGS [3]. Fabre et al. summarized the clinical features of 42 patients, and the most common manifestations were autoimmune cytopenia, lymphoproliferation, enteropathy, interstitial lung disease, thyroiditis, diabetes, and growth retardation; some of the patients had recurrent or opportunistic infections [14]. The onset age and major symptoms of our patient were similar to those of other patients reported previously [2, 3]. She developed diabetes during glucocorticoid therapy with normal glycated hemoglobin levels, which is different from the early-onset type 1 diabetes reported in the literature. Her Hb1c, insulin autoantibodies and oral glucose tolerance test indicated her diabetes was a side effect of glucocorticoid therapy. We also found that her bilateral lower limb weakness was related to immune myositis on MRI. The abnormal changes in the muscles improved after tocilizumab treatment (Fig. 5). Fig. 5 Magnetic resonance imaging of left lower limbs of patient 1. a and c revealed abnormal signals in muscle and fluid accumulation in the intermuscular space considering inflammatory changes. b and d revealed abnormal changes recovered after tocilizumab
According the functions of immune system, infection tendency, autoimmunity and extremely abnormal immune reactions are common manifestations of primary immunodeficiencies. So, we did NGS at the beginning of diagnose considering a genetic defect may exist. STAT3 GOF mutations were identified by gene sequencing in those with early-onset multi-organ autoimmunity.
Activation of STAT3 leads to the production of downstream cytokines, including glycoprotein 130 (a component of IL-6 and IL-27), common gamma chain cytokines, IL-10 family cytokines and IL-23. After cytokines bind to their receptors, one of four Janus kinases (JAKs) is activated and phosphorylates the cytokine receptor. STAT molecules are recruited to the phosphorylated receptor and then translocate to the nucleus, altering gene expression [15]. The proportions of regulatory T cells are reduced, while IL-17 levels are increased in patients with STAT3 GOF mutations [3, 8]. In vitro, IL-6R antagonists can reduce IL-17 secretion and improve immune dysregulation by increasing regulatory T cell differentiation [4]. Therefore, IL-6R antagonists and JAK inhibitors can inhibit STAT3 signaling pathway overactivation and be used to treat patients with STAT3 GOF mutations.
Twelve patients with STAT3 GOF mutations received targeted treatment in 5 reports [4, 5, 9–11]. Three (including our patient, P1) of the 13 patients were treated with tocilizumab alone, and all three improved (P1, P2, and P3); 1 patient improved with JAK inhibitor treatment alone (P7); the remaining 9 patients were treated successively or simultaneously with tocilizumab and JAK inhibitors because of disease severity or incomplete remission. Combination treatment could take the following factors into consideration: enteropathy (4/9), interstitial pulmonary disease (4/9), arthritis (2/9), hepatitis (3/9), splenomegaly (1/9), and cytopenia (2/9). Seven of the nine patients who received combined treatment achieved remission (Table 2). STAT3 GOF mutation patients manifesting with multiple clinical symptoms might need combination therapy if the tocilizumab or JAK inhibitors alone couldn’t control the disease. The outcomes of targeted therapy are summarized in Table 3. The symptoms of arthritis, cytopenia, hepatosplenomegaly and hepatitis were all alleviated. Three of the 13 patients died. P10 died of infection after transplant, while recurrent HLH was resolved by targeted treatment. P9 died of sepsis and diffuse intravascular coagulation. P13 died of respiratory failure. Considering cytopenia as the common adverse reaction to JAK inhibitors, two patients with the G421R mutant who recovered with tocilizumab alone have been reported in the literature [2, 4]. Therefore, we chose tocilizumab as the first targeted treatment for our patient. After 1 year of treatment, her whole blood cells stayed in the normal range with no serious infections. However, the EBV-DNA titer of peripheral blood leukocytes was higher than that at the beginning. This means that latency and active infections need to be monitored before and after targeted therapy. Table 2 Summary of targeted therapy in all the reported patients with a STAT3 GOF mutation
Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13
a. sex female male male female female female male female male female male male
b. onset age 3 mo 4 yr 6 mo 5 mo 1 yr 1 yr 1 mo 7 yr 3 yr 7 mo 7 yr
c. age 16 yr 10 yr 38 yr 19 yr 9 yr 21 yr 20 yr 8 yr 14 yr 3 yr 8 yr 13 yr 15 yr
d. infections Y Y Y Y Y
e. cytopenia Y Y Y Y Y Y Y Y
f. enteropathy Y Y Y Y Y Y Y Y Y
g. hepatitis Y Y Y Y Y
h. endocrine disease Y Y Y Y Y
i. arthritis Y Y Y Y Y
j. lymphadenopathy Y Y Y
k. hepatosplenomegaly Y Y Y Y Y Y Y Y Y Y
l. interstitial lung disease Y Y Y Y Y
m. short stature Y Y Y Y Y Y Y Y Y Y Y Y
n. reason of for targeted therapy pancytopenia, arthritis enteropathy, colitis interstitial lung disease arthritis, interstitial lung disease hepatosplenomegaly, hepatotitis, enteropathy, interstitial lung disease arthritis enteropathy,
hepatosplenomegaly dermopathy interstitial lung disease anemia enteropathy
HLH
interstitial lung disease
o. tocilizumab alone ✓ ✓ ✓
p. combination of tocilizumab and a JAK inhibitor ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
q. JAK inhibitor alone ✓
r. efficiency of targeted therapy yes yes yes yes yes yes yes yes no yes yes yes no
s. outcome alive alive alive alive alive alive alive alive dead dead dead alive dead
t. mutantmutation in of STAT3 G421R G421R G421R N401D E415L V393A M329K R152W F174S E286G Q344H G421R P715L
u. reference our report [2] [4] [13] [11] [12] [11] [10] [10] [10] [10] [10] [10]
Y represent YES, and slash indicate the parameter was not mentioned in the reference
p: combination of tocilizumab and JAK inhibitors
Patients 4, 5, 6, 9, 11 and 12 were treated with tocilizumab first, and then a JAK inhibitor was added later. Patients 8 and 10 were treated with two targeted drugs simultaneously. Patient 14 was treated with a JAK inhibitor first and then changed to tocilizumab
Table 3 Effect summary for targeted therapy
Cause of targeted therapy Case number Remission number No response Proportion of remission
enteropathy 5 3 2 60%
ILD 5 4 1 80%
arthritis 3 3 0 100%
cytopenia 3 3 0 100%
hepatosplenomegaly 2 2 0 100%
dermopathy 2 1 1 50%
hepatitis/liver failure 1 0 1 0%
The immunological features of STAT3 GOF mutations included hypogammaglobulinemia, increased Th17 cells and decreased Treg cells, which plays a critical role in the development of autoimmunity. While some case reports showed normal Th17 cells or Treg cells in the symptomatic STAT3 GOF patients [8]. There is no immunological index for starting and evaluating the efficacy of targeted therapy. The 12 patients reported above had no immunophenotypic changes with targeted treatment. One patient showed an improvement in the proportion of regulatory T cells after tocilizumab treatment [4]. We evaluated lymphocyte subpopulations before and after treatment. There were no significant improvements in those abnormal changes in our patient after 1 year of treatment. It cannot be ruled out that the immune phenotype changes later than clinical improvement. The relationship between immunological characteristics and mechanism of disease needs further research. The patient still requires monthly IVIG replacement with targeted therapy. Consistent with other reports [2, 16], she had hypogammaglobulinemia and a low proportion of memory B cells. However, the IgG level was higher than normal during the course of autoimmune pancytopenia due to the presence of autoantibodies. Therefore, her hypogammaglobulinemia was consistent with the reduced proportion of memory B cells regardless of the side effects of tocilizumab. The pathogenesis of the abnormal changes leading to reduced unswitched memory B cells and hypogammaglobulinemia require further study.
It has been reported that 5 patients underwent hematopoietic stem cell transplantation [2, 9, 17, 18], of whom four died due to complications, such as infection. The remaining patient was successfully transplanted and lived well. It is known from the reported cases that targeted therapy can effectively control and alleviate life-threatening autoimmune manifestations and lymphoproliferative disorders. The longest follow-up time for targeted therapy is 3.5 years [9]. Our patient was followed up for 2 years, and she had no obvious serious infections or adverse reactions. Aside from IL-6R antagonists and JAK inhibitors, whether better targeted drugs exist requires more clinical data and pathogenesis studies.
Conclusions
We reported the first case of tocilizumab therapy in immune dysregulation disorders caused by a STAT3 GOF mutation in mainland China. Gene sequencing should be performed for patients with early-onset refractory immune dysregulation diseases since routine immunological examination may be nonspecific. Targeted drugs can effectively improve the clinical problems associated with STAT3 gain-of-function mutations, while nontargeted immunosuppressive therapy is usually insufficient.
Methods
The study was carried out at Children’s hospital of Fudan University (Shanghai, China). The protocol 2020–453 was approved by the Ethics Committee of the Children’s Hospital of Fudan University. Because the patient was under the age of 18 years, her parents gave written informed consent to participate tocilizumab therapy and report data in accordance with the declaration of Helsinki.
Clinical data
We retrospectively summarized the clinical data of the STAT3 GOF patient.
Whole-exome sequencing
WES and analysis protocols were adapted for genetic analysis. After obtaining the informed consent from the parents, genomic DNA samples were extracted from the whole blood of the patient and her parents with the QIAamp® DNA Blood Mini Kit (Qiagen, Hilden, Germany). The concentration and quantity of the DNA samples were measured using a NanoDrop ultraviolet spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA) [19]. Genomic DNA fragments were enriched for the target region of the consensus coding sequence exons and sequenced on an Illumina HiSeq 2000 platform (Illumina, San Diego, CA) [19]. Data analyses were conducted by using ANNOVAR and VEP software in our clinical genetic laboratory by a bioinformatics team. The mutation was confirmed by Sanger sequencing.
Routine evaluation of immunological function
Immunological evaluations were carried out during routine clinical work. As previously reported, IgG, IgA, and IgM were detected by nephelometry; IgE was assessed by UniCAP (Pharmacia, Uppsala, Sweden) [20]. Lymphocyte subsets were analyzed by FACSCalibur flow cytometer (Becton Dickinson, Franklin Lakes, NJ, USA) [21]. Whole blood was used for staining of lymphocyte surface markers and analyzed according to a standard multicolor flow cytometric protocol with following antibodies [21]: anti-CD3 (UCHT1), anti-CD8 (RPA-T8), anti-CD27 (M-T271), anti-CD45RA (HI100), anti-CD4 (RPA-T4), anti-TCRαβ (T10B9.1A-31), anti-TCRγδ (B1), anti-CD19 (HIB19), anti-CD24 (ML5), anti-CD38 (HIT2), anti-IgD (IA6–2), and anti-CD57 (NK-1) (all from BD Biosciences).
Supplementary Information
Additional file 1: Supplement Table 1. Variants identified by WES.
Additional file 2: Supplement Table 2. OGTT results of our case (P1).
Abbreviations
STAT3 Signal transduction and activator of transcription 3
JAK Janus kinases
LOF Loss-of-function
GOF Gain-of-function
NGS Next generation sequencing
IUIS International union of immunological societies
HLH Lymphohistiocytosis syndrome
EBV Epstein-barr virus
EM Effector memory
IL-6CM Central memory
IVIG Intravenous immunoglobulin
Acknowledgements
Many thanks to the patient and her parents.
Authors’ contributions
W.X.C., S.J.Q., W.W.J. designed the study. W.X.C., S.J.Q., W.W.J., Y.W.J., H.J., Z.Q.H. diagnosed, treated, and followed up the patient. W.Y. performed the lymphocyte subpopulation analysis. W.W.J. and H.X.Y. abstracted the information from electronic medical chart and follow-up material. S.B.J .and Y.M. did the telephone interview. W.W.J. wrote the first draft. S.J.Q., W.W.J. and L.L.Y. reviewed and revised the manuscript. S.J.Q. and W.X.C. supervised the whole process of the study. The author(s) read and approved the final manuscript.
Funding
This study was funded by the National Natural Science Foundation of China (81373221).
Availability of data and materials
The datasets used and analyzed during the current study available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
The study was carried out at Children’s hospital of Fudan University (Shanghai, China). The protocol 2020–453 was approved by the Ethics Committee of the Children’s Hospital of Fudan University. Because the patient was under the age of 18 years, her parents gave written informed consent to participate tocilizumab therapy and report data in accordance with the declaration of Helsinki.
Consent for publication
Written informed consent for publication of identifying images and other personal or clinical details was obtained from the patient’s parents.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 1.6 MG/KG, 1X/DAY | DrugDosageText | CC BY | 33731004 | 19,866,414 | 2021-03-17 |
What was the outcome of reaction 'Drug ineffective'? | Efficacy of tocilizumab therapy in a patient with severe pancytopenia associated with a STAT3 gain-of-function mutation.
We aimed to report the clinical characteristics, immunological features, and treatment of one patient with a de novo STAT3 gain-of-function mutation identified by next generation sequencing. We investigated the efficacy of tocilizumab therapy in immune dysregulation diseases caused by STAT3 mutation.
The patient was a 16-year-old girl. She presented with recurrent respiratory infections and chronic diarrhea after birth. She had life-threatening autoimmune pancytopenia at 14 years old. After receiving glucocorticoid therapy, she developed diabetes. However, her pancytopenia relapsed when the glucocorticoid was tapered. Next-generation sequencing showed a de novo heterozygous mutation in the STAT3 gene, c.1261G > A (p. G421R), which was previously described as a gain-of-function mutation. After tocilizumab therapy, her pancytopenia fully resolved, and insulin and glucocorticoid therapies were gradually discontinued within 12 months. She had lymphopenia and an inverted CD4/CD8 ratio before therapy. Lymphocyte subpopulation analysis indicated an expansion of effector memory CD4+, effector memory CD8+ and central memory CD4+ T cells. The proportions of memory B cells and naive CD4+ T cells were decreased, and the proportion of naïve B cells was increased. None of the abnormal lymphocytic changes improved significantly. STAT3 GOF mutations were identified by next gene sequencing in those with early-onset multi-organ autoimmunity. Including our patient, 13 patients with STAT3 GOF mutations received targeted treatment. Twelve of them were treated with tocilizumab alone or combination tocilizumab with JAK inhibitor, and ten patients improved.
Gene sequencing should be performed for patients with early-onset refractory or multiorgan immune dysregulation diseases. Targeted drugs can effectively improve the clinical problems associated with STAT3 gain-of-function mutations, while nontargeted immunosuppressive therapy is usually insufficient.
Background
Signal Transduction and Activator of Transcription 3 (STAT3), one of the seven members of the STAT family of transcription factors, helps transmit key cytokine signals from cell membrane receptors to the nucleus using Janus kinases (JAKs). STATs are involved in multiple processes, including early development, cellular proliferation, survival, and differentiation. Germline STAT3 gene loss-of-function (LOF) mutations cause hyper IgE syndrome, which often manifests as special facial features, recurrent infections, eczema, and joint hyperextension [1]. STAT3 gain-of-function (GOF) mutations were first reported in 2014 [2–8]. In the phenotypical classification of inborn errors in human immunity by the International Union of Immunological Societies (IUIS) in the 2019 update [9], diseases of immune dysregulation were divided into two categories: a) hematopoietic lymphohistiocytosis syndrome (HLH) and Epstein-Barr virus (EBV) susceptibility and b) syndromes with autoimmunity and others. GOF mutation of the germline STAT3 gene is one of the regulatory T cell defects accompanied by autoimmune manifestations. These mutations cause early-onset lymphoproliferation with lymphadenopathy, hepatosplenomegaly and multiorgan autoimmunity, including cytopenia, hepatitis, inflammatory lung disease, enteropathy, and diabetes mellitus.
Patients with STAT3 GOF were treated with regular immunosuppressive treatments before the results of gene sequencing which always couldn’t control all the clinical manifestations [10–14]. Functional analyses of STAT3 GOF mutations demonstrated increased transcriptional activity of STAT3 in unstimulated and/or stimulated cells in vitro [3]. Because IL-6 is one of the primary cytokines that utilizes STAT3 for signal transduction, IL-6 receptor (IL-6R) antagonist therapy currently have been reported to be effective in these patients [4, 5, 10–13]. Here, we reviewed the clinical manifestations and immunological features of one patient with a STAT3 GOF mutation. Moreover, we aimed to investigate the efficacy of tocilizumab therapy.
Results
Case review
A 16-year-old girl born to nonconsanguineous Chinese parents presented with recurrent respiratory infections after birth and suffered at least 1–2 pneumonia events per year. She had chronic diarrhea from 3 months old. When she was 12 years old, she developed cervical adenopathy, alopecia, and bilateral lower limb weakness. She had life-threatening autoimmune pancytopenia with a positive Coomb’s test at the age of 14. She also presented with growth retardation and hepatosplenomegaly. Laboratory data showed that her peripheral blood leukocyte count was (0.90–1.36) × 109/L, her hemoglobin level was 87–106 g/L and her platelet count was (32–51) × 109/L. Her antinuclear antibody (ANA), extractable nuclear antibody (ENA) spectrum and anticardiolipin antibody detection were negative. Complement C3 and C4 were normal. She had lymphopenia and an inverted CD4/CD8 ratio before therapy, and her serum immunoglobulin G concentration was slightly higher than the normal range. Lymphocyte subpopulation analysis indicated expansion of effector memory (EM) CD4+ T, EM CD8+ T and central memory (CM) CD4+ T cells. The proportions of memory B cells and naive CD4+ T cells were decreased, and the proportion of naïve B cells was increased (Fig. 1). Magnetic resonance imaging of the lower limbs revealed abnormal signals in the muscles and fluid accumulation in the intermuscular space, which indicated inflammatory changes. Fig. 1 Lymphocyte subpopulaltions of our patient. A:CD19 + IgD + CD27– naïve B (94.2%), CD19 + IgD–CD27+ memory B (1.9%); B:CD38 + CD24+ transitional B (0%), CD38 + CD24– plasmablast B (1.7%); C: CD3 + CD4+ T (24.4%); CD3 + CD8+ T (66.3%); CD3 + CD4–CD8– double negative T (7.2%); D:subpopulaltions of CD4+ T cells: CD3 + CD4 + CD45RA + CD27+ naïve T (11%), CD3 + CD4 + CD45RO + CD27+ central memory T (49.6%), CD3 + CD4 + CD45RO + CD27– effector memory T (23.8%); E:subpopulaltions of CD8 + T cells: CD3 + CD8 + CD45RA + CD27+ naïve T (48.1%), CD3 + CD8 + CD45RO + CD27+ central memory T (13.7%), CD3 + CD8 + CD45RO + CD27– effect memory T (9.3%), CD3 + CD8 + CD45RA + CD27– TEMRA T (28.9%)
Gene analysis
Next-gene sequencing (NGS) revealed that she had a heterozygous de novo mutation in the STAT3 gene, while her parents were normal (Fig. 2). The missense mutation in the DNA binding domain (c.1261G > A, p. G421R) was described as a gain-of-function mutation in previous studies [2]. Fig. 2 Sanger sequence results of our patient and her parents
Treatment and follow-up
Before the gene sequencing results were available, the patient accepted intravenous methylprednisolone (1.6 mg/kg/day) for autoimmune pancytopenia. She was changed to the same dose of oral glucocorticoid tablet after Coomb’s test turned negative and pancytopenia improved. But the pancytopenia relapsed several times once the glucocorticoid dose was less than 2 mg/kg/day. Meanwhile, she developed diabetes and worse weakness of lower limbs during the glucocorticoid treatment. The fasting plasma glucose was 7.2 mmol/L, the glycated hemoglobin (Hb1c) was 5.8%, and all the insulin autoantibodies were negative. The oral glucose tolerance test showed increased C peptide and plasma glucose after 30 min, 60 min, 120 min, and 180 min of oral glucose, while plasma insulin level didn’t increase (supplement Table 2). So, we diagnosed diabetes and considered it as a side effect of glucocorticoid therapy. The blood biochemistry results were normal before and after treatment, including creatine kinase (CK), serum electrolytes, transaminase, and creatinine. The diagnosis of myositis was based on MRI abnormal signals in muscle and cutting movement assessment score (CMAS) was 15 of 52.
After obtaining informed consent from her parents, we administered IL-6R antagonist treatment (tocilizumab) at a dosage of 8 mg/kg intravenous infusion every 2 weeks. After 2 months of tocilizumab treatment, the patient’s pancytopenia fully resolved. She discontinued insulin injection after 4 months of tocilizumab therapy, and glucocorticoid therapy was gradually discontinued within 12 months. Her serum IL-6 levels increased before glucocorticoid therapy and improved for a while but fluctuated after glucocorticoid tapering and gradually decreased to normal after tocilizumab therapy (Fig. 3). She underwent intravenous immunoglobulin (IVIG) replacement after 6 months because of hypogammaglobulinemia. Beginning in the second year of therapy, she extended the interval of tocilizumab to every 4–6 weeks (240 mg/dose, after her weight was above 30 kg), with a good response evidenced by a normal hemoglobin level and negative Coomb’s test. Lymphadenopathy and hepatosplenomegaly returned to mild enlargement (Table 1). Fig. 3 Serum IL-6 before and after tocilizumab of our patient. She accepted glucocorticoid first from week − 18 to week 0
Table 1 Clinical features and immunotype of our patient with a STAT3 GOF mutation
tocilizumab therapy before after
lymphadenopathy yes no
hepatosplenomegaly yes (severe) mild
autoimmune pancytopenia yes no
myositis worse better
alopecia yes better
WBC
(×109/L)
0.90–1.36#
0.9–6.8##
4.7–8.3###
HB
g/L
87–106#
46–139##
112–139###
PLT
(×109/L)
32–51#
32–123##
107–178###
IgM 1.84 0.62
IgA 1.3 0.25
IgG 14.5 6.6 a
IgE < 2 < 2
CD3 89.13% (607) 82.87% (786)
CD4 32.41% (221) 30.61% (290)
CD8 51.17% (349) 48.70% (462)
CD4/CD8 0.63 0.63
CD19 8.74% (60) 9.08% (31)
NK 1.49% (10) 7.28% (69)
* with monthly IVIG replacement
# before glucocorticoid treatment, ## after glucocorticoid treatment;
### after 1 month of tocilizumab therapy
We regularly followed up for infection indicators during targeted therapy. She had cervical lymphadenitis and Candida albicans vaginitis once during 2 years of therapy. Her EBV-DNA load of whole leukocytes in the peripheral blood was higher than the level at the beginning, changing from 1.29 × 104 copies/ml to 3.58 × 106 copies/ml. In addition to treatment with targeted drugs, she accepted oral itraconazole and acyclovir tablets.
Her immune phenotypes after tocilizumab showed hypogammaglobulinemia after 6 months of therapy. All the abnormal lymphocytic changes (expansion of EM CD4+ T, EM CD8+ T and CM CD4+ T cells; decreased memory B cell and naive CD4+ T cell levels; and an increased naïve B cell level) did not improve significantly (Fig. 4). Fig. 4 Subpopulation of T/B lymphocytes of our patient before and 1 month, 12 months after tocilizumab
Discussion
STAT3 GOF mutations were reported in patients with multiple early-onset autoimmune manifestations by NGS [3]. Fabre et al. summarized the clinical features of 42 patients, and the most common manifestations were autoimmune cytopenia, lymphoproliferation, enteropathy, interstitial lung disease, thyroiditis, diabetes, and growth retardation; some of the patients had recurrent or opportunistic infections [14]. The onset age and major symptoms of our patient were similar to those of other patients reported previously [2, 3]. She developed diabetes during glucocorticoid therapy with normal glycated hemoglobin levels, which is different from the early-onset type 1 diabetes reported in the literature. Her Hb1c, insulin autoantibodies and oral glucose tolerance test indicated her diabetes was a side effect of glucocorticoid therapy. We also found that her bilateral lower limb weakness was related to immune myositis on MRI. The abnormal changes in the muscles improved after tocilizumab treatment (Fig. 5). Fig. 5 Magnetic resonance imaging of left lower limbs of patient 1. a and c revealed abnormal signals in muscle and fluid accumulation in the intermuscular space considering inflammatory changes. b and d revealed abnormal changes recovered after tocilizumab
According the functions of immune system, infection tendency, autoimmunity and extremely abnormal immune reactions are common manifestations of primary immunodeficiencies. So, we did NGS at the beginning of diagnose considering a genetic defect may exist. STAT3 GOF mutations were identified by gene sequencing in those with early-onset multi-organ autoimmunity.
Activation of STAT3 leads to the production of downstream cytokines, including glycoprotein 130 (a component of IL-6 and IL-27), common gamma chain cytokines, IL-10 family cytokines and IL-23. After cytokines bind to their receptors, one of four Janus kinases (JAKs) is activated and phosphorylates the cytokine receptor. STAT molecules are recruited to the phosphorylated receptor and then translocate to the nucleus, altering gene expression [15]. The proportions of regulatory T cells are reduced, while IL-17 levels are increased in patients with STAT3 GOF mutations [3, 8]. In vitro, IL-6R antagonists can reduce IL-17 secretion and improve immune dysregulation by increasing regulatory T cell differentiation [4]. Therefore, IL-6R antagonists and JAK inhibitors can inhibit STAT3 signaling pathway overactivation and be used to treat patients with STAT3 GOF mutations.
Twelve patients with STAT3 GOF mutations received targeted treatment in 5 reports [4, 5, 9–11]. Three (including our patient, P1) of the 13 patients were treated with tocilizumab alone, and all three improved (P1, P2, and P3); 1 patient improved with JAK inhibitor treatment alone (P7); the remaining 9 patients were treated successively or simultaneously with tocilizumab and JAK inhibitors because of disease severity or incomplete remission. Combination treatment could take the following factors into consideration: enteropathy (4/9), interstitial pulmonary disease (4/9), arthritis (2/9), hepatitis (3/9), splenomegaly (1/9), and cytopenia (2/9). Seven of the nine patients who received combined treatment achieved remission (Table 2). STAT3 GOF mutation patients manifesting with multiple clinical symptoms might need combination therapy if the tocilizumab or JAK inhibitors alone couldn’t control the disease. The outcomes of targeted therapy are summarized in Table 3. The symptoms of arthritis, cytopenia, hepatosplenomegaly and hepatitis were all alleviated. Three of the 13 patients died. P10 died of infection after transplant, while recurrent HLH was resolved by targeted treatment. P9 died of sepsis and diffuse intravascular coagulation. P13 died of respiratory failure. Considering cytopenia as the common adverse reaction to JAK inhibitors, two patients with the G421R mutant who recovered with tocilizumab alone have been reported in the literature [2, 4]. Therefore, we chose tocilizumab as the first targeted treatment for our patient. After 1 year of treatment, her whole blood cells stayed in the normal range with no serious infections. However, the EBV-DNA titer of peripheral blood leukocytes was higher than that at the beginning. This means that latency and active infections need to be monitored before and after targeted therapy. Table 2 Summary of targeted therapy in all the reported patients with a STAT3 GOF mutation
Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13
a. sex female male male female female female male female male female male male
b. onset age 3 mo 4 yr 6 mo 5 mo 1 yr 1 yr 1 mo 7 yr 3 yr 7 mo 7 yr
c. age 16 yr 10 yr 38 yr 19 yr 9 yr 21 yr 20 yr 8 yr 14 yr 3 yr 8 yr 13 yr 15 yr
d. infections Y Y Y Y Y
e. cytopenia Y Y Y Y Y Y Y Y
f. enteropathy Y Y Y Y Y Y Y Y Y
g. hepatitis Y Y Y Y Y
h. endocrine disease Y Y Y Y Y
i. arthritis Y Y Y Y Y
j. lymphadenopathy Y Y Y
k. hepatosplenomegaly Y Y Y Y Y Y Y Y Y Y
l. interstitial lung disease Y Y Y Y Y
m. short stature Y Y Y Y Y Y Y Y Y Y Y Y
n. reason of for targeted therapy pancytopenia, arthritis enteropathy, colitis interstitial lung disease arthritis, interstitial lung disease hepatosplenomegaly, hepatotitis, enteropathy, interstitial lung disease arthritis enteropathy,
hepatosplenomegaly dermopathy interstitial lung disease anemia enteropathy
HLH
interstitial lung disease
o. tocilizumab alone ✓ ✓ ✓
p. combination of tocilizumab and a JAK inhibitor ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
q. JAK inhibitor alone ✓
r. efficiency of targeted therapy yes yes yes yes yes yes yes yes no yes yes yes no
s. outcome alive alive alive alive alive alive alive alive dead dead dead alive dead
t. mutantmutation in of STAT3 G421R G421R G421R N401D E415L V393A M329K R152W F174S E286G Q344H G421R P715L
u. reference our report [2] [4] [13] [11] [12] [11] [10] [10] [10] [10] [10] [10]
Y represent YES, and slash indicate the parameter was not mentioned in the reference
p: combination of tocilizumab and JAK inhibitors
Patients 4, 5, 6, 9, 11 and 12 were treated with tocilizumab first, and then a JAK inhibitor was added later. Patients 8 and 10 were treated with two targeted drugs simultaneously. Patient 14 was treated with a JAK inhibitor first and then changed to tocilizumab
Table 3 Effect summary for targeted therapy
Cause of targeted therapy Case number Remission number No response Proportion of remission
enteropathy 5 3 2 60%
ILD 5 4 1 80%
arthritis 3 3 0 100%
cytopenia 3 3 0 100%
hepatosplenomegaly 2 2 0 100%
dermopathy 2 1 1 50%
hepatitis/liver failure 1 0 1 0%
The immunological features of STAT3 GOF mutations included hypogammaglobulinemia, increased Th17 cells and decreased Treg cells, which plays a critical role in the development of autoimmunity. While some case reports showed normal Th17 cells or Treg cells in the symptomatic STAT3 GOF patients [8]. There is no immunological index for starting and evaluating the efficacy of targeted therapy. The 12 patients reported above had no immunophenotypic changes with targeted treatment. One patient showed an improvement in the proportion of regulatory T cells after tocilizumab treatment [4]. We evaluated lymphocyte subpopulations before and after treatment. There were no significant improvements in those abnormal changes in our patient after 1 year of treatment. It cannot be ruled out that the immune phenotype changes later than clinical improvement. The relationship between immunological characteristics and mechanism of disease needs further research. The patient still requires monthly IVIG replacement with targeted therapy. Consistent with other reports [2, 16], she had hypogammaglobulinemia and a low proportion of memory B cells. However, the IgG level was higher than normal during the course of autoimmune pancytopenia due to the presence of autoantibodies. Therefore, her hypogammaglobulinemia was consistent with the reduced proportion of memory B cells regardless of the side effects of tocilizumab. The pathogenesis of the abnormal changes leading to reduced unswitched memory B cells and hypogammaglobulinemia require further study.
It has been reported that 5 patients underwent hematopoietic stem cell transplantation [2, 9, 17, 18], of whom four died due to complications, such as infection. The remaining patient was successfully transplanted and lived well. It is known from the reported cases that targeted therapy can effectively control and alleviate life-threatening autoimmune manifestations and lymphoproliferative disorders. The longest follow-up time for targeted therapy is 3.5 years [9]. Our patient was followed up for 2 years, and she had no obvious serious infections or adverse reactions. Aside from IL-6R antagonists and JAK inhibitors, whether better targeted drugs exist requires more clinical data and pathogenesis studies.
Conclusions
We reported the first case of tocilizumab therapy in immune dysregulation disorders caused by a STAT3 GOF mutation in mainland China. Gene sequencing should be performed for patients with early-onset refractory immune dysregulation diseases since routine immunological examination may be nonspecific. Targeted drugs can effectively improve the clinical problems associated with STAT3 gain-of-function mutations, while nontargeted immunosuppressive therapy is usually insufficient.
Methods
The study was carried out at Children’s hospital of Fudan University (Shanghai, China). The protocol 2020–453 was approved by the Ethics Committee of the Children’s Hospital of Fudan University. Because the patient was under the age of 18 years, her parents gave written informed consent to participate tocilizumab therapy and report data in accordance with the declaration of Helsinki.
Clinical data
We retrospectively summarized the clinical data of the STAT3 GOF patient.
Whole-exome sequencing
WES and analysis protocols were adapted for genetic analysis. After obtaining the informed consent from the parents, genomic DNA samples were extracted from the whole blood of the patient and her parents with the QIAamp® DNA Blood Mini Kit (Qiagen, Hilden, Germany). The concentration and quantity of the DNA samples were measured using a NanoDrop ultraviolet spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA) [19]. Genomic DNA fragments were enriched for the target region of the consensus coding sequence exons and sequenced on an Illumina HiSeq 2000 platform (Illumina, San Diego, CA) [19]. Data analyses were conducted by using ANNOVAR and VEP software in our clinical genetic laboratory by a bioinformatics team. The mutation was confirmed by Sanger sequencing.
Routine evaluation of immunological function
Immunological evaluations were carried out during routine clinical work. As previously reported, IgG, IgA, and IgM were detected by nephelometry; IgE was assessed by UniCAP (Pharmacia, Uppsala, Sweden) [20]. Lymphocyte subsets were analyzed by FACSCalibur flow cytometer (Becton Dickinson, Franklin Lakes, NJ, USA) [21]. Whole blood was used for staining of lymphocyte surface markers and analyzed according to a standard multicolor flow cytometric protocol with following antibodies [21]: anti-CD3 (UCHT1), anti-CD8 (RPA-T8), anti-CD27 (M-T271), anti-CD45RA (HI100), anti-CD4 (RPA-T4), anti-TCRαβ (T10B9.1A-31), anti-TCRγδ (B1), anti-CD19 (HIB19), anti-CD24 (ML5), anti-CD38 (HIT2), anti-IgD (IA6–2), and anti-CD57 (NK-1) (all from BD Biosciences).
Supplementary Information
Additional file 1: Supplement Table 1. Variants identified by WES.
Additional file 2: Supplement Table 2. OGTT results of our case (P1).
Abbreviations
STAT3 Signal transduction and activator of transcription 3
JAK Janus kinases
LOF Loss-of-function
GOF Gain-of-function
NGS Next generation sequencing
IUIS International union of immunological societies
HLH Lymphohistiocytosis syndrome
EBV Epstein-barr virus
EM Effector memory
IL-6CM Central memory
IVIG Intravenous immunoglobulin
Acknowledgements
Many thanks to the patient and her parents.
Authors’ contributions
W.X.C., S.J.Q., W.W.J. designed the study. W.X.C., S.J.Q., W.W.J., Y.W.J., H.J., Z.Q.H. diagnosed, treated, and followed up the patient. W.Y. performed the lymphocyte subpopulation analysis. W.W.J. and H.X.Y. abstracted the information from electronic medical chart and follow-up material. S.B.J .and Y.M. did the telephone interview. W.W.J. wrote the first draft. S.J.Q., W.W.J. and L.L.Y. reviewed and revised the manuscript. S.J.Q. and W.X.C. supervised the whole process of the study. The author(s) read and approved the final manuscript.
Funding
This study was funded by the National Natural Science Foundation of China (81373221).
Availability of data and materials
The datasets used and analyzed during the current study available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
The study was carried out at Children’s hospital of Fudan University (Shanghai, China). The protocol 2020–453 was approved by the Ethics Committee of the Children’s Hospital of Fudan University. Because the patient was under the age of 18 years, her parents gave written informed consent to participate tocilizumab therapy and report data in accordance with the declaration of Helsinki.
Consent for publication
Written informed consent for publication of identifying images and other personal or clinical details was obtained from the patient’s parents.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33731004 | 19,866,414 | 2021-03-17 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Infective aneurysm'. | Aortic aneurysm and aortic graft infection related to Mycobacterium bovis after intravesical Bacille Calmette-Guérin therapy-a case series.
BACKGROUND
So called "mycotic" aortic aneurysms account for only 0.7 to 1.3% of all aortic aneurysms and are commonly caused by Staphylococcus aureus and Salmonella species. Bacillus Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis, is part of the therapy of non-muscle-invasive bladder cancer (NMIBC).
METHODS
We report a case series of three patients with a mycobacterial graft infection related to BCG after surgical treatment of a presumed mycotic aortic aneurysm as an extremely rare complication after NMIBC treatment. All three patients developed aortic aneurysm after BCG instillation and subsequent mycobacterial graft infection.
CONCLUSIONS
Diagnosis requires a high degree of suspicion because of its nonspecific symptoms and imaging. The pathogen is not detected by standard microbiological testing. Treatment includes triple antimycobacterial therapy and radical surgical interventions. Graft preservation may be considered if no anastomosis is involved.
Background
Infectious or so called ‘mycotic’ aortic aneurysms represent merely 0.7 to 1.3% of all aortic aneurysms. Nevertheless, they constitute a life-threatening vascular complication associated with in-hospital mortality rates of up to 36% [1, 2]. Mycotic aortic aneurysms are usually caused by Staphylococcus aureus, followed by Salmonella spp., Streptococcus spp. and Escherichia coli. Mycotic aneurysms caused by mycobacterial infections are rare. Up to now, 44 cases in 42 case reports of mycotic aortic aneurysms caused by mycobacterial infection affecting the thoracoabdominal aorta after intravesical instillation of Bacillus Calmette–Guérin (BCG) have been reported (see Additional file 1: Table S1).
Intravesical BCG applications are standard of care for treating non-muscle-invasive bladder cancer (NMIBC) [3]. The live attenuated strain of Mycobacterium bovis is administered to patients with NMIBC after transurethral resection of bladder tumors (TURBT) to avert recurrence and reduce progression rates of intermediate- and high-risk tumors [4]. The incidence of BCG-related systemic complications including spondylodiscitis, psoas abscess or vascular complications remains unclear. In this case series, we report three cases of mycobacterial aortic graft infection related to intravesical application of BCG for NMIBC. This represents the largest case series in the current literature. The particular challenges for the diagnosis and treatment of this infrequent complication are discussed in this report.
Case presentations
Patient A
In November 2010, a 63-year-old man was referred to our clinic because of persistent weakness, fever, night sweat and unspecific abdominal pain lasting for two weeks. Three months before this episode, the patient had undergone emergency surgery for a ruptured infrarenal abdominal aortic aneurysm, which was treated with implantation of an aortobiiliac graft at another clinic. In 2008, the patient had been treated for NMIBC by transurethral resection and had received three cycles of intravesical BCG instillations (see Table 1). At the time of presentation, clinical examination and blood tests were unremarkable for inflammation except for a temperature of 37.6 °C. Ultrasound revealed a retroperitoneal fluid collection. Computed tomography (CT) demonstrated an extensive low-density collection surrounding the aortic prosthesis. The retroperitoneal mass was surgically removed and tissue samples were collected for histologic and microbiological studies. A specimen of the necrotic mass indicated chronic inflammation but tested negative for acid-fast bacilli (AFB) in Ziehl–Neelsen stain (Artisan™ Acid-Fast Bacillus (AFB) Stain Kit, Agilent, Santa Clara, United States). As no evidence for mycobacterial infection was found, the patient was discharged home in good condition, without antitubercular medication. Another two years later in August 2012, he presented again to our clinic with fever (40.4 °C), elevated white blood cell count (17.92/nl) and increased C-reactive protein (14.4 mg/l). CT scan revealed recurrence of a large mass in the retroperitoneum (Fig. 1). The patient underwent CT-guided aspiration. A drain was placed and specimens were sent to the microbiological laboratory. Microscopic examination showed necrotizing granulomatous inflammation with multinucleated giant cells. Direct Polymerase-chain-reaction (PCR, cobas® 6800 MTB Test, Roche, Rotkreuz, Switzerland) tested positive for Mycobacterium tuberculosis complex. Growth of Mycobacterium bovis in solid (BBL Stonebrink TB Medium + PACT + BBL Löwenstein-Jensen; Becton Dickinson, Rungis, France) and liquid culture (MGIT BBL; Becton Dickinson, Rungis, France) confirmed the suspected diagnosis. Antitubercular therapy with Isoniazid (INH), Rifampicin (RFP) and Ethambutol (EB) was started and the fluid collection was removed surgically. Intraoperatively, a partial affection of the left leg of the bifurcated graft by the necrotic mass was detected. After extensive debridement, vacuum assisted wound therapy was initiated. The possibility of an aortic reconstruction using autologous deep femoral vein or cryo-preserved homograft was evaluated but declined by the patient. After four weeks of negative pressure wound therapy, the wound could be closed in secondary intention. CT- scan showed no signs of persistent graft infection or retroperitoneal abscess. The patient was discharged in good condition. The triple antitubercular treatment was continued for six month and reduced to RFH and INH for another six months. As the patient remained free of symptoms, and CT scan was unremarkable, antitubercular therapy was subsequently terminated. After a follow-up of 84 months, the patient is in excellent condition and there is no CT- morphologic sign of recurrence of retroperitoneal abscess or inflammation of vascular graft.Table 1 Patient characteristics
Preliminary diagnoses Preliminary surgical procedures
Patient A
NMIBC in 2008 Aortobiiliac prosthesis in 2010
Ruptured aortic aneurysm in 2010
Chronic obstructive pulmonary disease
Disc prolaps L5/L6
Renal cysts
Patient B
NMIBC in 2014 None
Disc prolaps L2/L3 and L3/L4
Patient C
NMIBC in 2008 Aortocoronary bypass operation in 2011
Coronary artery disease Inguinal hernia repair
Cardial arrhythmia type II Wenckebach Dacron tube graft in 2015
Arterial hypertension
Hyperlipidemia
NMIBC Non-muscle-invasive bladder cancer
Fig. 1 CT- reconstruction showing massive retroperitoneal fluid mass affecting left branch of aortobiiliac graft
Patient B
In January 2018, a 78-year-old man presented with acute abdominal pain after a six-week history of chronic back pain. CT scan revealed a small-sized saccular aneurysmatic formation suspicious for a penetrating aortic ulcer (PAU) with contained rupture in the infrarenal aorta. Bone lesions in the vertebral bodies L2/L3 were highly suspicious for concomitant spondylodiscitis. The PAU was too small in size and anatomically too remote to represent a likely cause. Retrospectively, CT scan from 2014 did not show an aortic or vertebral pathology. The patient’s medical history was significant for NMIBC treated with TURBT and multiple intravesical BCG applications in 2014 (Table 1). The patient was hemodynamically stable and showed no notable physical examination findings. Except for increased C-reactive protein (25.1 mg/l), laboratory parameters were within normal limits. Because of close proximity of the PAU to the renal arteries resulting in a short neck, endovascular treatment was rejected. Immediate aortic reconstruction was performed by implantation of a rifampicin-soaked Dacron tube graft. Pathological examination and microbiological testing showed no evidence of mycobacterial infection or other pathogens in intraoperative specimens of the infrarenal aorta. The patient had an uneventful recovery and was discharged after two weeks. After four months of persisting lower back pain, biopsy extraction and spondylodesis of the concomitant spondylodiscitis was performed. The microbiological analysis tested negative for AFB in Ziehl–Neelsen stain but the growth of Mycobacterium bovis in solid and liquid culture confirmed the diagnosis of mycobacterial infection. Antitubercular treatment consisting of RFP, INH, and EB was administered. One year later, follow-up CT scan revealed dislocation of the former implanted spondylodesis which was surgically removed and replaced. Intraoperative samples showed no evidence of persisting mycobacterial infection with acid fast medium culture and PCR. The patient was discharged after eight days. Antitubercular triple therapy was continued for another six months. During follow-up of 20 months, the patient presented free of symptoms. CT scan showed a shrinking psoas abscess. Three months later, the patient presented to the emergency room with increasing left lower abdominal pain. CT examination showed a false aneurysm near the proximal anastomosis of the Dacron tube graft and a retroperitoneal periprosthetic fluid collection (Fig. 2), indicating an imminent rupture. Graft explantation and replacement with homograft was performed. Intraoperative sample material did not show any evidence of Mycobacterium bovis nor other pathogens. Due to the earlier confirmation of BCG- related graft infection, the anti-mycobacterial therapy was continued for another 12 months with Doxycyclin, RFP and INH. After an uncomplicated course, the patient was discharged to a rehabilitation center two weeks after surgery. Follow-up imaging was performed five months later revealing no residual fluid collection. The patient remained in good clinical condition without any signs of re-infection.Fig. 2 Progress of periprosthetic fluid mass highly suspicious for mycobacterial graft infection and anastomotic pseudoaneurysm of the former implanted Dacron tube graft
Patient C
In December 2017, a 79-year-old man presented as an outpatient to our clinic with night sweats and persisting weakness after treatment of a contained rupture of an infrarenal PAU with implantation of a Dacron tube graft at an external institution in 2015. Ultrasound examination and CT showed periprosthetic fluid collection. The patient’s medical history included NIMBC diagnosed in 2008 and treated with TURBT and a total of 36 intravesical BCG instillations (Table 1). Laboratory parameters were within normal limits (CRP: 4.7 mg/l; white blood cell count: 4.08/nl). Samples collected by CT-guided aspiration tested positive for AFB with Auramine-rhodamine stain (Wescor Aerospray TB 7722, ELITech Biomedical Systems, Logan, Utah, USA). PCR of the aspirated fluid was positive for Mycobacterium tuberculosis complex and incubation in solid and liquid culture showed growth of Mycobacterium bovis. Antimycobacterial treatment was initiated. Because of a critical interaction between Ranolexin (long-term medication), Rifampicin was replaced by Rifabutin in combination with INH and EB. After a follow-up period of six months, control CT scan revealed a false aneurysm in the infrarenal region near the proximal anastomosis of the Dacron tube graft and a progression of the fluid collection in the psoas muscle (Fig. 3). The Dacron tube graft was completely removed and replaced by deep femoral vein (Fig. S1 in Additional file 2). Despite a weak positive PCR for Mycobacterium complex, culture incubation showed no growth of Mycobacterium bovis. This was considered to be the result of an effective perioperative antimycotic therapy. After an uncomplicated postoperative course, the patient was discharged to an external rehabilitation center after 25 days. During routine outpatient follow-up 12 months after surgery, the patient was in good general condition. The CT scan showed no persistent prosthetic infection.Fig. 3 Anastomotic pseudoaneurysm and progression of both periprosthetic fluid mass and fluid collection in left psoas muscle
Discussion and conclusion
Intravesical instillation of BCG is widely used for the treatment of NMIBC. First used as a vaccine against tuberculosis, intravesical instillation of the live attenuated strain of Mycobacterium bovis has become standard care for NMIBC. The exact mechanism of its antitumor efficacy is not clarified yet. Although BCG instillation is generally considered safe, severe side effects have been reported. The incidence of mycotic aortic aneurysms caused by disseminated tuberculosis after BCG instillation remains unclear. Three different mechanisms are described that could lead to a systemic dissemination of and vascular affection by Mycobacterium bovis: (1) hematogenous dissemination followed by direct intimal colonization favored by preexisting atherosclerosis, (2) metastatic implantation through the vasa vasorum, or (3) continuous dissemination of adjacent infected tissue such as contiguous lymphadenitis or psoas abscess [5].
We report three cases of graft infection after surgical treatment of suspected mycotic aortic aneurysms as an extremely rare complication after intravesical BCG application. Our therapy was based on two pillars: drug-based antitubercular therapy as well as the individually adapted surgical treatment consisting of radical surgical debridement, vacuum therapy, drainage and in case of anastomotic leakage, graft explantation and aortic reconstruction using deep femoral vein or homograft.
So far, 44 cases of mycotic aortic aneurysms caused by disseminated mycobacterial infection have been published. Foreign material was implanted in 28 patients [6–32]. Postoperative graft infection was diagnosed in 10 out of 28 cases (35.7%) [6, 12, 17, 19–22, 32–34]. Of these 10 patients, six were discharged resulting in a hospital survival rate of 60%. A long-term follow-up of more than 12 months is reported by only one author [33]. Treatment included medical therapy alone (n = 1) [6], invasive therapy including either CT-guided drainage or surgical debridement with graft preservation (n = 2) [12, 19] and radical surgical therapy with partial (n = 1) [17] or complete graft explantation (n = 6) [20–22, 32–34]. Antitubercular medication was administered in 8 out of 10 cases [6, 12, 17, 19–22, 33]. Apart from one case [33], graft explantation was performed combined with aortic stump ligation and implantation of an extraanatomic axillofemoral bypass. Similar to our patients B and C, Santbergen et al. (33) focused on aortic reconstruction with autologous replacement material with an excellent postoperative result. Eighteen months after completion of the antimycobacterial medication, there was no clinical and morphological evidence of a persistent infection.
Diagnosis of mycotic aneurysms or vascular complications after intravesical BCG application is exceptionally challenging and a high level of suspicion is required. A thorough medical history with attention to past NMIBC and related BCG instillations is essential when a mycotic aneurysm or graft infection is suspected. Unspecific symptoms like night sweats, weight loss, malaise and persisting fever combined with an unremarkable clinical examination can draw suspicion to a chronic disease like disseminated BCG- infection. After obtaining sample material from affected regions, e.g. vertebral disc, fluid collection in psoas muscle, aortic wall, paraaortic lymph nodes, pathological and microbiological examination is required. Suspected diagnosis can only be confirmed by PCR and culture specific for mycobacterial pathogens. Standard microbiological testing is often negative.
All of our three patients had received BCG therapy several years before the primary intervention. Because of the slow replication rate of mycobacteria, symptomatic vascular disease will often occur with a long latency after BCG instillation. Delay in diagnosis will lead to a delay in starting antimycobacterial treatment, which may result in an increased risk of rupture and dissemination, further limiting surgical options.
Currently, no consensus guideline for optimal medical treatment options of graft infection secondary to BCG instillation is available. Given its rareness, a case by case decision has to be made. Antitubercular therapy should be administered immediately after confirmed diagnosis and should be continued for at least six to 12 months. This medical therapy should be supplemented by surgical treatment. Our first case was managed successfully without graft explantation, with repeated radical surgical debridement and vacuum therapy alone, as no anastomosis was involved in this case. In our two following cases, anastomotic aneurysm indicating imminent rupture was discovered during follow-up. In these cases, we decided to completely remove the infected graft and to reconstruct the aorta with deep femoral vein or homograft, respectively.
In conclusion, this three-case series represents our experience with this rare condition. We strongly suggest that in cases of aortic aneurysm or aortic graft infection in patients with previous BCG instillation, surgeons should be suspicious of BCG- infection and mycotic aneurysm and to initiate specific testing including PCR and culture for mycobacterial infection. In cases with involvement of any graft anastomosis, complete graft removal and replacement with biological material should be considered. In cases with no involvement of an anastomosis, graft preservation could be attempted. Adjuvant antimycobacterial treatment is essential and should be initiated as soon as diagnosis is confirmed.
Supplementary Information
Additional file 1: Table S1. Publications reporting aortic aneurysm secondary to intravesical application of Bacillus Calmette Guérin
Additional file 2: Fig. S1. Intraoperative situs showing exit of purulent granular material from the aneurysmatic formation (A) surrounding former implanted Dacron tube graft (B) and aortic reconstruction after graft removal and reconstruction with deep femoral vein (C)
Abbreviations
BCG Bacille Calmette–Guérin
NMIBC Non-muscle-invasive bladder cancer
TURBT Transurethral resection of bladder tumors
CT Computed tomography
AFB Acid-fast bacilli
PCR Polymerase-chain-reaction
PZA Pyrazinamide
INH Isoniazid
RFP Rifampicin
EB Ethambutol
PAU Penetrating aortic ulcer
MRI Magnetic resonance imaging
Acknowledgements
We acknowledge support from the German Research Foundation (DFG) and the Open Access Publication Fund of Charité–Universitätsmedizin Berlin.
Authors' contributions
The idea and initial findings of this seldomly occurring disease were made by JPF. During writing and revising this paper by MB, SK, SO, MS, JPF and AG where involved in constant discussions and improvements of manuscript. All relevant surgeries were performed by JPF or AG. For visual support MR created images that are used. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL.
Availability of data and materials
The data collection was done by reviewing the available literature and electronic health records at the Charité Universitätsmedizin Berlin. Relevant data was collected in Microsoft Excel and analysed descriptively. The data is stored on the Charité—server and, in order to avoid a violation of access rights, the data is encrypted using a password only known to the study physicians. The data that support the findings of this study is available, but restrictions apply to the availability of the data, which was used under license for the current study, and so is not publicly available. Data is however available from the authors upon reasonable request.
Declarations
Ethics approval and consent to participate
The need for approval was waived by our institutional review board.
Consent for publication
Written informed consent for publication of their clinical details and/or clinical images was obtained from all patients. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BACILLUS CALMETTE-GUERIN SUBSTRAIN TICE LIVE ANTIGEN | DrugsGivenReaction | CC BY | 33731071 | 19,110,873 | 2021-03-17 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Mycobacterial infection'. | Aortic aneurysm and aortic graft infection related to Mycobacterium bovis after intravesical Bacille Calmette-Guérin therapy-a case series.
BACKGROUND
So called "mycotic" aortic aneurysms account for only 0.7 to 1.3% of all aortic aneurysms and are commonly caused by Staphylococcus aureus and Salmonella species. Bacillus Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis, is part of the therapy of non-muscle-invasive bladder cancer (NMIBC).
METHODS
We report a case series of three patients with a mycobacterial graft infection related to BCG after surgical treatment of a presumed mycotic aortic aneurysm as an extremely rare complication after NMIBC treatment. All three patients developed aortic aneurysm after BCG instillation and subsequent mycobacterial graft infection.
CONCLUSIONS
Diagnosis requires a high degree of suspicion because of its nonspecific symptoms and imaging. The pathogen is not detected by standard microbiological testing. Treatment includes triple antimycobacterial therapy and radical surgical interventions. Graft preservation may be considered if no anastomosis is involved.
Background
Infectious or so called ‘mycotic’ aortic aneurysms represent merely 0.7 to 1.3% of all aortic aneurysms. Nevertheless, they constitute a life-threatening vascular complication associated with in-hospital mortality rates of up to 36% [1, 2]. Mycotic aortic aneurysms are usually caused by Staphylococcus aureus, followed by Salmonella spp., Streptococcus spp. and Escherichia coli. Mycotic aneurysms caused by mycobacterial infections are rare. Up to now, 44 cases in 42 case reports of mycotic aortic aneurysms caused by mycobacterial infection affecting the thoracoabdominal aorta after intravesical instillation of Bacillus Calmette–Guérin (BCG) have been reported (see Additional file 1: Table S1).
Intravesical BCG applications are standard of care for treating non-muscle-invasive bladder cancer (NMIBC) [3]. The live attenuated strain of Mycobacterium bovis is administered to patients with NMIBC after transurethral resection of bladder tumors (TURBT) to avert recurrence and reduce progression rates of intermediate- and high-risk tumors [4]. The incidence of BCG-related systemic complications including spondylodiscitis, psoas abscess or vascular complications remains unclear. In this case series, we report three cases of mycobacterial aortic graft infection related to intravesical application of BCG for NMIBC. This represents the largest case series in the current literature. The particular challenges for the diagnosis and treatment of this infrequent complication are discussed in this report.
Case presentations
Patient A
In November 2010, a 63-year-old man was referred to our clinic because of persistent weakness, fever, night sweat and unspecific abdominal pain lasting for two weeks. Three months before this episode, the patient had undergone emergency surgery for a ruptured infrarenal abdominal aortic aneurysm, which was treated with implantation of an aortobiiliac graft at another clinic. In 2008, the patient had been treated for NMIBC by transurethral resection and had received three cycles of intravesical BCG instillations (see Table 1). At the time of presentation, clinical examination and blood tests were unremarkable for inflammation except for a temperature of 37.6 °C. Ultrasound revealed a retroperitoneal fluid collection. Computed tomography (CT) demonstrated an extensive low-density collection surrounding the aortic prosthesis. The retroperitoneal mass was surgically removed and tissue samples were collected for histologic and microbiological studies. A specimen of the necrotic mass indicated chronic inflammation but tested negative for acid-fast bacilli (AFB) in Ziehl–Neelsen stain (Artisan™ Acid-Fast Bacillus (AFB) Stain Kit, Agilent, Santa Clara, United States). As no evidence for mycobacterial infection was found, the patient was discharged home in good condition, without antitubercular medication. Another two years later in August 2012, he presented again to our clinic with fever (40.4 °C), elevated white blood cell count (17.92/nl) and increased C-reactive protein (14.4 mg/l). CT scan revealed recurrence of a large mass in the retroperitoneum (Fig. 1). The patient underwent CT-guided aspiration. A drain was placed and specimens were sent to the microbiological laboratory. Microscopic examination showed necrotizing granulomatous inflammation with multinucleated giant cells. Direct Polymerase-chain-reaction (PCR, cobas® 6800 MTB Test, Roche, Rotkreuz, Switzerland) tested positive for Mycobacterium tuberculosis complex. Growth of Mycobacterium bovis in solid (BBL Stonebrink TB Medium + PACT + BBL Löwenstein-Jensen; Becton Dickinson, Rungis, France) and liquid culture (MGIT BBL; Becton Dickinson, Rungis, France) confirmed the suspected diagnosis. Antitubercular therapy with Isoniazid (INH), Rifampicin (RFP) and Ethambutol (EB) was started and the fluid collection was removed surgically. Intraoperatively, a partial affection of the left leg of the bifurcated graft by the necrotic mass was detected. After extensive debridement, vacuum assisted wound therapy was initiated. The possibility of an aortic reconstruction using autologous deep femoral vein or cryo-preserved homograft was evaluated but declined by the patient. After four weeks of negative pressure wound therapy, the wound could be closed in secondary intention. CT- scan showed no signs of persistent graft infection or retroperitoneal abscess. The patient was discharged in good condition. The triple antitubercular treatment was continued for six month and reduced to RFH and INH for another six months. As the patient remained free of symptoms, and CT scan was unremarkable, antitubercular therapy was subsequently terminated. After a follow-up of 84 months, the patient is in excellent condition and there is no CT- morphologic sign of recurrence of retroperitoneal abscess or inflammation of vascular graft.Table 1 Patient characteristics
Preliminary diagnoses Preliminary surgical procedures
Patient A
NMIBC in 2008 Aortobiiliac prosthesis in 2010
Ruptured aortic aneurysm in 2010
Chronic obstructive pulmonary disease
Disc prolaps L5/L6
Renal cysts
Patient B
NMIBC in 2014 None
Disc prolaps L2/L3 and L3/L4
Patient C
NMIBC in 2008 Aortocoronary bypass operation in 2011
Coronary artery disease Inguinal hernia repair
Cardial arrhythmia type II Wenckebach Dacron tube graft in 2015
Arterial hypertension
Hyperlipidemia
NMIBC Non-muscle-invasive bladder cancer
Fig. 1 CT- reconstruction showing massive retroperitoneal fluid mass affecting left branch of aortobiiliac graft
Patient B
In January 2018, a 78-year-old man presented with acute abdominal pain after a six-week history of chronic back pain. CT scan revealed a small-sized saccular aneurysmatic formation suspicious for a penetrating aortic ulcer (PAU) with contained rupture in the infrarenal aorta. Bone lesions in the vertebral bodies L2/L3 were highly suspicious for concomitant spondylodiscitis. The PAU was too small in size and anatomically too remote to represent a likely cause. Retrospectively, CT scan from 2014 did not show an aortic or vertebral pathology. The patient’s medical history was significant for NMIBC treated with TURBT and multiple intravesical BCG applications in 2014 (Table 1). The patient was hemodynamically stable and showed no notable physical examination findings. Except for increased C-reactive protein (25.1 mg/l), laboratory parameters were within normal limits. Because of close proximity of the PAU to the renal arteries resulting in a short neck, endovascular treatment was rejected. Immediate aortic reconstruction was performed by implantation of a rifampicin-soaked Dacron tube graft. Pathological examination and microbiological testing showed no evidence of mycobacterial infection or other pathogens in intraoperative specimens of the infrarenal aorta. The patient had an uneventful recovery and was discharged after two weeks. After four months of persisting lower back pain, biopsy extraction and spondylodesis of the concomitant spondylodiscitis was performed. The microbiological analysis tested negative for AFB in Ziehl–Neelsen stain but the growth of Mycobacterium bovis in solid and liquid culture confirmed the diagnosis of mycobacterial infection. Antitubercular treatment consisting of RFP, INH, and EB was administered. One year later, follow-up CT scan revealed dislocation of the former implanted spondylodesis which was surgically removed and replaced. Intraoperative samples showed no evidence of persisting mycobacterial infection with acid fast medium culture and PCR. The patient was discharged after eight days. Antitubercular triple therapy was continued for another six months. During follow-up of 20 months, the patient presented free of symptoms. CT scan showed a shrinking psoas abscess. Three months later, the patient presented to the emergency room with increasing left lower abdominal pain. CT examination showed a false aneurysm near the proximal anastomosis of the Dacron tube graft and a retroperitoneal periprosthetic fluid collection (Fig. 2), indicating an imminent rupture. Graft explantation and replacement with homograft was performed. Intraoperative sample material did not show any evidence of Mycobacterium bovis nor other pathogens. Due to the earlier confirmation of BCG- related graft infection, the anti-mycobacterial therapy was continued for another 12 months with Doxycyclin, RFP and INH. After an uncomplicated course, the patient was discharged to a rehabilitation center two weeks after surgery. Follow-up imaging was performed five months later revealing no residual fluid collection. The patient remained in good clinical condition without any signs of re-infection.Fig. 2 Progress of periprosthetic fluid mass highly suspicious for mycobacterial graft infection and anastomotic pseudoaneurysm of the former implanted Dacron tube graft
Patient C
In December 2017, a 79-year-old man presented as an outpatient to our clinic with night sweats and persisting weakness after treatment of a contained rupture of an infrarenal PAU with implantation of a Dacron tube graft at an external institution in 2015. Ultrasound examination and CT showed periprosthetic fluid collection. The patient’s medical history included NIMBC diagnosed in 2008 and treated with TURBT and a total of 36 intravesical BCG instillations (Table 1). Laboratory parameters were within normal limits (CRP: 4.7 mg/l; white blood cell count: 4.08/nl). Samples collected by CT-guided aspiration tested positive for AFB with Auramine-rhodamine stain (Wescor Aerospray TB 7722, ELITech Biomedical Systems, Logan, Utah, USA). PCR of the aspirated fluid was positive for Mycobacterium tuberculosis complex and incubation in solid and liquid culture showed growth of Mycobacterium bovis. Antimycobacterial treatment was initiated. Because of a critical interaction between Ranolexin (long-term medication), Rifampicin was replaced by Rifabutin in combination with INH and EB. After a follow-up period of six months, control CT scan revealed a false aneurysm in the infrarenal region near the proximal anastomosis of the Dacron tube graft and a progression of the fluid collection in the psoas muscle (Fig. 3). The Dacron tube graft was completely removed and replaced by deep femoral vein (Fig. S1 in Additional file 2). Despite a weak positive PCR for Mycobacterium complex, culture incubation showed no growth of Mycobacterium bovis. This was considered to be the result of an effective perioperative antimycotic therapy. After an uncomplicated postoperative course, the patient was discharged to an external rehabilitation center after 25 days. During routine outpatient follow-up 12 months after surgery, the patient was in good general condition. The CT scan showed no persistent prosthetic infection.Fig. 3 Anastomotic pseudoaneurysm and progression of both periprosthetic fluid mass and fluid collection in left psoas muscle
Discussion and conclusion
Intravesical instillation of BCG is widely used for the treatment of NMIBC. First used as a vaccine against tuberculosis, intravesical instillation of the live attenuated strain of Mycobacterium bovis has become standard care for NMIBC. The exact mechanism of its antitumor efficacy is not clarified yet. Although BCG instillation is generally considered safe, severe side effects have been reported. The incidence of mycotic aortic aneurysms caused by disseminated tuberculosis after BCG instillation remains unclear. Three different mechanisms are described that could lead to a systemic dissemination of and vascular affection by Mycobacterium bovis: (1) hematogenous dissemination followed by direct intimal colonization favored by preexisting atherosclerosis, (2) metastatic implantation through the vasa vasorum, or (3) continuous dissemination of adjacent infected tissue such as contiguous lymphadenitis or psoas abscess [5].
We report three cases of graft infection after surgical treatment of suspected mycotic aortic aneurysms as an extremely rare complication after intravesical BCG application. Our therapy was based on two pillars: drug-based antitubercular therapy as well as the individually adapted surgical treatment consisting of radical surgical debridement, vacuum therapy, drainage and in case of anastomotic leakage, graft explantation and aortic reconstruction using deep femoral vein or homograft.
So far, 44 cases of mycotic aortic aneurysms caused by disseminated mycobacterial infection have been published. Foreign material was implanted in 28 patients [6–32]. Postoperative graft infection was diagnosed in 10 out of 28 cases (35.7%) [6, 12, 17, 19–22, 32–34]. Of these 10 patients, six were discharged resulting in a hospital survival rate of 60%. A long-term follow-up of more than 12 months is reported by only one author [33]. Treatment included medical therapy alone (n = 1) [6], invasive therapy including either CT-guided drainage or surgical debridement with graft preservation (n = 2) [12, 19] and radical surgical therapy with partial (n = 1) [17] or complete graft explantation (n = 6) [20–22, 32–34]. Antitubercular medication was administered in 8 out of 10 cases [6, 12, 17, 19–22, 33]. Apart from one case [33], graft explantation was performed combined with aortic stump ligation and implantation of an extraanatomic axillofemoral bypass. Similar to our patients B and C, Santbergen et al. (33) focused on aortic reconstruction with autologous replacement material with an excellent postoperative result. Eighteen months after completion of the antimycobacterial medication, there was no clinical and morphological evidence of a persistent infection.
Diagnosis of mycotic aneurysms or vascular complications after intravesical BCG application is exceptionally challenging and a high level of suspicion is required. A thorough medical history with attention to past NMIBC and related BCG instillations is essential when a mycotic aneurysm or graft infection is suspected. Unspecific symptoms like night sweats, weight loss, malaise and persisting fever combined with an unremarkable clinical examination can draw suspicion to a chronic disease like disseminated BCG- infection. After obtaining sample material from affected regions, e.g. vertebral disc, fluid collection in psoas muscle, aortic wall, paraaortic lymph nodes, pathological and microbiological examination is required. Suspected diagnosis can only be confirmed by PCR and culture specific for mycobacterial pathogens. Standard microbiological testing is often negative.
All of our three patients had received BCG therapy several years before the primary intervention. Because of the slow replication rate of mycobacteria, symptomatic vascular disease will often occur with a long latency after BCG instillation. Delay in diagnosis will lead to a delay in starting antimycobacterial treatment, which may result in an increased risk of rupture and dissemination, further limiting surgical options.
Currently, no consensus guideline for optimal medical treatment options of graft infection secondary to BCG instillation is available. Given its rareness, a case by case decision has to be made. Antitubercular therapy should be administered immediately after confirmed diagnosis and should be continued for at least six to 12 months. This medical therapy should be supplemented by surgical treatment. Our first case was managed successfully without graft explantation, with repeated radical surgical debridement and vacuum therapy alone, as no anastomosis was involved in this case. In our two following cases, anastomotic aneurysm indicating imminent rupture was discovered during follow-up. In these cases, we decided to completely remove the infected graft and to reconstruct the aorta with deep femoral vein or homograft, respectively.
In conclusion, this three-case series represents our experience with this rare condition. We strongly suggest that in cases of aortic aneurysm or aortic graft infection in patients with previous BCG instillation, surgeons should be suspicious of BCG- infection and mycotic aneurysm and to initiate specific testing including PCR and culture for mycobacterial infection. In cases with involvement of any graft anastomosis, complete graft removal and replacement with biological material should be considered. In cases with no involvement of an anastomosis, graft preservation could be attempted. Adjuvant antimycobacterial treatment is essential and should be initiated as soon as diagnosis is confirmed.
Supplementary Information
Additional file 1: Table S1. Publications reporting aortic aneurysm secondary to intravesical application of Bacillus Calmette Guérin
Additional file 2: Fig. S1. Intraoperative situs showing exit of purulent granular material from the aneurysmatic formation (A) surrounding former implanted Dacron tube graft (B) and aortic reconstruction after graft removal and reconstruction with deep femoral vein (C)
Abbreviations
BCG Bacille Calmette–Guérin
NMIBC Non-muscle-invasive bladder cancer
TURBT Transurethral resection of bladder tumors
CT Computed tomography
AFB Acid-fast bacilli
PCR Polymerase-chain-reaction
PZA Pyrazinamide
INH Isoniazid
RFP Rifampicin
EB Ethambutol
PAU Penetrating aortic ulcer
MRI Magnetic resonance imaging
Acknowledgements
We acknowledge support from the German Research Foundation (DFG) and the Open Access Publication Fund of Charité–Universitätsmedizin Berlin.
Authors' contributions
The idea and initial findings of this seldomly occurring disease were made by JPF. During writing and revising this paper by MB, SK, SO, MS, JPF and AG where involved in constant discussions and improvements of manuscript. All relevant surgeries were performed by JPF or AG. For visual support MR created images that are used. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL.
Availability of data and materials
The data collection was done by reviewing the available literature and electronic health records at the Charité Universitätsmedizin Berlin. Relevant data was collected in Microsoft Excel and analysed descriptively. The data is stored on the Charité—server and, in order to avoid a violation of access rights, the data is encrypted using a password only known to the study physicians. The data that support the findings of this study is available, but restrictions apply to the availability of the data, which was used under license for the current study, and so is not publicly available. Data is however available from the authors upon reasonable request.
Declarations
Ethics approval and consent to participate
The need for approval was waived by our institutional review board.
Consent for publication
Written informed consent for publication of their clinical details and/or clinical images was obtained from all patients. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BACILLUS CALMETTE-GUERIN SUBSTRAIN TICE LIVE ANTIGEN | DrugsGivenReaction | CC BY | 33731071 | 19,110,873 | 2021-03-17 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vascular graft infection'. | Aortic aneurysm and aortic graft infection related to Mycobacterium bovis after intravesical Bacille Calmette-Guérin therapy-a case series.
BACKGROUND
So called "mycotic" aortic aneurysms account for only 0.7 to 1.3% of all aortic aneurysms and are commonly caused by Staphylococcus aureus and Salmonella species. Bacillus Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis, is part of the therapy of non-muscle-invasive bladder cancer (NMIBC).
METHODS
We report a case series of three patients with a mycobacterial graft infection related to BCG after surgical treatment of a presumed mycotic aortic aneurysm as an extremely rare complication after NMIBC treatment. All three patients developed aortic aneurysm after BCG instillation and subsequent mycobacterial graft infection.
CONCLUSIONS
Diagnosis requires a high degree of suspicion because of its nonspecific symptoms and imaging. The pathogen is not detected by standard microbiological testing. Treatment includes triple antimycobacterial therapy and radical surgical interventions. Graft preservation may be considered if no anastomosis is involved.
Background
Infectious or so called ‘mycotic’ aortic aneurysms represent merely 0.7 to 1.3% of all aortic aneurysms. Nevertheless, they constitute a life-threatening vascular complication associated with in-hospital mortality rates of up to 36% [1, 2]. Mycotic aortic aneurysms are usually caused by Staphylococcus aureus, followed by Salmonella spp., Streptococcus spp. and Escherichia coli. Mycotic aneurysms caused by mycobacterial infections are rare. Up to now, 44 cases in 42 case reports of mycotic aortic aneurysms caused by mycobacterial infection affecting the thoracoabdominal aorta after intravesical instillation of Bacillus Calmette–Guérin (BCG) have been reported (see Additional file 1: Table S1).
Intravesical BCG applications are standard of care for treating non-muscle-invasive bladder cancer (NMIBC) [3]. The live attenuated strain of Mycobacterium bovis is administered to patients with NMIBC after transurethral resection of bladder tumors (TURBT) to avert recurrence and reduce progression rates of intermediate- and high-risk tumors [4]. The incidence of BCG-related systemic complications including spondylodiscitis, psoas abscess or vascular complications remains unclear. In this case series, we report three cases of mycobacterial aortic graft infection related to intravesical application of BCG for NMIBC. This represents the largest case series in the current literature. The particular challenges for the diagnosis and treatment of this infrequent complication are discussed in this report.
Case presentations
Patient A
In November 2010, a 63-year-old man was referred to our clinic because of persistent weakness, fever, night sweat and unspecific abdominal pain lasting for two weeks. Three months before this episode, the patient had undergone emergency surgery for a ruptured infrarenal abdominal aortic aneurysm, which was treated with implantation of an aortobiiliac graft at another clinic. In 2008, the patient had been treated for NMIBC by transurethral resection and had received three cycles of intravesical BCG instillations (see Table 1). At the time of presentation, clinical examination and blood tests were unremarkable for inflammation except for a temperature of 37.6 °C. Ultrasound revealed a retroperitoneal fluid collection. Computed tomography (CT) demonstrated an extensive low-density collection surrounding the aortic prosthesis. The retroperitoneal mass was surgically removed and tissue samples were collected for histologic and microbiological studies. A specimen of the necrotic mass indicated chronic inflammation but tested negative for acid-fast bacilli (AFB) in Ziehl–Neelsen stain (Artisan™ Acid-Fast Bacillus (AFB) Stain Kit, Agilent, Santa Clara, United States). As no evidence for mycobacterial infection was found, the patient was discharged home in good condition, without antitubercular medication. Another two years later in August 2012, he presented again to our clinic with fever (40.4 °C), elevated white blood cell count (17.92/nl) and increased C-reactive protein (14.4 mg/l). CT scan revealed recurrence of a large mass in the retroperitoneum (Fig. 1). The patient underwent CT-guided aspiration. A drain was placed and specimens were sent to the microbiological laboratory. Microscopic examination showed necrotizing granulomatous inflammation with multinucleated giant cells. Direct Polymerase-chain-reaction (PCR, cobas® 6800 MTB Test, Roche, Rotkreuz, Switzerland) tested positive for Mycobacterium tuberculosis complex. Growth of Mycobacterium bovis in solid (BBL Stonebrink TB Medium + PACT + BBL Löwenstein-Jensen; Becton Dickinson, Rungis, France) and liquid culture (MGIT BBL; Becton Dickinson, Rungis, France) confirmed the suspected diagnosis. Antitubercular therapy with Isoniazid (INH), Rifampicin (RFP) and Ethambutol (EB) was started and the fluid collection was removed surgically. Intraoperatively, a partial affection of the left leg of the bifurcated graft by the necrotic mass was detected. After extensive debridement, vacuum assisted wound therapy was initiated. The possibility of an aortic reconstruction using autologous deep femoral vein or cryo-preserved homograft was evaluated but declined by the patient. After four weeks of negative pressure wound therapy, the wound could be closed in secondary intention. CT- scan showed no signs of persistent graft infection or retroperitoneal abscess. The patient was discharged in good condition. The triple antitubercular treatment was continued for six month and reduced to RFH and INH for another six months. As the patient remained free of symptoms, and CT scan was unremarkable, antitubercular therapy was subsequently terminated. After a follow-up of 84 months, the patient is in excellent condition and there is no CT- morphologic sign of recurrence of retroperitoneal abscess or inflammation of vascular graft.Table 1 Patient characteristics
Preliminary diagnoses Preliminary surgical procedures
Patient A
NMIBC in 2008 Aortobiiliac prosthesis in 2010
Ruptured aortic aneurysm in 2010
Chronic obstructive pulmonary disease
Disc prolaps L5/L6
Renal cysts
Patient B
NMIBC in 2014 None
Disc prolaps L2/L3 and L3/L4
Patient C
NMIBC in 2008 Aortocoronary bypass operation in 2011
Coronary artery disease Inguinal hernia repair
Cardial arrhythmia type II Wenckebach Dacron tube graft in 2015
Arterial hypertension
Hyperlipidemia
NMIBC Non-muscle-invasive bladder cancer
Fig. 1 CT- reconstruction showing massive retroperitoneal fluid mass affecting left branch of aortobiiliac graft
Patient B
In January 2018, a 78-year-old man presented with acute abdominal pain after a six-week history of chronic back pain. CT scan revealed a small-sized saccular aneurysmatic formation suspicious for a penetrating aortic ulcer (PAU) with contained rupture in the infrarenal aorta. Bone lesions in the vertebral bodies L2/L3 were highly suspicious for concomitant spondylodiscitis. The PAU was too small in size and anatomically too remote to represent a likely cause. Retrospectively, CT scan from 2014 did not show an aortic or vertebral pathology. The patient’s medical history was significant for NMIBC treated with TURBT and multiple intravesical BCG applications in 2014 (Table 1). The patient was hemodynamically stable and showed no notable physical examination findings. Except for increased C-reactive protein (25.1 mg/l), laboratory parameters were within normal limits. Because of close proximity of the PAU to the renal arteries resulting in a short neck, endovascular treatment was rejected. Immediate aortic reconstruction was performed by implantation of a rifampicin-soaked Dacron tube graft. Pathological examination and microbiological testing showed no evidence of mycobacterial infection or other pathogens in intraoperative specimens of the infrarenal aorta. The patient had an uneventful recovery and was discharged after two weeks. After four months of persisting lower back pain, biopsy extraction and spondylodesis of the concomitant spondylodiscitis was performed. The microbiological analysis tested negative for AFB in Ziehl–Neelsen stain but the growth of Mycobacterium bovis in solid and liquid culture confirmed the diagnosis of mycobacterial infection. Antitubercular treatment consisting of RFP, INH, and EB was administered. One year later, follow-up CT scan revealed dislocation of the former implanted spondylodesis which was surgically removed and replaced. Intraoperative samples showed no evidence of persisting mycobacterial infection with acid fast medium culture and PCR. The patient was discharged after eight days. Antitubercular triple therapy was continued for another six months. During follow-up of 20 months, the patient presented free of symptoms. CT scan showed a shrinking psoas abscess. Three months later, the patient presented to the emergency room with increasing left lower abdominal pain. CT examination showed a false aneurysm near the proximal anastomosis of the Dacron tube graft and a retroperitoneal periprosthetic fluid collection (Fig. 2), indicating an imminent rupture. Graft explantation and replacement with homograft was performed. Intraoperative sample material did not show any evidence of Mycobacterium bovis nor other pathogens. Due to the earlier confirmation of BCG- related graft infection, the anti-mycobacterial therapy was continued for another 12 months with Doxycyclin, RFP and INH. After an uncomplicated course, the patient was discharged to a rehabilitation center two weeks after surgery. Follow-up imaging was performed five months later revealing no residual fluid collection. The patient remained in good clinical condition without any signs of re-infection.Fig. 2 Progress of periprosthetic fluid mass highly suspicious for mycobacterial graft infection and anastomotic pseudoaneurysm of the former implanted Dacron tube graft
Patient C
In December 2017, a 79-year-old man presented as an outpatient to our clinic with night sweats and persisting weakness after treatment of a contained rupture of an infrarenal PAU with implantation of a Dacron tube graft at an external institution in 2015. Ultrasound examination and CT showed periprosthetic fluid collection. The patient’s medical history included NIMBC diagnosed in 2008 and treated with TURBT and a total of 36 intravesical BCG instillations (Table 1). Laboratory parameters were within normal limits (CRP: 4.7 mg/l; white blood cell count: 4.08/nl). Samples collected by CT-guided aspiration tested positive for AFB with Auramine-rhodamine stain (Wescor Aerospray TB 7722, ELITech Biomedical Systems, Logan, Utah, USA). PCR of the aspirated fluid was positive for Mycobacterium tuberculosis complex and incubation in solid and liquid culture showed growth of Mycobacterium bovis. Antimycobacterial treatment was initiated. Because of a critical interaction between Ranolexin (long-term medication), Rifampicin was replaced by Rifabutin in combination with INH and EB. After a follow-up period of six months, control CT scan revealed a false aneurysm in the infrarenal region near the proximal anastomosis of the Dacron tube graft and a progression of the fluid collection in the psoas muscle (Fig. 3). The Dacron tube graft was completely removed and replaced by deep femoral vein (Fig. S1 in Additional file 2). Despite a weak positive PCR for Mycobacterium complex, culture incubation showed no growth of Mycobacterium bovis. This was considered to be the result of an effective perioperative antimycotic therapy. After an uncomplicated postoperative course, the patient was discharged to an external rehabilitation center after 25 days. During routine outpatient follow-up 12 months after surgery, the patient was in good general condition. The CT scan showed no persistent prosthetic infection.Fig. 3 Anastomotic pseudoaneurysm and progression of both periprosthetic fluid mass and fluid collection in left psoas muscle
Discussion and conclusion
Intravesical instillation of BCG is widely used for the treatment of NMIBC. First used as a vaccine against tuberculosis, intravesical instillation of the live attenuated strain of Mycobacterium bovis has become standard care for NMIBC. The exact mechanism of its antitumor efficacy is not clarified yet. Although BCG instillation is generally considered safe, severe side effects have been reported. The incidence of mycotic aortic aneurysms caused by disseminated tuberculosis after BCG instillation remains unclear. Three different mechanisms are described that could lead to a systemic dissemination of and vascular affection by Mycobacterium bovis: (1) hematogenous dissemination followed by direct intimal colonization favored by preexisting atherosclerosis, (2) metastatic implantation through the vasa vasorum, or (3) continuous dissemination of adjacent infected tissue such as contiguous lymphadenitis or psoas abscess [5].
We report three cases of graft infection after surgical treatment of suspected mycotic aortic aneurysms as an extremely rare complication after intravesical BCG application. Our therapy was based on two pillars: drug-based antitubercular therapy as well as the individually adapted surgical treatment consisting of radical surgical debridement, vacuum therapy, drainage and in case of anastomotic leakage, graft explantation and aortic reconstruction using deep femoral vein or homograft.
So far, 44 cases of mycotic aortic aneurysms caused by disseminated mycobacterial infection have been published. Foreign material was implanted in 28 patients [6–32]. Postoperative graft infection was diagnosed in 10 out of 28 cases (35.7%) [6, 12, 17, 19–22, 32–34]. Of these 10 patients, six were discharged resulting in a hospital survival rate of 60%. A long-term follow-up of more than 12 months is reported by only one author [33]. Treatment included medical therapy alone (n = 1) [6], invasive therapy including either CT-guided drainage or surgical debridement with graft preservation (n = 2) [12, 19] and radical surgical therapy with partial (n = 1) [17] or complete graft explantation (n = 6) [20–22, 32–34]. Antitubercular medication was administered in 8 out of 10 cases [6, 12, 17, 19–22, 33]. Apart from one case [33], graft explantation was performed combined with aortic stump ligation and implantation of an extraanatomic axillofemoral bypass. Similar to our patients B and C, Santbergen et al. (33) focused on aortic reconstruction with autologous replacement material with an excellent postoperative result. Eighteen months after completion of the antimycobacterial medication, there was no clinical and morphological evidence of a persistent infection.
Diagnosis of mycotic aneurysms or vascular complications after intravesical BCG application is exceptionally challenging and a high level of suspicion is required. A thorough medical history with attention to past NMIBC and related BCG instillations is essential when a mycotic aneurysm or graft infection is suspected. Unspecific symptoms like night sweats, weight loss, malaise and persisting fever combined with an unremarkable clinical examination can draw suspicion to a chronic disease like disseminated BCG- infection. After obtaining sample material from affected regions, e.g. vertebral disc, fluid collection in psoas muscle, aortic wall, paraaortic lymph nodes, pathological and microbiological examination is required. Suspected diagnosis can only be confirmed by PCR and culture specific for mycobacterial pathogens. Standard microbiological testing is often negative.
All of our three patients had received BCG therapy several years before the primary intervention. Because of the slow replication rate of mycobacteria, symptomatic vascular disease will often occur with a long latency after BCG instillation. Delay in diagnosis will lead to a delay in starting antimycobacterial treatment, which may result in an increased risk of rupture and dissemination, further limiting surgical options.
Currently, no consensus guideline for optimal medical treatment options of graft infection secondary to BCG instillation is available. Given its rareness, a case by case decision has to be made. Antitubercular therapy should be administered immediately after confirmed diagnosis and should be continued for at least six to 12 months. This medical therapy should be supplemented by surgical treatment. Our first case was managed successfully without graft explantation, with repeated radical surgical debridement and vacuum therapy alone, as no anastomosis was involved in this case. In our two following cases, anastomotic aneurysm indicating imminent rupture was discovered during follow-up. In these cases, we decided to completely remove the infected graft and to reconstruct the aorta with deep femoral vein or homograft, respectively.
In conclusion, this three-case series represents our experience with this rare condition. We strongly suggest that in cases of aortic aneurysm or aortic graft infection in patients with previous BCG instillation, surgeons should be suspicious of BCG- infection and mycotic aneurysm and to initiate specific testing including PCR and culture for mycobacterial infection. In cases with involvement of any graft anastomosis, complete graft removal and replacement with biological material should be considered. In cases with no involvement of an anastomosis, graft preservation could be attempted. Adjuvant antimycobacterial treatment is essential and should be initiated as soon as diagnosis is confirmed.
Supplementary Information
Additional file 1: Table S1. Publications reporting aortic aneurysm secondary to intravesical application of Bacillus Calmette Guérin
Additional file 2: Fig. S1. Intraoperative situs showing exit of purulent granular material from the aneurysmatic formation (A) surrounding former implanted Dacron tube graft (B) and aortic reconstruction after graft removal and reconstruction with deep femoral vein (C)
Abbreviations
BCG Bacille Calmette–Guérin
NMIBC Non-muscle-invasive bladder cancer
TURBT Transurethral resection of bladder tumors
CT Computed tomography
AFB Acid-fast bacilli
PCR Polymerase-chain-reaction
PZA Pyrazinamide
INH Isoniazid
RFP Rifampicin
EB Ethambutol
PAU Penetrating aortic ulcer
MRI Magnetic resonance imaging
Acknowledgements
We acknowledge support from the German Research Foundation (DFG) and the Open Access Publication Fund of Charité–Universitätsmedizin Berlin.
Authors' contributions
The idea and initial findings of this seldomly occurring disease were made by JPF. During writing and revising this paper by MB, SK, SO, MS, JPF and AG where involved in constant discussions and improvements of manuscript. All relevant surgeries were performed by JPF or AG. For visual support MR created images that are used. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL.
Availability of data and materials
The data collection was done by reviewing the available literature and electronic health records at the Charité Universitätsmedizin Berlin. Relevant data was collected in Microsoft Excel and analysed descriptively. The data is stored on the Charité—server and, in order to avoid a violation of access rights, the data is encrypted using a password only known to the study physicians. The data that support the findings of this study is available, but restrictions apply to the availability of the data, which was used under license for the current study, and so is not publicly available. Data is however available from the authors upon reasonable request.
Declarations
Ethics approval and consent to participate
The need for approval was waived by our institutional review board.
Consent for publication
Written informed consent for publication of their clinical details and/or clinical images was obtained from all patients. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BACILLUS CALMETTE-GUERIN SUBSTRAIN TICE LIVE ANTIGEN | DrugsGivenReaction | CC BY | 33731071 | 19,110,873 | 2021-03-17 |
What was the administration route of drug 'BACILLUS CALMETTE-GUERIN SUBSTRAIN TICE LIVE ANTIGEN'? | Aortic aneurysm and aortic graft infection related to Mycobacterium bovis after intravesical Bacille Calmette-Guérin therapy-a case series.
BACKGROUND
So called "mycotic" aortic aneurysms account for only 0.7 to 1.3% of all aortic aneurysms and are commonly caused by Staphylococcus aureus and Salmonella species. Bacillus Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis, is part of the therapy of non-muscle-invasive bladder cancer (NMIBC).
METHODS
We report a case series of three patients with a mycobacterial graft infection related to BCG after surgical treatment of a presumed mycotic aortic aneurysm as an extremely rare complication after NMIBC treatment. All three patients developed aortic aneurysm after BCG instillation and subsequent mycobacterial graft infection.
CONCLUSIONS
Diagnosis requires a high degree of suspicion because of its nonspecific symptoms and imaging. The pathogen is not detected by standard microbiological testing. Treatment includes triple antimycobacterial therapy and radical surgical interventions. Graft preservation may be considered if no anastomosis is involved.
Background
Infectious or so called ‘mycotic’ aortic aneurysms represent merely 0.7 to 1.3% of all aortic aneurysms. Nevertheless, they constitute a life-threatening vascular complication associated with in-hospital mortality rates of up to 36% [1, 2]. Mycotic aortic aneurysms are usually caused by Staphylococcus aureus, followed by Salmonella spp., Streptococcus spp. and Escherichia coli. Mycotic aneurysms caused by mycobacterial infections are rare. Up to now, 44 cases in 42 case reports of mycotic aortic aneurysms caused by mycobacterial infection affecting the thoracoabdominal aorta after intravesical instillation of Bacillus Calmette–Guérin (BCG) have been reported (see Additional file 1: Table S1).
Intravesical BCG applications are standard of care for treating non-muscle-invasive bladder cancer (NMIBC) [3]. The live attenuated strain of Mycobacterium bovis is administered to patients with NMIBC after transurethral resection of bladder tumors (TURBT) to avert recurrence and reduce progression rates of intermediate- and high-risk tumors [4]. The incidence of BCG-related systemic complications including spondylodiscitis, psoas abscess or vascular complications remains unclear. In this case series, we report three cases of mycobacterial aortic graft infection related to intravesical application of BCG for NMIBC. This represents the largest case series in the current literature. The particular challenges for the diagnosis and treatment of this infrequent complication are discussed in this report.
Case presentations
Patient A
In November 2010, a 63-year-old man was referred to our clinic because of persistent weakness, fever, night sweat and unspecific abdominal pain lasting for two weeks. Three months before this episode, the patient had undergone emergency surgery for a ruptured infrarenal abdominal aortic aneurysm, which was treated with implantation of an aortobiiliac graft at another clinic. In 2008, the patient had been treated for NMIBC by transurethral resection and had received three cycles of intravesical BCG instillations (see Table 1). At the time of presentation, clinical examination and blood tests were unremarkable for inflammation except for a temperature of 37.6 °C. Ultrasound revealed a retroperitoneal fluid collection. Computed tomography (CT) demonstrated an extensive low-density collection surrounding the aortic prosthesis. The retroperitoneal mass was surgically removed and tissue samples were collected for histologic and microbiological studies. A specimen of the necrotic mass indicated chronic inflammation but tested negative for acid-fast bacilli (AFB) in Ziehl–Neelsen stain (Artisan™ Acid-Fast Bacillus (AFB) Stain Kit, Agilent, Santa Clara, United States). As no evidence for mycobacterial infection was found, the patient was discharged home in good condition, without antitubercular medication. Another two years later in August 2012, he presented again to our clinic with fever (40.4 °C), elevated white blood cell count (17.92/nl) and increased C-reactive protein (14.4 mg/l). CT scan revealed recurrence of a large mass in the retroperitoneum (Fig. 1). The patient underwent CT-guided aspiration. A drain was placed and specimens were sent to the microbiological laboratory. Microscopic examination showed necrotizing granulomatous inflammation with multinucleated giant cells. Direct Polymerase-chain-reaction (PCR, cobas® 6800 MTB Test, Roche, Rotkreuz, Switzerland) tested positive for Mycobacterium tuberculosis complex. Growth of Mycobacterium bovis in solid (BBL Stonebrink TB Medium + PACT + BBL Löwenstein-Jensen; Becton Dickinson, Rungis, France) and liquid culture (MGIT BBL; Becton Dickinson, Rungis, France) confirmed the suspected diagnosis. Antitubercular therapy with Isoniazid (INH), Rifampicin (RFP) and Ethambutol (EB) was started and the fluid collection was removed surgically. Intraoperatively, a partial affection of the left leg of the bifurcated graft by the necrotic mass was detected. After extensive debridement, vacuum assisted wound therapy was initiated. The possibility of an aortic reconstruction using autologous deep femoral vein or cryo-preserved homograft was evaluated but declined by the patient. After four weeks of negative pressure wound therapy, the wound could be closed in secondary intention. CT- scan showed no signs of persistent graft infection or retroperitoneal abscess. The patient was discharged in good condition. The triple antitubercular treatment was continued for six month and reduced to RFH and INH for another six months. As the patient remained free of symptoms, and CT scan was unremarkable, antitubercular therapy was subsequently terminated. After a follow-up of 84 months, the patient is in excellent condition and there is no CT- morphologic sign of recurrence of retroperitoneal abscess or inflammation of vascular graft.Table 1 Patient characteristics
Preliminary diagnoses Preliminary surgical procedures
Patient A
NMIBC in 2008 Aortobiiliac prosthesis in 2010
Ruptured aortic aneurysm in 2010
Chronic obstructive pulmonary disease
Disc prolaps L5/L6
Renal cysts
Patient B
NMIBC in 2014 None
Disc prolaps L2/L3 and L3/L4
Patient C
NMIBC in 2008 Aortocoronary bypass operation in 2011
Coronary artery disease Inguinal hernia repair
Cardial arrhythmia type II Wenckebach Dacron tube graft in 2015
Arterial hypertension
Hyperlipidemia
NMIBC Non-muscle-invasive bladder cancer
Fig. 1 CT- reconstruction showing massive retroperitoneal fluid mass affecting left branch of aortobiiliac graft
Patient B
In January 2018, a 78-year-old man presented with acute abdominal pain after a six-week history of chronic back pain. CT scan revealed a small-sized saccular aneurysmatic formation suspicious for a penetrating aortic ulcer (PAU) with contained rupture in the infrarenal aorta. Bone lesions in the vertebral bodies L2/L3 were highly suspicious for concomitant spondylodiscitis. The PAU was too small in size and anatomically too remote to represent a likely cause. Retrospectively, CT scan from 2014 did not show an aortic or vertebral pathology. The patient’s medical history was significant for NMIBC treated with TURBT and multiple intravesical BCG applications in 2014 (Table 1). The patient was hemodynamically stable and showed no notable physical examination findings. Except for increased C-reactive protein (25.1 mg/l), laboratory parameters were within normal limits. Because of close proximity of the PAU to the renal arteries resulting in a short neck, endovascular treatment was rejected. Immediate aortic reconstruction was performed by implantation of a rifampicin-soaked Dacron tube graft. Pathological examination and microbiological testing showed no evidence of mycobacterial infection or other pathogens in intraoperative specimens of the infrarenal aorta. The patient had an uneventful recovery and was discharged after two weeks. After four months of persisting lower back pain, biopsy extraction and spondylodesis of the concomitant spondylodiscitis was performed. The microbiological analysis tested negative for AFB in Ziehl–Neelsen stain but the growth of Mycobacterium bovis in solid and liquid culture confirmed the diagnosis of mycobacterial infection. Antitubercular treatment consisting of RFP, INH, and EB was administered. One year later, follow-up CT scan revealed dislocation of the former implanted spondylodesis which was surgically removed and replaced. Intraoperative samples showed no evidence of persisting mycobacterial infection with acid fast medium culture and PCR. The patient was discharged after eight days. Antitubercular triple therapy was continued for another six months. During follow-up of 20 months, the patient presented free of symptoms. CT scan showed a shrinking psoas abscess. Three months later, the patient presented to the emergency room with increasing left lower abdominal pain. CT examination showed a false aneurysm near the proximal anastomosis of the Dacron tube graft and a retroperitoneal periprosthetic fluid collection (Fig. 2), indicating an imminent rupture. Graft explantation and replacement with homograft was performed. Intraoperative sample material did not show any evidence of Mycobacterium bovis nor other pathogens. Due to the earlier confirmation of BCG- related graft infection, the anti-mycobacterial therapy was continued for another 12 months with Doxycyclin, RFP and INH. After an uncomplicated course, the patient was discharged to a rehabilitation center two weeks after surgery. Follow-up imaging was performed five months later revealing no residual fluid collection. The patient remained in good clinical condition without any signs of re-infection.Fig. 2 Progress of periprosthetic fluid mass highly suspicious for mycobacterial graft infection and anastomotic pseudoaneurysm of the former implanted Dacron tube graft
Patient C
In December 2017, a 79-year-old man presented as an outpatient to our clinic with night sweats and persisting weakness after treatment of a contained rupture of an infrarenal PAU with implantation of a Dacron tube graft at an external institution in 2015. Ultrasound examination and CT showed periprosthetic fluid collection. The patient’s medical history included NIMBC diagnosed in 2008 and treated with TURBT and a total of 36 intravesical BCG instillations (Table 1). Laboratory parameters were within normal limits (CRP: 4.7 mg/l; white blood cell count: 4.08/nl). Samples collected by CT-guided aspiration tested positive for AFB with Auramine-rhodamine stain (Wescor Aerospray TB 7722, ELITech Biomedical Systems, Logan, Utah, USA). PCR of the aspirated fluid was positive for Mycobacterium tuberculosis complex and incubation in solid and liquid culture showed growth of Mycobacterium bovis. Antimycobacterial treatment was initiated. Because of a critical interaction between Ranolexin (long-term medication), Rifampicin was replaced by Rifabutin in combination with INH and EB. After a follow-up period of six months, control CT scan revealed a false aneurysm in the infrarenal region near the proximal anastomosis of the Dacron tube graft and a progression of the fluid collection in the psoas muscle (Fig. 3). The Dacron tube graft was completely removed and replaced by deep femoral vein (Fig. S1 in Additional file 2). Despite a weak positive PCR for Mycobacterium complex, culture incubation showed no growth of Mycobacterium bovis. This was considered to be the result of an effective perioperative antimycotic therapy. After an uncomplicated postoperative course, the patient was discharged to an external rehabilitation center after 25 days. During routine outpatient follow-up 12 months after surgery, the patient was in good general condition. The CT scan showed no persistent prosthetic infection.Fig. 3 Anastomotic pseudoaneurysm and progression of both periprosthetic fluid mass and fluid collection in left psoas muscle
Discussion and conclusion
Intravesical instillation of BCG is widely used for the treatment of NMIBC. First used as a vaccine against tuberculosis, intravesical instillation of the live attenuated strain of Mycobacterium bovis has become standard care for NMIBC. The exact mechanism of its antitumor efficacy is not clarified yet. Although BCG instillation is generally considered safe, severe side effects have been reported. The incidence of mycotic aortic aneurysms caused by disseminated tuberculosis after BCG instillation remains unclear. Three different mechanisms are described that could lead to a systemic dissemination of and vascular affection by Mycobacterium bovis: (1) hematogenous dissemination followed by direct intimal colonization favored by preexisting atherosclerosis, (2) metastatic implantation through the vasa vasorum, or (3) continuous dissemination of adjacent infected tissue such as contiguous lymphadenitis or psoas abscess [5].
We report three cases of graft infection after surgical treatment of suspected mycotic aortic aneurysms as an extremely rare complication after intravesical BCG application. Our therapy was based on two pillars: drug-based antitubercular therapy as well as the individually adapted surgical treatment consisting of radical surgical debridement, vacuum therapy, drainage and in case of anastomotic leakage, graft explantation and aortic reconstruction using deep femoral vein or homograft.
So far, 44 cases of mycotic aortic aneurysms caused by disseminated mycobacterial infection have been published. Foreign material was implanted in 28 patients [6–32]. Postoperative graft infection was diagnosed in 10 out of 28 cases (35.7%) [6, 12, 17, 19–22, 32–34]. Of these 10 patients, six were discharged resulting in a hospital survival rate of 60%. A long-term follow-up of more than 12 months is reported by only one author [33]. Treatment included medical therapy alone (n = 1) [6], invasive therapy including either CT-guided drainage or surgical debridement with graft preservation (n = 2) [12, 19] and radical surgical therapy with partial (n = 1) [17] or complete graft explantation (n = 6) [20–22, 32–34]. Antitubercular medication was administered in 8 out of 10 cases [6, 12, 17, 19–22, 33]. Apart from one case [33], graft explantation was performed combined with aortic stump ligation and implantation of an extraanatomic axillofemoral bypass. Similar to our patients B and C, Santbergen et al. (33) focused on aortic reconstruction with autologous replacement material with an excellent postoperative result. Eighteen months after completion of the antimycobacterial medication, there was no clinical and morphological evidence of a persistent infection.
Diagnosis of mycotic aneurysms or vascular complications after intravesical BCG application is exceptionally challenging and a high level of suspicion is required. A thorough medical history with attention to past NMIBC and related BCG instillations is essential when a mycotic aneurysm or graft infection is suspected. Unspecific symptoms like night sweats, weight loss, malaise and persisting fever combined with an unremarkable clinical examination can draw suspicion to a chronic disease like disseminated BCG- infection. After obtaining sample material from affected regions, e.g. vertebral disc, fluid collection in psoas muscle, aortic wall, paraaortic lymph nodes, pathological and microbiological examination is required. Suspected diagnosis can only be confirmed by PCR and culture specific for mycobacterial pathogens. Standard microbiological testing is often negative.
All of our three patients had received BCG therapy several years before the primary intervention. Because of the slow replication rate of mycobacteria, symptomatic vascular disease will often occur with a long latency after BCG instillation. Delay in diagnosis will lead to a delay in starting antimycobacterial treatment, which may result in an increased risk of rupture and dissemination, further limiting surgical options.
Currently, no consensus guideline for optimal medical treatment options of graft infection secondary to BCG instillation is available. Given its rareness, a case by case decision has to be made. Antitubercular therapy should be administered immediately after confirmed diagnosis and should be continued for at least six to 12 months. This medical therapy should be supplemented by surgical treatment. Our first case was managed successfully without graft explantation, with repeated radical surgical debridement and vacuum therapy alone, as no anastomosis was involved in this case. In our two following cases, anastomotic aneurysm indicating imminent rupture was discovered during follow-up. In these cases, we decided to completely remove the infected graft and to reconstruct the aorta with deep femoral vein or homograft, respectively.
In conclusion, this three-case series represents our experience with this rare condition. We strongly suggest that in cases of aortic aneurysm or aortic graft infection in patients with previous BCG instillation, surgeons should be suspicious of BCG- infection and mycotic aneurysm and to initiate specific testing including PCR and culture for mycobacterial infection. In cases with involvement of any graft anastomosis, complete graft removal and replacement with biological material should be considered. In cases with no involvement of an anastomosis, graft preservation could be attempted. Adjuvant antimycobacterial treatment is essential and should be initiated as soon as diagnosis is confirmed.
Supplementary Information
Additional file 1: Table S1. Publications reporting aortic aneurysm secondary to intravesical application of Bacillus Calmette Guérin
Additional file 2: Fig. S1. Intraoperative situs showing exit of purulent granular material from the aneurysmatic formation (A) surrounding former implanted Dacron tube graft (B) and aortic reconstruction after graft removal and reconstruction with deep femoral vein (C)
Abbreviations
BCG Bacille Calmette–Guérin
NMIBC Non-muscle-invasive bladder cancer
TURBT Transurethral resection of bladder tumors
CT Computed tomography
AFB Acid-fast bacilli
PCR Polymerase-chain-reaction
PZA Pyrazinamide
INH Isoniazid
RFP Rifampicin
EB Ethambutol
PAU Penetrating aortic ulcer
MRI Magnetic resonance imaging
Acknowledgements
We acknowledge support from the German Research Foundation (DFG) and the Open Access Publication Fund of Charité–Universitätsmedizin Berlin.
Authors' contributions
The idea and initial findings of this seldomly occurring disease were made by JPF. During writing and revising this paper by MB, SK, SO, MS, JPF and AG where involved in constant discussions and improvements of manuscript. All relevant surgeries were performed by JPF or AG. For visual support MR created images that are used. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL.
Availability of data and materials
The data collection was done by reviewing the available literature and electronic health records at the Charité Universitätsmedizin Berlin. Relevant data was collected in Microsoft Excel and analysed descriptively. The data is stored on the Charité—server and, in order to avoid a violation of access rights, the data is encrypted using a password only known to the study physicians. The data that support the findings of this study is available, but restrictions apply to the availability of the data, which was used under license for the current study, and so is not publicly available. Data is however available from the authors upon reasonable request.
Declarations
Ethics approval and consent to participate
The need for approval was waived by our institutional review board.
Consent for publication
Written informed consent for publication of their clinical details and/or clinical images was obtained from all patients. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Intravesical | DrugAdministrationRoute | CC BY | 33731071 | 19,110,873 | 2021-03-17 |
What was the dosage of drug 'BACILLUS CALMETTE-GUERIN SUBSTRAIN TICE LIVE ANTIGEN'? | Aortic aneurysm and aortic graft infection related to Mycobacterium bovis after intravesical Bacille Calmette-Guérin therapy-a case series.
BACKGROUND
So called "mycotic" aortic aneurysms account for only 0.7 to 1.3% of all aortic aneurysms and are commonly caused by Staphylococcus aureus and Salmonella species. Bacillus Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis, is part of the therapy of non-muscle-invasive bladder cancer (NMIBC).
METHODS
We report a case series of three patients with a mycobacterial graft infection related to BCG after surgical treatment of a presumed mycotic aortic aneurysm as an extremely rare complication after NMIBC treatment. All three patients developed aortic aneurysm after BCG instillation and subsequent mycobacterial graft infection.
CONCLUSIONS
Diagnosis requires a high degree of suspicion because of its nonspecific symptoms and imaging. The pathogen is not detected by standard microbiological testing. Treatment includes triple antimycobacterial therapy and radical surgical interventions. Graft preservation may be considered if no anastomosis is involved.
Background
Infectious or so called ‘mycotic’ aortic aneurysms represent merely 0.7 to 1.3% of all aortic aneurysms. Nevertheless, they constitute a life-threatening vascular complication associated with in-hospital mortality rates of up to 36% [1, 2]. Mycotic aortic aneurysms are usually caused by Staphylococcus aureus, followed by Salmonella spp., Streptococcus spp. and Escherichia coli. Mycotic aneurysms caused by mycobacterial infections are rare. Up to now, 44 cases in 42 case reports of mycotic aortic aneurysms caused by mycobacterial infection affecting the thoracoabdominal aorta after intravesical instillation of Bacillus Calmette–Guérin (BCG) have been reported (see Additional file 1: Table S1).
Intravesical BCG applications are standard of care for treating non-muscle-invasive bladder cancer (NMIBC) [3]. The live attenuated strain of Mycobacterium bovis is administered to patients with NMIBC after transurethral resection of bladder tumors (TURBT) to avert recurrence and reduce progression rates of intermediate- and high-risk tumors [4]. The incidence of BCG-related systemic complications including spondylodiscitis, psoas abscess or vascular complications remains unclear. In this case series, we report three cases of mycobacterial aortic graft infection related to intravesical application of BCG for NMIBC. This represents the largest case series in the current literature. The particular challenges for the diagnosis and treatment of this infrequent complication are discussed in this report.
Case presentations
Patient A
In November 2010, a 63-year-old man was referred to our clinic because of persistent weakness, fever, night sweat and unspecific abdominal pain lasting for two weeks. Three months before this episode, the patient had undergone emergency surgery for a ruptured infrarenal abdominal aortic aneurysm, which was treated with implantation of an aortobiiliac graft at another clinic. In 2008, the patient had been treated for NMIBC by transurethral resection and had received three cycles of intravesical BCG instillations (see Table 1). At the time of presentation, clinical examination and blood tests were unremarkable for inflammation except for a temperature of 37.6 °C. Ultrasound revealed a retroperitoneal fluid collection. Computed tomography (CT) demonstrated an extensive low-density collection surrounding the aortic prosthesis. The retroperitoneal mass was surgically removed and tissue samples were collected for histologic and microbiological studies. A specimen of the necrotic mass indicated chronic inflammation but tested negative for acid-fast bacilli (AFB) in Ziehl–Neelsen stain (Artisan™ Acid-Fast Bacillus (AFB) Stain Kit, Agilent, Santa Clara, United States). As no evidence for mycobacterial infection was found, the patient was discharged home in good condition, without antitubercular medication. Another two years later in August 2012, he presented again to our clinic with fever (40.4 °C), elevated white blood cell count (17.92/nl) and increased C-reactive protein (14.4 mg/l). CT scan revealed recurrence of a large mass in the retroperitoneum (Fig. 1). The patient underwent CT-guided aspiration. A drain was placed and specimens were sent to the microbiological laboratory. Microscopic examination showed necrotizing granulomatous inflammation with multinucleated giant cells. Direct Polymerase-chain-reaction (PCR, cobas® 6800 MTB Test, Roche, Rotkreuz, Switzerland) tested positive for Mycobacterium tuberculosis complex. Growth of Mycobacterium bovis in solid (BBL Stonebrink TB Medium + PACT + BBL Löwenstein-Jensen; Becton Dickinson, Rungis, France) and liquid culture (MGIT BBL; Becton Dickinson, Rungis, France) confirmed the suspected diagnosis. Antitubercular therapy with Isoniazid (INH), Rifampicin (RFP) and Ethambutol (EB) was started and the fluid collection was removed surgically. Intraoperatively, a partial affection of the left leg of the bifurcated graft by the necrotic mass was detected. After extensive debridement, vacuum assisted wound therapy was initiated. The possibility of an aortic reconstruction using autologous deep femoral vein or cryo-preserved homograft was evaluated but declined by the patient. After four weeks of negative pressure wound therapy, the wound could be closed in secondary intention. CT- scan showed no signs of persistent graft infection or retroperitoneal abscess. The patient was discharged in good condition. The triple antitubercular treatment was continued for six month and reduced to RFH and INH for another six months. As the patient remained free of symptoms, and CT scan was unremarkable, antitubercular therapy was subsequently terminated. After a follow-up of 84 months, the patient is in excellent condition and there is no CT- morphologic sign of recurrence of retroperitoneal abscess or inflammation of vascular graft.Table 1 Patient characteristics
Preliminary diagnoses Preliminary surgical procedures
Patient A
NMIBC in 2008 Aortobiiliac prosthesis in 2010
Ruptured aortic aneurysm in 2010
Chronic obstructive pulmonary disease
Disc prolaps L5/L6
Renal cysts
Patient B
NMIBC in 2014 None
Disc prolaps L2/L3 and L3/L4
Patient C
NMIBC in 2008 Aortocoronary bypass operation in 2011
Coronary artery disease Inguinal hernia repair
Cardial arrhythmia type II Wenckebach Dacron tube graft in 2015
Arterial hypertension
Hyperlipidemia
NMIBC Non-muscle-invasive bladder cancer
Fig. 1 CT- reconstruction showing massive retroperitoneal fluid mass affecting left branch of aortobiiliac graft
Patient B
In January 2018, a 78-year-old man presented with acute abdominal pain after a six-week history of chronic back pain. CT scan revealed a small-sized saccular aneurysmatic formation suspicious for a penetrating aortic ulcer (PAU) with contained rupture in the infrarenal aorta. Bone lesions in the vertebral bodies L2/L3 were highly suspicious for concomitant spondylodiscitis. The PAU was too small in size and anatomically too remote to represent a likely cause. Retrospectively, CT scan from 2014 did not show an aortic or vertebral pathology. The patient’s medical history was significant for NMIBC treated with TURBT and multiple intravesical BCG applications in 2014 (Table 1). The patient was hemodynamically stable and showed no notable physical examination findings. Except for increased C-reactive protein (25.1 mg/l), laboratory parameters were within normal limits. Because of close proximity of the PAU to the renal arteries resulting in a short neck, endovascular treatment was rejected. Immediate aortic reconstruction was performed by implantation of a rifampicin-soaked Dacron tube graft. Pathological examination and microbiological testing showed no evidence of mycobacterial infection or other pathogens in intraoperative specimens of the infrarenal aorta. The patient had an uneventful recovery and was discharged after two weeks. After four months of persisting lower back pain, biopsy extraction and spondylodesis of the concomitant spondylodiscitis was performed. The microbiological analysis tested negative for AFB in Ziehl–Neelsen stain but the growth of Mycobacterium bovis in solid and liquid culture confirmed the diagnosis of mycobacterial infection. Antitubercular treatment consisting of RFP, INH, and EB was administered. One year later, follow-up CT scan revealed dislocation of the former implanted spondylodesis which was surgically removed and replaced. Intraoperative samples showed no evidence of persisting mycobacterial infection with acid fast medium culture and PCR. The patient was discharged after eight days. Antitubercular triple therapy was continued for another six months. During follow-up of 20 months, the patient presented free of symptoms. CT scan showed a shrinking psoas abscess. Three months later, the patient presented to the emergency room with increasing left lower abdominal pain. CT examination showed a false aneurysm near the proximal anastomosis of the Dacron tube graft and a retroperitoneal periprosthetic fluid collection (Fig. 2), indicating an imminent rupture. Graft explantation and replacement with homograft was performed. Intraoperative sample material did not show any evidence of Mycobacterium bovis nor other pathogens. Due to the earlier confirmation of BCG- related graft infection, the anti-mycobacterial therapy was continued for another 12 months with Doxycyclin, RFP and INH. After an uncomplicated course, the patient was discharged to a rehabilitation center two weeks after surgery. Follow-up imaging was performed five months later revealing no residual fluid collection. The patient remained in good clinical condition without any signs of re-infection.Fig. 2 Progress of periprosthetic fluid mass highly suspicious for mycobacterial graft infection and anastomotic pseudoaneurysm of the former implanted Dacron tube graft
Patient C
In December 2017, a 79-year-old man presented as an outpatient to our clinic with night sweats and persisting weakness after treatment of a contained rupture of an infrarenal PAU with implantation of a Dacron tube graft at an external institution in 2015. Ultrasound examination and CT showed periprosthetic fluid collection. The patient’s medical history included NIMBC diagnosed in 2008 and treated with TURBT and a total of 36 intravesical BCG instillations (Table 1). Laboratory parameters were within normal limits (CRP: 4.7 mg/l; white blood cell count: 4.08/nl). Samples collected by CT-guided aspiration tested positive for AFB with Auramine-rhodamine stain (Wescor Aerospray TB 7722, ELITech Biomedical Systems, Logan, Utah, USA). PCR of the aspirated fluid was positive for Mycobacterium tuberculosis complex and incubation in solid and liquid culture showed growth of Mycobacterium bovis. Antimycobacterial treatment was initiated. Because of a critical interaction between Ranolexin (long-term medication), Rifampicin was replaced by Rifabutin in combination with INH and EB. After a follow-up period of six months, control CT scan revealed a false aneurysm in the infrarenal region near the proximal anastomosis of the Dacron tube graft and a progression of the fluid collection in the psoas muscle (Fig. 3). The Dacron tube graft was completely removed and replaced by deep femoral vein (Fig. S1 in Additional file 2). Despite a weak positive PCR for Mycobacterium complex, culture incubation showed no growth of Mycobacterium bovis. This was considered to be the result of an effective perioperative antimycotic therapy. After an uncomplicated postoperative course, the patient was discharged to an external rehabilitation center after 25 days. During routine outpatient follow-up 12 months after surgery, the patient was in good general condition. The CT scan showed no persistent prosthetic infection.Fig. 3 Anastomotic pseudoaneurysm and progression of both periprosthetic fluid mass and fluid collection in left psoas muscle
Discussion and conclusion
Intravesical instillation of BCG is widely used for the treatment of NMIBC. First used as a vaccine against tuberculosis, intravesical instillation of the live attenuated strain of Mycobacterium bovis has become standard care for NMIBC. The exact mechanism of its antitumor efficacy is not clarified yet. Although BCG instillation is generally considered safe, severe side effects have been reported. The incidence of mycotic aortic aneurysms caused by disseminated tuberculosis after BCG instillation remains unclear. Three different mechanisms are described that could lead to a systemic dissemination of and vascular affection by Mycobacterium bovis: (1) hematogenous dissemination followed by direct intimal colonization favored by preexisting atherosclerosis, (2) metastatic implantation through the vasa vasorum, or (3) continuous dissemination of adjacent infected tissue such as contiguous lymphadenitis or psoas abscess [5].
We report three cases of graft infection after surgical treatment of suspected mycotic aortic aneurysms as an extremely rare complication after intravesical BCG application. Our therapy was based on two pillars: drug-based antitubercular therapy as well as the individually adapted surgical treatment consisting of radical surgical debridement, vacuum therapy, drainage and in case of anastomotic leakage, graft explantation and aortic reconstruction using deep femoral vein or homograft.
So far, 44 cases of mycotic aortic aneurysms caused by disseminated mycobacterial infection have been published. Foreign material was implanted in 28 patients [6–32]. Postoperative graft infection was diagnosed in 10 out of 28 cases (35.7%) [6, 12, 17, 19–22, 32–34]. Of these 10 patients, six were discharged resulting in a hospital survival rate of 60%. A long-term follow-up of more than 12 months is reported by only one author [33]. Treatment included medical therapy alone (n = 1) [6], invasive therapy including either CT-guided drainage or surgical debridement with graft preservation (n = 2) [12, 19] and radical surgical therapy with partial (n = 1) [17] or complete graft explantation (n = 6) [20–22, 32–34]. Antitubercular medication was administered in 8 out of 10 cases [6, 12, 17, 19–22, 33]. Apart from one case [33], graft explantation was performed combined with aortic stump ligation and implantation of an extraanatomic axillofemoral bypass. Similar to our patients B and C, Santbergen et al. (33) focused on aortic reconstruction with autologous replacement material with an excellent postoperative result. Eighteen months after completion of the antimycobacterial medication, there was no clinical and morphological evidence of a persistent infection.
Diagnosis of mycotic aneurysms or vascular complications after intravesical BCG application is exceptionally challenging and a high level of suspicion is required. A thorough medical history with attention to past NMIBC and related BCG instillations is essential when a mycotic aneurysm or graft infection is suspected. Unspecific symptoms like night sweats, weight loss, malaise and persisting fever combined with an unremarkable clinical examination can draw suspicion to a chronic disease like disseminated BCG- infection. After obtaining sample material from affected regions, e.g. vertebral disc, fluid collection in psoas muscle, aortic wall, paraaortic lymph nodes, pathological and microbiological examination is required. Suspected diagnosis can only be confirmed by PCR and culture specific for mycobacterial pathogens. Standard microbiological testing is often negative.
All of our three patients had received BCG therapy several years before the primary intervention. Because of the slow replication rate of mycobacteria, symptomatic vascular disease will often occur with a long latency after BCG instillation. Delay in diagnosis will lead to a delay in starting antimycobacterial treatment, which may result in an increased risk of rupture and dissemination, further limiting surgical options.
Currently, no consensus guideline for optimal medical treatment options of graft infection secondary to BCG instillation is available. Given its rareness, a case by case decision has to be made. Antitubercular therapy should be administered immediately after confirmed diagnosis and should be continued for at least six to 12 months. This medical therapy should be supplemented by surgical treatment. Our first case was managed successfully without graft explantation, with repeated radical surgical debridement and vacuum therapy alone, as no anastomosis was involved in this case. In our two following cases, anastomotic aneurysm indicating imminent rupture was discovered during follow-up. In these cases, we decided to completely remove the infected graft and to reconstruct the aorta with deep femoral vein or homograft, respectively.
In conclusion, this three-case series represents our experience with this rare condition. We strongly suggest that in cases of aortic aneurysm or aortic graft infection in patients with previous BCG instillation, surgeons should be suspicious of BCG- infection and mycotic aneurysm and to initiate specific testing including PCR and culture for mycobacterial infection. In cases with involvement of any graft anastomosis, complete graft removal and replacement with biological material should be considered. In cases with no involvement of an anastomosis, graft preservation could be attempted. Adjuvant antimycobacterial treatment is essential and should be initiated as soon as diagnosis is confirmed.
Supplementary Information
Additional file 1: Table S1. Publications reporting aortic aneurysm secondary to intravesical application of Bacillus Calmette Guérin
Additional file 2: Fig. S1. Intraoperative situs showing exit of purulent granular material from the aneurysmatic formation (A) surrounding former implanted Dacron tube graft (B) and aortic reconstruction after graft removal and reconstruction with deep femoral vein (C)
Abbreviations
BCG Bacille Calmette–Guérin
NMIBC Non-muscle-invasive bladder cancer
TURBT Transurethral resection of bladder tumors
CT Computed tomography
AFB Acid-fast bacilli
PCR Polymerase-chain-reaction
PZA Pyrazinamide
INH Isoniazid
RFP Rifampicin
EB Ethambutol
PAU Penetrating aortic ulcer
MRI Magnetic resonance imaging
Acknowledgements
We acknowledge support from the German Research Foundation (DFG) and the Open Access Publication Fund of Charité–Universitätsmedizin Berlin.
Authors' contributions
The idea and initial findings of this seldomly occurring disease were made by JPF. During writing and revising this paper by MB, SK, SO, MS, JPF and AG where involved in constant discussions and improvements of manuscript. All relevant surgeries were performed by JPF or AG. For visual support MR created images that are used. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL.
Availability of data and materials
The data collection was done by reviewing the available literature and electronic health records at the Charité Universitätsmedizin Berlin. Relevant data was collected in Microsoft Excel and analysed descriptively. The data is stored on the Charité—server and, in order to avoid a violation of access rights, the data is encrypted using a password only known to the study physicians. The data that support the findings of this study is available, but restrictions apply to the availability of the data, which was used under license for the current study, and so is not publicly available. Data is however available from the authors upon reasonable request.
Declarations
Ethics approval and consent to participate
The need for approval was waived by our institutional review board.
Consent for publication
Written informed consent for publication of their clinical details and/or clinical images was obtained from all patients. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | MULTIPLE APLLICATIONS | DrugDosageText | CC BY | 33731071 | 19,110,873 | 2021-03-17 |
What was the outcome of reaction 'Infective aneurysm'? | Aortic aneurysm and aortic graft infection related to Mycobacterium bovis after intravesical Bacille Calmette-Guérin therapy-a case series.
BACKGROUND
So called "mycotic" aortic aneurysms account for only 0.7 to 1.3% of all aortic aneurysms and are commonly caused by Staphylococcus aureus and Salmonella species. Bacillus Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis, is part of the therapy of non-muscle-invasive bladder cancer (NMIBC).
METHODS
We report a case series of three patients with a mycobacterial graft infection related to BCG after surgical treatment of a presumed mycotic aortic aneurysm as an extremely rare complication after NMIBC treatment. All three patients developed aortic aneurysm after BCG instillation and subsequent mycobacterial graft infection.
CONCLUSIONS
Diagnosis requires a high degree of suspicion because of its nonspecific symptoms and imaging. The pathogen is not detected by standard microbiological testing. Treatment includes triple antimycobacterial therapy and radical surgical interventions. Graft preservation may be considered if no anastomosis is involved.
Background
Infectious or so called ‘mycotic’ aortic aneurysms represent merely 0.7 to 1.3% of all aortic aneurysms. Nevertheless, they constitute a life-threatening vascular complication associated with in-hospital mortality rates of up to 36% [1, 2]. Mycotic aortic aneurysms are usually caused by Staphylococcus aureus, followed by Salmonella spp., Streptococcus spp. and Escherichia coli. Mycotic aneurysms caused by mycobacterial infections are rare. Up to now, 44 cases in 42 case reports of mycotic aortic aneurysms caused by mycobacterial infection affecting the thoracoabdominal aorta after intravesical instillation of Bacillus Calmette–Guérin (BCG) have been reported (see Additional file 1: Table S1).
Intravesical BCG applications are standard of care for treating non-muscle-invasive bladder cancer (NMIBC) [3]. The live attenuated strain of Mycobacterium bovis is administered to patients with NMIBC after transurethral resection of bladder tumors (TURBT) to avert recurrence and reduce progression rates of intermediate- and high-risk tumors [4]. The incidence of BCG-related systemic complications including spondylodiscitis, psoas abscess or vascular complications remains unclear. In this case series, we report three cases of mycobacterial aortic graft infection related to intravesical application of BCG for NMIBC. This represents the largest case series in the current literature. The particular challenges for the diagnosis and treatment of this infrequent complication are discussed in this report.
Case presentations
Patient A
In November 2010, a 63-year-old man was referred to our clinic because of persistent weakness, fever, night sweat and unspecific abdominal pain lasting for two weeks. Three months before this episode, the patient had undergone emergency surgery for a ruptured infrarenal abdominal aortic aneurysm, which was treated with implantation of an aortobiiliac graft at another clinic. In 2008, the patient had been treated for NMIBC by transurethral resection and had received three cycles of intravesical BCG instillations (see Table 1). At the time of presentation, clinical examination and blood tests were unremarkable for inflammation except for a temperature of 37.6 °C. Ultrasound revealed a retroperitoneal fluid collection. Computed tomography (CT) demonstrated an extensive low-density collection surrounding the aortic prosthesis. The retroperitoneal mass was surgically removed and tissue samples were collected for histologic and microbiological studies. A specimen of the necrotic mass indicated chronic inflammation but tested negative for acid-fast bacilli (AFB) in Ziehl–Neelsen stain (Artisan™ Acid-Fast Bacillus (AFB) Stain Kit, Agilent, Santa Clara, United States). As no evidence for mycobacterial infection was found, the patient was discharged home in good condition, without antitubercular medication. Another two years later in August 2012, he presented again to our clinic with fever (40.4 °C), elevated white blood cell count (17.92/nl) and increased C-reactive protein (14.4 mg/l). CT scan revealed recurrence of a large mass in the retroperitoneum (Fig. 1). The patient underwent CT-guided aspiration. A drain was placed and specimens were sent to the microbiological laboratory. Microscopic examination showed necrotizing granulomatous inflammation with multinucleated giant cells. Direct Polymerase-chain-reaction (PCR, cobas® 6800 MTB Test, Roche, Rotkreuz, Switzerland) tested positive for Mycobacterium tuberculosis complex. Growth of Mycobacterium bovis in solid (BBL Stonebrink TB Medium + PACT + BBL Löwenstein-Jensen; Becton Dickinson, Rungis, France) and liquid culture (MGIT BBL; Becton Dickinson, Rungis, France) confirmed the suspected diagnosis. Antitubercular therapy with Isoniazid (INH), Rifampicin (RFP) and Ethambutol (EB) was started and the fluid collection was removed surgically. Intraoperatively, a partial affection of the left leg of the bifurcated graft by the necrotic mass was detected. After extensive debridement, vacuum assisted wound therapy was initiated. The possibility of an aortic reconstruction using autologous deep femoral vein or cryo-preserved homograft was evaluated but declined by the patient. After four weeks of negative pressure wound therapy, the wound could be closed in secondary intention. CT- scan showed no signs of persistent graft infection or retroperitoneal abscess. The patient was discharged in good condition. The triple antitubercular treatment was continued for six month and reduced to RFH and INH for another six months. As the patient remained free of symptoms, and CT scan was unremarkable, antitubercular therapy was subsequently terminated. After a follow-up of 84 months, the patient is in excellent condition and there is no CT- morphologic sign of recurrence of retroperitoneal abscess or inflammation of vascular graft.Table 1 Patient characteristics
Preliminary diagnoses Preliminary surgical procedures
Patient A
NMIBC in 2008 Aortobiiliac prosthesis in 2010
Ruptured aortic aneurysm in 2010
Chronic obstructive pulmonary disease
Disc prolaps L5/L6
Renal cysts
Patient B
NMIBC in 2014 None
Disc prolaps L2/L3 and L3/L4
Patient C
NMIBC in 2008 Aortocoronary bypass operation in 2011
Coronary artery disease Inguinal hernia repair
Cardial arrhythmia type II Wenckebach Dacron tube graft in 2015
Arterial hypertension
Hyperlipidemia
NMIBC Non-muscle-invasive bladder cancer
Fig. 1 CT- reconstruction showing massive retroperitoneal fluid mass affecting left branch of aortobiiliac graft
Patient B
In January 2018, a 78-year-old man presented with acute abdominal pain after a six-week history of chronic back pain. CT scan revealed a small-sized saccular aneurysmatic formation suspicious for a penetrating aortic ulcer (PAU) with contained rupture in the infrarenal aorta. Bone lesions in the vertebral bodies L2/L3 were highly suspicious for concomitant spondylodiscitis. The PAU was too small in size and anatomically too remote to represent a likely cause. Retrospectively, CT scan from 2014 did not show an aortic or vertebral pathology. The patient’s medical history was significant for NMIBC treated with TURBT and multiple intravesical BCG applications in 2014 (Table 1). The patient was hemodynamically stable and showed no notable physical examination findings. Except for increased C-reactive protein (25.1 mg/l), laboratory parameters were within normal limits. Because of close proximity of the PAU to the renal arteries resulting in a short neck, endovascular treatment was rejected. Immediate aortic reconstruction was performed by implantation of a rifampicin-soaked Dacron tube graft. Pathological examination and microbiological testing showed no evidence of mycobacterial infection or other pathogens in intraoperative specimens of the infrarenal aorta. The patient had an uneventful recovery and was discharged after two weeks. After four months of persisting lower back pain, biopsy extraction and spondylodesis of the concomitant spondylodiscitis was performed. The microbiological analysis tested negative for AFB in Ziehl–Neelsen stain but the growth of Mycobacterium bovis in solid and liquid culture confirmed the diagnosis of mycobacterial infection. Antitubercular treatment consisting of RFP, INH, and EB was administered. One year later, follow-up CT scan revealed dislocation of the former implanted spondylodesis which was surgically removed and replaced. Intraoperative samples showed no evidence of persisting mycobacterial infection with acid fast medium culture and PCR. The patient was discharged after eight days. Antitubercular triple therapy was continued for another six months. During follow-up of 20 months, the patient presented free of symptoms. CT scan showed a shrinking psoas abscess. Three months later, the patient presented to the emergency room with increasing left lower abdominal pain. CT examination showed a false aneurysm near the proximal anastomosis of the Dacron tube graft and a retroperitoneal periprosthetic fluid collection (Fig. 2), indicating an imminent rupture. Graft explantation and replacement with homograft was performed. Intraoperative sample material did not show any evidence of Mycobacterium bovis nor other pathogens. Due to the earlier confirmation of BCG- related graft infection, the anti-mycobacterial therapy was continued for another 12 months with Doxycyclin, RFP and INH. After an uncomplicated course, the patient was discharged to a rehabilitation center two weeks after surgery. Follow-up imaging was performed five months later revealing no residual fluid collection. The patient remained in good clinical condition without any signs of re-infection.Fig. 2 Progress of periprosthetic fluid mass highly suspicious for mycobacterial graft infection and anastomotic pseudoaneurysm of the former implanted Dacron tube graft
Patient C
In December 2017, a 79-year-old man presented as an outpatient to our clinic with night sweats and persisting weakness after treatment of a contained rupture of an infrarenal PAU with implantation of a Dacron tube graft at an external institution in 2015. Ultrasound examination and CT showed periprosthetic fluid collection. The patient’s medical history included NIMBC diagnosed in 2008 and treated with TURBT and a total of 36 intravesical BCG instillations (Table 1). Laboratory parameters were within normal limits (CRP: 4.7 mg/l; white blood cell count: 4.08/nl). Samples collected by CT-guided aspiration tested positive for AFB with Auramine-rhodamine stain (Wescor Aerospray TB 7722, ELITech Biomedical Systems, Logan, Utah, USA). PCR of the aspirated fluid was positive for Mycobacterium tuberculosis complex and incubation in solid and liquid culture showed growth of Mycobacterium bovis. Antimycobacterial treatment was initiated. Because of a critical interaction between Ranolexin (long-term medication), Rifampicin was replaced by Rifabutin in combination with INH and EB. After a follow-up period of six months, control CT scan revealed a false aneurysm in the infrarenal region near the proximal anastomosis of the Dacron tube graft and a progression of the fluid collection in the psoas muscle (Fig. 3). The Dacron tube graft was completely removed and replaced by deep femoral vein (Fig. S1 in Additional file 2). Despite a weak positive PCR for Mycobacterium complex, culture incubation showed no growth of Mycobacterium bovis. This was considered to be the result of an effective perioperative antimycotic therapy. After an uncomplicated postoperative course, the patient was discharged to an external rehabilitation center after 25 days. During routine outpatient follow-up 12 months after surgery, the patient was in good general condition. The CT scan showed no persistent prosthetic infection.Fig. 3 Anastomotic pseudoaneurysm and progression of both periprosthetic fluid mass and fluid collection in left psoas muscle
Discussion and conclusion
Intravesical instillation of BCG is widely used for the treatment of NMIBC. First used as a vaccine against tuberculosis, intravesical instillation of the live attenuated strain of Mycobacterium bovis has become standard care for NMIBC. The exact mechanism of its antitumor efficacy is not clarified yet. Although BCG instillation is generally considered safe, severe side effects have been reported. The incidence of mycotic aortic aneurysms caused by disseminated tuberculosis after BCG instillation remains unclear. Three different mechanisms are described that could lead to a systemic dissemination of and vascular affection by Mycobacterium bovis: (1) hematogenous dissemination followed by direct intimal colonization favored by preexisting atherosclerosis, (2) metastatic implantation through the vasa vasorum, or (3) continuous dissemination of adjacent infected tissue such as contiguous lymphadenitis or psoas abscess [5].
We report three cases of graft infection after surgical treatment of suspected mycotic aortic aneurysms as an extremely rare complication after intravesical BCG application. Our therapy was based on two pillars: drug-based antitubercular therapy as well as the individually adapted surgical treatment consisting of radical surgical debridement, vacuum therapy, drainage and in case of anastomotic leakage, graft explantation and aortic reconstruction using deep femoral vein or homograft.
So far, 44 cases of mycotic aortic aneurysms caused by disseminated mycobacterial infection have been published. Foreign material was implanted in 28 patients [6–32]. Postoperative graft infection was diagnosed in 10 out of 28 cases (35.7%) [6, 12, 17, 19–22, 32–34]. Of these 10 patients, six were discharged resulting in a hospital survival rate of 60%. A long-term follow-up of more than 12 months is reported by only one author [33]. Treatment included medical therapy alone (n = 1) [6], invasive therapy including either CT-guided drainage or surgical debridement with graft preservation (n = 2) [12, 19] and radical surgical therapy with partial (n = 1) [17] or complete graft explantation (n = 6) [20–22, 32–34]. Antitubercular medication was administered in 8 out of 10 cases [6, 12, 17, 19–22, 33]. Apart from one case [33], graft explantation was performed combined with aortic stump ligation and implantation of an extraanatomic axillofemoral bypass. Similar to our patients B and C, Santbergen et al. (33) focused on aortic reconstruction with autologous replacement material with an excellent postoperative result. Eighteen months after completion of the antimycobacterial medication, there was no clinical and morphological evidence of a persistent infection.
Diagnosis of mycotic aneurysms or vascular complications after intravesical BCG application is exceptionally challenging and a high level of suspicion is required. A thorough medical history with attention to past NMIBC and related BCG instillations is essential when a mycotic aneurysm or graft infection is suspected. Unspecific symptoms like night sweats, weight loss, malaise and persisting fever combined with an unremarkable clinical examination can draw suspicion to a chronic disease like disseminated BCG- infection. After obtaining sample material from affected regions, e.g. vertebral disc, fluid collection in psoas muscle, aortic wall, paraaortic lymph nodes, pathological and microbiological examination is required. Suspected diagnosis can only be confirmed by PCR and culture specific for mycobacterial pathogens. Standard microbiological testing is often negative.
All of our three patients had received BCG therapy several years before the primary intervention. Because of the slow replication rate of mycobacteria, symptomatic vascular disease will often occur with a long latency after BCG instillation. Delay in diagnosis will lead to a delay in starting antimycobacterial treatment, which may result in an increased risk of rupture and dissemination, further limiting surgical options.
Currently, no consensus guideline for optimal medical treatment options of graft infection secondary to BCG instillation is available. Given its rareness, a case by case decision has to be made. Antitubercular therapy should be administered immediately after confirmed diagnosis and should be continued for at least six to 12 months. This medical therapy should be supplemented by surgical treatment. Our first case was managed successfully without graft explantation, with repeated radical surgical debridement and vacuum therapy alone, as no anastomosis was involved in this case. In our two following cases, anastomotic aneurysm indicating imminent rupture was discovered during follow-up. In these cases, we decided to completely remove the infected graft and to reconstruct the aorta with deep femoral vein or homograft, respectively.
In conclusion, this three-case series represents our experience with this rare condition. We strongly suggest that in cases of aortic aneurysm or aortic graft infection in patients with previous BCG instillation, surgeons should be suspicious of BCG- infection and mycotic aneurysm and to initiate specific testing including PCR and culture for mycobacterial infection. In cases with involvement of any graft anastomosis, complete graft removal and replacement with biological material should be considered. In cases with no involvement of an anastomosis, graft preservation could be attempted. Adjuvant antimycobacterial treatment is essential and should be initiated as soon as diagnosis is confirmed.
Supplementary Information
Additional file 1: Table S1. Publications reporting aortic aneurysm secondary to intravesical application of Bacillus Calmette Guérin
Additional file 2: Fig. S1. Intraoperative situs showing exit of purulent granular material from the aneurysmatic formation (A) surrounding former implanted Dacron tube graft (B) and aortic reconstruction after graft removal and reconstruction with deep femoral vein (C)
Abbreviations
BCG Bacille Calmette–Guérin
NMIBC Non-muscle-invasive bladder cancer
TURBT Transurethral resection of bladder tumors
CT Computed tomography
AFB Acid-fast bacilli
PCR Polymerase-chain-reaction
PZA Pyrazinamide
INH Isoniazid
RFP Rifampicin
EB Ethambutol
PAU Penetrating aortic ulcer
MRI Magnetic resonance imaging
Acknowledgements
We acknowledge support from the German Research Foundation (DFG) and the Open Access Publication Fund of Charité–Universitätsmedizin Berlin.
Authors' contributions
The idea and initial findings of this seldomly occurring disease were made by JPF. During writing and revising this paper by MB, SK, SO, MS, JPF and AG where involved in constant discussions and improvements of manuscript. All relevant surgeries were performed by JPF or AG. For visual support MR created images that are used. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL.
Availability of data and materials
The data collection was done by reviewing the available literature and electronic health records at the Charité Universitätsmedizin Berlin. Relevant data was collected in Microsoft Excel and analysed descriptively. The data is stored on the Charité—server and, in order to avoid a violation of access rights, the data is encrypted using a password only known to the study physicians. The data that support the findings of this study is available, but restrictions apply to the availability of the data, which was used under license for the current study, and so is not publicly available. Data is however available from the authors upon reasonable request.
Declarations
Ethics approval and consent to participate
The need for approval was waived by our institutional review board.
Consent for publication
Written informed consent for publication of their clinical details and/or clinical images was obtained from all patients. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33731071 | 19,110,873 | 2021-03-17 |
What was the outcome of reaction 'Mycobacterial infection'? | Aortic aneurysm and aortic graft infection related to Mycobacterium bovis after intravesical Bacille Calmette-Guérin therapy-a case series.
BACKGROUND
So called "mycotic" aortic aneurysms account for only 0.7 to 1.3% of all aortic aneurysms and are commonly caused by Staphylococcus aureus and Salmonella species. Bacillus Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis, is part of the therapy of non-muscle-invasive bladder cancer (NMIBC).
METHODS
We report a case series of three patients with a mycobacterial graft infection related to BCG after surgical treatment of a presumed mycotic aortic aneurysm as an extremely rare complication after NMIBC treatment. All three patients developed aortic aneurysm after BCG instillation and subsequent mycobacterial graft infection.
CONCLUSIONS
Diagnosis requires a high degree of suspicion because of its nonspecific symptoms and imaging. The pathogen is not detected by standard microbiological testing. Treatment includes triple antimycobacterial therapy and radical surgical interventions. Graft preservation may be considered if no anastomosis is involved.
Background
Infectious or so called ‘mycotic’ aortic aneurysms represent merely 0.7 to 1.3% of all aortic aneurysms. Nevertheless, they constitute a life-threatening vascular complication associated with in-hospital mortality rates of up to 36% [1, 2]. Mycotic aortic aneurysms are usually caused by Staphylococcus aureus, followed by Salmonella spp., Streptococcus spp. and Escherichia coli. Mycotic aneurysms caused by mycobacterial infections are rare. Up to now, 44 cases in 42 case reports of mycotic aortic aneurysms caused by mycobacterial infection affecting the thoracoabdominal aorta after intravesical instillation of Bacillus Calmette–Guérin (BCG) have been reported (see Additional file 1: Table S1).
Intravesical BCG applications are standard of care for treating non-muscle-invasive bladder cancer (NMIBC) [3]. The live attenuated strain of Mycobacterium bovis is administered to patients with NMIBC after transurethral resection of bladder tumors (TURBT) to avert recurrence and reduce progression rates of intermediate- and high-risk tumors [4]. The incidence of BCG-related systemic complications including spondylodiscitis, psoas abscess or vascular complications remains unclear. In this case series, we report three cases of mycobacterial aortic graft infection related to intravesical application of BCG for NMIBC. This represents the largest case series in the current literature. The particular challenges for the diagnosis and treatment of this infrequent complication are discussed in this report.
Case presentations
Patient A
In November 2010, a 63-year-old man was referred to our clinic because of persistent weakness, fever, night sweat and unspecific abdominal pain lasting for two weeks. Three months before this episode, the patient had undergone emergency surgery for a ruptured infrarenal abdominal aortic aneurysm, which was treated with implantation of an aortobiiliac graft at another clinic. In 2008, the patient had been treated for NMIBC by transurethral resection and had received three cycles of intravesical BCG instillations (see Table 1). At the time of presentation, clinical examination and blood tests were unremarkable for inflammation except for a temperature of 37.6 °C. Ultrasound revealed a retroperitoneal fluid collection. Computed tomography (CT) demonstrated an extensive low-density collection surrounding the aortic prosthesis. The retroperitoneal mass was surgically removed and tissue samples were collected for histologic and microbiological studies. A specimen of the necrotic mass indicated chronic inflammation but tested negative for acid-fast bacilli (AFB) in Ziehl–Neelsen stain (Artisan™ Acid-Fast Bacillus (AFB) Stain Kit, Agilent, Santa Clara, United States). As no evidence for mycobacterial infection was found, the patient was discharged home in good condition, without antitubercular medication. Another two years later in August 2012, he presented again to our clinic with fever (40.4 °C), elevated white blood cell count (17.92/nl) and increased C-reactive protein (14.4 mg/l). CT scan revealed recurrence of a large mass in the retroperitoneum (Fig. 1). The patient underwent CT-guided aspiration. A drain was placed and specimens were sent to the microbiological laboratory. Microscopic examination showed necrotizing granulomatous inflammation with multinucleated giant cells. Direct Polymerase-chain-reaction (PCR, cobas® 6800 MTB Test, Roche, Rotkreuz, Switzerland) tested positive for Mycobacterium tuberculosis complex. Growth of Mycobacterium bovis in solid (BBL Stonebrink TB Medium + PACT + BBL Löwenstein-Jensen; Becton Dickinson, Rungis, France) and liquid culture (MGIT BBL; Becton Dickinson, Rungis, France) confirmed the suspected diagnosis. Antitubercular therapy with Isoniazid (INH), Rifampicin (RFP) and Ethambutol (EB) was started and the fluid collection was removed surgically. Intraoperatively, a partial affection of the left leg of the bifurcated graft by the necrotic mass was detected. After extensive debridement, vacuum assisted wound therapy was initiated. The possibility of an aortic reconstruction using autologous deep femoral vein or cryo-preserved homograft was evaluated but declined by the patient. After four weeks of negative pressure wound therapy, the wound could be closed in secondary intention. CT- scan showed no signs of persistent graft infection or retroperitoneal abscess. The patient was discharged in good condition. The triple antitubercular treatment was continued for six month and reduced to RFH and INH for another six months. As the patient remained free of symptoms, and CT scan was unremarkable, antitubercular therapy was subsequently terminated. After a follow-up of 84 months, the patient is in excellent condition and there is no CT- morphologic sign of recurrence of retroperitoneal abscess or inflammation of vascular graft.Table 1 Patient characteristics
Preliminary diagnoses Preliminary surgical procedures
Patient A
NMIBC in 2008 Aortobiiliac prosthesis in 2010
Ruptured aortic aneurysm in 2010
Chronic obstructive pulmonary disease
Disc prolaps L5/L6
Renal cysts
Patient B
NMIBC in 2014 None
Disc prolaps L2/L3 and L3/L4
Patient C
NMIBC in 2008 Aortocoronary bypass operation in 2011
Coronary artery disease Inguinal hernia repair
Cardial arrhythmia type II Wenckebach Dacron tube graft in 2015
Arterial hypertension
Hyperlipidemia
NMIBC Non-muscle-invasive bladder cancer
Fig. 1 CT- reconstruction showing massive retroperitoneal fluid mass affecting left branch of aortobiiliac graft
Patient B
In January 2018, a 78-year-old man presented with acute abdominal pain after a six-week history of chronic back pain. CT scan revealed a small-sized saccular aneurysmatic formation suspicious for a penetrating aortic ulcer (PAU) with contained rupture in the infrarenal aorta. Bone lesions in the vertebral bodies L2/L3 were highly suspicious for concomitant spondylodiscitis. The PAU was too small in size and anatomically too remote to represent a likely cause. Retrospectively, CT scan from 2014 did not show an aortic or vertebral pathology. The patient’s medical history was significant for NMIBC treated with TURBT and multiple intravesical BCG applications in 2014 (Table 1). The patient was hemodynamically stable and showed no notable physical examination findings. Except for increased C-reactive protein (25.1 mg/l), laboratory parameters were within normal limits. Because of close proximity of the PAU to the renal arteries resulting in a short neck, endovascular treatment was rejected. Immediate aortic reconstruction was performed by implantation of a rifampicin-soaked Dacron tube graft. Pathological examination and microbiological testing showed no evidence of mycobacterial infection or other pathogens in intraoperative specimens of the infrarenal aorta. The patient had an uneventful recovery and was discharged after two weeks. After four months of persisting lower back pain, biopsy extraction and spondylodesis of the concomitant spondylodiscitis was performed. The microbiological analysis tested negative for AFB in Ziehl–Neelsen stain but the growth of Mycobacterium bovis in solid and liquid culture confirmed the diagnosis of mycobacterial infection. Antitubercular treatment consisting of RFP, INH, and EB was administered. One year later, follow-up CT scan revealed dislocation of the former implanted spondylodesis which was surgically removed and replaced. Intraoperative samples showed no evidence of persisting mycobacterial infection with acid fast medium culture and PCR. The patient was discharged after eight days. Antitubercular triple therapy was continued for another six months. During follow-up of 20 months, the patient presented free of symptoms. CT scan showed a shrinking psoas abscess. Three months later, the patient presented to the emergency room with increasing left lower abdominal pain. CT examination showed a false aneurysm near the proximal anastomosis of the Dacron tube graft and a retroperitoneal periprosthetic fluid collection (Fig. 2), indicating an imminent rupture. Graft explantation and replacement with homograft was performed. Intraoperative sample material did not show any evidence of Mycobacterium bovis nor other pathogens. Due to the earlier confirmation of BCG- related graft infection, the anti-mycobacterial therapy was continued for another 12 months with Doxycyclin, RFP and INH. After an uncomplicated course, the patient was discharged to a rehabilitation center two weeks after surgery. Follow-up imaging was performed five months later revealing no residual fluid collection. The patient remained in good clinical condition without any signs of re-infection.Fig. 2 Progress of periprosthetic fluid mass highly suspicious for mycobacterial graft infection and anastomotic pseudoaneurysm of the former implanted Dacron tube graft
Patient C
In December 2017, a 79-year-old man presented as an outpatient to our clinic with night sweats and persisting weakness after treatment of a contained rupture of an infrarenal PAU with implantation of a Dacron tube graft at an external institution in 2015. Ultrasound examination and CT showed periprosthetic fluid collection. The patient’s medical history included NIMBC diagnosed in 2008 and treated with TURBT and a total of 36 intravesical BCG instillations (Table 1). Laboratory parameters were within normal limits (CRP: 4.7 mg/l; white blood cell count: 4.08/nl). Samples collected by CT-guided aspiration tested positive for AFB with Auramine-rhodamine stain (Wescor Aerospray TB 7722, ELITech Biomedical Systems, Logan, Utah, USA). PCR of the aspirated fluid was positive for Mycobacterium tuberculosis complex and incubation in solid and liquid culture showed growth of Mycobacterium bovis. Antimycobacterial treatment was initiated. Because of a critical interaction between Ranolexin (long-term medication), Rifampicin was replaced by Rifabutin in combination with INH and EB. After a follow-up period of six months, control CT scan revealed a false aneurysm in the infrarenal region near the proximal anastomosis of the Dacron tube graft and a progression of the fluid collection in the psoas muscle (Fig. 3). The Dacron tube graft was completely removed and replaced by deep femoral vein (Fig. S1 in Additional file 2). Despite a weak positive PCR for Mycobacterium complex, culture incubation showed no growth of Mycobacterium bovis. This was considered to be the result of an effective perioperative antimycotic therapy. After an uncomplicated postoperative course, the patient was discharged to an external rehabilitation center after 25 days. During routine outpatient follow-up 12 months after surgery, the patient was in good general condition. The CT scan showed no persistent prosthetic infection.Fig. 3 Anastomotic pseudoaneurysm and progression of both periprosthetic fluid mass and fluid collection in left psoas muscle
Discussion and conclusion
Intravesical instillation of BCG is widely used for the treatment of NMIBC. First used as a vaccine against tuberculosis, intravesical instillation of the live attenuated strain of Mycobacterium bovis has become standard care for NMIBC. The exact mechanism of its antitumor efficacy is not clarified yet. Although BCG instillation is generally considered safe, severe side effects have been reported. The incidence of mycotic aortic aneurysms caused by disseminated tuberculosis after BCG instillation remains unclear. Three different mechanisms are described that could lead to a systemic dissemination of and vascular affection by Mycobacterium bovis: (1) hematogenous dissemination followed by direct intimal colonization favored by preexisting atherosclerosis, (2) metastatic implantation through the vasa vasorum, or (3) continuous dissemination of adjacent infected tissue such as contiguous lymphadenitis or psoas abscess [5].
We report three cases of graft infection after surgical treatment of suspected mycotic aortic aneurysms as an extremely rare complication after intravesical BCG application. Our therapy was based on two pillars: drug-based antitubercular therapy as well as the individually adapted surgical treatment consisting of radical surgical debridement, vacuum therapy, drainage and in case of anastomotic leakage, graft explantation and aortic reconstruction using deep femoral vein or homograft.
So far, 44 cases of mycotic aortic aneurysms caused by disseminated mycobacterial infection have been published. Foreign material was implanted in 28 patients [6–32]. Postoperative graft infection was diagnosed in 10 out of 28 cases (35.7%) [6, 12, 17, 19–22, 32–34]. Of these 10 patients, six were discharged resulting in a hospital survival rate of 60%. A long-term follow-up of more than 12 months is reported by only one author [33]. Treatment included medical therapy alone (n = 1) [6], invasive therapy including either CT-guided drainage or surgical debridement with graft preservation (n = 2) [12, 19] and radical surgical therapy with partial (n = 1) [17] or complete graft explantation (n = 6) [20–22, 32–34]. Antitubercular medication was administered in 8 out of 10 cases [6, 12, 17, 19–22, 33]. Apart from one case [33], graft explantation was performed combined with aortic stump ligation and implantation of an extraanatomic axillofemoral bypass. Similar to our patients B and C, Santbergen et al. (33) focused on aortic reconstruction with autologous replacement material with an excellent postoperative result. Eighteen months after completion of the antimycobacterial medication, there was no clinical and morphological evidence of a persistent infection.
Diagnosis of mycotic aneurysms or vascular complications after intravesical BCG application is exceptionally challenging and a high level of suspicion is required. A thorough medical history with attention to past NMIBC and related BCG instillations is essential when a mycotic aneurysm or graft infection is suspected. Unspecific symptoms like night sweats, weight loss, malaise and persisting fever combined with an unremarkable clinical examination can draw suspicion to a chronic disease like disseminated BCG- infection. After obtaining sample material from affected regions, e.g. vertebral disc, fluid collection in psoas muscle, aortic wall, paraaortic lymph nodes, pathological and microbiological examination is required. Suspected diagnosis can only be confirmed by PCR and culture specific for mycobacterial pathogens. Standard microbiological testing is often negative.
All of our three patients had received BCG therapy several years before the primary intervention. Because of the slow replication rate of mycobacteria, symptomatic vascular disease will often occur with a long latency after BCG instillation. Delay in diagnosis will lead to a delay in starting antimycobacterial treatment, which may result in an increased risk of rupture and dissemination, further limiting surgical options.
Currently, no consensus guideline for optimal medical treatment options of graft infection secondary to BCG instillation is available. Given its rareness, a case by case decision has to be made. Antitubercular therapy should be administered immediately after confirmed diagnosis and should be continued for at least six to 12 months. This medical therapy should be supplemented by surgical treatment. Our first case was managed successfully without graft explantation, with repeated radical surgical debridement and vacuum therapy alone, as no anastomosis was involved in this case. In our two following cases, anastomotic aneurysm indicating imminent rupture was discovered during follow-up. In these cases, we decided to completely remove the infected graft and to reconstruct the aorta with deep femoral vein or homograft, respectively.
In conclusion, this three-case series represents our experience with this rare condition. We strongly suggest that in cases of aortic aneurysm or aortic graft infection in patients with previous BCG instillation, surgeons should be suspicious of BCG- infection and mycotic aneurysm and to initiate specific testing including PCR and culture for mycobacterial infection. In cases with involvement of any graft anastomosis, complete graft removal and replacement with biological material should be considered. In cases with no involvement of an anastomosis, graft preservation could be attempted. Adjuvant antimycobacterial treatment is essential and should be initiated as soon as diagnosis is confirmed.
Supplementary Information
Additional file 1: Table S1. Publications reporting aortic aneurysm secondary to intravesical application of Bacillus Calmette Guérin
Additional file 2: Fig. S1. Intraoperative situs showing exit of purulent granular material from the aneurysmatic formation (A) surrounding former implanted Dacron tube graft (B) and aortic reconstruction after graft removal and reconstruction with deep femoral vein (C)
Abbreviations
BCG Bacille Calmette–Guérin
NMIBC Non-muscle-invasive bladder cancer
TURBT Transurethral resection of bladder tumors
CT Computed tomography
AFB Acid-fast bacilli
PCR Polymerase-chain-reaction
PZA Pyrazinamide
INH Isoniazid
RFP Rifampicin
EB Ethambutol
PAU Penetrating aortic ulcer
MRI Magnetic resonance imaging
Acknowledgements
We acknowledge support from the German Research Foundation (DFG) and the Open Access Publication Fund of Charité–Universitätsmedizin Berlin.
Authors' contributions
The idea and initial findings of this seldomly occurring disease were made by JPF. During writing and revising this paper by MB, SK, SO, MS, JPF and AG where involved in constant discussions and improvements of manuscript. All relevant surgeries were performed by JPF or AG. For visual support MR created images that are used. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL.
Availability of data and materials
The data collection was done by reviewing the available literature and electronic health records at the Charité Universitätsmedizin Berlin. Relevant data was collected in Microsoft Excel and analysed descriptively. The data is stored on the Charité—server and, in order to avoid a violation of access rights, the data is encrypted using a password only known to the study physicians. The data that support the findings of this study is available, but restrictions apply to the availability of the data, which was used under license for the current study, and so is not publicly available. Data is however available from the authors upon reasonable request.
Declarations
Ethics approval and consent to participate
The need for approval was waived by our institutional review board.
Consent for publication
Written informed consent for publication of their clinical details and/or clinical images was obtained from all patients. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33731071 | 19,110,873 | 2021-03-17 |
What was the outcome of reaction 'Vascular graft infection'? | Aortic aneurysm and aortic graft infection related to Mycobacterium bovis after intravesical Bacille Calmette-Guérin therapy-a case series.
BACKGROUND
So called "mycotic" aortic aneurysms account for only 0.7 to 1.3% of all aortic aneurysms and are commonly caused by Staphylococcus aureus and Salmonella species. Bacillus Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis, is part of the therapy of non-muscle-invasive bladder cancer (NMIBC).
METHODS
We report a case series of three patients with a mycobacterial graft infection related to BCG after surgical treatment of a presumed mycotic aortic aneurysm as an extremely rare complication after NMIBC treatment. All three patients developed aortic aneurysm after BCG instillation and subsequent mycobacterial graft infection.
CONCLUSIONS
Diagnosis requires a high degree of suspicion because of its nonspecific symptoms and imaging. The pathogen is not detected by standard microbiological testing. Treatment includes triple antimycobacterial therapy and radical surgical interventions. Graft preservation may be considered if no anastomosis is involved.
Background
Infectious or so called ‘mycotic’ aortic aneurysms represent merely 0.7 to 1.3% of all aortic aneurysms. Nevertheless, they constitute a life-threatening vascular complication associated with in-hospital mortality rates of up to 36% [1, 2]. Mycotic aortic aneurysms are usually caused by Staphylococcus aureus, followed by Salmonella spp., Streptococcus spp. and Escherichia coli. Mycotic aneurysms caused by mycobacterial infections are rare. Up to now, 44 cases in 42 case reports of mycotic aortic aneurysms caused by mycobacterial infection affecting the thoracoabdominal aorta after intravesical instillation of Bacillus Calmette–Guérin (BCG) have been reported (see Additional file 1: Table S1).
Intravesical BCG applications are standard of care for treating non-muscle-invasive bladder cancer (NMIBC) [3]. The live attenuated strain of Mycobacterium bovis is administered to patients with NMIBC after transurethral resection of bladder tumors (TURBT) to avert recurrence and reduce progression rates of intermediate- and high-risk tumors [4]. The incidence of BCG-related systemic complications including spondylodiscitis, psoas abscess or vascular complications remains unclear. In this case series, we report three cases of mycobacterial aortic graft infection related to intravesical application of BCG for NMIBC. This represents the largest case series in the current literature. The particular challenges for the diagnosis and treatment of this infrequent complication are discussed in this report.
Case presentations
Patient A
In November 2010, a 63-year-old man was referred to our clinic because of persistent weakness, fever, night sweat and unspecific abdominal pain lasting for two weeks. Three months before this episode, the patient had undergone emergency surgery for a ruptured infrarenal abdominal aortic aneurysm, which was treated with implantation of an aortobiiliac graft at another clinic. In 2008, the patient had been treated for NMIBC by transurethral resection and had received three cycles of intravesical BCG instillations (see Table 1). At the time of presentation, clinical examination and blood tests were unremarkable for inflammation except for a temperature of 37.6 °C. Ultrasound revealed a retroperitoneal fluid collection. Computed tomography (CT) demonstrated an extensive low-density collection surrounding the aortic prosthesis. The retroperitoneal mass was surgically removed and tissue samples were collected for histologic and microbiological studies. A specimen of the necrotic mass indicated chronic inflammation but tested negative for acid-fast bacilli (AFB) in Ziehl–Neelsen stain (Artisan™ Acid-Fast Bacillus (AFB) Stain Kit, Agilent, Santa Clara, United States). As no evidence for mycobacterial infection was found, the patient was discharged home in good condition, without antitubercular medication. Another two years later in August 2012, he presented again to our clinic with fever (40.4 °C), elevated white blood cell count (17.92/nl) and increased C-reactive protein (14.4 mg/l). CT scan revealed recurrence of a large mass in the retroperitoneum (Fig. 1). The patient underwent CT-guided aspiration. A drain was placed and specimens were sent to the microbiological laboratory. Microscopic examination showed necrotizing granulomatous inflammation with multinucleated giant cells. Direct Polymerase-chain-reaction (PCR, cobas® 6800 MTB Test, Roche, Rotkreuz, Switzerland) tested positive for Mycobacterium tuberculosis complex. Growth of Mycobacterium bovis in solid (BBL Stonebrink TB Medium + PACT + BBL Löwenstein-Jensen; Becton Dickinson, Rungis, France) and liquid culture (MGIT BBL; Becton Dickinson, Rungis, France) confirmed the suspected diagnosis. Antitubercular therapy with Isoniazid (INH), Rifampicin (RFP) and Ethambutol (EB) was started and the fluid collection was removed surgically. Intraoperatively, a partial affection of the left leg of the bifurcated graft by the necrotic mass was detected. After extensive debridement, vacuum assisted wound therapy was initiated. The possibility of an aortic reconstruction using autologous deep femoral vein or cryo-preserved homograft was evaluated but declined by the patient. After four weeks of negative pressure wound therapy, the wound could be closed in secondary intention. CT- scan showed no signs of persistent graft infection or retroperitoneal abscess. The patient was discharged in good condition. The triple antitubercular treatment was continued for six month and reduced to RFH and INH for another six months. As the patient remained free of symptoms, and CT scan was unremarkable, antitubercular therapy was subsequently terminated. After a follow-up of 84 months, the patient is in excellent condition and there is no CT- morphologic sign of recurrence of retroperitoneal abscess or inflammation of vascular graft.Table 1 Patient characteristics
Preliminary diagnoses Preliminary surgical procedures
Patient A
NMIBC in 2008 Aortobiiliac prosthesis in 2010
Ruptured aortic aneurysm in 2010
Chronic obstructive pulmonary disease
Disc prolaps L5/L6
Renal cysts
Patient B
NMIBC in 2014 None
Disc prolaps L2/L3 and L3/L4
Patient C
NMIBC in 2008 Aortocoronary bypass operation in 2011
Coronary artery disease Inguinal hernia repair
Cardial arrhythmia type II Wenckebach Dacron tube graft in 2015
Arterial hypertension
Hyperlipidemia
NMIBC Non-muscle-invasive bladder cancer
Fig. 1 CT- reconstruction showing massive retroperitoneal fluid mass affecting left branch of aortobiiliac graft
Patient B
In January 2018, a 78-year-old man presented with acute abdominal pain after a six-week history of chronic back pain. CT scan revealed a small-sized saccular aneurysmatic formation suspicious for a penetrating aortic ulcer (PAU) with contained rupture in the infrarenal aorta. Bone lesions in the vertebral bodies L2/L3 were highly suspicious for concomitant spondylodiscitis. The PAU was too small in size and anatomically too remote to represent a likely cause. Retrospectively, CT scan from 2014 did not show an aortic or vertebral pathology. The patient’s medical history was significant for NMIBC treated with TURBT and multiple intravesical BCG applications in 2014 (Table 1). The patient was hemodynamically stable and showed no notable physical examination findings. Except for increased C-reactive protein (25.1 mg/l), laboratory parameters were within normal limits. Because of close proximity of the PAU to the renal arteries resulting in a short neck, endovascular treatment was rejected. Immediate aortic reconstruction was performed by implantation of a rifampicin-soaked Dacron tube graft. Pathological examination and microbiological testing showed no evidence of mycobacterial infection or other pathogens in intraoperative specimens of the infrarenal aorta. The patient had an uneventful recovery and was discharged after two weeks. After four months of persisting lower back pain, biopsy extraction and spondylodesis of the concomitant spondylodiscitis was performed. The microbiological analysis tested negative for AFB in Ziehl–Neelsen stain but the growth of Mycobacterium bovis in solid and liquid culture confirmed the diagnosis of mycobacterial infection. Antitubercular treatment consisting of RFP, INH, and EB was administered. One year later, follow-up CT scan revealed dislocation of the former implanted spondylodesis which was surgically removed and replaced. Intraoperative samples showed no evidence of persisting mycobacterial infection with acid fast medium culture and PCR. The patient was discharged after eight days. Antitubercular triple therapy was continued for another six months. During follow-up of 20 months, the patient presented free of symptoms. CT scan showed a shrinking psoas abscess. Three months later, the patient presented to the emergency room with increasing left lower abdominal pain. CT examination showed a false aneurysm near the proximal anastomosis of the Dacron tube graft and a retroperitoneal periprosthetic fluid collection (Fig. 2), indicating an imminent rupture. Graft explantation and replacement with homograft was performed. Intraoperative sample material did not show any evidence of Mycobacterium bovis nor other pathogens. Due to the earlier confirmation of BCG- related graft infection, the anti-mycobacterial therapy was continued for another 12 months with Doxycyclin, RFP and INH. After an uncomplicated course, the patient was discharged to a rehabilitation center two weeks after surgery. Follow-up imaging was performed five months later revealing no residual fluid collection. The patient remained in good clinical condition without any signs of re-infection.Fig. 2 Progress of periprosthetic fluid mass highly suspicious for mycobacterial graft infection and anastomotic pseudoaneurysm of the former implanted Dacron tube graft
Patient C
In December 2017, a 79-year-old man presented as an outpatient to our clinic with night sweats and persisting weakness after treatment of a contained rupture of an infrarenal PAU with implantation of a Dacron tube graft at an external institution in 2015. Ultrasound examination and CT showed periprosthetic fluid collection. The patient’s medical history included NIMBC diagnosed in 2008 and treated with TURBT and a total of 36 intravesical BCG instillations (Table 1). Laboratory parameters were within normal limits (CRP: 4.7 mg/l; white blood cell count: 4.08/nl). Samples collected by CT-guided aspiration tested positive for AFB with Auramine-rhodamine stain (Wescor Aerospray TB 7722, ELITech Biomedical Systems, Logan, Utah, USA). PCR of the aspirated fluid was positive for Mycobacterium tuberculosis complex and incubation in solid and liquid culture showed growth of Mycobacterium bovis. Antimycobacterial treatment was initiated. Because of a critical interaction between Ranolexin (long-term medication), Rifampicin was replaced by Rifabutin in combination with INH and EB. After a follow-up period of six months, control CT scan revealed a false aneurysm in the infrarenal region near the proximal anastomosis of the Dacron tube graft and a progression of the fluid collection in the psoas muscle (Fig. 3). The Dacron tube graft was completely removed and replaced by deep femoral vein (Fig. S1 in Additional file 2). Despite a weak positive PCR for Mycobacterium complex, culture incubation showed no growth of Mycobacterium bovis. This was considered to be the result of an effective perioperative antimycotic therapy. After an uncomplicated postoperative course, the patient was discharged to an external rehabilitation center after 25 days. During routine outpatient follow-up 12 months after surgery, the patient was in good general condition. The CT scan showed no persistent prosthetic infection.Fig. 3 Anastomotic pseudoaneurysm and progression of both periprosthetic fluid mass and fluid collection in left psoas muscle
Discussion and conclusion
Intravesical instillation of BCG is widely used for the treatment of NMIBC. First used as a vaccine against tuberculosis, intravesical instillation of the live attenuated strain of Mycobacterium bovis has become standard care for NMIBC. The exact mechanism of its antitumor efficacy is not clarified yet. Although BCG instillation is generally considered safe, severe side effects have been reported. The incidence of mycotic aortic aneurysms caused by disseminated tuberculosis after BCG instillation remains unclear. Three different mechanisms are described that could lead to a systemic dissemination of and vascular affection by Mycobacterium bovis: (1) hematogenous dissemination followed by direct intimal colonization favored by preexisting atherosclerosis, (2) metastatic implantation through the vasa vasorum, or (3) continuous dissemination of adjacent infected tissue such as contiguous lymphadenitis or psoas abscess [5].
We report three cases of graft infection after surgical treatment of suspected mycotic aortic aneurysms as an extremely rare complication after intravesical BCG application. Our therapy was based on two pillars: drug-based antitubercular therapy as well as the individually adapted surgical treatment consisting of radical surgical debridement, vacuum therapy, drainage and in case of anastomotic leakage, graft explantation and aortic reconstruction using deep femoral vein or homograft.
So far, 44 cases of mycotic aortic aneurysms caused by disseminated mycobacterial infection have been published. Foreign material was implanted in 28 patients [6–32]. Postoperative graft infection was diagnosed in 10 out of 28 cases (35.7%) [6, 12, 17, 19–22, 32–34]. Of these 10 patients, six were discharged resulting in a hospital survival rate of 60%. A long-term follow-up of more than 12 months is reported by only one author [33]. Treatment included medical therapy alone (n = 1) [6], invasive therapy including either CT-guided drainage or surgical debridement with graft preservation (n = 2) [12, 19] and radical surgical therapy with partial (n = 1) [17] or complete graft explantation (n = 6) [20–22, 32–34]. Antitubercular medication was administered in 8 out of 10 cases [6, 12, 17, 19–22, 33]. Apart from one case [33], graft explantation was performed combined with aortic stump ligation and implantation of an extraanatomic axillofemoral bypass. Similar to our patients B and C, Santbergen et al. (33) focused on aortic reconstruction with autologous replacement material with an excellent postoperative result. Eighteen months after completion of the antimycobacterial medication, there was no clinical and morphological evidence of a persistent infection.
Diagnosis of mycotic aneurysms or vascular complications after intravesical BCG application is exceptionally challenging and a high level of suspicion is required. A thorough medical history with attention to past NMIBC and related BCG instillations is essential when a mycotic aneurysm or graft infection is suspected. Unspecific symptoms like night sweats, weight loss, malaise and persisting fever combined with an unremarkable clinical examination can draw suspicion to a chronic disease like disseminated BCG- infection. After obtaining sample material from affected regions, e.g. vertebral disc, fluid collection in psoas muscle, aortic wall, paraaortic lymph nodes, pathological and microbiological examination is required. Suspected diagnosis can only be confirmed by PCR and culture specific for mycobacterial pathogens. Standard microbiological testing is often negative.
All of our three patients had received BCG therapy several years before the primary intervention. Because of the slow replication rate of mycobacteria, symptomatic vascular disease will often occur with a long latency after BCG instillation. Delay in diagnosis will lead to a delay in starting antimycobacterial treatment, which may result in an increased risk of rupture and dissemination, further limiting surgical options.
Currently, no consensus guideline for optimal medical treatment options of graft infection secondary to BCG instillation is available. Given its rareness, a case by case decision has to be made. Antitubercular therapy should be administered immediately after confirmed diagnosis and should be continued for at least six to 12 months. This medical therapy should be supplemented by surgical treatment. Our first case was managed successfully without graft explantation, with repeated radical surgical debridement and vacuum therapy alone, as no anastomosis was involved in this case. In our two following cases, anastomotic aneurysm indicating imminent rupture was discovered during follow-up. In these cases, we decided to completely remove the infected graft and to reconstruct the aorta with deep femoral vein or homograft, respectively.
In conclusion, this three-case series represents our experience with this rare condition. We strongly suggest that in cases of aortic aneurysm or aortic graft infection in patients with previous BCG instillation, surgeons should be suspicious of BCG- infection and mycotic aneurysm and to initiate specific testing including PCR and culture for mycobacterial infection. In cases with involvement of any graft anastomosis, complete graft removal and replacement with biological material should be considered. In cases with no involvement of an anastomosis, graft preservation could be attempted. Adjuvant antimycobacterial treatment is essential and should be initiated as soon as diagnosis is confirmed.
Supplementary Information
Additional file 1: Table S1. Publications reporting aortic aneurysm secondary to intravesical application of Bacillus Calmette Guérin
Additional file 2: Fig. S1. Intraoperative situs showing exit of purulent granular material from the aneurysmatic formation (A) surrounding former implanted Dacron tube graft (B) and aortic reconstruction after graft removal and reconstruction with deep femoral vein (C)
Abbreviations
BCG Bacille Calmette–Guérin
NMIBC Non-muscle-invasive bladder cancer
TURBT Transurethral resection of bladder tumors
CT Computed tomography
AFB Acid-fast bacilli
PCR Polymerase-chain-reaction
PZA Pyrazinamide
INH Isoniazid
RFP Rifampicin
EB Ethambutol
PAU Penetrating aortic ulcer
MRI Magnetic resonance imaging
Acknowledgements
We acknowledge support from the German Research Foundation (DFG) and the Open Access Publication Fund of Charité–Universitätsmedizin Berlin.
Authors' contributions
The idea and initial findings of this seldomly occurring disease were made by JPF. During writing and revising this paper by MB, SK, SO, MS, JPF and AG where involved in constant discussions and improvements of manuscript. All relevant surgeries were performed by JPF or AG. For visual support MR created images that are used. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL.
Availability of data and materials
The data collection was done by reviewing the available literature and electronic health records at the Charité Universitätsmedizin Berlin. Relevant data was collected in Microsoft Excel and analysed descriptively. The data is stored on the Charité—server and, in order to avoid a violation of access rights, the data is encrypted using a password only known to the study physicians. The data that support the findings of this study is available, but restrictions apply to the availability of the data, which was used under license for the current study, and so is not publicly available. Data is however available from the authors upon reasonable request.
Declarations
Ethics approval and consent to participate
The need for approval was waived by our institutional review board.
Consent for publication
Written informed consent for publication of their clinical details and/or clinical images was obtained from all patients. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33731071 | 19,110,873 | 2021-03-17 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease progression'. | Non-secretory multiple myeloma with unusual TFG-ALK fusion showed dramatic response to ALK inhibition.
Non-secretory multiple myeloma (NSMM) constitutes a distinct entity of multiple myeloma characterized by the absence of detectable monoclonal protein and rarely an absence of free light chains in the serum and urine. Given its rarity, the genomic landscape, clinical course, and prognosis of NSSM are not well characterized. Here, we report a case of a patient with relapsed and refractory NSMM with brain metastasis harboring a TFG-ALK fusion showing a dramatic and durable (over two years) response to commercially available anaplastic lymphoma kinase (ALK) inhibitors. The case emphasizes the beneficial role of molecular profiling in this target-poor disease.
Introduction
Non–secretory multiple myeloma (NSMM) is a rare variant of multiple myeloma (MM) and constitutes 3% of total MM cases1. The underlying pathology of NSMM is reported to be either failure of malignant plasma cells to form immunoglobulin (non-producer) or a failure to secrete heavy or light chains (non-secretor)2. Pathogenesis in MM is governed by the acquisition of multiple somatic sub-clonal secondary genomic events, including copy number abnormalities, secondary translocations, acquired genomic and epigenetic mutations, and DNA hypomethylation3,4. Subclonal events include deletion of RB1, TP53, PTEN, amplification of chromosome 1q, activating point mutations in KRAS, NRAS, and BRAF, though they can be clonal and may occur at any point in the disease course5,6, A recent study by Morgan et al.6, has shown low frequency (2.7%, n = 958) of non-immunoglobulin fusions in MM patients. These fusion genes were present in smoldering MM, newly diagnosed MM, and relapsed MM patients, indicating these fusion genes occur early in the disease process. Fifty-four percent of these fusion genes were in-frame fusions, potentially resulting in functional oncogenic fusion proteins. Most of these in-frame tyrosine kinase fusions were sub-clonal and therefore, secondary events. The exception is the EML4-ALK fusion gene, which was clonal and thus, therapeutically targetable with anaplastic lymphoma kinase (ALK) inhibitors. ALK fusion partners are identified as driver events in nearly twenty different human malignancies, including non-small cell lung cancers (NSCLC), anaplastic non-Hodgkin lymphoma, diffuse large B cell lymphoma, renal carcinoma, thyroid cancers, breast cancer, ovarian carcinoma, leukemia, and MM6–8. These fusions lead to constitutive activation of ALK kinase which subsequently induces the activation of downstream pathways, including PI3K/protein kinase B and the extracellular signal-regulated kinase (ERK)/MAPK pathway9.
In the rapidly evolving field of MM, we have seen a remarkable reduction in mortality rates in clinical trials and population-based studies. Unfortunately, patients with NSMM are frequently excluded from clinical trials. Furthermore, molecular studies in NSMM are lacking. Here, we report a case of patient with NSMM harboring a trafficking from ER to Golgi regulator gene (TFG, formerly TRK fused gene) and ALK fusion (TFG-ALK fusion), which demonstrated a dramatic response to ALK inhibition.
Results
Case
A 49-year-old Caucasian gentleman initially underwent surgical resection of an 8.7 cm transmural jejunal mass. Pathology was consistent with a kappa-restricted plasmacytoma with multiple negative adjacent lymph nodes. He had a normal renal function, calcium, complete blood count, serum and urine immunofixation electrophoresis as follows: serum-free light chains, free Kappa 14.7 mg/L (Normal value: 3.3–19.4 mg/L), free Lambda 14.5 mg/L (Normal value: 3.3–19.4 mg/L) and Kappa/Lambda ratio 1.01 (Normal value: 0.26–1.65). The skeletal survey and positron emission tomography (PET)/CT did not show lytic lesions. Bone marrow biopsy was negative for clonal plasma cells. The patient was closely followed by imaging surveillance for an isolated plasmacytoma.
Three years later, he presented with right cervical lymphadenopathy and a new nasopharyngeal mass. Lymph node biopsy was consistent with kappa-restricted plasmacytoma. Repeat paraproteinemia workup was consistent with NSMM. Re-staging PET/CT showed multiple abnormal radiotracer uptake areas, including the nasopharyngeal mass (5.4 × 4.9 × 4.0 cm, SUV 18.4), necrotic right cervical lymph node, a focal area in the jejunum, right adrenal gland, and soft-tissue chest nodules. He was treated with KRd (carfilzomib, lenalidomide, dexamethasone). His tumor initially responded to the KRd regimen with a complete metabolic response on imaging, but after six cycles of KRd, the tumor recurred with a small bowel mass with an SUV of 14.1 on PET/CT. Unfortunately, he continued to progress despite changing therapies including, KCd (carfilzomib, cyclophosphamide, dexamethasone), local radiation to the jejunal mass, and the DPd regimen (daratumumab, pomalidomide, dexamethasone). Within two months after starting the DPd regimen, he developed diffuse hepatic lesions and a loculated pelvic mass (Supplementary Fig. 1A, B). Liver biopsy showed kappa restricted plasma cells, consistent with plasmacytoma (Supplementary Fig. 2A–D). These plasma cells are characterized by increased nuclear to cytoplasm ratio, variable dispersed chromatin, prominent nucleoli, and modest eosinophilic cytoplasm. Broad immunohistochemistry panel was performed including CD3, CD5, CD19,CD20, CD33, CD34, LCA, CD56, CD68, CD79a, CD117, CD138 CAM5.2, myeloperoxidase, pankeratin, Cyclin D1, IgA, IgD, IgG, IgM, lysozyme, MUM-1, PAX5, ALK-1, HHV8, EBV, and kappa and lambda. The neoplastic plasma cells showed a diffuse proliferation of CD138+ plasma cells. In situ hybridization for kappa and lambda light chains demonstrates a kappa restricted plasma cell population. CD19 and CD20 were negative on neoplastic plasma cells. CD43, LCA, and CD117 were partially positive. Additional testing including BRAF mutation by PCR and ALK-1 stain were negative. Multiple pathology consultations were obtained at different institutes, and the consensus opinion was that findings were consistent with plasmacytoma. Fluorescent in-situ hybridization (FISH) showed 17p13.1 and trisomy 7 in 63% and 60% plasma cells, respectively. The patient received two cycles of salvage chemotherapy with VPD-PACE (bortezomib, pomalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide) with complete metabolic response followed by autologous stem cell transplant (ASCT). Post-ASCT, he started maintenance therapy with the VPd regimen (bortezomib, pomalidomide, and dexamethasone). However, within six months, he developed multiple new foci of PET FDG uptake involving the thoracic spine, mediastinum, and the abdomen.
After obtaining informed consent, we obtained a liver biopsy and collected peripheral blood for a commercially available CLIA certified genomic assay. Whole-genome sequencing (WGS) and RNA sequencing were performed using the commercially available NantHealth platform. A total of 591 somatic variants were identified in this patient’s tumor, including 147 non-synonymous variants, for an estimated exonic mutation rate of 5.8 mutations per megabase (Mb), suggesting a low tumor mutation burden (TMB). Among the somatic variants identified, three variants were considered to be pathogenic (1 nonsense mutation in MYO6 and two frame-shift mutations in TP53 and TNFAIP3). Two variants were considered likely pathogenic (HGF and GRID1), both of which were missense mutations. Five hundred forty-nine genes were considered benign or likely benign, with 37 variants currently of unknown significance. Details of pathogenic alterations are detailed in Table 1. No actionable mutations were identified based on whole-genome sequencing. RNA sequencing to detect the presence of possible fusions between two transcripts (with one of the transcripts belonging to one of 74 genes commonly found in oncogenic fusions) was assessed. Reportable fusions must both be classified as functional and have greater than eight reads supporting the fusion junction was considered significant. Based on this analysis, one fusion transcript was identified: TFG-ALK, with protein description as t(3;2)(TFG:p.M1_N138; ALK:p.V1058_*1621), and exon composition as TFG(e1-4) + ALK(e20-29) (Table 1). The case was presented in Molecular Tumor Board and ALK inhibitor therapy was discussed.Table 1 Genomic characteristics of TFG-ALK fusion and pathologic gene signature of liver biopsy.
Fusion TFG-ALK
Protein discription (3;2) (TFGp.M1_n138; ALK:p.V1058_*1621)
Exon composition TFG(e1-4) + ALK(e20-29)
TFG RNA expression 62.2 TPM*
ALK RNA expression 13.0 TPM*
TFG-ALK Fusion Support 154 reads
Gene Pathogenicity Mutation Type DNA VAF^ (%) RNA VAF^ (%)
TP53 p.H178Tfs*69 Pathogenic Frameshift 45.0 36.4
TNFAIP3 p.C627Ffs*44 Pathogenic Frameshift 25.0 1.9
MYO6 p.E953* Pathogenic Nonsense 28.2 11.1
HGF p. G674D Likely Pathogenic Missense 37.6 1.4
GRID1 p.S556Y Likely Pathogenic Missense 27.5 0.0
*TPM transcripts per kilobase Million, ^VAF Varient Allele Frequency.
Since this particular TFG-ALK t(3;2) fusion had structural similarity to other well-known ALK fusion variants, it was expected to be targetable by an ALK inhibitor. The patient was initiated on compassionate treatment with the second-generation ALK inhibitor, alectinib 600 mg twice daily. Repeat PET/CT imaging after two months showed resolution of the thoracic lesion and abdominal lymph nodes (Fig. 1). After two months on alectinib, the patient did not have access to further treatment and unfortunately demonstrated relapsed disease in the brain involving multiple innumerable diffuse enhancing lesions with surrounding vasogenic edema involving the right frontal lobe and bilateral cerebellar predominance (Fig. 2). Cerebrospinal fluid (CSF) analysis showed evidence of plasmablasts (not seen on his previous CSF analysis) (Supplementary Fig. 3). He was treated with whole-brain radiation therapy, intrathecal methotrexate, and started on lorlatinib, a 3rd generation ALK inhibitor at 100 mg orally daily. At the time of writing this report, the patient has been maintained for >2 years on lorlatinib. His brain MRI and PET/CT are negative for recurrence (Figs. 1 and 2), demonstrating a durable response to targeted ALK inhibition surpassing conventional systemic myeloma therapy including autologous stem cell transplantation.Fig. 1 PET Scan results.
A Before initiation of Alectinib. Foci of increased uptake in a mediastinal lymph node (max SUV 6.3), retrocaval lymph node (max SUV 10.6), right T3/T4 intervertebral foramen (max SUV 14) on PET-CT. B Complete response after 2 months of alectinib. Complete resolution of prior noted upper thoracic spine lesion and upper abdominal pericaval nodule.
Fig. 2 MRI Brain before and after Loralatinib treatment.
A, B, C MRI of the brain before starting Lorlatinib (pre-treatment) showing innumerable diffuse enhancing lesions with surrounding vasogenic edema, with a right frontal lobe and bilateral cerebellar predominance. D, E, F Treatment response to lorlatinib with markedly decrease in size and number of brain metastasis and markedly improved cerebral edema.
Discussion
This is a unique case demonstrating significant clinical response using commercially available ALK inhibitors in a TFG-ALK fusion in relapsed/refractory NSMM. The ALK gene encodes the ALK tyrosine-kinase protein, a receptor tyrosine kinase, known to have vital roles in normal physiologic processes, including the transmission of extracellular signals implicated in proliferation, differentiation, and survival (Fig. 3). Plasma cell neoplasms are distinct hematologic neoplasms where the diagnosis is based on morphology, immunohistochemistry, FISH, and conventional karyotyping. Case studies have previously reported ALK fusion partners EML4-ALK and CLTC-ALK in these patients6,10.Fig. 3 TFG-ALK fusion and downstream pathway activation.
TFG-ALK fusion product is displayed as a t(3;2) fusion at exon 4 of TFG (blue) and exon 20 of ALK (red). The point of the fusion is indicated by the yellow triangle. The druggable ALK kinase domain resides downstream of ALK exon 20. The upregulated ALK pathway by means of fusion product is implicated in many oncogenic cellular pathways including JAK/STAT, PI3K/mTOR, and RAS/RAF.
The TFG was previously identified as a fusion partner for ALK in cases of Anaplastic large cell lymphoma (ALCL) t(2;3) (p23;q21). The ALK breakpoint in these translocations was the same as in the classical t(2:5). The chimeric protein contains cytoplasmic domain ALK and coiled-coil domain of TFG. The fusion protein was thus able to dimerize, resulting in constitutive kinase activity11. Alectinib is currently Food and Drug Administration (FDA) approved for ALK-positive metastatic NSCLC. It is an orally bioavailable TKI that inhibits ALK and RET proteins by preventing their phosphorylation. The inhibition of activation of ALK impairs downstream signaling of cell proliferation12. Lorlatinib is approved in NSCLC carrying ALK fusion and has shown superior intracranial activity even in patients treated with other ALK inhibitors13. Therefore, it was an ideal choice for our patient after CNS metastasis development.
Our case highlights that a small percentage of patients with plasma cell neoplasms carries ALK fusion and may benefit from ALK inhibition. The diagnosis of ALK+ NSMM versus large B cell lymphoma is challenging because of its rarity, unique morphologic characteristics, and unusual immunophenotypic features, which significantly overlap with other hematologic and nonhematologic neoplasms. Little is known about the clinical behavior of NSMM. We acknowledge that the clinical behavior of NSMM may resemble plasmablastic lymphoma. Due to these concerns, we have obtained multiple opinions on pathology and there is a uniform consensus on the diagnosis of plasmacytomas (NSMM). In addition, ALK-1 stain and EBV stain were absent on plasmacytomas. We believe 17p deletion, which is considered a high-risk mutation in these patients, is most likely the cause of aggressive clinical behavior in our case. This case demonstrates the potential role of next-generation sequencing (NGS) in NSMM, a disease where NGS is not currently standard of care and morphological or immunophenotypical features define diagnosis and influence treatment decisions. NGS may identify unrecognized targetable oncogenic drivers such as ALK-fusions. Detection of these gene alterations not only improves our understanding of disease pathogenesis but may also be used to exploit the therapeutic vulnerabilities of these tumors. The therapeutic success seen in this case emphasizes the need to identify such molecular targets and unique driver alterations, especially in the relapsed setting with a disease that was refractory to traditional treatment options. Our knowledge of mechanisms involved in MM, especially NSMM oncogenesis, is incomplete and further molecular studies are warranted to better understand biological underpinnings that may improve outcomes in these patients. After failing more than five lines of systemic treatment, our patient is currently in clinical and radiographic remission with ALK inhibitor over two years. Our case is a successful example of utilizing NGS-based mutational profiling and incorporating unconventional targeted agents into clinical practice in a rare disease.
Methods
The patient provided written informed consent for carrying out Next-Generation Sequencing and publication of case reports using CLIA certified commercially available Nant platform, as previously described14. The analysis is also described in the Nant GPS report. Briefly, DNA libraries were prepared using the KAPA Hyper prep kit and sequencing on Illumina sequencing platform. DNA sequencing data was aligned to Genome Reference Consortium Human Build 37 using Burrows-Wheeler Aligner15. The germline, somatic variant detection, insertion, and deletions were carried out using the NantOmics Contraster pipeline16–18. RNA-seq libraries were prepared using KAPA Stranded RNA-Seq with RiboErase kit and sequenced on the Illumina Sequencing platform. RNA sequencing data was aligned used bowtie219. RNA transcript expression was assessed by RSEM20. RNA fusions are detected using transcriptome-aligned RNA sequencing data. When there is evidence of gene-fusion using clusters of spanning reads between two transcripts, the Nant team performs de novo assembly on all sequencing data to detect the precise location of fusion transcript. Only fusion with open reading frames that extend to the downstream partner’s stop codon is reported.
The patient was treated with lorlatinib and alectinib within an individual program after informed consent. IRB approval (St. Luke’s Hospital, Kansas City, MO) was waived by the IRB.
Imaging
PET-CT and MRI imaging were obtained as standard of care.
Reporting summary
Further information on research design is available in the Nature Research Reporting Summary linked to this article.
Supplementary information
Supplementary Information
Reporting Summary
Supplementary information
The online version contains supplementary material available at 10.1038/s41525-021-00186-9.
Acknowledgements
We would like to thank Roche and Pfizer for their support in providing compassionate use of medication.
Author contributions
A.M., J.S., S.R. conceived the idea and design the study and drafted the initial manuscript and supervision of the work. S.A., P.R. contributed equally in data gathering and manuscript writing. B.G. provided pharmacological details on the patient. D.N. and S.N. provided details on pathology. T.C., S.L., A.S., A.P., T.K., M.L. reviewed the draft and provided meaningful addition to the manuscript. A.M. and S.R. supervised the project. All authors again approved of the final changes before submission.
Data availability
The authors declare that data supporting the findings of this study are available within the paper. RAW data files Including FASTQ and BAM files are the property of commercial platform NANTOMICS and authors do not have access to these files. The de-identified HIPAA compliant clinical Genomics report of the current study is available.
Competing interests
The authors declare no competing financial or non-financial interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BORTEZOMIB, DEXAMETHASONE, POMALIDOMIDE | DrugsGivenReaction | CC BY | 33731690 | 20,634,941 | 2021-03-17 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metastases to central nervous system'. | Non-secretory multiple myeloma with unusual TFG-ALK fusion showed dramatic response to ALK inhibition.
Non-secretory multiple myeloma (NSMM) constitutes a distinct entity of multiple myeloma characterized by the absence of detectable monoclonal protein and rarely an absence of free light chains in the serum and urine. Given its rarity, the genomic landscape, clinical course, and prognosis of NSSM are not well characterized. Here, we report a case of a patient with relapsed and refractory NSMM with brain metastasis harboring a TFG-ALK fusion showing a dramatic and durable (over two years) response to commercially available anaplastic lymphoma kinase (ALK) inhibitors. The case emphasizes the beneficial role of molecular profiling in this target-poor disease.
Introduction
Non–secretory multiple myeloma (NSMM) is a rare variant of multiple myeloma (MM) and constitutes 3% of total MM cases1. The underlying pathology of NSMM is reported to be either failure of malignant plasma cells to form immunoglobulin (non-producer) or a failure to secrete heavy or light chains (non-secretor)2. Pathogenesis in MM is governed by the acquisition of multiple somatic sub-clonal secondary genomic events, including copy number abnormalities, secondary translocations, acquired genomic and epigenetic mutations, and DNA hypomethylation3,4. Subclonal events include deletion of RB1, TP53, PTEN, amplification of chromosome 1q, activating point mutations in KRAS, NRAS, and BRAF, though they can be clonal and may occur at any point in the disease course5,6, A recent study by Morgan et al.6, has shown low frequency (2.7%, n = 958) of non-immunoglobulin fusions in MM patients. These fusion genes were present in smoldering MM, newly diagnosed MM, and relapsed MM patients, indicating these fusion genes occur early in the disease process. Fifty-four percent of these fusion genes were in-frame fusions, potentially resulting in functional oncogenic fusion proteins. Most of these in-frame tyrosine kinase fusions were sub-clonal and therefore, secondary events. The exception is the EML4-ALK fusion gene, which was clonal and thus, therapeutically targetable with anaplastic lymphoma kinase (ALK) inhibitors. ALK fusion partners are identified as driver events in nearly twenty different human malignancies, including non-small cell lung cancers (NSCLC), anaplastic non-Hodgkin lymphoma, diffuse large B cell lymphoma, renal carcinoma, thyroid cancers, breast cancer, ovarian carcinoma, leukemia, and MM6–8. These fusions lead to constitutive activation of ALK kinase which subsequently induces the activation of downstream pathways, including PI3K/protein kinase B and the extracellular signal-regulated kinase (ERK)/MAPK pathway9.
In the rapidly evolving field of MM, we have seen a remarkable reduction in mortality rates in clinical trials and population-based studies. Unfortunately, patients with NSMM are frequently excluded from clinical trials. Furthermore, molecular studies in NSMM are lacking. Here, we report a case of patient with NSMM harboring a trafficking from ER to Golgi regulator gene (TFG, formerly TRK fused gene) and ALK fusion (TFG-ALK fusion), which demonstrated a dramatic response to ALK inhibition.
Results
Case
A 49-year-old Caucasian gentleman initially underwent surgical resection of an 8.7 cm transmural jejunal mass. Pathology was consistent with a kappa-restricted plasmacytoma with multiple negative adjacent lymph nodes. He had a normal renal function, calcium, complete blood count, serum and urine immunofixation electrophoresis as follows: serum-free light chains, free Kappa 14.7 mg/L (Normal value: 3.3–19.4 mg/L), free Lambda 14.5 mg/L (Normal value: 3.3–19.4 mg/L) and Kappa/Lambda ratio 1.01 (Normal value: 0.26–1.65). The skeletal survey and positron emission tomography (PET)/CT did not show lytic lesions. Bone marrow biopsy was negative for clonal plasma cells. The patient was closely followed by imaging surveillance for an isolated plasmacytoma.
Three years later, he presented with right cervical lymphadenopathy and a new nasopharyngeal mass. Lymph node biopsy was consistent with kappa-restricted plasmacytoma. Repeat paraproteinemia workup was consistent with NSMM. Re-staging PET/CT showed multiple abnormal radiotracer uptake areas, including the nasopharyngeal mass (5.4 × 4.9 × 4.0 cm, SUV 18.4), necrotic right cervical lymph node, a focal area in the jejunum, right adrenal gland, and soft-tissue chest nodules. He was treated with KRd (carfilzomib, lenalidomide, dexamethasone). His tumor initially responded to the KRd regimen with a complete metabolic response on imaging, but after six cycles of KRd, the tumor recurred with a small bowel mass with an SUV of 14.1 on PET/CT. Unfortunately, he continued to progress despite changing therapies including, KCd (carfilzomib, cyclophosphamide, dexamethasone), local radiation to the jejunal mass, and the DPd regimen (daratumumab, pomalidomide, dexamethasone). Within two months after starting the DPd regimen, he developed diffuse hepatic lesions and a loculated pelvic mass (Supplementary Fig. 1A, B). Liver biopsy showed kappa restricted plasma cells, consistent with plasmacytoma (Supplementary Fig. 2A–D). These plasma cells are characterized by increased nuclear to cytoplasm ratio, variable dispersed chromatin, prominent nucleoli, and modest eosinophilic cytoplasm. Broad immunohistochemistry panel was performed including CD3, CD5, CD19,CD20, CD33, CD34, LCA, CD56, CD68, CD79a, CD117, CD138 CAM5.2, myeloperoxidase, pankeratin, Cyclin D1, IgA, IgD, IgG, IgM, lysozyme, MUM-1, PAX5, ALK-1, HHV8, EBV, and kappa and lambda. The neoplastic plasma cells showed a diffuse proliferation of CD138+ plasma cells. In situ hybridization for kappa and lambda light chains demonstrates a kappa restricted plasma cell population. CD19 and CD20 were negative on neoplastic plasma cells. CD43, LCA, and CD117 were partially positive. Additional testing including BRAF mutation by PCR and ALK-1 stain were negative. Multiple pathology consultations were obtained at different institutes, and the consensus opinion was that findings were consistent with plasmacytoma. Fluorescent in-situ hybridization (FISH) showed 17p13.1 and trisomy 7 in 63% and 60% plasma cells, respectively. The patient received two cycles of salvage chemotherapy with VPD-PACE (bortezomib, pomalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide) with complete metabolic response followed by autologous stem cell transplant (ASCT). Post-ASCT, he started maintenance therapy with the VPd regimen (bortezomib, pomalidomide, and dexamethasone). However, within six months, he developed multiple new foci of PET FDG uptake involving the thoracic spine, mediastinum, and the abdomen.
After obtaining informed consent, we obtained a liver biopsy and collected peripheral blood for a commercially available CLIA certified genomic assay. Whole-genome sequencing (WGS) and RNA sequencing were performed using the commercially available NantHealth platform. A total of 591 somatic variants were identified in this patient’s tumor, including 147 non-synonymous variants, for an estimated exonic mutation rate of 5.8 mutations per megabase (Mb), suggesting a low tumor mutation burden (TMB). Among the somatic variants identified, three variants were considered to be pathogenic (1 nonsense mutation in MYO6 and two frame-shift mutations in TP53 and TNFAIP3). Two variants were considered likely pathogenic (HGF and GRID1), both of which were missense mutations. Five hundred forty-nine genes were considered benign or likely benign, with 37 variants currently of unknown significance. Details of pathogenic alterations are detailed in Table 1. No actionable mutations were identified based on whole-genome sequencing. RNA sequencing to detect the presence of possible fusions between two transcripts (with one of the transcripts belonging to one of 74 genes commonly found in oncogenic fusions) was assessed. Reportable fusions must both be classified as functional and have greater than eight reads supporting the fusion junction was considered significant. Based on this analysis, one fusion transcript was identified: TFG-ALK, with protein description as t(3;2)(TFG:p.M1_N138; ALK:p.V1058_*1621), and exon composition as TFG(e1-4) + ALK(e20-29) (Table 1). The case was presented in Molecular Tumor Board and ALK inhibitor therapy was discussed.Table 1 Genomic characteristics of TFG-ALK fusion and pathologic gene signature of liver biopsy.
Fusion TFG-ALK
Protein discription (3;2) (TFGp.M1_n138; ALK:p.V1058_*1621)
Exon composition TFG(e1-4) + ALK(e20-29)
TFG RNA expression 62.2 TPM*
ALK RNA expression 13.0 TPM*
TFG-ALK Fusion Support 154 reads
Gene Pathogenicity Mutation Type DNA VAF^ (%) RNA VAF^ (%)
TP53 p.H178Tfs*69 Pathogenic Frameshift 45.0 36.4
TNFAIP3 p.C627Ffs*44 Pathogenic Frameshift 25.0 1.9
MYO6 p.E953* Pathogenic Nonsense 28.2 11.1
HGF p. G674D Likely Pathogenic Missense 37.6 1.4
GRID1 p.S556Y Likely Pathogenic Missense 27.5 0.0
*TPM transcripts per kilobase Million, ^VAF Varient Allele Frequency.
Since this particular TFG-ALK t(3;2) fusion had structural similarity to other well-known ALK fusion variants, it was expected to be targetable by an ALK inhibitor. The patient was initiated on compassionate treatment with the second-generation ALK inhibitor, alectinib 600 mg twice daily. Repeat PET/CT imaging after two months showed resolution of the thoracic lesion and abdominal lymph nodes (Fig. 1). After two months on alectinib, the patient did not have access to further treatment and unfortunately demonstrated relapsed disease in the brain involving multiple innumerable diffuse enhancing lesions with surrounding vasogenic edema involving the right frontal lobe and bilateral cerebellar predominance (Fig. 2). Cerebrospinal fluid (CSF) analysis showed evidence of plasmablasts (not seen on his previous CSF analysis) (Supplementary Fig. 3). He was treated with whole-brain radiation therapy, intrathecal methotrexate, and started on lorlatinib, a 3rd generation ALK inhibitor at 100 mg orally daily. At the time of writing this report, the patient has been maintained for >2 years on lorlatinib. His brain MRI and PET/CT are negative for recurrence (Figs. 1 and 2), demonstrating a durable response to targeted ALK inhibition surpassing conventional systemic myeloma therapy including autologous stem cell transplantation.Fig. 1 PET Scan results.
A Before initiation of Alectinib. Foci of increased uptake in a mediastinal lymph node (max SUV 6.3), retrocaval lymph node (max SUV 10.6), right T3/T4 intervertebral foramen (max SUV 14) on PET-CT. B Complete response after 2 months of alectinib. Complete resolution of prior noted upper thoracic spine lesion and upper abdominal pericaval nodule.
Fig. 2 MRI Brain before and after Loralatinib treatment.
A, B, C MRI of the brain before starting Lorlatinib (pre-treatment) showing innumerable diffuse enhancing lesions with surrounding vasogenic edema, with a right frontal lobe and bilateral cerebellar predominance. D, E, F Treatment response to lorlatinib with markedly decrease in size and number of brain metastasis and markedly improved cerebral edema.
Discussion
This is a unique case demonstrating significant clinical response using commercially available ALK inhibitors in a TFG-ALK fusion in relapsed/refractory NSMM. The ALK gene encodes the ALK tyrosine-kinase protein, a receptor tyrosine kinase, known to have vital roles in normal physiologic processes, including the transmission of extracellular signals implicated in proliferation, differentiation, and survival (Fig. 3). Plasma cell neoplasms are distinct hematologic neoplasms where the diagnosis is based on morphology, immunohistochemistry, FISH, and conventional karyotyping. Case studies have previously reported ALK fusion partners EML4-ALK and CLTC-ALK in these patients6,10.Fig. 3 TFG-ALK fusion and downstream pathway activation.
TFG-ALK fusion product is displayed as a t(3;2) fusion at exon 4 of TFG (blue) and exon 20 of ALK (red). The point of the fusion is indicated by the yellow triangle. The druggable ALK kinase domain resides downstream of ALK exon 20. The upregulated ALK pathway by means of fusion product is implicated in many oncogenic cellular pathways including JAK/STAT, PI3K/mTOR, and RAS/RAF.
The TFG was previously identified as a fusion partner for ALK in cases of Anaplastic large cell lymphoma (ALCL) t(2;3) (p23;q21). The ALK breakpoint in these translocations was the same as in the classical t(2:5). The chimeric protein contains cytoplasmic domain ALK and coiled-coil domain of TFG. The fusion protein was thus able to dimerize, resulting in constitutive kinase activity11. Alectinib is currently Food and Drug Administration (FDA) approved for ALK-positive metastatic NSCLC. It is an orally bioavailable TKI that inhibits ALK and RET proteins by preventing their phosphorylation. The inhibition of activation of ALK impairs downstream signaling of cell proliferation12. Lorlatinib is approved in NSCLC carrying ALK fusion and has shown superior intracranial activity even in patients treated with other ALK inhibitors13. Therefore, it was an ideal choice for our patient after CNS metastasis development.
Our case highlights that a small percentage of patients with plasma cell neoplasms carries ALK fusion and may benefit from ALK inhibition. The diagnosis of ALK+ NSMM versus large B cell lymphoma is challenging because of its rarity, unique morphologic characteristics, and unusual immunophenotypic features, which significantly overlap with other hematologic and nonhematologic neoplasms. Little is known about the clinical behavior of NSMM. We acknowledge that the clinical behavior of NSMM may resemble plasmablastic lymphoma. Due to these concerns, we have obtained multiple opinions on pathology and there is a uniform consensus on the diagnosis of plasmacytomas (NSMM). In addition, ALK-1 stain and EBV stain were absent on plasmacytomas. We believe 17p deletion, which is considered a high-risk mutation in these patients, is most likely the cause of aggressive clinical behavior in our case. This case demonstrates the potential role of next-generation sequencing (NGS) in NSMM, a disease where NGS is not currently standard of care and morphological or immunophenotypical features define diagnosis and influence treatment decisions. NGS may identify unrecognized targetable oncogenic drivers such as ALK-fusions. Detection of these gene alterations not only improves our understanding of disease pathogenesis but may also be used to exploit the therapeutic vulnerabilities of these tumors. The therapeutic success seen in this case emphasizes the need to identify such molecular targets and unique driver alterations, especially in the relapsed setting with a disease that was refractory to traditional treatment options. Our knowledge of mechanisms involved in MM, especially NSMM oncogenesis, is incomplete and further molecular studies are warranted to better understand biological underpinnings that may improve outcomes in these patients. After failing more than five lines of systemic treatment, our patient is currently in clinical and radiographic remission with ALK inhibitor over two years. Our case is a successful example of utilizing NGS-based mutational profiling and incorporating unconventional targeted agents into clinical practice in a rare disease.
Methods
The patient provided written informed consent for carrying out Next-Generation Sequencing and publication of case reports using CLIA certified commercially available Nant platform, as previously described14. The analysis is also described in the Nant GPS report. Briefly, DNA libraries were prepared using the KAPA Hyper prep kit and sequencing on Illumina sequencing platform. DNA sequencing data was aligned to Genome Reference Consortium Human Build 37 using Burrows-Wheeler Aligner15. The germline, somatic variant detection, insertion, and deletions were carried out using the NantOmics Contraster pipeline16–18. RNA-seq libraries were prepared using KAPA Stranded RNA-Seq with RiboErase kit and sequenced on the Illumina Sequencing platform. RNA sequencing data was aligned used bowtie219. RNA transcript expression was assessed by RSEM20. RNA fusions are detected using transcriptome-aligned RNA sequencing data. When there is evidence of gene-fusion using clusters of spanning reads between two transcripts, the Nant team performs de novo assembly on all sequencing data to detect the precise location of fusion transcript. Only fusion with open reading frames that extend to the downstream partner’s stop codon is reported.
The patient was treated with lorlatinib and alectinib within an individual program after informed consent. IRB approval (St. Luke’s Hospital, Kansas City, MO) was waived by the IRB.
Imaging
PET-CT and MRI imaging were obtained as standard of care.
Reporting summary
Further information on research design is available in the Nature Research Reporting Summary linked to this article.
Supplementary information
Supplementary Information
Reporting Summary
Supplementary information
The online version contains supplementary material available at 10.1038/s41525-021-00186-9.
Acknowledgements
We would like to thank Roche and Pfizer for their support in providing compassionate use of medication.
Author contributions
A.M., J.S., S.R. conceived the idea and design the study and drafted the initial manuscript and supervision of the work. S.A., P.R. contributed equally in data gathering and manuscript writing. B.G. provided pharmacological details on the patient. D.N. and S.N. provided details on pathology. T.C., S.L., A.S., A.P., T.K., M.L. reviewed the draft and provided meaningful addition to the manuscript. A.M. and S.R. supervised the project. All authors again approved of the final changes before submission.
Data availability
The authors declare that data supporting the findings of this study are available within the paper. RAW data files Including FASTQ and BAM files are the property of commercial platform NANTOMICS and authors do not have access to these files. The de-identified HIPAA compliant clinical Genomics report of the current study is available.
Competing interests
The authors declare no competing financial or non-financial interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CARFILZOMIB, CYCLOPHOSPHAMIDE, DARATUMUMAB, DEXAMETHASONE, LENALIDOMIDE, POMALIDOMIDE | DrugsGivenReaction | CC BY | 33731690 | 19,386,747 | 2021-03-17 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Non-secretory multiple myeloma with unusual TFG-ALK fusion showed dramatic response to ALK inhibition.
Non-secretory multiple myeloma (NSMM) constitutes a distinct entity of multiple myeloma characterized by the absence of detectable monoclonal protein and rarely an absence of free light chains in the serum and urine. Given its rarity, the genomic landscape, clinical course, and prognosis of NSSM are not well characterized. Here, we report a case of a patient with relapsed and refractory NSMM with brain metastasis harboring a TFG-ALK fusion showing a dramatic and durable (over two years) response to commercially available anaplastic lymphoma kinase (ALK) inhibitors. The case emphasizes the beneficial role of molecular profiling in this target-poor disease.
Introduction
Non–secretory multiple myeloma (NSMM) is a rare variant of multiple myeloma (MM) and constitutes 3% of total MM cases1. The underlying pathology of NSMM is reported to be either failure of malignant plasma cells to form immunoglobulin (non-producer) or a failure to secrete heavy or light chains (non-secretor)2. Pathogenesis in MM is governed by the acquisition of multiple somatic sub-clonal secondary genomic events, including copy number abnormalities, secondary translocations, acquired genomic and epigenetic mutations, and DNA hypomethylation3,4. Subclonal events include deletion of RB1, TP53, PTEN, amplification of chromosome 1q, activating point mutations in KRAS, NRAS, and BRAF, though they can be clonal and may occur at any point in the disease course5,6, A recent study by Morgan et al.6, has shown low frequency (2.7%, n = 958) of non-immunoglobulin fusions in MM patients. These fusion genes were present in smoldering MM, newly diagnosed MM, and relapsed MM patients, indicating these fusion genes occur early in the disease process. Fifty-four percent of these fusion genes were in-frame fusions, potentially resulting in functional oncogenic fusion proteins. Most of these in-frame tyrosine kinase fusions were sub-clonal and therefore, secondary events. The exception is the EML4-ALK fusion gene, which was clonal and thus, therapeutically targetable with anaplastic lymphoma kinase (ALK) inhibitors. ALK fusion partners are identified as driver events in nearly twenty different human malignancies, including non-small cell lung cancers (NSCLC), anaplastic non-Hodgkin lymphoma, diffuse large B cell lymphoma, renal carcinoma, thyroid cancers, breast cancer, ovarian carcinoma, leukemia, and MM6–8. These fusions lead to constitutive activation of ALK kinase which subsequently induces the activation of downstream pathways, including PI3K/protein kinase B and the extracellular signal-regulated kinase (ERK)/MAPK pathway9.
In the rapidly evolving field of MM, we have seen a remarkable reduction in mortality rates in clinical trials and population-based studies. Unfortunately, patients with NSMM are frequently excluded from clinical trials. Furthermore, molecular studies in NSMM are lacking. Here, we report a case of patient with NSMM harboring a trafficking from ER to Golgi regulator gene (TFG, formerly TRK fused gene) and ALK fusion (TFG-ALK fusion), which demonstrated a dramatic response to ALK inhibition.
Results
Case
A 49-year-old Caucasian gentleman initially underwent surgical resection of an 8.7 cm transmural jejunal mass. Pathology was consistent with a kappa-restricted plasmacytoma with multiple negative adjacent lymph nodes. He had a normal renal function, calcium, complete blood count, serum and urine immunofixation electrophoresis as follows: serum-free light chains, free Kappa 14.7 mg/L (Normal value: 3.3–19.4 mg/L), free Lambda 14.5 mg/L (Normal value: 3.3–19.4 mg/L) and Kappa/Lambda ratio 1.01 (Normal value: 0.26–1.65). The skeletal survey and positron emission tomography (PET)/CT did not show lytic lesions. Bone marrow biopsy was negative for clonal plasma cells. The patient was closely followed by imaging surveillance for an isolated plasmacytoma.
Three years later, he presented with right cervical lymphadenopathy and a new nasopharyngeal mass. Lymph node biopsy was consistent with kappa-restricted plasmacytoma. Repeat paraproteinemia workup was consistent with NSMM. Re-staging PET/CT showed multiple abnormal radiotracer uptake areas, including the nasopharyngeal mass (5.4 × 4.9 × 4.0 cm, SUV 18.4), necrotic right cervical lymph node, a focal area in the jejunum, right adrenal gland, and soft-tissue chest nodules. He was treated with KRd (carfilzomib, lenalidomide, dexamethasone). His tumor initially responded to the KRd regimen with a complete metabolic response on imaging, but after six cycles of KRd, the tumor recurred with a small bowel mass with an SUV of 14.1 on PET/CT. Unfortunately, he continued to progress despite changing therapies including, KCd (carfilzomib, cyclophosphamide, dexamethasone), local radiation to the jejunal mass, and the DPd regimen (daratumumab, pomalidomide, dexamethasone). Within two months after starting the DPd regimen, he developed diffuse hepatic lesions and a loculated pelvic mass (Supplementary Fig. 1A, B). Liver biopsy showed kappa restricted plasma cells, consistent with plasmacytoma (Supplementary Fig. 2A–D). These plasma cells are characterized by increased nuclear to cytoplasm ratio, variable dispersed chromatin, prominent nucleoli, and modest eosinophilic cytoplasm. Broad immunohistochemistry panel was performed including CD3, CD5, CD19,CD20, CD33, CD34, LCA, CD56, CD68, CD79a, CD117, CD138 CAM5.2, myeloperoxidase, pankeratin, Cyclin D1, IgA, IgD, IgG, IgM, lysozyme, MUM-1, PAX5, ALK-1, HHV8, EBV, and kappa and lambda. The neoplastic plasma cells showed a diffuse proliferation of CD138+ plasma cells. In situ hybridization for kappa and lambda light chains demonstrates a kappa restricted plasma cell population. CD19 and CD20 were negative on neoplastic plasma cells. CD43, LCA, and CD117 were partially positive. Additional testing including BRAF mutation by PCR and ALK-1 stain were negative. Multiple pathology consultations were obtained at different institutes, and the consensus opinion was that findings were consistent with plasmacytoma. Fluorescent in-situ hybridization (FISH) showed 17p13.1 and trisomy 7 in 63% and 60% plasma cells, respectively. The patient received two cycles of salvage chemotherapy with VPD-PACE (bortezomib, pomalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide) with complete metabolic response followed by autologous stem cell transplant (ASCT). Post-ASCT, he started maintenance therapy with the VPd regimen (bortezomib, pomalidomide, and dexamethasone). However, within six months, he developed multiple new foci of PET FDG uptake involving the thoracic spine, mediastinum, and the abdomen.
After obtaining informed consent, we obtained a liver biopsy and collected peripheral blood for a commercially available CLIA certified genomic assay. Whole-genome sequencing (WGS) and RNA sequencing were performed using the commercially available NantHealth platform. A total of 591 somatic variants were identified in this patient’s tumor, including 147 non-synonymous variants, for an estimated exonic mutation rate of 5.8 mutations per megabase (Mb), suggesting a low tumor mutation burden (TMB). Among the somatic variants identified, three variants were considered to be pathogenic (1 nonsense mutation in MYO6 and two frame-shift mutations in TP53 and TNFAIP3). Two variants were considered likely pathogenic (HGF and GRID1), both of which were missense mutations. Five hundred forty-nine genes were considered benign or likely benign, with 37 variants currently of unknown significance. Details of pathogenic alterations are detailed in Table 1. No actionable mutations were identified based on whole-genome sequencing. RNA sequencing to detect the presence of possible fusions between two transcripts (with one of the transcripts belonging to one of 74 genes commonly found in oncogenic fusions) was assessed. Reportable fusions must both be classified as functional and have greater than eight reads supporting the fusion junction was considered significant. Based on this analysis, one fusion transcript was identified: TFG-ALK, with protein description as t(3;2)(TFG:p.M1_N138; ALK:p.V1058_*1621), and exon composition as TFG(e1-4) + ALK(e20-29) (Table 1). The case was presented in Molecular Tumor Board and ALK inhibitor therapy was discussed.Table 1 Genomic characteristics of TFG-ALK fusion and pathologic gene signature of liver biopsy.
Fusion TFG-ALK
Protein discription (3;2) (TFGp.M1_n138; ALK:p.V1058_*1621)
Exon composition TFG(e1-4) + ALK(e20-29)
TFG RNA expression 62.2 TPM*
ALK RNA expression 13.0 TPM*
TFG-ALK Fusion Support 154 reads
Gene Pathogenicity Mutation Type DNA VAF^ (%) RNA VAF^ (%)
TP53 p.H178Tfs*69 Pathogenic Frameshift 45.0 36.4
TNFAIP3 p.C627Ffs*44 Pathogenic Frameshift 25.0 1.9
MYO6 p.E953* Pathogenic Nonsense 28.2 11.1
HGF p. G674D Likely Pathogenic Missense 37.6 1.4
GRID1 p.S556Y Likely Pathogenic Missense 27.5 0.0
*TPM transcripts per kilobase Million, ^VAF Varient Allele Frequency.
Since this particular TFG-ALK t(3;2) fusion had structural similarity to other well-known ALK fusion variants, it was expected to be targetable by an ALK inhibitor. The patient was initiated on compassionate treatment with the second-generation ALK inhibitor, alectinib 600 mg twice daily. Repeat PET/CT imaging after two months showed resolution of the thoracic lesion and abdominal lymph nodes (Fig. 1). After two months on alectinib, the patient did not have access to further treatment and unfortunately demonstrated relapsed disease in the brain involving multiple innumerable diffuse enhancing lesions with surrounding vasogenic edema involving the right frontal lobe and bilateral cerebellar predominance (Fig. 2). Cerebrospinal fluid (CSF) analysis showed evidence of plasmablasts (not seen on his previous CSF analysis) (Supplementary Fig. 3). He was treated with whole-brain radiation therapy, intrathecal methotrexate, and started on lorlatinib, a 3rd generation ALK inhibitor at 100 mg orally daily. At the time of writing this report, the patient has been maintained for >2 years on lorlatinib. His brain MRI and PET/CT are negative for recurrence (Figs. 1 and 2), demonstrating a durable response to targeted ALK inhibition surpassing conventional systemic myeloma therapy including autologous stem cell transplantation.Fig. 1 PET Scan results.
A Before initiation of Alectinib. Foci of increased uptake in a mediastinal lymph node (max SUV 6.3), retrocaval lymph node (max SUV 10.6), right T3/T4 intervertebral foramen (max SUV 14) on PET-CT. B Complete response after 2 months of alectinib. Complete resolution of prior noted upper thoracic spine lesion and upper abdominal pericaval nodule.
Fig. 2 MRI Brain before and after Loralatinib treatment.
A, B, C MRI of the brain before starting Lorlatinib (pre-treatment) showing innumerable diffuse enhancing lesions with surrounding vasogenic edema, with a right frontal lobe and bilateral cerebellar predominance. D, E, F Treatment response to lorlatinib with markedly decrease in size and number of brain metastasis and markedly improved cerebral edema.
Discussion
This is a unique case demonstrating significant clinical response using commercially available ALK inhibitors in a TFG-ALK fusion in relapsed/refractory NSMM. The ALK gene encodes the ALK tyrosine-kinase protein, a receptor tyrosine kinase, known to have vital roles in normal physiologic processes, including the transmission of extracellular signals implicated in proliferation, differentiation, and survival (Fig. 3). Plasma cell neoplasms are distinct hematologic neoplasms where the diagnosis is based on morphology, immunohistochemistry, FISH, and conventional karyotyping. Case studies have previously reported ALK fusion partners EML4-ALK and CLTC-ALK in these patients6,10.Fig. 3 TFG-ALK fusion and downstream pathway activation.
TFG-ALK fusion product is displayed as a t(3;2) fusion at exon 4 of TFG (blue) and exon 20 of ALK (red). The point of the fusion is indicated by the yellow triangle. The druggable ALK kinase domain resides downstream of ALK exon 20. The upregulated ALK pathway by means of fusion product is implicated in many oncogenic cellular pathways including JAK/STAT, PI3K/mTOR, and RAS/RAF.
The TFG was previously identified as a fusion partner for ALK in cases of Anaplastic large cell lymphoma (ALCL) t(2;3) (p23;q21). The ALK breakpoint in these translocations was the same as in the classical t(2:5). The chimeric protein contains cytoplasmic domain ALK and coiled-coil domain of TFG. The fusion protein was thus able to dimerize, resulting in constitutive kinase activity11. Alectinib is currently Food and Drug Administration (FDA) approved for ALK-positive metastatic NSCLC. It is an orally bioavailable TKI that inhibits ALK and RET proteins by preventing their phosphorylation. The inhibition of activation of ALK impairs downstream signaling of cell proliferation12. Lorlatinib is approved in NSCLC carrying ALK fusion and has shown superior intracranial activity even in patients treated with other ALK inhibitors13. Therefore, it was an ideal choice for our patient after CNS metastasis development.
Our case highlights that a small percentage of patients with plasma cell neoplasms carries ALK fusion and may benefit from ALK inhibition. The diagnosis of ALK+ NSMM versus large B cell lymphoma is challenging because of its rarity, unique morphologic characteristics, and unusual immunophenotypic features, which significantly overlap with other hematologic and nonhematologic neoplasms. Little is known about the clinical behavior of NSMM. We acknowledge that the clinical behavior of NSMM may resemble plasmablastic lymphoma. Due to these concerns, we have obtained multiple opinions on pathology and there is a uniform consensus on the diagnosis of plasmacytomas (NSMM). In addition, ALK-1 stain and EBV stain were absent on plasmacytomas. We believe 17p deletion, which is considered a high-risk mutation in these patients, is most likely the cause of aggressive clinical behavior in our case. This case demonstrates the potential role of next-generation sequencing (NGS) in NSMM, a disease where NGS is not currently standard of care and morphological or immunophenotypical features define diagnosis and influence treatment decisions. NGS may identify unrecognized targetable oncogenic drivers such as ALK-fusions. Detection of these gene alterations not only improves our understanding of disease pathogenesis but may also be used to exploit the therapeutic vulnerabilities of these tumors. The therapeutic success seen in this case emphasizes the need to identify such molecular targets and unique driver alterations, especially in the relapsed setting with a disease that was refractory to traditional treatment options. Our knowledge of mechanisms involved in MM, especially NSMM oncogenesis, is incomplete and further molecular studies are warranted to better understand biological underpinnings that may improve outcomes in these patients. After failing more than five lines of systemic treatment, our patient is currently in clinical and radiographic remission with ALK inhibitor over two years. Our case is a successful example of utilizing NGS-based mutational profiling and incorporating unconventional targeted agents into clinical practice in a rare disease.
Methods
The patient provided written informed consent for carrying out Next-Generation Sequencing and publication of case reports using CLIA certified commercially available Nant platform, as previously described14. The analysis is also described in the Nant GPS report. Briefly, DNA libraries were prepared using the KAPA Hyper prep kit and sequencing on Illumina sequencing platform. DNA sequencing data was aligned to Genome Reference Consortium Human Build 37 using Burrows-Wheeler Aligner15. The germline, somatic variant detection, insertion, and deletions were carried out using the NantOmics Contraster pipeline16–18. RNA-seq libraries were prepared using KAPA Stranded RNA-Seq with RiboErase kit and sequenced on the Illumina Sequencing platform. RNA sequencing data was aligned used bowtie219. RNA transcript expression was assessed by RSEM20. RNA fusions are detected using transcriptome-aligned RNA sequencing data. When there is evidence of gene-fusion using clusters of spanning reads between two transcripts, the Nant team performs de novo assembly on all sequencing data to detect the precise location of fusion transcript. Only fusion with open reading frames that extend to the downstream partner’s stop codon is reported.
The patient was treated with lorlatinib and alectinib within an individual program after informed consent. IRB approval (St. Luke’s Hospital, Kansas City, MO) was waived by the IRB.
Imaging
PET-CT and MRI imaging were obtained as standard of care.
Reporting summary
Further information on research design is available in the Nature Research Reporting Summary linked to this article.
Supplementary information
Supplementary Information
Reporting Summary
Supplementary information
The online version contains supplementary material available at 10.1038/s41525-021-00186-9.
Acknowledgements
We would like to thank Roche and Pfizer for their support in providing compassionate use of medication.
Author contributions
A.M., J.S., S.R. conceived the idea and design the study and drafted the initial manuscript and supervision of the work. S.A., P.R. contributed equally in data gathering and manuscript writing. B.G. provided pharmacological details on the patient. D.N. and S.N. provided details on pathology. T.C., S.L., A.S., A.P., T.K., M.L. reviewed the draft and provided meaningful addition to the manuscript. A.M. and S.R. supervised the project. All authors again approved of the final changes before submission.
Data availability
The authors declare that data supporting the findings of this study are available within the paper. RAW data files Including FASTQ and BAM files are the property of commercial platform NANTOMICS and authors do not have access to these files. The de-identified HIPAA compliant clinical Genomics report of the current study is available.
Competing interests
The authors declare no competing financial or non-financial interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CARFILZOMIB, CYCLOPHOSPHAMIDE, DARATUMUMAB, DEXAMETHASONE, LENALIDOMIDE, POMALIDOMIDE | DrugsGivenReaction | CC BY | 33731690 | 19,386,747 | 2021-03-17 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Plasma cell myeloma recurrent'. | Non-secretory multiple myeloma with unusual TFG-ALK fusion showed dramatic response to ALK inhibition.
Non-secretory multiple myeloma (NSMM) constitutes a distinct entity of multiple myeloma characterized by the absence of detectable monoclonal protein and rarely an absence of free light chains in the serum and urine. Given its rarity, the genomic landscape, clinical course, and prognosis of NSSM are not well characterized. Here, we report a case of a patient with relapsed and refractory NSMM with brain metastasis harboring a TFG-ALK fusion showing a dramatic and durable (over two years) response to commercially available anaplastic lymphoma kinase (ALK) inhibitors. The case emphasizes the beneficial role of molecular profiling in this target-poor disease.
Introduction
Non–secretory multiple myeloma (NSMM) is a rare variant of multiple myeloma (MM) and constitutes 3% of total MM cases1. The underlying pathology of NSMM is reported to be either failure of malignant plasma cells to form immunoglobulin (non-producer) or a failure to secrete heavy or light chains (non-secretor)2. Pathogenesis in MM is governed by the acquisition of multiple somatic sub-clonal secondary genomic events, including copy number abnormalities, secondary translocations, acquired genomic and epigenetic mutations, and DNA hypomethylation3,4. Subclonal events include deletion of RB1, TP53, PTEN, amplification of chromosome 1q, activating point mutations in KRAS, NRAS, and BRAF, though they can be clonal and may occur at any point in the disease course5,6, A recent study by Morgan et al.6, has shown low frequency (2.7%, n = 958) of non-immunoglobulin fusions in MM patients. These fusion genes were present in smoldering MM, newly diagnosed MM, and relapsed MM patients, indicating these fusion genes occur early in the disease process. Fifty-four percent of these fusion genes were in-frame fusions, potentially resulting in functional oncogenic fusion proteins. Most of these in-frame tyrosine kinase fusions were sub-clonal and therefore, secondary events. The exception is the EML4-ALK fusion gene, which was clonal and thus, therapeutically targetable with anaplastic lymphoma kinase (ALK) inhibitors. ALK fusion partners are identified as driver events in nearly twenty different human malignancies, including non-small cell lung cancers (NSCLC), anaplastic non-Hodgkin lymphoma, diffuse large B cell lymphoma, renal carcinoma, thyroid cancers, breast cancer, ovarian carcinoma, leukemia, and MM6–8. These fusions lead to constitutive activation of ALK kinase which subsequently induces the activation of downstream pathways, including PI3K/protein kinase B and the extracellular signal-regulated kinase (ERK)/MAPK pathway9.
In the rapidly evolving field of MM, we have seen a remarkable reduction in mortality rates in clinical trials and population-based studies. Unfortunately, patients with NSMM are frequently excluded from clinical trials. Furthermore, molecular studies in NSMM are lacking. Here, we report a case of patient with NSMM harboring a trafficking from ER to Golgi regulator gene (TFG, formerly TRK fused gene) and ALK fusion (TFG-ALK fusion), which demonstrated a dramatic response to ALK inhibition.
Results
Case
A 49-year-old Caucasian gentleman initially underwent surgical resection of an 8.7 cm transmural jejunal mass. Pathology was consistent with a kappa-restricted plasmacytoma with multiple negative adjacent lymph nodes. He had a normal renal function, calcium, complete blood count, serum and urine immunofixation electrophoresis as follows: serum-free light chains, free Kappa 14.7 mg/L (Normal value: 3.3–19.4 mg/L), free Lambda 14.5 mg/L (Normal value: 3.3–19.4 mg/L) and Kappa/Lambda ratio 1.01 (Normal value: 0.26–1.65). The skeletal survey and positron emission tomography (PET)/CT did not show lytic lesions. Bone marrow biopsy was negative for clonal plasma cells. The patient was closely followed by imaging surveillance for an isolated plasmacytoma.
Three years later, he presented with right cervical lymphadenopathy and a new nasopharyngeal mass. Lymph node biopsy was consistent with kappa-restricted plasmacytoma. Repeat paraproteinemia workup was consistent with NSMM. Re-staging PET/CT showed multiple abnormal radiotracer uptake areas, including the nasopharyngeal mass (5.4 × 4.9 × 4.0 cm, SUV 18.4), necrotic right cervical lymph node, a focal area in the jejunum, right adrenal gland, and soft-tissue chest nodules. He was treated with KRd (carfilzomib, lenalidomide, dexamethasone). His tumor initially responded to the KRd regimen with a complete metabolic response on imaging, but after six cycles of KRd, the tumor recurred with a small bowel mass with an SUV of 14.1 on PET/CT. Unfortunately, he continued to progress despite changing therapies including, KCd (carfilzomib, cyclophosphamide, dexamethasone), local radiation to the jejunal mass, and the DPd regimen (daratumumab, pomalidomide, dexamethasone). Within two months after starting the DPd regimen, he developed diffuse hepatic lesions and a loculated pelvic mass (Supplementary Fig. 1A, B). Liver biopsy showed kappa restricted plasma cells, consistent with plasmacytoma (Supplementary Fig. 2A–D). These plasma cells are characterized by increased nuclear to cytoplasm ratio, variable dispersed chromatin, prominent nucleoli, and modest eosinophilic cytoplasm. Broad immunohistochemistry panel was performed including CD3, CD5, CD19,CD20, CD33, CD34, LCA, CD56, CD68, CD79a, CD117, CD138 CAM5.2, myeloperoxidase, pankeratin, Cyclin D1, IgA, IgD, IgG, IgM, lysozyme, MUM-1, PAX5, ALK-1, HHV8, EBV, and kappa and lambda. The neoplastic plasma cells showed a diffuse proliferation of CD138+ plasma cells. In situ hybridization for kappa and lambda light chains demonstrates a kappa restricted plasma cell population. CD19 and CD20 were negative on neoplastic plasma cells. CD43, LCA, and CD117 were partially positive. Additional testing including BRAF mutation by PCR and ALK-1 stain were negative. Multiple pathology consultations were obtained at different institutes, and the consensus opinion was that findings were consistent with plasmacytoma. Fluorescent in-situ hybridization (FISH) showed 17p13.1 and trisomy 7 in 63% and 60% plasma cells, respectively. The patient received two cycles of salvage chemotherapy with VPD-PACE (bortezomib, pomalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide) with complete metabolic response followed by autologous stem cell transplant (ASCT). Post-ASCT, he started maintenance therapy with the VPd regimen (bortezomib, pomalidomide, and dexamethasone). However, within six months, he developed multiple new foci of PET FDG uptake involving the thoracic spine, mediastinum, and the abdomen.
After obtaining informed consent, we obtained a liver biopsy and collected peripheral blood for a commercially available CLIA certified genomic assay. Whole-genome sequencing (WGS) and RNA sequencing were performed using the commercially available NantHealth platform. A total of 591 somatic variants were identified in this patient’s tumor, including 147 non-synonymous variants, for an estimated exonic mutation rate of 5.8 mutations per megabase (Mb), suggesting a low tumor mutation burden (TMB). Among the somatic variants identified, three variants were considered to be pathogenic (1 nonsense mutation in MYO6 and two frame-shift mutations in TP53 and TNFAIP3). Two variants were considered likely pathogenic (HGF and GRID1), both of which were missense mutations. Five hundred forty-nine genes were considered benign or likely benign, with 37 variants currently of unknown significance. Details of pathogenic alterations are detailed in Table 1. No actionable mutations were identified based on whole-genome sequencing. RNA sequencing to detect the presence of possible fusions between two transcripts (with one of the transcripts belonging to one of 74 genes commonly found in oncogenic fusions) was assessed. Reportable fusions must both be classified as functional and have greater than eight reads supporting the fusion junction was considered significant. Based on this analysis, one fusion transcript was identified: TFG-ALK, with protein description as t(3;2)(TFG:p.M1_N138; ALK:p.V1058_*1621), and exon composition as TFG(e1-4) + ALK(e20-29) (Table 1). The case was presented in Molecular Tumor Board and ALK inhibitor therapy was discussed.Table 1 Genomic characteristics of TFG-ALK fusion and pathologic gene signature of liver biopsy.
Fusion TFG-ALK
Protein discription (3;2) (TFGp.M1_n138; ALK:p.V1058_*1621)
Exon composition TFG(e1-4) + ALK(e20-29)
TFG RNA expression 62.2 TPM*
ALK RNA expression 13.0 TPM*
TFG-ALK Fusion Support 154 reads
Gene Pathogenicity Mutation Type DNA VAF^ (%) RNA VAF^ (%)
TP53 p.H178Tfs*69 Pathogenic Frameshift 45.0 36.4
TNFAIP3 p.C627Ffs*44 Pathogenic Frameshift 25.0 1.9
MYO6 p.E953* Pathogenic Nonsense 28.2 11.1
HGF p. G674D Likely Pathogenic Missense 37.6 1.4
GRID1 p.S556Y Likely Pathogenic Missense 27.5 0.0
*TPM transcripts per kilobase Million, ^VAF Varient Allele Frequency.
Since this particular TFG-ALK t(3;2) fusion had structural similarity to other well-known ALK fusion variants, it was expected to be targetable by an ALK inhibitor. The patient was initiated on compassionate treatment with the second-generation ALK inhibitor, alectinib 600 mg twice daily. Repeat PET/CT imaging after two months showed resolution of the thoracic lesion and abdominal lymph nodes (Fig. 1). After two months on alectinib, the patient did not have access to further treatment and unfortunately demonstrated relapsed disease in the brain involving multiple innumerable diffuse enhancing lesions with surrounding vasogenic edema involving the right frontal lobe and bilateral cerebellar predominance (Fig. 2). Cerebrospinal fluid (CSF) analysis showed evidence of plasmablasts (not seen on his previous CSF analysis) (Supplementary Fig. 3). He was treated with whole-brain radiation therapy, intrathecal methotrexate, and started on lorlatinib, a 3rd generation ALK inhibitor at 100 mg orally daily. At the time of writing this report, the patient has been maintained for >2 years on lorlatinib. His brain MRI and PET/CT are negative for recurrence (Figs. 1 and 2), demonstrating a durable response to targeted ALK inhibition surpassing conventional systemic myeloma therapy including autologous stem cell transplantation.Fig. 1 PET Scan results.
A Before initiation of Alectinib. Foci of increased uptake in a mediastinal lymph node (max SUV 6.3), retrocaval lymph node (max SUV 10.6), right T3/T4 intervertebral foramen (max SUV 14) on PET-CT. B Complete response after 2 months of alectinib. Complete resolution of prior noted upper thoracic spine lesion and upper abdominal pericaval nodule.
Fig. 2 MRI Brain before and after Loralatinib treatment.
A, B, C MRI of the brain before starting Lorlatinib (pre-treatment) showing innumerable diffuse enhancing lesions with surrounding vasogenic edema, with a right frontal lobe and bilateral cerebellar predominance. D, E, F Treatment response to lorlatinib with markedly decrease in size and number of brain metastasis and markedly improved cerebral edema.
Discussion
This is a unique case demonstrating significant clinical response using commercially available ALK inhibitors in a TFG-ALK fusion in relapsed/refractory NSMM. The ALK gene encodes the ALK tyrosine-kinase protein, a receptor tyrosine kinase, known to have vital roles in normal physiologic processes, including the transmission of extracellular signals implicated in proliferation, differentiation, and survival (Fig. 3). Plasma cell neoplasms are distinct hematologic neoplasms where the diagnosis is based on morphology, immunohistochemistry, FISH, and conventional karyotyping. Case studies have previously reported ALK fusion partners EML4-ALK and CLTC-ALK in these patients6,10.Fig. 3 TFG-ALK fusion and downstream pathway activation.
TFG-ALK fusion product is displayed as a t(3;2) fusion at exon 4 of TFG (blue) and exon 20 of ALK (red). The point of the fusion is indicated by the yellow triangle. The druggable ALK kinase domain resides downstream of ALK exon 20. The upregulated ALK pathway by means of fusion product is implicated in many oncogenic cellular pathways including JAK/STAT, PI3K/mTOR, and RAS/RAF.
The TFG was previously identified as a fusion partner for ALK in cases of Anaplastic large cell lymphoma (ALCL) t(2;3) (p23;q21). The ALK breakpoint in these translocations was the same as in the classical t(2:5). The chimeric protein contains cytoplasmic domain ALK and coiled-coil domain of TFG. The fusion protein was thus able to dimerize, resulting in constitutive kinase activity11. Alectinib is currently Food and Drug Administration (FDA) approved for ALK-positive metastatic NSCLC. It is an orally bioavailable TKI that inhibits ALK and RET proteins by preventing their phosphorylation. The inhibition of activation of ALK impairs downstream signaling of cell proliferation12. Lorlatinib is approved in NSCLC carrying ALK fusion and has shown superior intracranial activity even in patients treated with other ALK inhibitors13. Therefore, it was an ideal choice for our patient after CNS metastasis development.
Our case highlights that a small percentage of patients with plasma cell neoplasms carries ALK fusion and may benefit from ALK inhibition. The diagnosis of ALK+ NSMM versus large B cell lymphoma is challenging because of its rarity, unique morphologic characteristics, and unusual immunophenotypic features, which significantly overlap with other hematologic and nonhematologic neoplasms. Little is known about the clinical behavior of NSMM. We acknowledge that the clinical behavior of NSMM may resemble plasmablastic lymphoma. Due to these concerns, we have obtained multiple opinions on pathology and there is a uniform consensus on the diagnosis of plasmacytomas (NSMM). In addition, ALK-1 stain and EBV stain were absent on plasmacytomas. We believe 17p deletion, which is considered a high-risk mutation in these patients, is most likely the cause of aggressive clinical behavior in our case. This case demonstrates the potential role of next-generation sequencing (NGS) in NSMM, a disease where NGS is not currently standard of care and morphological or immunophenotypical features define diagnosis and influence treatment decisions. NGS may identify unrecognized targetable oncogenic drivers such as ALK-fusions. Detection of these gene alterations not only improves our understanding of disease pathogenesis but may also be used to exploit the therapeutic vulnerabilities of these tumors. The therapeutic success seen in this case emphasizes the need to identify such molecular targets and unique driver alterations, especially in the relapsed setting with a disease that was refractory to traditional treatment options. Our knowledge of mechanisms involved in MM, especially NSMM oncogenesis, is incomplete and further molecular studies are warranted to better understand biological underpinnings that may improve outcomes in these patients. After failing more than five lines of systemic treatment, our patient is currently in clinical and radiographic remission with ALK inhibitor over two years. Our case is a successful example of utilizing NGS-based mutational profiling and incorporating unconventional targeted agents into clinical practice in a rare disease.
Methods
The patient provided written informed consent for carrying out Next-Generation Sequencing and publication of case reports using CLIA certified commercially available Nant platform, as previously described14. The analysis is also described in the Nant GPS report. Briefly, DNA libraries were prepared using the KAPA Hyper prep kit and sequencing on Illumina sequencing platform. DNA sequencing data was aligned to Genome Reference Consortium Human Build 37 using Burrows-Wheeler Aligner15. The germline, somatic variant detection, insertion, and deletions were carried out using the NantOmics Contraster pipeline16–18. RNA-seq libraries were prepared using KAPA Stranded RNA-Seq with RiboErase kit and sequenced on the Illumina Sequencing platform. RNA sequencing data was aligned used bowtie219. RNA transcript expression was assessed by RSEM20. RNA fusions are detected using transcriptome-aligned RNA sequencing data. When there is evidence of gene-fusion using clusters of spanning reads between two transcripts, the Nant team performs de novo assembly on all sequencing data to detect the precise location of fusion transcript. Only fusion with open reading frames that extend to the downstream partner’s stop codon is reported.
The patient was treated with lorlatinib and alectinib within an individual program after informed consent. IRB approval (St. Luke’s Hospital, Kansas City, MO) was waived by the IRB.
Imaging
PET-CT and MRI imaging were obtained as standard of care.
Reporting summary
Further information on research design is available in the Nature Research Reporting Summary linked to this article.
Supplementary information
Supplementary Information
Reporting Summary
Supplementary information
The online version contains supplementary material available at 10.1038/s41525-021-00186-9.
Acknowledgements
We would like to thank Roche and Pfizer for their support in providing compassionate use of medication.
Author contributions
A.M., J.S., S.R. conceived the idea and design the study and drafted the initial manuscript and supervision of the work. S.A., P.R. contributed equally in data gathering and manuscript writing. B.G. provided pharmacological details on the patient. D.N. and S.N. provided details on pathology. T.C., S.L., A.S., A.P., T.K., M.L. reviewed the draft and provided meaningful addition to the manuscript. A.M. and S.R. supervised the project. All authors again approved of the final changes before submission.
Data availability
The authors declare that data supporting the findings of this study are available within the paper. RAW data files Including FASTQ and BAM files are the property of commercial platform NANTOMICS and authors do not have access to these files. The de-identified HIPAA compliant clinical Genomics report of the current study is available.
Competing interests
The authors declare no competing financial or non-financial interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CARFILZOMIB, CYCLOPHOSPHAMIDE, DARATUMUMAB, DEXAMETHASONE, LENALIDOMIDE, POMALIDOMIDE | DrugsGivenReaction | CC BY | 33731690 | 19,386,747 | 2021-03-17 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Treatment failure'. | Non-secretory multiple myeloma with unusual TFG-ALK fusion showed dramatic response to ALK inhibition.
Non-secretory multiple myeloma (NSMM) constitutes a distinct entity of multiple myeloma characterized by the absence of detectable monoclonal protein and rarely an absence of free light chains in the serum and urine. Given its rarity, the genomic landscape, clinical course, and prognosis of NSSM are not well characterized. Here, we report a case of a patient with relapsed and refractory NSMM with brain metastasis harboring a TFG-ALK fusion showing a dramatic and durable (over two years) response to commercially available anaplastic lymphoma kinase (ALK) inhibitors. The case emphasizes the beneficial role of molecular profiling in this target-poor disease.
Introduction
Non–secretory multiple myeloma (NSMM) is a rare variant of multiple myeloma (MM) and constitutes 3% of total MM cases1. The underlying pathology of NSMM is reported to be either failure of malignant plasma cells to form immunoglobulin (non-producer) or a failure to secrete heavy or light chains (non-secretor)2. Pathogenesis in MM is governed by the acquisition of multiple somatic sub-clonal secondary genomic events, including copy number abnormalities, secondary translocations, acquired genomic and epigenetic mutations, and DNA hypomethylation3,4. Subclonal events include deletion of RB1, TP53, PTEN, amplification of chromosome 1q, activating point mutations in KRAS, NRAS, and BRAF, though they can be clonal and may occur at any point in the disease course5,6, A recent study by Morgan et al.6, has shown low frequency (2.7%, n = 958) of non-immunoglobulin fusions in MM patients. These fusion genes were present in smoldering MM, newly diagnosed MM, and relapsed MM patients, indicating these fusion genes occur early in the disease process. Fifty-four percent of these fusion genes were in-frame fusions, potentially resulting in functional oncogenic fusion proteins. Most of these in-frame tyrosine kinase fusions were sub-clonal and therefore, secondary events. The exception is the EML4-ALK fusion gene, which was clonal and thus, therapeutically targetable with anaplastic lymphoma kinase (ALK) inhibitors. ALK fusion partners are identified as driver events in nearly twenty different human malignancies, including non-small cell lung cancers (NSCLC), anaplastic non-Hodgkin lymphoma, diffuse large B cell lymphoma, renal carcinoma, thyroid cancers, breast cancer, ovarian carcinoma, leukemia, and MM6–8. These fusions lead to constitutive activation of ALK kinase which subsequently induces the activation of downstream pathways, including PI3K/protein kinase B and the extracellular signal-regulated kinase (ERK)/MAPK pathway9.
In the rapidly evolving field of MM, we have seen a remarkable reduction in mortality rates in clinical trials and population-based studies. Unfortunately, patients with NSMM are frequently excluded from clinical trials. Furthermore, molecular studies in NSMM are lacking. Here, we report a case of patient with NSMM harboring a trafficking from ER to Golgi regulator gene (TFG, formerly TRK fused gene) and ALK fusion (TFG-ALK fusion), which demonstrated a dramatic response to ALK inhibition.
Results
Case
A 49-year-old Caucasian gentleman initially underwent surgical resection of an 8.7 cm transmural jejunal mass. Pathology was consistent with a kappa-restricted plasmacytoma with multiple negative adjacent lymph nodes. He had a normal renal function, calcium, complete blood count, serum and urine immunofixation electrophoresis as follows: serum-free light chains, free Kappa 14.7 mg/L (Normal value: 3.3–19.4 mg/L), free Lambda 14.5 mg/L (Normal value: 3.3–19.4 mg/L) and Kappa/Lambda ratio 1.01 (Normal value: 0.26–1.65). The skeletal survey and positron emission tomography (PET)/CT did not show lytic lesions. Bone marrow biopsy was negative for clonal plasma cells. The patient was closely followed by imaging surveillance for an isolated plasmacytoma.
Three years later, he presented with right cervical lymphadenopathy and a new nasopharyngeal mass. Lymph node biopsy was consistent with kappa-restricted plasmacytoma. Repeat paraproteinemia workup was consistent with NSMM. Re-staging PET/CT showed multiple abnormal radiotracer uptake areas, including the nasopharyngeal mass (5.4 × 4.9 × 4.0 cm, SUV 18.4), necrotic right cervical lymph node, a focal area in the jejunum, right adrenal gland, and soft-tissue chest nodules. He was treated with KRd (carfilzomib, lenalidomide, dexamethasone). His tumor initially responded to the KRd regimen with a complete metabolic response on imaging, but after six cycles of KRd, the tumor recurred with a small bowel mass with an SUV of 14.1 on PET/CT. Unfortunately, he continued to progress despite changing therapies including, KCd (carfilzomib, cyclophosphamide, dexamethasone), local radiation to the jejunal mass, and the DPd regimen (daratumumab, pomalidomide, dexamethasone). Within two months after starting the DPd regimen, he developed diffuse hepatic lesions and a loculated pelvic mass (Supplementary Fig. 1A, B). Liver biopsy showed kappa restricted plasma cells, consistent with plasmacytoma (Supplementary Fig. 2A–D). These plasma cells are characterized by increased nuclear to cytoplasm ratio, variable dispersed chromatin, prominent nucleoli, and modest eosinophilic cytoplasm. Broad immunohistochemistry panel was performed including CD3, CD5, CD19,CD20, CD33, CD34, LCA, CD56, CD68, CD79a, CD117, CD138 CAM5.2, myeloperoxidase, pankeratin, Cyclin D1, IgA, IgD, IgG, IgM, lysozyme, MUM-1, PAX5, ALK-1, HHV8, EBV, and kappa and lambda. The neoplastic plasma cells showed a diffuse proliferation of CD138+ plasma cells. In situ hybridization for kappa and lambda light chains demonstrates a kappa restricted plasma cell population. CD19 and CD20 were negative on neoplastic plasma cells. CD43, LCA, and CD117 were partially positive. Additional testing including BRAF mutation by PCR and ALK-1 stain were negative. Multiple pathology consultations were obtained at different institutes, and the consensus opinion was that findings were consistent with plasmacytoma. Fluorescent in-situ hybridization (FISH) showed 17p13.1 and trisomy 7 in 63% and 60% plasma cells, respectively. The patient received two cycles of salvage chemotherapy with VPD-PACE (bortezomib, pomalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide) with complete metabolic response followed by autologous stem cell transplant (ASCT). Post-ASCT, he started maintenance therapy with the VPd regimen (bortezomib, pomalidomide, and dexamethasone). However, within six months, he developed multiple new foci of PET FDG uptake involving the thoracic spine, mediastinum, and the abdomen.
After obtaining informed consent, we obtained a liver biopsy and collected peripheral blood for a commercially available CLIA certified genomic assay. Whole-genome sequencing (WGS) and RNA sequencing were performed using the commercially available NantHealth platform. A total of 591 somatic variants were identified in this patient’s tumor, including 147 non-synonymous variants, for an estimated exonic mutation rate of 5.8 mutations per megabase (Mb), suggesting a low tumor mutation burden (TMB). Among the somatic variants identified, three variants were considered to be pathogenic (1 nonsense mutation in MYO6 and two frame-shift mutations in TP53 and TNFAIP3). Two variants were considered likely pathogenic (HGF and GRID1), both of which were missense mutations. Five hundred forty-nine genes were considered benign or likely benign, with 37 variants currently of unknown significance. Details of pathogenic alterations are detailed in Table 1. No actionable mutations were identified based on whole-genome sequencing. RNA sequencing to detect the presence of possible fusions between two transcripts (with one of the transcripts belonging to one of 74 genes commonly found in oncogenic fusions) was assessed. Reportable fusions must both be classified as functional and have greater than eight reads supporting the fusion junction was considered significant. Based on this analysis, one fusion transcript was identified: TFG-ALK, with protein description as t(3;2)(TFG:p.M1_N138; ALK:p.V1058_*1621), and exon composition as TFG(e1-4) + ALK(e20-29) (Table 1). The case was presented in Molecular Tumor Board and ALK inhibitor therapy was discussed.Table 1 Genomic characteristics of TFG-ALK fusion and pathologic gene signature of liver biopsy.
Fusion TFG-ALK
Protein discription (3;2) (TFGp.M1_n138; ALK:p.V1058_*1621)
Exon composition TFG(e1-4) + ALK(e20-29)
TFG RNA expression 62.2 TPM*
ALK RNA expression 13.0 TPM*
TFG-ALK Fusion Support 154 reads
Gene Pathogenicity Mutation Type DNA VAF^ (%) RNA VAF^ (%)
TP53 p.H178Tfs*69 Pathogenic Frameshift 45.0 36.4
TNFAIP3 p.C627Ffs*44 Pathogenic Frameshift 25.0 1.9
MYO6 p.E953* Pathogenic Nonsense 28.2 11.1
HGF p. G674D Likely Pathogenic Missense 37.6 1.4
GRID1 p.S556Y Likely Pathogenic Missense 27.5 0.0
*TPM transcripts per kilobase Million, ^VAF Varient Allele Frequency.
Since this particular TFG-ALK t(3;2) fusion had structural similarity to other well-known ALK fusion variants, it was expected to be targetable by an ALK inhibitor. The patient was initiated on compassionate treatment with the second-generation ALK inhibitor, alectinib 600 mg twice daily. Repeat PET/CT imaging after two months showed resolution of the thoracic lesion and abdominal lymph nodes (Fig. 1). After two months on alectinib, the patient did not have access to further treatment and unfortunately demonstrated relapsed disease in the brain involving multiple innumerable diffuse enhancing lesions with surrounding vasogenic edema involving the right frontal lobe and bilateral cerebellar predominance (Fig. 2). Cerebrospinal fluid (CSF) analysis showed evidence of plasmablasts (not seen on his previous CSF analysis) (Supplementary Fig. 3). He was treated with whole-brain radiation therapy, intrathecal methotrexate, and started on lorlatinib, a 3rd generation ALK inhibitor at 100 mg orally daily. At the time of writing this report, the patient has been maintained for >2 years on lorlatinib. His brain MRI and PET/CT are negative for recurrence (Figs. 1 and 2), demonstrating a durable response to targeted ALK inhibition surpassing conventional systemic myeloma therapy including autologous stem cell transplantation.Fig. 1 PET Scan results.
A Before initiation of Alectinib. Foci of increased uptake in a mediastinal lymph node (max SUV 6.3), retrocaval lymph node (max SUV 10.6), right T3/T4 intervertebral foramen (max SUV 14) on PET-CT. B Complete response after 2 months of alectinib. Complete resolution of prior noted upper thoracic spine lesion and upper abdominal pericaval nodule.
Fig. 2 MRI Brain before and after Loralatinib treatment.
A, B, C MRI of the brain before starting Lorlatinib (pre-treatment) showing innumerable diffuse enhancing lesions with surrounding vasogenic edema, with a right frontal lobe and bilateral cerebellar predominance. D, E, F Treatment response to lorlatinib with markedly decrease in size and number of brain metastasis and markedly improved cerebral edema.
Discussion
This is a unique case demonstrating significant clinical response using commercially available ALK inhibitors in a TFG-ALK fusion in relapsed/refractory NSMM. The ALK gene encodes the ALK tyrosine-kinase protein, a receptor tyrosine kinase, known to have vital roles in normal physiologic processes, including the transmission of extracellular signals implicated in proliferation, differentiation, and survival (Fig. 3). Plasma cell neoplasms are distinct hematologic neoplasms where the diagnosis is based on morphology, immunohistochemistry, FISH, and conventional karyotyping. Case studies have previously reported ALK fusion partners EML4-ALK and CLTC-ALK in these patients6,10.Fig. 3 TFG-ALK fusion and downstream pathway activation.
TFG-ALK fusion product is displayed as a t(3;2) fusion at exon 4 of TFG (blue) and exon 20 of ALK (red). The point of the fusion is indicated by the yellow triangle. The druggable ALK kinase domain resides downstream of ALK exon 20. The upregulated ALK pathway by means of fusion product is implicated in many oncogenic cellular pathways including JAK/STAT, PI3K/mTOR, and RAS/RAF.
The TFG was previously identified as a fusion partner for ALK in cases of Anaplastic large cell lymphoma (ALCL) t(2;3) (p23;q21). The ALK breakpoint in these translocations was the same as in the classical t(2:5). The chimeric protein contains cytoplasmic domain ALK and coiled-coil domain of TFG. The fusion protein was thus able to dimerize, resulting in constitutive kinase activity11. Alectinib is currently Food and Drug Administration (FDA) approved for ALK-positive metastatic NSCLC. It is an orally bioavailable TKI that inhibits ALK and RET proteins by preventing their phosphorylation. The inhibition of activation of ALK impairs downstream signaling of cell proliferation12. Lorlatinib is approved in NSCLC carrying ALK fusion and has shown superior intracranial activity even in patients treated with other ALK inhibitors13. Therefore, it was an ideal choice for our patient after CNS metastasis development.
Our case highlights that a small percentage of patients with plasma cell neoplasms carries ALK fusion and may benefit from ALK inhibition. The diagnosis of ALK+ NSMM versus large B cell lymphoma is challenging because of its rarity, unique morphologic characteristics, and unusual immunophenotypic features, which significantly overlap with other hematologic and nonhematologic neoplasms. Little is known about the clinical behavior of NSMM. We acknowledge that the clinical behavior of NSMM may resemble plasmablastic lymphoma. Due to these concerns, we have obtained multiple opinions on pathology and there is a uniform consensus on the diagnosis of plasmacytomas (NSMM). In addition, ALK-1 stain and EBV stain were absent on plasmacytomas. We believe 17p deletion, which is considered a high-risk mutation in these patients, is most likely the cause of aggressive clinical behavior in our case. This case demonstrates the potential role of next-generation sequencing (NGS) in NSMM, a disease where NGS is not currently standard of care and morphological or immunophenotypical features define diagnosis and influence treatment decisions. NGS may identify unrecognized targetable oncogenic drivers such as ALK-fusions. Detection of these gene alterations not only improves our understanding of disease pathogenesis but may also be used to exploit the therapeutic vulnerabilities of these tumors. The therapeutic success seen in this case emphasizes the need to identify such molecular targets and unique driver alterations, especially in the relapsed setting with a disease that was refractory to traditional treatment options. Our knowledge of mechanisms involved in MM, especially NSMM oncogenesis, is incomplete and further molecular studies are warranted to better understand biological underpinnings that may improve outcomes in these patients. After failing more than five lines of systemic treatment, our patient is currently in clinical and radiographic remission with ALK inhibitor over two years. Our case is a successful example of utilizing NGS-based mutational profiling and incorporating unconventional targeted agents into clinical practice in a rare disease.
Methods
The patient provided written informed consent for carrying out Next-Generation Sequencing and publication of case reports using CLIA certified commercially available Nant platform, as previously described14. The analysis is also described in the Nant GPS report. Briefly, DNA libraries were prepared using the KAPA Hyper prep kit and sequencing on Illumina sequencing platform. DNA sequencing data was aligned to Genome Reference Consortium Human Build 37 using Burrows-Wheeler Aligner15. The germline, somatic variant detection, insertion, and deletions were carried out using the NantOmics Contraster pipeline16–18. RNA-seq libraries were prepared using KAPA Stranded RNA-Seq with RiboErase kit and sequenced on the Illumina Sequencing platform. RNA sequencing data was aligned used bowtie219. RNA transcript expression was assessed by RSEM20. RNA fusions are detected using transcriptome-aligned RNA sequencing data. When there is evidence of gene-fusion using clusters of spanning reads between two transcripts, the Nant team performs de novo assembly on all sequencing data to detect the precise location of fusion transcript. Only fusion with open reading frames that extend to the downstream partner’s stop codon is reported.
The patient was treated with lorlatinib and alectinib within an individual program after informed consent. IRB approval (St. Luke’s Hospital, Kansas City, MO) was waived by the IRB.
Imaging
PET-CT and MRI imaging were obtained as standard of care.
Reporting summary
Further information on research design is available in the Nature Research Reporting Summary linked to this article.
Supplementary information
Supplementary Information
Reporting Summary
Supplementary information
The online version contains supplementary material available at 10.1038/s41525-021-00186-9.
Acknowledgements
We would like to thank Roche and Pfizer for their support in providing compassionate use of medication.
Author contributions
A.M., J.S., S.R. conceived the idea and design the study and drafted the initial manuscript and supervision of the work. S.A., P.R. contributed equally in data gathering and manuscript writing. B.G. provided pharmacological details on the patient. D.N. and S.N. provided details on pathology. T.C., S.L., A.S., A.P., T.K., M.L. reviewed the draft and provided meaningful addition to the manuscript. A.M. and S.R. supervised the project. All authors again approved of the final changes before submission.
Data availability
The authors declare that data supporting the findings of this study are available within the paper. RAW data files Including FASTQ and BAM files are the property of commercial platform NANTOMICS and authors do not have access to these files. The de-identified HIPAA compliant clinical Genomics report of the current study is available.
Competing interests
The authors declare no competing financial or non-financial interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BORTEZOMIB, CISPLATIN, CYCLOPHOSPHAMIDE, DEXAMETHASONE, DOXORUBICIN HYDROCHLORIDE, ETOPOSIDE, POMALIDOMIDE | DrugsGivenReaction | CC BY | 33731690 | 19,443,402 | 2021-03-17 |
What was the outcome of reaction 'Metastases to central nervous system'? | Non-secretory multiple myeloma with unusual TFG-ALK fusion showed dramatic response to ALK inhibition.
Non-secretory multiple myeloma (NSMM) constitutes a distinct entity of multiple myeloma characterized by the absence of detectable monoclonal protein and rarely an absence of free light chains in the serum and urine. Given its rarity, the genomic landscape, clinical course, and prognosis of NSSM are not well characterized. Here, we report a case of a patient with relapsed and refractory NSMM with brain metastasis harboring a TFG-ALK fusion showing a dramatic and durable (over two years) response to commercially available anaplastic lymphoma kinase (ALK) inhibitors. The case emphasizes the beneficial role of molecular profiling in this target-poor disease.
Introduction
Non–secretory multiple myeloma (NSMM) is a rare variant of multiple myeloma (MM) and constitutes 3% of total MM cases1. The underlying pathology of NSMM is reported to be either failure of malignant plasma cells to form immunoglobulin (non-producer) or a failure to secrete heavy or light chains (non-secretor)2. Pathogenesis in MM is governed by the acquisition of multiple somatic sub-clonal secondary genomic events, including copy number abnormalities, secondary translocations, acquired genomic and epigenetic mutations, and DNA hypomethylation3,4. Subclonal events include deletion of RB1, TP53, PTEN, amplification of chromosome 1q, activating point mutations in KRAS, NRAS, and BRAF, though they can be clonal and may occur at any point in the disease course5,6, A recent study by Morgan et al.6, has shown low frequency (2.7%, n = 958) of non-immunoglobulin fusions in MM patients. These fusion genes were present in smoldering MM, newly diagnosed MM, and relapsed MM patients, indicating these fusion genes occur early in the disease process. Fifty-four percent of these fusion genes were in-frame fusions, potentially resulting in functional oncogenic fusion proteins. Most of these in-frame tyrosine kinase fusions were sub-clonal and therefore, secondary events. The exception is the EML4-ALK fusion gene, which was clonal and thus, therapeutically targetable with anaplastic lymphoma kinase (ALK) inhibitors. ALK fusion partners are identified as driver events in nearly twenty different human malignancies, including non-small cell lung cancers (NSCLC), anaplastic non-Hodgkin lymphoma, diffuse large B cell lymphoma, renal carcinoma, thyroid cancers, breast cancer, ovarian carcinoma, leukemia, and MM6–8. These fusions lead to constitutive activation of ALK kinase which subsequently induces the activation of downstream pathways, including PI3K/protein kinase B and the extracellular signal-regulated kinase (ERK)/MAPK pathway9.
In the rapidly evolving field of MM, we have seen a remarkable reduction in mortality rates in clinical trials and population-based studies. Unfortunately, patients with NSMM are frequently excluded from clinical trials. Furthermore, molecular studies in NSMM are lacking. Here, we report a case of patient with NSMM harboring a trafficking from ER to Golgi regulator gene (TFG, formerly TRK fused gene) and ALK fusion (TFG-ALK fusion), which demonstrated a dramatic response to ALK inhibition.
Results
Case
A 49-year-old Caucasian gentleman initially underwent surgical resection of an 8.7 cm transmural jejunal mass. Pathology was consistent with a kappa-restricted plasmacytoma with multiple negative adjacent lymph nodes. He had a normal renal function, calcium, complete blood count, serum and urine immunofixation electrophoresis as follows: serum-free light chains, free Kappa 14.7 mg/L (Normal value: 3.3–19.4 mg/L), free Lambda 14.5 mg/L (Normal value: 3.3–19.4 mg/L) and Kappa/Lambda ratio 1.01 (Normal value: 0.26–1.65). The skeletal survey and positron emission tomography (PET)/CT did not show lytic lesions. Bone marrow biopsy was negative for clonal plasma cells. The patient was closely followed by imaging surveillance for an isolated plasmacytoma.
Three years later, he presented with right cervical lymphadenopathy and a new nasopharyngeal mass. Lymph node biopsy was consistent with kappa-restricted plasmacytoma. Repeat paraproteinemia workup was consistent with NSMM. Re-staging PET/CT showed multiple abnormal radiotracer uptake areas, including the nasopharyngeal mass (5.4 × 4.9 × 4.0 cm, SUV 18.4), necrotic right cervical lymph node, a focal area in the jejunum, right adrenal gland, and soft-tissue chest nodules. He was treated with KRd (carfilzomib, lenalidomide, dexamethasone). His tumor initially responded to the KRd regimen with a complete metabolic response on imaging, but after six cycles of KRd, the tumor recurred with a small bowel mass with an SUV of 14.1 on PET/CT. Unfortunately, he continued to progress despite changing therapies including, KCd (carfilzomib, cyclophosphamide, dexamethasone), local radiation to the jejunal mass, and the DPd regimen (daratumumab, pomalidomide, dexamethasone). Within two months after starting the DPd regimen, he developed diffuse hepatic lesions and a loculated pelvic mass (Supplementary Fig. 1A, B). Liver biopsy showed kappa restricted plasma cells, consistent with plasmacytoma (Supplementary Fig. 2A–D). These plasma cells are characterized by increased nuclear to cytoplasm ratio, variable dispersed chromatin, prominent nucleoli, and modest eosinophilic cytoplasm. Broad immunohistochemistry panel was performed including CD3, CD5, CD19,CD20, CD33, CD34, LCA, CD56, CD68, CD79a, CD117, CD138 CAM5.2, myeloperoxidase, pankeratin, Cyclin D1, IgA, IgD, IgG, IgM, lysozyme, MUM-1, PAX5, ALK-1, HHV8, EBV, and kappa and lambda. The neoplastic plasma cells showed a diffuse proliferation of CD138+ plasma cells. In situ hybridization for kappa and lambda light chains demonstrates a kappa restricted plasma cell population. CD19 and CD20 were negative on neoplastic plasma cells. CD43, LCA, and CD117 were partially positive. Additional testing including BRAF mutation by PCR and ALK-1 stain were negative. Multiple pathology consultations were obtained at different institutes, and the consensus opinion was that findings were consistent with plasmacytoma. Fluorescent in-situ hybridization (FISH) showed 17p13.1 and trisomy 7 in 63% and 60% plasma cells, respectively. The patient received two cycles of salvage chemotherapy with VPD-PACE (bortezomib, pomalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide) with complete metabolic response followed by autologous stem cell transplant (ASCT). Post-ASCT, he started maintenance therapy with the VPd regimen (bortezomib, pomalidomide, and dexamethasone). However, within six months, he developed multiple new foci of PET FDG uptake involving the thoracic spine, mediastinum, and the abdomen.
After obtaining informed consent, we obtained a liver biopsy and collected peripheral blood for a commercially available CLIA certified genomic assay. Whole-genome sequencing (WGS) and RNA sequencing were performed using the commercially available NantHealth platform. A total of 591 somatic variants were identified in this patient’s tumor, including 147 non-synonymous variants, for an estimated exonic mutation rate of 5.8 mutations per megabase (Mb), suggesting a low tumor mutation burden (TMB). Among the somatic variants identified, three variants were considered to be pathogenic (1 nonsense mutation in MYO6 and two frame-shift mutations in TP53 and TNFAIP3). Two variants were considered likely pathogenic (HGF and GRID1), both of which were missense mutations. Five hundred forty-nine genes were considered benign or likely benign, with 37 variants currently of unknown significance. Details of pathogenic alterations are detailed in Table 1. No actionable mutations were identified based on whole-genome sequencing. RNA sequencing to detect the presence of possible fusions between two transcripts (with one of the transcripts belonging to one of 74 genes commonly found in oncogenic fusions) was assessed. Reportable fusions must both be classified as functional and have greater than eight reads supporting the fusion junction was considered significant. Based on this analysis, one fusion transcript was identified: TFG-ALK, with protein description as t(3;2)(TFG:p.M1_N138; ALK:p.V1058_*1621), and exon composition as TFG(e1-4) + ALK(e20-29) (Table 1). The case was presented in Molecular Tumor Board and ALK inhibitor therapy was discussed.Table 1 Genomic characteristics of TFG-ALK fusion and pathologic gene signature of liver biopsy.
Fusion TFG-ALK
Protein discription (3;2) (TFGp.M1_n138; ALK:p.V1058_*1621)
Exon composition TFG(e1-4) + ALK(e20-29)
TFG RNA expression 62.2 TPM*
ALK RNA expression 13.0 TPM*
TFG-ALK Fusion Support 154 reads
Gene Pathogenicity Mutation Type DNA VAF^ (%) RNA VAF^ (%)
TP53 p.H178Tfs*69 Pathogenic Frameshift 45.0 36.4
TNFAIP3 p.C627Ffs*44 Pathogenic Frameshift 25.0 1.9
MYO6 p.E953* Pathogenic Nonsense 28.2 11.1
HGF p. G674D Likely Pathogenic Missense 37.6 1.4
GRID1 p.S556Y Likely Pathogenic Missense 27.5 0.0
*TPM transcripts per kilobase Million, ^VAF Varient Allele Frequency.
Since this particular TFG-ALK t(3;2) fusion had structural similarity to other well-known ALK fusion variants, it was expected to be targetable by an ALK inhibitor. The patient was initiated on compassionate treatment with the second-generation ALK inhibitor, alectinib 600 mg twice daily. Repeat PET/CT imaging after two months showed resolution of the thoracic lesion and abdominal lymph nodes (Fig. 1). After two months on alectinib, the patient did not have access to further treatment and unfortunately demonstrated relapsed disease in the brain involving multiple innumerable diffuse enhancing lesions with surrounding vasogenic edema involving the right frontal lobe and bilateral cerebellar predominance (Fig. 2). Cerebrospinal fluid (CSF) analysis showed evidence of plasmablasts (not seen on his previous CSF analysis) (Supplementary Fig. 3). He was treated with whole-brain radiation therapy, intrathecal methotrexate, and started on lorlatinib, a 3rd generation ALK inhibitor at 100 mg orally daily. At the time of writing this report, the patient has been maintained for >2 years on lorlatinib. His brain MRI and PET/CT are negative for recurrence (Figs. 1 and 2), demonstrating a durable response to targeted ALK inhibition surpassing conventional systemic myeloma therapy including autologous stem cell transplantation.Fig. 1 PET Scan results.
A Before initiation of Alectinib. Foci of increased uptake in a mediastinal lymph node (max SUV 6.3), retrocaval lymph node (max SUV 10.6), right T3/T4 intervertebral foramen (max SUV 14) on PET-CT. B Complete response after 2 months of alectinib. Complete resolution of prior noted upper thoracic spine lesion and upper abdominal pericaval nodule.
Fig. 2 MRI Brain before and after Loralatinib treatment.
A, B, C MRI of the brain before starting Lorlatinib (pre-treatment) showing innumerable diffuse enhancing lesions with surrounding vasogenic edema, with a right frontal lobe and bilateral cerebellar predominance. D, E, F Treatment response to lorlatinib with markedly decrease in size and number of brain metastasis and markedly improved cerebral edema.
Discussion
This is a unique case demonstrating significant clinical response using commercially available ALK inhibitors in a TFG-ALK fusion in relapsed/refractory NSMM. The ALK gene encodes the ALK tyrosine-kinase protein, a receptor tyrosine kinase, known to have vital roles in normal physiologic processes, including the transmission of extracellular signals implicated in proliferation, differentiation, and survival (Fig. 3). Plasma cell neoplasms are distinct hematologic neoplasms where the diagnosis is based on morphology, immunohistochemistry, FISH, and conventional karyotyping. Case studies have previously reported ALK fusion partners EML4-ALK and CLTC-ALK in these patients6,10.Fig. 3 TFG-ALK fusion and downstream pathway activation.
TFG-ALK fusion product is displayed as a t(3;2) fusion at exon 4 of TFG (blue) and exon 20 of ALK (red). The point of the fusion is indicated by the yellow triangle. The druggable ALK kinase domain resides downstream of ALK exon 20. The upregulated ALK pathway by means of fusion product is implicated in many oncogenic cellular pathways including JAK/STAT, PI3K/mTOR, and RAS/RAF.
The TFG was previously identified as a fusion partner for ALK in cases of Anaplastic large cell lymphoma (ALCL) t(2;3) (p23;q21). The ALK breakpoint in these translocations was the same as in the classical t(2:5). The chimeric protein contains cytoplasmic domain ALK and coiled-coil domain of TFG. The fusion protein was thus able to dimerize, resulting in constitutive kinase activity11. Alectinib is currently Food and Drug Administration (FDA) approved for ALK-positive metastatic NSCLC. It is an orally bioavailable TKI that inhibits ALK and RET proteins by preventing their phosphorylation. The inhibition of activation of ALK impairs downstream signaling of cell proliferation12. Lorlatinib is approved in NSCLC carrying ALK fusion and has shown superior intracranial activity even in patients treated with other ALK inhibitors13. Therefore, it was an ideal choice for our patient after CNS metastasis development.
Our case highlights that a small percentage of patients with plasma cell neoplasms carries ALK fusion and may benefit from ALK inhibition. The diagnosis of ALK+ NSMM versus large B cell lymphoma is challenging because of its rarity, unique morphologic characteristics, and unusual immunophenotypic features, which significantly overlap with other hematologic and nonhematologic neoplasms. Little is known about the clinical behavior of NSMM. We acknowledge that the clinical behavior of NSMM may resemble plasmablastic lymphoma. Due to these concerns, we have obtained multiple opinions on pathology and there is a uniform consensus on the diagnosis of plasmacytomas (NSMM). In addition, ALK-1 stain and EBV stain were absent on plasmacytomas. We believe 17p deletion, which is considered a high-risk mutation in these patients, is most likely the cause of aggressive clinical behavior in our case. This case demonstrates the potential role of next-generation sequencing (NGS) in NSMM, a disease where NGS is not currently standard of care and morphological or immunophenotypical features define diagnosis and influence treatment decisions. NGS may identify unrecognized targetable oncogenic drivers such as ALK-fusions. Detection of these gene alterations not only improves our understanding of disease pathogenesis but may also be used to exploit the therapeutic vulnerabilities of these tumors. The therapeutic success seen in this case emphasizes the need to identify such molecular targets and unique driver alterations, especially in the relapsed setting with a disease that was refractory to traditional treatment options. Our knowledge of mechanisms involved in MM, especially NSMM oncogenesis, is incomplete and further molecular studies are warranted to better understand biological underpinnings that may improve outcomes in these patients. After failing more than five lines of systemic treatment, our patient is currently in clinical and radiographic remission with ALK inhibitor over two years. Our case is a successful example of utilizing NGS-based mutational profiling and incorporating unconventional targeted agents into clinical practice in a rare disease.
Methods
The patient provided written informed consent for carrying out Next-Generation Sequencing and publication of case reports using CLIA certified commercially available Nant platform, as previously described14. The analysis is also described in the Nant GPS report. Briefly, DNA libraries were prepared using the KAPA Hyper prep kit and sequencing on Illumina sequencing platform. DNA sequencing data was aligned to Genome Reference Consortium Human Build 37 using Burrows-Wheeler Aligner15. The germline, somatic variant detection, insertion, and deletions were carried out using the NantOmics Contraster pipeline16–18. RNA-seq libraries were prepared using KAPA Stranded RNA-Seq with RiboErase kit and sequenced on the Illumina Sequencing platform. RNA sequencing data was aligned used bowtie219. RNA transcript expression was assessed by RSEM20. RNA fusions are detected using transcriptome-aligned RNA sequencing data. When there is evidence of gene-fusion using clusters of spanning reads between two transcripts, the Nant team performs de novo assembly on all sequencing data to detect the precise location of fusion transcript. Only fusion with open reading frames that extend to the downstream partner’s stop codon is reported.
The patient was treated with lorlatinib and alectinib within an individual program after informed consent. IRB approval (St. Luke’s Hospital, Kansas City, MO) was waived by the IRB.
Imaging
PET-CT and MRI imaging were obtained as standard of care.
Reporting summary
Further information on research design is available in the Nature Research Reporting Summary linked to this article.
Supplementary information
Supplementary Information
Reporting Summary
Supplementary information
The online version contains supplementary material available at 10.1038/s41525-021-00186-9.
Acknowledgements
We would like to thank Roche and Pfizer for their support in providing compassionate use of medication.
Author contributions
A.M., J.S., S.R. conceived the idea and design the study and drafted the initial manuscript and supervision of the work. S.A., P.R. contributed equally in data gathering and manuscript writing. B.G. provided pharmacological details on the patient. D.N. and S.N. provided details on pathology. T.C., S.L., A.S., A.P., T.K., M.L. reviewed the draft and provided meaningful addition to the manuscript. A.M. and S.R. supervised the project. All authors again approved of the final changes before submission.
Data availability
The authors declare that data supporting the findings of this study are available within the paper. RAW data files Including FASTQ and BAM files are the property of commercial platform NANTOMICS and authors do not have access to these files. The de-identified HIPAA compliant clinical Genomics report of the current study is available.
Competing interests
The authors declare no competing financial or non-financial interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33731690 | 19,386,747 | 2021-03-17 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Urachal carcinoma revealed by isolated hematuria.
Urachal carcinoma is an aggressive and rare neoplasia of bladder cancer involving the urachus. The diagnostic failure is due to its insidious development as well as its non-specific clinical signs. Management constitutes a real dilemma for urological surgeons. We describe two pathological cases of urachal adenocarcinoma revealed by isolated hematuria.
1 Introduction
Urachal adenocarcinoma is an extremely rare tumor that accounts for less than 1% of all bladder cancers [1]. It is characterized by three clues, late presentation of symptoms, early local invasion and distant metastasis which determines its poor prognosis [2]. The scarcity of cases explains the low number of studies carried out and an evidence-based management strategy is lacking.
The histogenesis is not yet well elucidated, it is based on two rather old hypotheses, the metaplastic theory and the dysplastic theory. Various recommended treatments based on surgery first [1]. The role of chemotherapy and radiotherapy is not yet well established. The prognosis of these tumors remains poor in the majority of cases. We describe two pathological cases of urachal adenocarcinoma revealed by isolated hematuria reported according to the SCARE 2020 criteria [2].
1.1 Case presentation
1.1.1 Case 1
Mr. E.A., 46 years old, father of 6 children, the patient had a history of pulmonary tuberculosis treated 20 years ago and pericardial effusion drained 6 years ago, chronic tobacco user at 26 PA weaned 7 years ago. Symptoms go back to 4 months, marked by the appearance of terminal clot hematuria without other associated signs.
The abdominal examination is without abnormalities. The rectal examination finds a homogeneous prostate of 25 g without a suspect nodule. All evolving in a context of declining general condition (ASA2).
Abdominal ultrasound revealed a heterogeneous tissue process budding endovesical, the site of a few cystic areas and calcifications, with irregular contours, vascularized by color Doppler. This process measuring 67.4 × 53 × 42.4mm, continues at the top and follows the path of the urachus (Fig. 1).Fig. 1 Ultrasound bladder revealed a heterogeneous tissue process budding endovesically.
Fig. 1
The patient underwent a cystoscopy which found a budding tumor with a large implantation base in the anterior wall and bladder dome. The histological study, after endoscopic resection, revealed a tumor proliferation made up of tall columnar cells, provided with a large nucleus, a fine chromatin. These cells are arranged in a villous structure, and dilated tubes filled with mucus. It is an isolated tubulovillous adenocarcinoma and infiltrating the superficial chorion of the bladder mucosa.
An immunohistochemical study which objectified an aspect compatible with a moderately differentiated CK7 positive adenocarcinoma (TTF 1 and CK20 are negative).
Computed tomography revealed the presence of a budding wall thickening of the anterior wall of the bladder, with endo and exophytic development in the peritoneum with preservation of a fatty border of separation with the digestive loops. It measures 52 × 49 mm. He also presents in the lungs an inferior left lobe tissue process (Fig. 2, Fig. 3).Fig. 2 Abdomino-pelvic CT scan showed budding wall thickening of the anterior wall of the bladder.
Fig. 2
Fig. 3 Abdomino-pelvic CT scan revealed wall thickening, budding from the anterior wall of the bladder.
Fig. 3
The chest x-ray showed a left basal opacity and at the level of the left middle arch associated with a mediastinal widening with widening of the angle of the carina (Fig. 4).Fig. 4 X-ray of chest face revealed opacity at the level of the left middle arch with opening of the angle of the keel.
Fig. 4
The patient underwent a bronchoscopy which showed a budding tumor located at the bottom of the left main bronchus with thickened keel. The bronchial biopsy discovers the presence of glandular-looking carcinomatous masses, concluding in a bronchial localization of a glandular-like carcinoma suggesting a secondary localization of a urachal adenocarcinoma.
After multidisciplinary consultation, it was decided to treat the patient with chemotherapy alone due to the metastatic aspect. He received three courses of Folfox-type chemotherapy. Fifteen days later, he presented aplastic anemia with grade 3 mucositis and oral candidiasis.
The patient received medical treatment, rehydration, and increased monitoring for the risk of infection. After his discharge, the patient was lost to follow-up.
1.1.2 Case 2
Mr. L.M, 52 years old, 30 pack-year smoking history. The symptoms go back to 1 month marked by the appearance of a terminal clotting hematuria without other urinary disorders, all evolving in a context of preservation of the general condition.
The physical examination found hypogastric pain without a palpable mass, the lumbar fossae were free, The digital rectal examination found a firm prostate of 20 g, without suspicious nodules and the remainder of the clinical examination was unremarkable.
The abdominal ultrasound revealed a tumor mass of the anterior wall of the bladder associated with dilation of the intestinal loops.
The cystoscopy found a budding tumor of 4 cm located at the level of the bladder dome. The histological study, after endoscopic resection, shows a bladder localization of a colloid mucous adenocarcinoma infiltrating the muscularis (Detrusor): pT2 at least.
An immunohistochemical study was carried out to discuss the primary or secondary nature of this tumor, in particular CK7, CK20, PSA, and CDX2, this analysis revealed an immunohistochemical aspect compatible with a bladder localization of an adenocarcinoma of digestive origin (CK20 and CDX2 are positive, CK7 and PSA are negative).
Computed tomography showed a circumferential infiltration of the anterior bladder wall related to a tumor of the urachus (Fig. 5). The rectosigmoidoscopy looking for a neighboring tumor was performed twice and did not reveal anything in particular. The chest x-ray was normal.Fig. 5 Computed tomography showed circumferential infiltration of the anterior bladder wall related to a tumor of the urachus.
Fig. 5
The patient refused the surgical treatment proposed by the oncology-urology committee, which consisted of a cystectomy. Six months later, the patient was admitted for consultation with a deterioration in general condition.
Computed tomography showed a voluminous perivesical process with endo and exo-vesical development, related to the urachus tumor measuring 72 × 61mm, arriving in contact with the umbilicus, of heterogeneous density with area of necrosis, site of microcalcifications central and peripheral (Fig. 6).Fig. 6 Abdomino-pelvic CT scan demonstrated a large perivesical process with endo and exo-vesical development related to the urachus tumor.
Fig. 6
PET-SCAN demonstrated a hypermetabolic partially calcified tumor process located in the pre-bladder space. Associated with mediastinal lymph nodes, diffuse bone lesions, and abdominal and pelvic lymph nodes (Fig. 7, Fig. 8, Fig. 9).Fig. 7 PET-SCAN showed a partly calcified hypermetabolic tumor process located in the pre-bladder space. Associated with mediastinal lymph nodes, diffuse bone lesions, abdominal and pelvic lymph nodes.
Fig. 7
Fig. 8 PET-SCAN revealed a partially calcified hypermetabolic tumor process located in the retropubic space. Associated with mediastinal lymph nodes, diffuse bone lesions, abdominal and pelvic lymph nodes.
Fig. 8
Fig. 9 PET-SCAN objectified hypermetabolic lesions inside the left psoas, suggesting a large lymphadenopathy.
Fig. 9
After a multidisciplinary consultation meeting, it was decided to start palliative chemotherapy based on capecitabine 1500 mg/day in three doses per day for 15 days. After a week of treatment, the patient developed eating disorders with dizziness, vomiting, and diffuse bone pain. Analgesic rehabilitation and an adequate nutritional regime have been implemented for better support. An evaluation at 3 months shows a good tolerance to the chemotherapy.
2 Discussion
Urachal adenocarcinoma is an extremely rare tumor that accounts for less than 1% of all bladder cancers [1]. The incidence of urachal adenocarcinoma is estimated to be 0.01% of all cancers in adults. It accounts for 0.5–2% of all bladder tumors and 20–40% of primary bladder adenocarcinomas [3,4].
The majority of urachal tumors 93% are adenocarcinomas, and 48% produce mucin [[5], [6], [7]]. More than half of patients with adenocarcinoma of urachus are over 50 years old (58%) [6]. In previous studies, the average age of diagnosis ranged from 50 to 58 years [[8], [9], [10]].
For JOHNSON, who presented the largest world series in his time, it is difficult to incriminate the role of intra-vesical carcinogens (tobacco, chemical agents of paint such as arylamines, cyclophosphamide, etc.), because even if the urachus was permeable, the urinary reflux inside seems unlikely because of its narrow caliber and the presence of epithelial secretions which obstruct the lumen.
Because urachal cancer is poorly symptomatic, patients often present at diagnosis with a more advanced stage and a poor prognosis. The clinical signs are generally determined by the location, volume and possible extension to neighboring organs. Hematuria is the main symptom, it occurs in 90% of patients but is rarely isolated.
Voiding disturbances may manifest as signs of bladder irritation such as urination burns, urge, or pollakiuria. They reflect bladder irritation secondary to parietal invasion and the growth of the tumor above the bladder, which interferes with bladder dynamics. Obstructive signs such as dysuria can also be seen and are rather due to infiltration of the bladder wall.
The emission of mucus in the urine is rare and is only present in 25% of cases, this mucus secretion when it exists is highly suggestive of a mucosecreting adenocarcinoma (but not specific to urachal).
Hypogastric pain can be present in patients, like suprapubic pain, which was the case in only one patient in our study. A sensitive suprapubic mass can be found clinically in 25% of cases. The umbilical aspect such as an umbilical deformity with emission of pus, or blood can be revealing according to the Descazeaud study. The metastases were reported by VERGOS in a case of urachal adenocarcinoma revealed by skin metastases, The incidental finding is usually given the clinical latency [11].
The bladder ultrasound specifies the ultrasound criteria of the median mass, makes it possible to detect bladder invasion and to look for possible metastatic locations.
Computed tomography makes it possible to better visualize the extra-bladder part of the tumor, to assess the possible extension to neighboring organs, and to look for lymph node or metastatic involvement. Calcifications are found in 5–10% of these tumors [12].
Regarding the tumor site, the major part of the tumor can be seen outside the bladder lumen (88% of cases), and invasion of the bladder wall is observed in 92% of adenocarcinomas. Distant metastases are found in 48% of cases.
On MRI, sagittal images are important in defining the location of the tumor. High-intensity focal areas on the T2 sequence are produced by the mucosal component and are strongly suggestive of adenocarcinoma. The solid component is isointense to soft tissue on T1 and improves post-contrast administration.
Besides, slices in sagittal reconstruction by MRI are interesting for specifying the surgical approach.
Cystoscopy with biopsy is the key examination, it allows visualization of the location, size, and degree of invasion as well as the performance of a biopsy. Eighty percent of cases the intravesical part of the tumor, located at the level of the bladder dome [13].
Tumor markers namely CA 125, carbohydrate-antigen 19-9 (CA 19-9), and carcinoembryonic antigen (CEA) are of great interest for post-operative follow-up and monitoring of therapeutic efficacy [14].
As part of an extension assessment, it is imperatively recommended to perform an upper gastrointestinal endoscopy, a colonoscopy and a gynecological examination in search of a primary and/or a secondary location of the adenocarcinoma of the urachus. In our study, all of our patients underwent a complete clinical workup with pelvic examinations and colonoscopy, endoscopy which came back negative.
A work-up combining an upper gastrointestinal endoscopy, colonoscopy, and gynecological examination should be performed to rule out an extension to urachus of colorectal, gastric, or gynecological cancer.
There is currently no effective treatment for this rare disease, surgery is the main treatment option [15]. No definitive evidence regarding the curative effect of chemotherapy and radiotherapy. Various protocols have been studied, some based on cisplatin, others based on fluoro-uracil [15].
The tumor generally progresses towards the extension to neighboring organs (rectal, colic, and uterine) and towards the anterior abdominal wall. Lymph node extension is early, the tumor spreads lymphatically to the iliac, obturator, preaortic and cervical lymph nodes. About 21% of affected patients had distant metastasis at their first presentation. The main metastatic sites are lymph node, pulmonary, bone, and peritoneal. Other sites are also possible, such as the ovaries and peri-rectal soft tissue. The most frequent local recurrences are localized to the pelvis, the bladder, and the abdominal wall [16].
3 Conclusion
Urachal adenocarcinoma is a very rare tumor accounting for 0.2–2% of malignant bladder tumors. They affect men twice as much as women. The histogenesis is not yet elucidated, the metaplastic theory is however the most accepted, adenocarcinoma represents the most frequent histological type, 85% of cases. Although the treatment is not well codified but early diagnosis, radical surgery and adjuvant chemotherapy remains the gold standard in the management of this neoplasia.
Sources of funding
Not applicable.
Guarantor
Dr. Jandou issam.
Ethical approval
The study committee of the jura sud hospital center approves the favorable opinion to publish this work.
Consent to publication
The consent to publish this information was obtained from study participants. We confirm that written proof of consent to publish study participants are available when requested and at any time.
Author's contributions
Dr. IJ, Dr. EA analysed and performed the literature research, Pr. AM, Pr. MD, Pr. AD, Pr. RA performed the examination and performed the scientific validation of the manuscript. Issam Jandou was the major contributors to the writing of the manuscript. All authors read and approved the manuscript.
Trial registry number
Name of the registry:
Unique Identifying number or registration ID:
Hyperlink to your specific registration (must be publicly accessible and will be checked):
Availability of data and material
The datasets in this article are available in the repository of the urology database, Chu Ibn-Rochd Casablanca, upon request, from the corresponding author.
Declaration of competing interest
The authors state that they do not have competing interests. | FLUOROURACIL, LEUCOVORIN CALCIUM, OXALIPLATIN | DrugsGivenReaction | CC BY | 33732451 | 19,185,715 | 2021-03 |
What was the dosage of drug 'FLUOROURACIL'? | Urachal carcinoma revealed by isolated hematuria.
Urachal carcinoma is an aggressive and rare neoplasia of bladder cancer involving the urachus. The diagnostic failure is due to its insidious development as well as its non-specific clinical signs. Management constitutes a real dilemma for urological surgeons. We describe two pathological cases of urachal adenocarcinoma revealed by isolated hematuria.
1 Introduction
Urachal adenocarcinoma is an extremely rare tumor that accounts for less than 1% of all bladder cancers [1]. It is characterized by three clues, late presentation of symptoms, early local invasion and distant metastasis which determines its poor prognosis [2]. The scarcity of cases explains the low number of studies carried out and an evidence-based management strategy is lacking.
The histogenesis is not yet well elucidated, it is based on two rather old hypotheses, the metaplastic theory and the dysplastic theory. Various recommended treatments based on surgery first [1]. The role of chemotherapy and radiotherapy is not yet well established. The prognosis of these tumors remains poor in the majority of cases. We describe two pathological cases of urachal adenocarcinoma revealed by isolated hematuria reported according to the SCARE 2020 criteria [2].
1.1 Case presentation
1.1.1 Case 1
Mr. E.A., 46 years old, father of 6 children, the patient had a history of pulmonary tuberculosis treated 20 years ago and pericardial effusion drained 6 years ago, chronic tobacco user at 26 PA weaned 7 years ago. Symptoms go back to 4 months, marked by the appearance of terminal clot hematuria without other associated signs.
The abdominal examination is without abnormalities. The rectal examination finds a homogeneous prostate of 25 g without a suspect nodule. All evolving in a context of declining general condition (ASA2).
Abdominal ultrasound revealed a heterogeneous tissue process budding endovesical, the site of a few cystic areas and calcifications, with irregular contours, vascularized by color Doppler. This process measuring 67.4 × 53 × 42.4mm, continues at the top and follows the path of the urachus (Fig. 1).Fig. 1 Ultrasound bladder revealed a heterogeneous tissue process budding endovesically.
Fig. 1
The patient underwent a cystoscopy which found a budding tumor with a large implantation base in the anterior wall and bladder dome. The histological study, after endoscopic resection, revealed a tumor proliferation made up of tall columnar cells, provided with a large nucleus, a fine chromatin. These cells are arranged in a villous structure, and dilated tubes filled with mucus. It is an isolated tubulovillous adenocarcinoma and infiltrating the superficial chorion of the bladder mucosa.
An immunohistochemical study which objectified an aspect compatible with a moderately differentiated CK7 positive adenocarcinoma (TTF 1 and CK20 are negative).
Computed tomography revealed the presence of a budding wall thickening of the anterior wall of the bladder, with endo and exophytic development in the peritoneum with preservation of a fatty border of separation with the digestive loops. It measures 52 × 49 mm. He also presents in the lungs an inferior left lobe tissue process (Fig. 2, Fig. 3).Fig. 2 Abdomino-pelvic CT scan showed budding wall thickening of the anterior wall of the bladder.
Fig. 2
Fig. 3 Abdomino-pelvic CT scan revealed wall thickening, budding from the anterior wall of the bladder.
Fig. 3
The chest x-ray showed a left basal opacity and at the level of the left middle arch associated with a mediastinal widening with widening of the angle of the carina (Fig. 4).Fig. 4 X-ray of chest face revealed opacity at the level of the left middle arch with opening of the angle of the keel.
Fig. 4
The patient underwent a bronchoscopy which showed a budding tumor located at the bottom of the left main bronchus with thickened keel. The bronchial biopsy discovers the presence of glandular-looking carcinomatous masses, concluding in a bronchial localization of a glandular-like carcinoma suggesting a secondary localization of a urachal adenocarcinoma.
After multidisciplinary consultation, it was decided to treat the patient with chemotherapy alone due to the metastatic aspect. He received three courses of Folfox-type chemotherapy. Fifteen days later, he presented aplastic anemia with grade 3 mucositis and oral candidiasis.
The patient received medical treatment, rehydration, and increased monitoring for the risk of infection. After his discharge, the patient was lost to follow-up.
1.1.2 Case 2
Mr. L.M, 52 years old, 30 pack-year smoking history. The symptoms go back to 1 month marked by the appearance of a terminal clotting hematuria without other urinary disorders, all evolving in a context of preservation of the general condition.
The physical examination found hypogastric pain without a palpable mass, the lumbar fossae were free, The digital rectal examination found a firm prostate of 20 g, without suspicious nodules and the remainder of the clinical examination was unremarkable.
The abdominal ultrasound revealed a tumor mass of the anterior wall of the bladder associated with dilation of the intestinal loops.
The cystoscopy found a budding tumor of 4 cm located at the level of the bladder dome. The histological study, after endoscopic resection, shows a bladder localization of a colloid mucous adenocarcinoma infiltrating the muscularis (Detrusor): pT2 at least.
An immunohistochemical study was carried out to discuss the primary or secondary nature of this tumor, in particular CK7, CK20, PSA, and CDX2, this analysis revealed an immunohistochemical aspect compatible with a bladder localization of an adenocarcinoma of digestive origin (CK20 and CDX2 are positive, CK7 and PSA are negative).
Computed tomography showed a circumferential infiltration of the anterior bladder wall related to a tumor of the urachus (Fig. 5). The rectosigmoidoscopy looking for a neighboring tumor was performed twice and did not reveal anything in particular. The chest x-ray was normal.Fig. 5 Computed tomography showed circumferential infiltration of the anterior bladder wall related to a tumor of the urachus.
Fig. 5
The patient refused the surgical treatment proposed by the oncology-urology committee, which consisted of a cystectomy. Six months later, the patient was admitted for consultation with a deterioration in general condition.
Computed tomography showed a voluminous perivesical process with endo and exo-vesical development, related to the urachus tumor measuring 72 × 61mm, arriving in contact with the umbilicus, of heterogeneous density with area of necrosis, site of microcalcifications central and peripheral (Fig. 6).Fig. 6 Abdomino-pelvic CT scan demonstrated a large perivesical process with endo and exo-vesical development related to the urachus tumor.
Fig. 6
PET-SCAN demonstrated a hypermetabolic partially calcified tumor process located in the pre-bladder space. Associated with mediastinal lymph nodes, diffuse bone lesions, and abdominal and pelvic lymph nodes (Fig. 7, Fig. 8, Fig. 9).Fig. 7 PET-SCAN showed a partly calcified hypermetabolic tumor process located in the pre-bladder space. Associated with mediastinal lymph nodes, diffuse bone lesions, abdominal and pelvic lymph nodes.
Fig. 7
Fig. 8 PET-SCAN revealed a partially calcified hypermetabolic tumor process located in the retropubic space. Associated with mediastinal lymph nodes, diffuse bone lesions, abdominal and pelvic lymph nodes.
Fig. 8
Fig. 9 PET-SCAN objectified hypermetabolic lesions inside the left psoas, suggesting a large lymphadenopathy.
Fig. 9
After a multidisciplinary consultation meeting, it was decided to start palliative chemotherapy based on capecitabine 1500 mg/day in three doses per day for 15 days. After a week of treatment, the patient developed eating disorders with dizziness, vomiting, and diffuse bone pain. Analgesic rehabilitation and an adequate nutritional regime have been implemented for better support. An evaluation at 3 months shows a good tolerance to the chemotherapy.
2 Discussion
Urachal adenocarcinoma is an extremely rare tumor that accounts for less than 1% of all bladder cancers [1]. The incidence of urachal adenocarcinoma is estimated to be 0.01% of all cancers in adults. It accounts for 0.5–2% of all bladder tumors and 20–40% of primary bladder adenocarcinomas [3,4].
The majority of urachal tumors 93% are adenocarcinomas, and 48% produce mucin [[5], [6], [7]]. More than half of patients with adenocarcinoma of urachus are over 50 years old (58%) [6]. In previous studies, the average age of diagnosis ranged from 50 to 58 years [[8], [9], [10]].
For JOHNSON, who presented the largest world series in his time, it is difficult to incriminate the role of intra-vesical carcinogens (tobacco, chemical agents of paint such as arylamines, cyclophosphamide, etc.), because even if the urachus was permeable, the urinary reflux inside seems unlikely because of its narrow caliber and the presence of epithelial secretions which obstruct the lumen.
Because urachal cancer is poorly symptomatic, patients often present at diagnosis with a more advanced stage and a poor prognosis. The clinical signs are generally determined by the location, volume and possible extension to neighboring organs. Hematuria is the main symptom, it occurs in 90% of patients but is rarely isolated.
Voiding disturbances may manifest as signs of bladder irritation such as urination burns, urge, or pollakiuria. They reflect bladder irritation secondary to parietal invasion and the growth of the tumor above the bladder, which interferes with bladder dynamics. Obstructive signs such as dysuria can also be seen and are rather due to infiltration of the bladder wall.
The emission of mucus in the urine is rare and is only present in 25% of cases, this mucus secretion when it exists is highly suggestive of a mucosecreting adenocarcinoma (but not specific to urachal).
Hypogastric pain can be present in patients, like suprapubic pain, which was the case in only one patient in our study. A sensitive suprapubic mass can be found clinically in 25% of cases. The umbilical aspect such as an umbilical deformity with emission of pus, or blood can be revealing according to the Descazeaud study. The metastases were reported by VERGOS in a case of urachal adenocarcinoma revealed by skin metastases, The incidental finding is usually given the clinical latency [11].
The bladder ultrasound specifies the ultrasound criteria of the median mass, makes it possible to detect bladder invasion and to look for possible metastatic locations.
Computed tomography makes it possible to better visualize the extra-bladder part of the tumor, to assess the possible extension to neighboring organs, and to look for lymph node or metastatic involvement. Calcifications are found in 5–10% of these tumors [12].
Regarding the tumor site, the major part of the tumor can be seen outside the bladder lumen (88% of cases), and invasion of the bladder wall is observed in 92% of adenocarcinomas. Distant metastases are found in 48% of cases.
On MRI, sagittal images are important in defining the location of the tumor. High-intensity focal areas on the T2 sequence are produced by the mucosal component and are strongly suggestive of adenocarcinoma. The solid component is isointense to soft tissue on T1 and improves post-contrast administration.
Besides, slices in sagittal reconstruction by MRI are interesting for specifying the surgical approach.
Cystoscopy with biopsy is the key examination, it allows visualization of the location, size, and degree of invasion as well as the performance of a biopsy. Eighty percent of cases the intravesical part of the tumor, located at the level of the bladder dome [13].
Tumor markers namely CA 125, carbohydrate-antigen 19-9 (CA 19-9), and carcinoembryonic antigen (CEA) are of great interest for post-operative follow-up and monitoring of therapeutic efficacy [14].
As part of an extension assessment, it is imperatively recommended to perform an upper gastrointestinal endoscopy, a colonoscopy and a gynecological examination in search of a primary and/or a secondary location of the adenocarcinoma of the urachus. In our study, all of our patients underwent a complete clinical workup with pelvic examinations and colonoscopy, endoscopy which came back negative.
A work-up combining an upper gastrointestinal endoscopy, colonoscopy, and gynecological examination should be performed to rule out an extension to urachus of colorectal, gastric, or gynecological cancer.
There is currently no effective treatment for this rare disease, surgery is the main treatment option [15]. No definitive evidence regarding the curative effect of chemotherapy and radiotherapy. Various protocols have been studied, some based on cisplatin, others based on fluoro-uracil [15].
The tumor generally progresses towards the extension to neighboring organs (rectal, colic, and uterine) and towards the anterior abdominal wall. Lymph node extension is early, the tumor spreads lymphatically to the iliac, obturator, preaortic and cervical lymph nodes. About 21% of affected patients had distant metastasis at their first presentation. The main metastatic sites are lymph node, pulmonary, bone, and peritoneal. Other sites are also possible, such as the ovaries and peri-rectal soft tissue. The most frequent local recurrences are localized to the pelvis, the bladder, and the abdominal wall [16].
3 Conclusion
Urachal adenocarcinoma is a very rare tumor accounting for 0.2–2% of malignant bladder tumors. They affect men twice as much as women. The histogenesis is not yet elucidated, the metaplastic theory is however the most accepted, adenocarcinoma represents the most frequent histological type, 85% of cases. Although the treatment is not well codified but early diagnosis, radical surgery and adjuvant chemotherapy remains the gold standard in the management of this neoplasia.
Sources of funding
Not applicable.
Guarantor
Dr. Jandou issam.
Ethical approval
The study committee of the jura sud hospital center approves the favorable opinion to publish this work.
Consent to publication
The consent to publish this information was obtained from study participants. We confirm that written proof of consent to publish study participants are available when requested and at any time.
Author's contributions
Dr. IJ, Dr. EA analysed and performed the literature research, Pr. AM, Pr. MD, Pr. AD, Pr. RA performed the examination and performed the scientific validation of the manuscript. Issam Jandou was the major contributors to the writing of the manuscript. All authors read and approved the manuscript.
Trial registry number
Name of the registry:
Unique Identifying number or registration ID:
Hyperlink to your specific registration (must be publicly accessible and will be checked):
Availability of data and material
The datasets in this article are available in the repository of the urology database, Chu Ibn-Rochd Casablanca, upon request, from the corresponding author.
Declaration of competing interest
The authors state that they do not have competing interests. | 3 CYCLIC | DrugDosageText | CC BY | 33732451 | 19,185,715 | 2021-03 |
What was the dosage of drug 'LEUCOVORIN CALCIUM'? | Urachal carcinoma revealed by isolated hematuria.
Urachal carcinoma is an aggressive and rare neoplasia of bladder cancer involving the urachus. The diagnostic failure is due to its insidious development as well as its non-specific clinical signs. Management constitutes a real dilemma for urological surgeons. We describe two pathological cases of urachal adenocarcinoma revealed by isolated hematuria.
1 Introduction
Urachal adenocarcinoma is an extremely rare tumor that accounts for less than 1% of all bladder cancers [1]. It is characterized by three clues, late presentation of symptoms, early local invasion and distant metastasis which determines its poor prognosis [2]. The scarcity of cases explains the low number of studies carried out and an evidence-based management strategy is lacking.
The histogenesis is not yet well elucidated, it is based on two rather old hypotheses, the metaplastic theory and the dysplastic theory. Various recommended treatments based on surgery first [1]. The role of chemotherapy and radiotherapy is not yet well established. The prognosis of these tumors remains poor in the majority of cases. We describe two pathological cases of urachal adenocarcinoma revealed by isolated hematuria reported according to the SCARE 2020 criteria [2].
1.1 Case presentation
1.1.1 Case 1
Mr. E.A., 46 years old, father of 6 children, the patient had a history of pulmonary tuberculosis treated 20 years ago and pericardial effusion drained 6 years ago, chronic tobacco user at 26 PA weaned 7 years ago. Symptoms go back to 4 months, marked by the appearance of terminal clot hematuria without other associated signs.
The abdominal examination is without abnormalities. The rectal examination finds a homogeneous prostate of 25 g without a suspect nodule. All evolving in a context of declining general condition (ASA2).
Abdominal ultrasound revealed a heterogeneous tissue process budding endovesical, the site of a few cystic areas and calcifications, with irregular contours, vascularized by color Doppler. This process measuring 67.4 × 53 × 42.4mm, continues at the top and follows the path of the urachus (Fig. 1).Fig. 1 Ultrasound bladder revealed a heterogeneous tissue process budding endovesically.
Fig. 1
The patient underwent a cystoscopy which found a budding tumor with a large implantation base in the anterior wall and bladder dome. The histological study, after endoscopic resection, revealed a tumor proliferation made up of tall columnar cells, provided with a large nucleus, a fine chromatin. These cells are arranged in a villous structure, and dilated tubes filled with mucus. It is an isolated tubulovillous adenocarcinoma and infiltrating the superficial chorion of the bladder mucosa.
An immunohistochemical study which objectified an aspect compatible with a moderately differentiated CK7 positive adenocarcinoma (TTF 1 and CK20 are negative).
Computed tomography revealed the presence of a budding wall thickening of the anterior wall of the bladder, with endo and exophytic development in the peritoneum with preservation of a fatty border of separation with the digestive loops. It measures 52 × 49 mm. He also presents in the lungs an inferior left lobe tissue process (Fig. 2, Fig. 3).Fig. 2 Abdomino-pelvic CT scan showed budding wall thickening of the anterior wall of the bladder.
Fig. 2
Fig. 3 Abdomino-pelvic CT scan revealed wall thickening, budding from the anterior wall of the bladder.
Fig. 3
The chest x-ray showed a left basal opacity and at the level of the left middle arch associated with a mediastinal widening with widening of the angle of the carina (Fig. 4).Fig. 4 X-ray of chest face revealed opacity at the level of the left middle arch with opening of the angle of the keel.
Fig. 4
The patient underwent a bronchoscopy which showed a budding tumor located at the bottom of the left main bronchus with thickened keel. The bronchial biopsy discovers the presence of glandular-looking carcinomatous masses, concluding in a bronchial localization of a glandular-like carcinoma suggesting a secondary localization of a urachal adenocarcinoma.
After multidisciplinary consultation, it was decided to treat the patient with chemotherapy alone due to the metastatic aspect. He received three courses of Folfox-type chemotherapy. Fifteen days later, he presented aplastic anemia with grade 3 mucositis and oral candidiasis.
The patient received medical treatment, rehydration, and increased monitoring for the risk of infection. After his discharge, the patient was lost to follow-up.
1.1.2 Case 2
Mr. L.M, 52 years old, 30 pack-year smoking history. The symptoms go back to 1 month marked by the appearance of a terminal clotting hematuria without other urinary disorders, all evolving in a context of preservation of the general condition.
The physical examination found hypogastric pain without a palpable mass, the lumbar fossae were free, The digital rectal examination found a firm prostate of 20 g, without suspicious nodules and the remainder of the clinical examination was unremarkable.
The abdominal ultrasound revealed a tumor mass of the anterior wall of the bladder associated with dilation of the intestinal loops.
The cystoscopy found a budding tumor of 4 cm located at the level of the bladder dome. The histological study, after endoscopic resection, shows a bladder localization of a colloid mucous adenocarcinoma infiltrating the muscularis (Detrusor): pT2 at least.
An immunohistochemical study was carried out to discuss the primary or secondary nature of this tumor, in particular CK7, CK20, PSA, and CDX2, this analysis revealed an immunohistochemical aspect compatible with a bladder localization of an adenocarcinoma of digestive origin (CK20 and CDX2 are positive, CK7 and PSA are negative).
Computed tomography showed a circumferential infiltration of the anterior bladder wall related to a tumor of the urachus (Fig. 5). The rectosigmoidoscopy looking for a neighboring tumor was performed twice and did not reveal anything in particular. The chest x-ray was normal.Fig. 5 Computed tomography showed circumferential infiltration of the anterior bladder wall related to a tumor of the urachus.
Fig. 5
The patient refused the surgical treatment proposed by the oncology-urology committee, which consisted of a cystectomy. Six months later, the patient was admitted for consultation with a deterioration in general condition.
Computed tomography showed a voluminous perivesical process with endo and exo-vesical development, related to the urachus tumor measuring 72 × 61mm, arriving in contact with the umbilicus, of heterogeneous density with area of necrosis, site of microcalcifications central and peripheral (Fig. 6).Fig. 6 Abdomino-pelvic CT scan demonstrated a large perivesical process with endo and exo-vesical development related to the urachus tumor.
Fig. 6
PET-SCAN demonstrated a hypermetabolic partially calcified tumor process located in the pre-bladder space. Associated with mediastinal lymph nodes, diffuse bone lesions, and abdominal and pelvic lymph nodes (Fig. 7, Fig. 8, Fig. 9).Fig. 7 PET-SCAN showed a partly calcified hypermetabolic tumor process located in the pre-bladder space. Associated with mediastinal lymph nodes, diffuse bone lesions, abdominal and pelvic lymph nodes.
Fig. 7
Fig. 8 PET-SCAN revealed a partially calcified hypermetabolic tumor process located in the retropubic space. Associated with mediastinal lymph nodes, diffuse bone lesions, abdominal and pelvic lymph nodes.
Fig. 8
Fig. 9 PET-SCAN objectified hypermetabolic lesions inside the left psoas, suggesting a large lymphadenopathy.
Fig. 9
After a multidisciplinary consultation meeting, it was decided to start palliative chemotherapy based on capecitabine 1500 mg/day in three doses per day for 15 days. After a week of treatment, the patient developed eating disorders with dizziness, vomiting, and diffuse bone pain. Analgesic rehabilitation and an adequate nutritional regime have been implemented for better support. An evaluation at 3 months shows a good tolerance to the chemotherapy.
2 Discussion
Urachal adenocarcinoma is an extremely rare tumor that accounts for less than 1% of all bladder cancers [1]. The incidence of urachal adenocarcinoma is estimated to be 0.01% of all cancers in adults. It accounts for 0.5–2% of all bladder tumors and 20–40% of primary bladder adenocarcinomas [3,4].
The majority of urachal tumors 93% are adenocarcinomas, and 48% produce mucin [[5], [6], [7]]. More than half of patients with adenocarcinoma of urachus are over 50 years old (58%) [6]. In previous studies, the average age of diagnosis ranged from 50 to 58 years [[8], [9], [10]].
For JOHNSON, who presented the largest world series in his time, it is difficult to incriminate the role of intra-vesical carcinogens (tobacco, chemical agents of paint such as arylamines, cyclophosphamide, etc.), because even if the urachus was permeable, the urinary reflux inside seems unlikely because of its narrow caliber and the presence of epithelial secretions which obstruct the lumen.
Because urachal cancer is poorly symptomatic, patients often present at diagnosis with a more advanced stage and a poor prognosis. The clinical signs are generally determined by the location, volume and possible extension to neighboring organs. Hematuria is the main symptom, it occurs in 90% of patients but is rarely isolated.
Voiding disturbances may manifest as signs of bladder irritation such as urination burns, urge, or pollakiuria. They reflect bladder irritation secondary to parietal invasion and the growth of the tumor above the bladder, which interferes with bladder dynamics. Obstructive signs such as dysuria can also be seen and are rather due to infiltration of the bladder wall.
The emission of mucus in the urine is rare and is only present in 25% of cases, this mucus secretion when it exists is highly suggestive of a mucosecreting adenocarcinoma (but not specific to urachal).
Hypogastric pain can be present in patients, like suprapubic pain, which was the case in only one patient in our study. A sensitive suprapubic mass can be found clinically in 25% of cases. The umbilical aspect such as an umbilical deformity with emission of pus, or blood can be revealing according to the Descazeaud study. The metastases were reported by VERGOS in a case of urachal adenocarcinoma revealed by skin metastases, The incidental finding is usually given the clinical latency [11].
The bladder ultrasound specifies the ultrasound criteria of the median mass, makes it possible to detect bladder invasion and to look for possible metastatic locations.
Computed tomography makes it possible to better visualize the extra-bladder part of the tumor, to assess the possible extension to neighboring organs, and to look for lymph node or metastatic involvement. Calcifications are found in 5–10% of these tumors [12].
Regarding the tumor site, the major part of the tumor can be seen outside the bladder lumen (88% of cases), and invasion of the bladder wall is observed in 92% of adenocarcinomas. Distant metastases are found in 48% of cases.
On MRI, sagittal images are important in defining the location of the tumor. High-intensity focal areas on the T2 sequence are produced by the mucosal component and are strongly suggestive of adenocarcinoma. The solid component is isointense to soft tissue on T1 and improves post-contrast administration.
Besides, slices in sagittal reconstruction by MRI are interesting for specifying the surgical approach.
Cystoscopy with biopsy is the key examination, it allows visualization of the location, size, and degree of invasion as well as the performance of a biopsy. Eighty percent of cases the intravesical part of the tumor, located at the level of the bladder dome [13].
Tumor markers namely CA 125, carbohydrate-antigen 19-9 (CA 19-9), and carcinoembryonic antigen (CEA) are of great interest for post-operative follow-up and monitoring of therapeutic efficacy [14].
As part of an extension assessment, it is imperatively recommended to perform an upper gastrointestinal endoscopy, a colonoscopy and a gynecological examination in search of a primary and/or a secondary location of the adenocarcinoma of the urachus. In our study, all of our patients underwent a complete clinical workup with pelvic examinations and colonoscopy, endoscopy which came back negative.
A work-up combining an upper gastrointestinal endoscopy, colonoscopy, and gynecological examination should be performed to rule out an extension to urachus of colorectal, gastric, or gynecological cancer.
There is currently no effective treatment for this rare disease, surgery is the main treatment option [15]. No definitive evidence regarding the curative effect of chemotherapy and radiotherapy. Various protocols have been studied, some based on cisplatin, others based on fluoro-uracil [15].
The tumor generally progresses towards the extension to neighboring organs (rectal, colic, and uterine) and towards the anterior abdominal wall. Lymph node extension is early, the tumor spreads lymphatically to the iliac, obturator, preaortic and cervical lymph nodes. About 21% of affected patients had distant metastasis at their first presentation. The main metastatic sites are lymph node, pulmonary, bone, and peritoneal. Other sites are also possible, such as the ovaries and peri-rectal soft tissue. The most frequent local recurrences are localized to the pelvis, the bladder, and the abdominal wall [16].
3 Conclusion
Urachal adenocarcinoma is a very rare tumor accounting for 0.2–2% of malignant bladder tumors. They affect men twice as much as women. The histogenesis is not yet elucidated, the metaplastic theory is however the most accepted, adenocarcinoma represents the most frequent histological type, 85% of cases. Although the treatment is not well codified but early diagnosis, radical surgery and adjuvant chemotherapy remains the gold standard in the management of this neoplasia.
Sources of funding
Not applicable.
Guarantor
Dr. Jandou issam.
Ethical approval
The study committee of the jura sud hospital center approves the favorable opinion to publish this work.
Consent to publication
The consent to publish this information was obtained from study participants. We confirm that written proof of consent to publish study participants are available when requested and at any time.
Author's contributions
Dr. IJ, Dr. EA analysed and performed the literature research, Pr. AM, Pr. MD, Pr. AD, Pr. RA performed the examination and performed the scientific validation of the manuscript. Issam Jandou was the major contributors to the writing of the manuscript. All authors read and approved the manuscript.
Trial registry number
Name of the registry:
Unique Identifying number or registration ID:
Hyperlink to your specific registration (must be publicly accessible and will be checked):
Availability of data and material
The datasets in this article are available in the repository of the urology database, Chu Ibn-Rochd Casablanca, upon request, from the corresponding author.
Declaration of competing interest
The authors state that they do not have competing interests. | 3 CYCLIC | DrugDosageText | CC BY | 33732451 | 19,185,715 | 2021-03 |
What was the dosage of drug 'OXALIPLATIN'? | Urachal carcinoma revealed by isolated hematuria.
Urachal carcinoma is an aggressive and rare neoplasia of bladder cancer involving the urachus. The diagnostic failure is due to its insidious development as well as its non-specific clinical signs. Management constitutes a real dilemma for urological surgeons. We describe two pathological cases of urachal adenocarcinoma revealed by isolated hematuria.
1 Introduction
Urachal adenocarcinoma is an extremely rare tumor that accounts for less than 1% of all bladder cancers [1]. It is characterized by three clues, late presentation of symptoms, early local invasion and distant metastasis which determines its poor prognosis [2]. The scarcity of cases explains the low number of studies carried out and an evidence-based management strategy is lacking.
The histogenesis is not yet well elucidated, it is based on two rather old hypotheses, the metaplastic theory and the dysplastic theory. Various recommended treatments based on surgery first [1]. The role of chemotherapy and radiotherapy is not yet well established. The prognosis of these tumors remains poor in the majority of cases. We describe two pathological cases of urachal adenocarcinoma revealed by isolated hematuria reported according to the SCARE 2020 criteria [2].
1.1 Case presentation
1.1.1 Case 1
Mr. E.A., 46 years old, father of 6 children, the patient had a history of pulmonary tuberculosis treated 20 years ago and pericardial effusion drained 6 years ago, chronic tobacco user at 26 PA weaned 7 years ago. Symptoms go back to 4 months, marked by the appearance of terminal clot hematuria without other associated signs.
The abdominal examination is without abnormalities. The rectal examination finds a homogeneous prostate of 25 g without a suspect nodule. All evolving in a context of declining general condition (ASA2).
Abdominal ultrasound revealed a heterogeneous tissue process budding endovesical, the site of a few cystic areas and calcifications, with irregular contours, vascularized by color Doppler. This process measuring 67.4 × 53 × 42.4mm, continues at the top and follows the path of the urachus (Fig. 1).Fig. 1 Ultrasound bladder revealed a heterogeneous tissue process budding endovesically.
Fig. 1
The patient underwent a cystoscopy which found a budding tumor with a large implantation base in the anterior wall and bladder dome. The histological study, after endoscopic resection, revealed a tumor proliferation made up of tall columnar cells, provided with a large nucleus, a fine chromatin. These cells are arranged in a villous structure, and dilated tubes filled with mucus. It is an isolated tubulovillous adenocarcinoma and infiltrating the superficial chorion of the bladder mucosa.
An immunohistochemical study which objectified an aspect compatible with a moderately differentiated CK7 positive adenocarcinoma (TTF 1 and CK20 are negative).
Computed tomography revealed the presence of a budding wall thickening of the anterior wall of the bladder, with endo and exophytic development in the peritoneum with preservation of a fatty border of separation with the digestive loops. It measures 52 × 49 mm. He also presents in the lungs an inferior left lobe tissue process (Fig. 2, Fig. 3).Fig. 2 Abdomino-pelvic CT scan showed budding wall thickening of the anterior wall of the bladder.
Fig. 2
Fig. 3 Abdomino-pelvic CT scan revealed wall thickening, budding from the anterior wall of the bladder.
Fig. 3
The chest x-ray showed a left basal opacity and at the level of the left middle arch associated with a mediastinal widening with widening of the angle of the carina (Fig. 4).Fig. 4 X-ray of chest face revealed opacity at the level of the left middle arch with opening of the angle of the keel.
Fig. 4
The patient underwent a bronchoscopy which showed a budding tumor located at the bottom of the left main bronchus with thickened keel. The bronchial biopsy discovers the presence of glandular-looking carcinomatous masses, concluding in a bronchial localization of a glandular-like carcinoma suggesting a secondary localization of a urachal adenocarcinoma.
After multidisciplinary consultation, it was decided to treat the patient with chemotherapy alone due to the metastatic aspect. He received three courses of Folfox-type chemotherapy. Fifteen days later, he presented aplastic anemia with grade 3 mucositis and oral candidiasis.
The patient received medical treatment, rehydration, and increased monitoring for the risk of infection. After his discharge, the patient was lost to follow-up.
1.1.2 Case 2
Mr. L.M, 52 years old, 30 pack-year smoking history. The symptoms go back to 1 month marked by the appearance of a terminal clotting hematuria without other urinary disorders, all evolving in a context of preservation of the general condition.
The physical examination found hypogastric pain without a palpable mass, the lumbar fossae were free, The digital rectal examination found a firm prostate of 20 g, without suspicious nodules and the remainder of the clinical examination was unremarkable.
The abdominal ultrasound revealed a tumor mass of the anterior wall of the bladder associated with dilation of the intestinal loops.
The cystoscopy found a budding tumor of 4 cm located at the level of the bladder dome. The histological study, after endoscopic resection, shows a bladder localization of a colloid mucous adenocarcinoma infiltrating the muscularis (Detrusor): pT2 at least.
An immunohistochemical study was carried out to discuss the primary or secondary nature of this tumor, in particular CK7, CK20, PSA, and CDX2, this analysis revealed an immunohistochemical aspect compatible with a bladder localization of an adenocarcinoma of digestive origin (CK20 and CDX2 are positive, CK7 and PSA are negative).
Computed tomography showed a circumferential infiltration of the anterior bladder wall related to a tumor of the urachus (Fig. 5). The rectosigmoidoscopy looking for a neighboring tumor was performed twice and did not reveal anything in particular. The chest x-ray was normal.Fig. 5 Computed tomography showed circumferential infiltration of the anterior bladder wall related to a tumor of the urachus.
Fig. 5
The patient refused the surgical treatment proposed by the oncology-urology committee, which consisted of a cystectomy. Six months later, the patient was admitted for consultation with a deterioration in general condition.
Computed tomography showed a voluminous perivesical process with endo and exo-vesical development, related to the urachus tumor measuring 72 × 61mm, arriving in contact with the umbilicus, of heterogeneous density with area of necrosis, site of microcalcifications central and peripheral (Fig. 6).Fig. 6 Abdomino-pelvic CT scan demonstrated a large perivesical process with endo and exo-vesical development related to the urachus tumor.
Fig. 6
PET-SCAN demonstrated a hypermetabolic partially calcified tumor process located in the pre-bladder space. Associated with mediastinal lymph nodes, diffuse bone lesions, and abdominal and pelvic lymph nodes (Fig. 7, Fig. 8, Fig. 9).Fig. 7 PET-SCAN showed a partly calcified hypermetabolic tumor process located in the pre-bladder space. Associated with mediastinal lymph nodes, diffuse bone lesions, abdominal and pelvic lymph nodes.
Fig. 7
Fig. 8 PET-SCAN revealed a partially calcified hypermetabolic tumor process located in the retropubic space. Associated with mediastinal lymph nodes, diffuse bone lesions, abdominal and pelvic lymph nodes.
Fig. 8
Fig. 9 PET-SCAN objectified hypermetabolic lesions inside the left psoas, suggesting a large lymphadenopathy.
Fig. 9
After a multidisciplinary consultation meeting, it was decided to start palliative chemotherapy based on capecitabine 1500 mg/day in three doses per day for 15 days. After a week of treatment, the patient developed eating disorders with dizziness, vomiting, and diffuse bone pain. Analgesic rehabilitation and an adequate nutritional regime have been implemented for better support. An evaluation at 3 months shows a good tolerance to the chemotherapy.
2 Discussion
Urachal adenocarcinoma is an extremely rare tumor that accounts for less than 1% of all bladder cancers [1]. The incidence of urachal adenocarcinoma is estimated to be 0.01% of all cancers in adults. It accounts for 0.5–2% of all bladder tumors and 20–40% of primary bladder adenocarcinomas [3,4].
The majority of urachal tumors 93% are adenocarcinomas, and 48% produce mucin [[5], [6], [7]]. More than half of patients with adenocarcinoma of urachus are over 50 years old (58%) [6]. In previous studies, the average age of diagnosis ranged from 50 to 58 years [[8], [9], [10]].
For JOHNSON, who presented the largest world series in his time, it is difficult to incriminate the role of intra-vesical carcinogens (tobacco, chemical agents of paint such as arylamines, cyclophosphamide, etc.), because even if the urachus was permeable, the urinary reflux inside seems unlikely because of its narrow caliber and the presence of epithelial secretions which obstruct the lumen.
Because urachal cancer is poorly symptomatic, patients often present at diagnosis with a more advanced stage and a poor prognosis. The clinical signs are generally determined by the location, volume and possible extension to neighboring organs. Hematuria is the main symptom, it occurs in 90% of patients but is rarely isolated.
Voiding disturbances may manifest as signs of bladder irritation such as urination burns, urge, or pollakiuria. They reflect bladder irritation secondary to parietal invasion and the growth of the tumor above the bladder, which interferes with bladder dynamics. Obstructive signs such as dysuria can also be seen and are rather due to infiltration of the bladder wall.
The emission of mucus in the urine is rare and is only present in 25% of cases, this mucus secretion when it exists is highly suggestive of a mucosecreting adenocarcinoma (but not specific to urachal).
Hypogastric pain can be present in patients, like suprapubic pain, which was the case in only one patient in our study. A sensitive suprapubic mass can be found clinically in 25% of cases. The umbilical aspect such as an umbilical deformity with emission of pus, or blood can be revealing according to the Descazeaud study. The metastases were reported by VERGOS in a case of urachal adenocarcinoma revealed by skin metastases, The incidental finding is usually given the clinical latency [11].
The bladder ultrasound specifies the ultrasound criteria of the median mass, makes it possible to detect bladder invasion and to look for possible metastatic locations.
Computed tomography makes it possible to better visualize the extra-bladder part of the tumor, to assess the possible extension to neighboring organs, and to look for lymph node or metastatic involvement. Calcifications are found in 5–10% of these tumors [12].
Regarding the tumor site, the major part of the tumor can be seen outside the bladder lumen (88% of cases), and invasion of the bladder wall is observed in 92% of adenocarcinomas. Distant metastases are found in 48% of cases.
On MRI, sagittal images are important in defining the location of the tumor. High-intensity focal areas on the T2 sequence are produced by the mucosal component and are strongly suggestive of adenocarcinoma. The solid component is isointense to soft tissue on T1 and improves post-contrast administration.
Besides, slices in sagittal reconstruction by MRI are interesting for specifying the surgical approach.
Cystoscopy with biopsy is the key examination, it allows visualization of the location, size, and degree of invasion as well as the performance of a biopsy. Eighty percent of cases the intravesical part of the tumor, located at the level of the bladder dome [13].
Tumor markers namely CA 125, carbohydrate-antigen 19-9 (CA 19-9), and carcinoembryonic antigen (CEA) are of great interest for post-operative follow-up and monitoring of therapeutic efficacy [14].
As part of an extension assessment, it is imperatively recommended to perform an upper gastrointestinal endoscopy, a colonoscopy and a gynecological examination in search of a primary and/or a secondary location of the adenocarcinoma of the urachus. In our study, all of our patients underwent a complete clinical workup with pelvic examinations and colonoscopy, endoscopy which came back negative.
A work-up combining an upper gastrointestinal endoscopy, colonoscopy, and gynecological examination should be performed to rule out an extension to urachus of colorectal, gastric, or gynecological cancer.
There is currently no effective treatment for this rare disease, surgery is the main treatment option [15]. No definitive evidence regarding the curative effect of chemotherapy and radiotherapy. Various protocols have been studied, some based on cisplatin, others based on fluoro-uracil [15].
The tumor generally progresses towards the extension to neighboring organs (rectal, colic, and uterine) and towards the anterior abdominal wall. Lymph node extension is early, the tumor spreads lymphatically to the iliac, obturator, preaortic and cervical lymph nodes. About 21% of affected patients had distant metastasis at their first presentation. The main metastatic sites are lymph node, pulmonary, bone, and peritoneal. Other sites are also possible, such as the ovaries and peri-rectal soft tissue. The most frequent local recurrences are localized to the pelvis, the bladder, and the abdominal wall [16].
3 Conclusion
Urachal adenocarcinoma is a very rare tumor accounting for 0.2–2% of malignant bladder tumors. They affect men twice as much as women. The histogenesis is not yet elucidated, the metaplastic theory is however the most accepted, adenocarcinoma represents the most frequent histological type, 85% of cases. Although the treatment is not well codified but early diagnosis, radical surgery and adjuvant chemotherapy remains the gold standard in the management of this neoplasia.
Sources of funding
Not applicable.
Guarantor
Dr. Jandou issam.
Ethical approval
The study committee of the jura sud hospital center approves the favorable opinion to publish this work.
Consent to publication
The consent to publish this information was obtained from study participants. We confirm that written proof of consent to publish study participants are available when requested and at any time.
Author's contributions
Dr. IJ, Dr. EA analysed and performed the literature research, Pr. AM, Pr. MD, Pr. AD, Pr. RA performed the examination and performed the scientific validation of the manuscript. Issam Jandou was the major contributors to the writing of the manuscript. All authors read and approved the manuscript.
Trial registry number
Name of the registry:
Unique Identifying number or registration ID:
Hyperlink to your specific registration (must be publicly accessible and will be checked):
Availability of data and material
The datasets in this article are available in the repository of the urology database, Chu Ibn-Rochd Casablanca, upon request, from the corresponding author.
Declaration of competing interest
The authors state that they do not have competing interests. | 3 CYCLIC | DrugDosageText | CC BY | 33732451 | 19,185,715 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Compression fracture'. | Long-term disease control of metastatic type 2 papillary renal cell carcinoma using local treatment and molecular targeted therapy: A case report.
A 46-year-old man underwent right partial nephrectomy for type 2 papillary renal cell carcinoma (PRCC) in 2011. Lung metastasis and lymph node (LN) metastases around the inferior vena cave appeared in 2012. A right radical nephrectomy and extensive LN dissection was performed and the resection of lung metastasis was performed one month after the nephrectomy. Mediastinal LN metastases occurred in 2013, and resection of the affected LNs was performed. Sunitinib and zoledronic acid was started in 2014 because mediastinal LN swelling and multiple bone metastases appeared. Sunitinib treatment was stopped soon after due to adverse events and axitinib treatment was started. Axitinib was effective and the patient had stable disease for 30 months. Adverse events were successfully controlled by dose reduction and periodic drug withdrawal schedules (for example, 5 days on, 2 days off). Axitinib was further continued for 19 months as the metastatic lesions had progressed slowly. Temsirolimus treatment was started in 2019, but it was stopped after three cycles due to interstitial pneumonia. The patient died 80 months after the initial recurrence. Using multidisciplinary treatment, durable disease control was achieved in a patient with metastatic type 2 PRCC.
Introductions
Recently, the prognosis of patients with metastatic renal cell carcinoma (RCC) has been improved by molecular targeted therapies (1) and immune checkpoint inhibitors (2). However, optimal treatment strategies for metastatic non-clear cell RCC (nccRCC) has yet to be established. In previous studies, molecular targeted therapies, especially sunitinib, have shown clinical efficacy for the treatment of metastatic nccRCC (3-7). The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is recommended at present for metastatic nccRCC. In nccRCC papillary renal cell carcinoma (PRCC) is the leading histology (8). PRCC is divided into type 1 and type 2, with type 2 PRCC showing worse prognosis compared with type 1(9). In phase 2 clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, overall survival (OS) of type1 PRCC was 17.8 months, and that of type 2 was 12.4 months (10).
In this report, we present a patient with metastatic type 2 PRCC whose metastatic lesions were controlled for a long time by multidisciplinary treatments including metastasectomies, axitinib, zoledronic acid (ZA), and radiation therapy.
Case report
A 46-year-old man with hematospermia was presented to a urologic clinic in April, 2011. A right renal tumor was found by ultrasound, and the patient was referred to our hospital. The tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected by contrast-enhanced computed tomography (CT) (Fig. 1A and B). A right partial nephrectomy was performed in July, 2011. Pathological diagnosis was type2 PRCC (Fig. 1C and D). A lung metastasis (S6) and paracaval lymph node (LN) metastases appeared in March, 2012 (Fig. 2A and B). After five cycles of temsirolimus, right radical nephrectomy and extensive LN dissection around the inferior vena cava (IVC) and right common iliac vein were performed in June, 2012, and the resection of the lung metastasis was performed one month after the nephrectomy. Then, radiological complete remission was achieved. LN swellings at the right tracheal bifurcation was found by CT in August, 2013 (Fig. 2C). After three cycles of temsirolimus, mediastinal LN dissection was performed in October, 2013. Mediastinal LNs (Fig. 2D) were swollen again, and multiple bone metastases [sternum, right fifth rib, thoracic spine (5-7th vertebrae), left ilium, and right pubis] appeared in 2014. The clinical course of the patient, including local treatments, medical treatments, and treatment-related adverse events are shown in Fig. 3. Sunitinib (37.5 mg/day) and ZA (4 mg/month) were started in June, 2014. Sunitinib was stopped within two weeks because of adverse events (AEs) including fever, malaise, and liver dysfunction. After the patient had recovered from the AEs, axitinib (10 mg/day) was started as a second-line treatment in July, 2014. ZA was continued after the axitinib administration. Because of diarrhea and hoarseness, the treatment schedule of axitinib was changed to a periodic drug withdrawal schedule (5 days-on, 2 days-off) in October, 2014. Next, the daily dose of axitinib was reduced to 8 mg (5 days-on, 2 days-off) to control severe diarrhea in December, 2014. Stereotactic radiation therapy (total 30 Gray, 10 fractions) was performed for bone metastasis at the left ilium in November, 2015 because only the iliac metastasis appeared to be an active lesion among all bone metastases in the bone scintigraphy. The periodic drug withdrawal schedule of axitinib (8 mg/day, 5 days-on, 2 days-off) was changed to the next schedule (8 mg/day, 4 days-on, 3 days-off) due to renal dysfunction and proteinuria in April, 2017. Mediastinal LN metastases and bone metastases was stable for 30 months after the axitinib administration (Fig. 4). Disease progression was confirmed in June, 2017 due to the appearance of multiple small lung metastases. Because the metastatic lesions progressed slowly after the disease progression, axitinib was continued for another 19 months in accordance with the patient's request. The schedule of axitinib was then changed to a third schedule (8 mg/day, 3 days-on, 3 days-off) due to symptoms of anorexia, dyspnea, and muscle pain in April, 2018. Patient was hospitalized due to severe back pain in September, 2018, and palliative radiotherapy was performed for a compression fracture due to metastasis (L1 lumber vertebrae). Axitinib was stopped in October, 2019. Temsirolimus was then administered, but interstitial pneumonia occurred after three cycles of temsirolimus. Although steroid pulse therapy was performed, respiratory and general condition became worse. The patient died in November, 2019. By multidisciplinary treatments including metastasectomy, axitinib, ZA, and radiation therapy, the patient survived for 80 months after the initial recurrence.
Discussion
This patient with metastatic type 2 PRCC could survive 80 months after the initial recurrence by multidisciplinary treatments including metastasectomies, axitinib, ZA, and radiation therapy. Patients with metastatic type 2 PRCC generally have poor prognosis. In a clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median OS in type 2 PRCC was 12.4 months (10). Metastasectomies and axitinib appeared to be especially effective in the present case.
The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is the recommended treatment for metastatic nccRCC, and cabozantinib and everolimus are options. At the beginning of targeted era, mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, was reportedly effective compared with interferon-α for metastatic nccRCC (11). A comparative study between temsirolimus and tyrosine kinase inhibitors (TKIs) in metastatic nccRCC does not exist at present. The superiority of sunitinib compared with everolimus in nccRCC treatment has been reported in two clinical trials (12,13). The ASPEN trial reported that the progression-free survival (PFS) of sunitinib was longer than that of everolimus (12). The ESPN trial reported that both PFS and OS of sunitinib were longer than those of everolimus (13). Among other TKIs, the overall response rate of pazopanib was reportedly 39% in the treatment of metastatic nccRCC (6). There are few studies evaluating the clinical efficacy of systemic therapies in metastatic PRCC. In clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median PFS and OS were 6.6 and 17.8 months in type 1 PRCC, and 5.5 and 12.4 months in type 2, respectively (10). In a Japanese multicenter study evaluating metastatic PRCC in which most PRCC cases (91.4%) were type 2, the prognosis in the era of targeted therapy (OS=22.5 months) was improved compared with that in the cytokine era (OS=6.3 months). PRCC patients treated with TKIs in both first-line and second-line treatments (OS=31.4 months) showed better prognosis than those with mTOR inhibitors in first-line or second-line (OS=12.9 months) (14).
In our case, the second-line use of axitinib was effective and achieved a durable stable disease (SD). There have been few reports in which axitinib showed efficacies for metastatic PRCC (15,16). In our case, AEs were relieved by dose reduction and the setting of periodic drug withdrawal schedules of axitinib, and axitinib could be continued for a long time. The half-life period of axitinib was reportedly short (4.8-5.9 h) (17). Axitinib has a characteristic that AEs can be relieved in a short period because of its short half-life period. Then, axitinib can be started again after the short drug withdrawal period. The risk of regrowth should be low due to the short drug withdrawal. In our previous report of a clear cell RCC patient with metastasis at the paranasal sinus, AEs could be relieved effectively by using periodic drug withdrawal schedules of axitinib and axitinib could be used for more than 30 months (18). Takayama et al also reported a similar RCC case in which intermittent use of axitinib was effective (19).
There is a possibility that prognosis of this patient was improved by metastasectomies. LN metastases around the right common iliac vein and IVC at the time of LN dissection were pathologically confirmed. However, the relapse did not occur in the abdominal and pelvic areas after the extensive LN dissection. This appeared to indicate that LN metastases in the abdominal and the pelvic areas were completely resected by the initial LN dissection. Moreover, the three metastasectomies including the initial LN dissection around the IVC and right iliac vein, the resection of lung metastasis, and the mediastinal LN dissection could delay the timing of TKI administration for two years. Those metastasectomies might contribute to improve the patient's prognosis. In the cytokine era, an efficacy of LN dissection on radical nephrectomy was suggested in PRCC (20). Metastatectomy should be performed appropriately for patients with metastatic PRCC similar to clear cell RCC when radiological complete remission can be achieved by metastasectomy.
Although it is difficult to evaluate the effectiveness of ZA and local radiation therapy in this case, these treatments might present some positive effects for disease control.
We were able to control metastatic lesions of type 2 PRCC for a relatively long term by multidisciplinary treatment. Axitinib was effective and periodic drug withdrawal schedules could reduce AEs and enable to continue axitinib usage.
Acknowledgements
Not applicable.
Availability of data and materials
Data sharing is not applicable to this article, as no datasets were generated or analyzed during the present study.
Authors' contributions
YA contributed to the study concept, design, data collection and writing of the manuscript. YK contributed to data collection and the revision of the manuscript. MH contributed to data collection and the revision of the manuscript. HH contributed to data collection and the revision of the manuscript. KM contributed to data collection, pathological diagnosis and the revision of the manuscript. AH contributed to the study concept, design and the revision of the manuscript. KI contributed to the study concept, design, data collection, writing and the revision of the manuscript, and the supervision of the manuscript. The authenticity of all the raw data was assessed by YA, KM, AH and KI. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Ethical approval was granted from the Ethics Committee of National Defense Medical College.
Patient consent for publication
Written informed consent for the publication of any associated data was obtained from the patient's wife.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Radiological and pathological findings of the primary tumor. (A and B) Contrast-enhanced computed tomography images. A tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected. (C and D) Microscopically, the tumor had papillary architecture. The tumor cells contained abundant eosinophilic cytoplasm with high nuclear grade (Fuhrman nuclear grade 3). The tumor was diagnosed as type 2 papillary RCC. (C) magnification, x100; scale bar, 200 µm. (D) magnification, x400; scale bar, 50 µm. RCC, renal cell carcinoma.
Figure 2 CE-CT images. (A and B) CE-CT images of a (A) lung metastasis (S6) (black arrow) and (B) paracaval lymph node metastases (black arrow) that appeared in 2012. (C) CE-CT of lymph node swellings at the right tracheal bifurcation (white arrow) found in 2013. (D) CE-CT of mediastinal lymph nodes (white arrows) that were swollen again in 2014. CE-CT, Contrast-enhanced computed tomography.
Figure 3 The time course of treatments for the patient with metastatic type 2 papillary renal cell carcinoma. Axi, axitinib; HT, hypertension; IVC, inferior vena cava; LND, lymph node dissection; LNM, lymph node metastasis; RNx, radical nephrectomy; SD, stable disease; SU, sunitinib; TEM, temsirolimus; ZA, zoledronic acid.
Figure 4 CT images during axitinib treatment. (A) CT at axitinib administration. White arrows indicate mediastinal lymph node metastases. (B) CT 7 months after axitinib administration. Lymph node metastases shrunk by using axitinib (partial response, judged by RECIST version 1.1). (C) CT 19 months after axitinib administration. The response was maintained. (D) CT 30 months after axitinib administration. The response was still maintained. (E) Representative bone metastasis (left ilium) at axitinib administration. (F) CT 7 months after axitinib administration. (G) CT 19 months after axitinib administration. (H) CT 30 months after axitinib administration. The bone metastasis in the ilium grew slightly compared with that at axitinib administration (<10%, stable disease, judged by RECIST version 1.1). | SUNITINIB, TEMSIROLIMUS, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33732457 | 19,952,254 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Decreased appetite'. | Long-term disease control of metastatic type 2 papillary renal cell carcinoma using local treatment and molecular targeted therapy: A case report.
A 46-year-old man underwent right partial nephrectomy for type 2 papillary renal cell carcinoma (PRCC) in 2011. Lung metastasis and lymph node (LN) metastases around the inferior vena cave appeared in 2012. A right radical nephrectomy and extensive LN dissection was performed and the resection of lung metastasis was performed one month after the nephrectomy. Mediastinal LN metastases occurred in 2013, and resection of the affected LNs was performed. Sunitinib and zoledronic acid was started in 2014 because mediastinal LN swelling and multiple bone metastases appeared. Sunitinib treatment was stopped soon after due to adverse events and axitinib treatment was started. Axitinib was effective and the patient had stable disease for 30 months. Adverse events were successfully controlled by dose reduction and periodic drug withdrawal schedules (for example, 5 days on, 2 days off). Axitinib was further continued for 19 months as the metastatic lesions had progressed slowly. Temsirolimus treatment was started in 2019, but it was stopped after three cycles due to interstitial pneumonia. The patient died 80 months after the initial recurrence. Using multidisciplinary treatment, durable disease control was achieved in a patient with metastatic type 2 PRCC.
Introductions
Recently, the prognosis of patients with metastatic renal cell carcinoma (RCC) has been improved by molecular targeted therapies (1) and immune checkpoint inhibitors (2). However, optimal treatment strategies for metastatic non-clear cell RCC (nccRCC) has yet to be established. In previous studies, molecular targeted therapies, especially sunitinib, have shown clinical efficacy for the treatment of metastatic nccRCC (3-7). The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is recommended at present for metastatic nccRCC. In nccRCC papillary renal cell carcinoma (PRCC) is the leading histology (8). PRCC is divided into type 1 and type 2, with type 2 PRCC showing worse prognosis compared with type 1(9). In phase 2 clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, overall survival (OS) of type1 PRCC was 17.8 months, and that of type 2 was 12.4 months (10).
In this report, we present a patient with metastatic type 2 PRCC whose metastatic lesions were controlled for a long time by multidisciplinary treatments including metastasectomies, axitinib, zoledronic acid (ZA), and radiation therapy.
Case report
A 46-year-old man with hematospermia was presented to a urologic clinic in April, 2011. A right renal tumor was found by ultrasound, and the patient was referred to our hospital. The tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected by contrast-enhanced computed tomography (CT) (Fig. 1A and B). A right partial nephrectomy was performed in July, 2011. Pathological diagnosis was type2 PRCC (Fig. 1C and D). A lung metastasis (S6) and paracaval lymph node (LN) metastases appeared in March, 2012 (Fig. 2A and B). After five cycles of temsirolimus, right radical nephrectomy and extensive LN dissection around the inferior vena cava (IVC) and right common iliac vein were performed in June, 2012, and the resection of the lung metastasis was performed one month after the nephrectomy. Then, radiological complete remission was achieved. LN swellings at the right tracheal bifurcation was found by CT in August, 2013 (Fig. 2C). After three cycles of temsirolimus, mediastinal LN dissection was performed in October, 2013. Mediastinal LNs (Fig. 2D) were swollen again, and multiple bone metastases [sternum, right fifth rib, thoracic spine (5-7th vertebrae), left ilium, and right pubis] appeared in 2014. The clinical course of the patient, including local treatments, medical treatments, and treatment-related adverse events are shown in Fig. 3. Sunitinib (37.5 mg/day) and ZA (4 mg/month) were started in June, 2014. Sunitinib was stopped within two weeks because of adverse events (AEs) including fever, malaise, and liver dysfunction. After the patient had recovered from the AEs, axitinib (10 mg/day) was started as a second-line treatment in July, 2014. ZA was continued after the axitinib administration. Because of diarrhea and hoarseness, the treatment schedule of axitinib was changed to a periodic drug withdrawal schedule (5 days-on, 2 days-off) in October, 2014. Next, the daily dose of axitinib was reduced to 8 mg (5 days-on, 2 days-off) to control severe diarrhea in December, 2014. Stereotactic radiation therapy (total 30 Gray, 10 fractions) was performed for bone metastasis at the left ilium in November, 2015 because only the iliac metastasis appeared to be an active lesion among all bone metastases in the bone scintigraphy. The periodic drug withdrawal schedule of axitinib (8 mg/day, 5 days-on, 2 days-off) was changed to the next schedule (8 mg/day, 4 days-on, 3 days-off) due to renal dysfunction and proteinuria in April, 2017. Mediastinal LN metastases and bone metastases was stable for 30 months after the axitinib administration (Fig. 4). Disease progression was confirmed in June, 2017 due to the appearance of multiple small lung metastases. Because the metastatic lesions progressed slowly after the disease progression, axitinib was continued for another 19 months in accordance with the patient's request. The schedule of axitinib was then changed to a third schedule (8 mg/day, 3 days-on, 3 days-off) due to symptoms of anorexia, dyspnea, and muscle pain in April, 2018. Patient was hospitalized due to severe back pain in September, 2018, and palliative radiotherapy was performed for a compression fracture due to metastasis (L1 lumber vertebrae). Axitinib was stopped in October, 2019. Temsirolimus was then administered, but interstitial pneumonia occurred after three cycles of temsirolimus. Although steroid pulse therapy was performed, respiratory and general condition became worse. The patient died in November, 2019. By multidisciplinary treatments including metastasectomy, axitinib, ZA, and radiation therapy, the patient survived for 80 months after the initial recurrence.
Discussion
This patient with metastatic type 2 PRCC could survive 80 months after the initial recurrence by multidisciplinary treatments including metastasectomies, axitinib, ZA, and radiation therapy. Patients with metastatic type 2 PRCC generally have poor prognosis. In a clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median OS in type 2 PRCC was 12.4 months (10). Metastasectomies and axitinib appeared to be especially effective in the present case.
The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is the recommended treatment for metastatic nccRCC, and cabozantinib and everolimus are options. At the beginning of targeted era, mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, was reportedly effective compared with interferon-α for metastatic nccRCC (11). A comparative study between temsirolimus and tyrosine kinase inhibitors (TKIs) in metastatic nccRCC does not exist at present. The superiority of sunitinib compared with everolimus in nccRCC treatment has been reported in two clinical trials (12,13). The ASPEN trial reported that the progression-free survival (PFS) of sunitinib was longer than that of everolimus (12). The ESPN trial reported that both PFS and OS of sunitinib were longer than those of everolimus (13). Among other TKIs, the overall response rate of pazopanib was reportedly 39% in the treatment of metastatic nccRCC (6). There are few studies evaluating the clinical efficacy of systemic therapies in metastatic PRCC. In clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median PFS and OS were 6.6 and 17.8 months in type 1 PRCC, and 5.5 and 12.4 months in type 2, respectively (10). In a Japanese multicenter study evaluating metastatic PRCC in which most PRCC cases (91.4%) were type 2, the prognosis in the era of targeted therapy (OS=22.5 months) was improved compared with that in the cytokine era (OS=6.3 months). PRCC patients treated with TKIs in both first-line and second-line treatments (OS=31.4 months) showed better prognosis than those with mTOR inhibitors in first-line or second-line (OS=12.9 months) (14).
In our case, the second-line use of axitinib was effective and achieved a durable stable disease (SD). There have been few reports in which axitinib showed efficacies for metastatic PRCC (15,16). In our case, AEs were relieved by dose reduction and the setting of periodic drug withdrawal schedules of axitinib, and axitinib could be continued for a long time. The half-life period of axitinib was reportedly short (4.8-5.9 h) (17). Axitinib has a characteristic that AEs can be relieved in a short period because of its short half-life period. Then, axitinib can be started again after the short drug withdrawal period. The risk of regrowth should be low due to the short drug withdrawal. In our previous report of a clear cell RCC patient with metastasis at the paranasal sinus, AEs could be relieved effectively by using periodic drug withdrawal schedules of axitinib and axitinib could be used for more than 30 months (18). Takayama et al also reported a similar RCC case in which intermittent use of axitinib was effective (19).
There is a possibility that prognosis of this patient was improved by metastasectomies. LN metastases around the right common iliac vein and IVC at the time of LN dissection were pathologically confirmed. However, the relapse did not occur in the abdominal and pelvic areas after the extensive LN dissection. This appeared to indicate that LN metastases in the abdominal and the pelvic areas were completely resected by the initial LN dissection. Moreover, the three metastasectomies including the initial LN dissection around the IVC and right iliac vein, the resection of lung metastasis, and the mediastinal LN dissection could delay the timing of TKI administration for two years. Those metastasectomies might contribute to improve the patient's prognosis. In the cytokine era, an efficacy of LN dissection on radical nephrectomy was suggested in PRCC (20). Metastatectomy should be performed appropriately for patients with metastatic PRCC similar to clear cell RCC when radiological complete remission can be achieved by metastasectomy.
Although it is difficult to evaluate the effectiveness of ZA and local radiation therapy in this case, these treatments might present some positive effects for disease control.
We were able to control metastatic lesions of type 2 PRCC for a relatively long term by multidisciplinary treatment. Axitinib was effective and periodic drug withdrawal schedules could reduce AEs and enable to continue axitinib usage.
Acknowledgements
Not applicable.
Availability of data and materials
Data sharing is not applicable to this article, as no datasets were generated or analyzed during the present study.
Authors' contributions
YA contributed to the study concept, design, data collection and writing of the manuscript. YK contributed to data collection and the revision of the manuscript. MH contributed to data collection and the revision of the manuscript. HH contributed to data collection and the revision of the manuscript. KM contributed to data collection, pathological diagnosis and the revision of the manuscript. AH contributed to the study concept, design and the revision of the manuscript. KI contributed to the study concept, design, data collection, writing and the revision of the manuscript, and the supervision of the manuscript. The authenticity of all the raw data was assessed by YA, KM, AH and KI. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Ethical approval was granted from the Ethics Committee of National Defense Medical College.
Patient consent for publication
Written informed consent for the publication of any associated data was obtained from the patient's wife.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Radiological and pathological findings of the primary tumor. (A and B) Contrast-enhanced computed tomography images. A tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected. (C and D) Microscopically, the tumor had papillary architecture. The tumor cells contained abundant eosinophilic cytoplasm with high nuclear grade (Fuhrman nuclear grade 3). The tumor was diagnosed as type 2 papillary RCC. (C) magnification, x100; scale bar, 200 µm. (D) magnification, x400; scale bar, 50 µm. RCC, renal cell carcinoma.
Figure 2 CE-CT images. (A and B) CE-CT images of a (A) lung metastasis (S6) (black arrow) and (B) paracaval lymph node metastases (black arrow) that appeared in 2012. (C) CE-CT of lymph node swellings at the right tracheal bifurcation (white arrow) found in 2013. (D) CE-CT of mediastinal lymph nodes (white arrows) that were swollen again in 2014. CE-CT, Contrast-enhanced computed tomography.
Figure 3 The time course of treatments for the patient with metastatic type 2 papillary renal cell carcinoma. Axi, axitinib; HT, hypertension; IVC, inferior vena cava; LND, lymph node dissection; LNM, lymph node metastasis; RNx, radical nephrectomy; SD, stable disease; SU, sunitinib; TEM, temsirolimus; ZA, zoledronic acid.
Figure 4 CT images during axitinib treatment. (A) CT at axitinib administration. White arrows indicate mediastinal lymph node metastases. (B) CT 7 months after axitinib administration. Lymph node metastases shrunk by using axitinib (partial response, judged by RECIST version 1.1). (C) CT 19 months after axitinib administration. The response was maintained. (D) CT 30 months after axitinib administration. The response was still maintained. (E) Representative bone metastasis (left ilium) at axitinib administration. (F) CT 7 months after axitinib administration. (G) CT 19 months after axitinib administration. (H) CT 30 months after axitinib administration. The bone metastasis in the ilium grew slightly compared with that at axitinib administration (<10%, stable disease, judged by RECIST version 1.1). | AXITINIB, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33732457 | 19,122,950 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diarrhoea'. | Long-term disease control of metastatic type 2 papillary renal cell carcinoma using local treatment and molecular targeted therapy: A case report.
A 46-year-old man underwent right partial nephrectomy for type 2 papillary renal cell carcinoma (PRCC) in 2011. Lung metastasis and lymph node (LN) metastases around the inferior vena cave appeared in 2012. A right radical nephrectomy and extensive LN dissection was performed and the resection of lung metastasis was performed one month after the nephrectomy. Mediastinal LN metastases occurred in 2013, and resection of the affected LNs was performed. Sunitinib and zoledronic acid was started in 2014 because mediastinal LN swelling and multiple bone metastases appeared. Sunitinib treatment was stopped soon after due to adverse events and axitinib treatment was started. Axitinib was effective and the patient had stable disease for 30 months. Adverse events were successfully controlled by dose reduction and periodic drug withdrawal schedules (for example, 5 days on, 2 days off). Axitinib was further continued for 19 months as the metastatic lesions had progressed slowly. Temsirolimus treatment was started in 2019, but it was stopped after three cycles due to interstitial pneumonia. The patient died 80 months after the initial recurrence. Using multidisciplinary treatment, durable disease control was achieved in a patient with metastatic type 2 PRCC.
Introductions
Recently, the prognosis of patients with metastatic renal cell carcinoma (RCC) has been improved by molecular targeted therapies (1) and immune checkpoint inhibitors (2). However, optimal treatment strategies for metastatic non-clear cell RCC (nccRCC) has yet to be established. In previous studies, molecular targeted therapies, especially sunitinib, have shown clinical efficacy for the treatment of metastatic nccRCC (3-7). The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is recommended at present for metastatic nccRCC. In nccRCC papillary renal cell carcinoma (PRCC) is the leading histology (8). PRCC is divided into type 1 and type 2, with type 2 PRCC showing worse prognosis compared with type 1(9). In phase 2 clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, overall survival (OS) of type1 PRCC was 17.8 months, and that of type 2 was 12.4 months (10).
In this report, we present a patient with metastatic type 2 PRCC whose metastatic lesions were controlled for a long time by multidisciplinary treatments including metastasectomies, axitinib, zoledronic acid (ZA), and radiation therapy.
Case report
A 46-year-old man with hematospermia was presented to a urologic clinic in April, 2011. A right renal tumor was found by ultrasound, and the patient was referred to our hospital. The tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected by contrast-enhanced computed tomography (CT) (Fig. 1A and B). A right partial nephrectomy was performed in July, 2011. Pathological diagnosis was type2 PRCC (Fig. 1C and D). A lung metastasis (S6) and paracaval lymph node (LN) metastases appeared in March, 2012 (Fig. 2A and B). After five cycles of temsirolimus, right radical nephrectomy and extensive LN dissection around the inferior vena cava (IVC) and right common iliac vein were performed in June, 2012, and the resection of the lung metastasis was performed one month after the nephrectomy. Then, radiological complete remission was achieved. LN swellings at the right tracheal bifurcation was found by CT in August, 2013 (Fig. 2C). After three cycles of temsirolimus, mediastinal LN dissection was performed in October, 2013. Mediastinal LNs (Fig. 2D) were swollen again, and multiple bone metastases [sternum, right fifth rib, thoracic spine (5-7th vertebrae), left ilium, and right pubis] appeared in 2014. The clinical course of the patient, including local treatments, medical treatments, and treatment-related adverse events are shown in Fig. 3. Sunitinib (37.5 mg/day) and ZA (4 mg/month) were started in June, 2014. Sunitinib was stopped within two weeks because of adverse events (AEs) including fever, malaise, and liver dysfunction. After the patient had recovered from the AEs, axitinib (10 mg/day) was started as a second-line treatment in July, 2014. ZA was continued after the axitinib administration. Because of diarrhea and hoarseness, the treatment schedule of axitinib was changed to a periodic drug withdrawal schedule (5 days-on, 2 days-off) in October, 2014. Next, the daily dose of axitinib was reduced to 8 mg (5 days-on, 2 days-off) to control severe diarrhea in December, 2014. Stereotactic radiation therapy (total 30 Gray, 10 fractions) was performed for bone metastasis at the left ilium in November, 2015 because only the iliac metastasis appeared to be an active lesion among all bone metastases in the bone scintigraphy. The periodic drug withdrawal schedule of axitinib (8 mg/day, 5 days-on, 2 days-off) was changed to the next schedule (8 mg/day, 4 days-on, 3 days-off) due to renal dysfunction and proteinuria in April, 2017. Mediastinal LN metastases and bone metastases was stable for 30 months after the axitinib administration (Fig. 4). Disease progression was confirmed in June, 2017 due to the appearance of multiple small lung metastases. Because the metastatic lesions progressed slowly after the disease progression, axitinib was continued for another 19 months in accordance with the patient's request. The schedule of axitinib was then changed to a third schedule (8 mg/day, 3 days-on, 3 days-off) due to symptoms of anorexia, dyspnea, and muscle pain in April, 2018. Patient was hospitalized due to severe back pain in September, 2018, and palliative radiotherapy was performed for a compression fracture due to metastasis (L1 lumber vertebrae). Axitinib was stopped in October, 2019. Temsirolimus was then administered, but interstitial pneumonia occurred after three cycles of temsirolimus. Although steroid pulse therapy was performed, respiratory and general condition became worse. The patient died in November, 2019. By multidisciplinary treatments including metastasectomy, axitinib, ZA, and radiation therapy, the patient survived for 80 months after the initial recurrence.
Discussion
This patient with metastatic type 2 PRCC could survive 80 months after the initial recurrence by multidisciplinary treatments including metastasectomies, axitinib, ZA, and radiation therapy. Patients with metastatic type 2 PRCC generally have poor prognosis. In a clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median OS in type 2 PRCC was 12.4 months (10). Metastasectomies and axitinib appeared to be especially effective in the present case.
The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is the recommended treatment for metastatic nccRCC, and cabozantinib and everolimus are options. At the beginning of targeted era, mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, was reportedly effective compared with interferon-α for metastatic nccRCC (11). A comparative study between temsirolimus and tyrosine kinase inhibitors (TKIs) in metastatic nccRCC does not exist at present. The superiority of sunitinib compared with everolimus in nccRCC treatment has been reported in two clinical trials (12,13). The ASPEN trial reported that the progression-free survival (PFS) of sunitinib was longer than that of everolimus (12). The ESPN trial reported that both PFS and OS of sunitinib were longer than those of everolimus (13). Among other TKIs, the overall response rate of pazopanib was reportedly 39% in the treatment of metastatic nccRCC (6). There are few studies evaluating the clinical efficacy of systemic therapies in metastatic PRCC. In clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median PFS and OS were 6.6 and 17.8 months in type 1 PRCC, and 5.5 and 12.4 months in type 2, respectively (10). In a Japanese multicenter study evaluating metastatic PRCC in which most PRCC cases (91.4%) were type 2, the prognosis in the era of targeted therapy (OS=22.5 months) was improved compared with that in the cytokine era (OS=6.3 months). PRCC patients treated with TKIs in both first-line and second-line treatments (OS=31.4 months) showed better prognosis than those with mTOR inhibitors in first-line or second-line (OS=12.9 months) (14).
In our case, the second-line use of axitinib was effective and achieved a durable stable disease (SD). There have been few reports in which axitinib showed efficacies for metastatic PRCC (15,16). In our case, AEs were relieved by dose reduction and the setting of periodic drug withdrawal schedules of axitinib, and axitinib could be continued for a long time. The half-life period of axitinib was reportedly short (4.8-5.9 h) (17). Axitinib has a characteristic that AEs can be relieved in a short period because of its short half-life period. Then, axitinib can be started again after the short drug withdrawal period. The risk of regrowth should be low due to the short drug withdrawal. In our previous report of a clear cell RCC patient with metastasis at the paranasal sinus, AEs could be relieved effectively by using periodic drug withdrawal schedules of axitinib and axitinib could be used for more than 30 months (18). Takayama et al also reported a similar RCC case in which intermittent use of axitinib was effective (19).
There is a possibility that prognosis of this patient was improved by metastasectomies. LN metastases around the right common iliac vein and IVC at the time of LN dissection were pathologically confirmed. However, the relapse did not occur in the abdominal and pelvic areas after the extensive LN dissection. This appeared to indicate that LN metastases in the abdominal and the pelvic areas were completely resected by the initial LN dissection. Moreover, the three metastasectomies including the initial LN dissection around the IVC and right iliac vein, the resection of lung metastasis, and the mediastinal LN dissection could delay the timing of TKI administration for two years. Those metastasectomies might contribute to improve the patient's prognosis. In the cytokine era, an efficacy of LN dissection on radical nephrectomy was suggested in PRCC (20). Metastatectomy should be performed appropriately for patients with metastatic PRCC similar to clear cell RCC when radiological complete remission can be achieved by metastasectomy.
Although it is difficult to evaluate the effectiveness of ZA and local radiation therapy in this case, these treatments might present some positive effects for disease control.
We were able to control metastatic lesions of type 2 PRCC for a relatively long term by multidisciplinary treatment. Axitinib was effective and periodic drug withdrawal schedules could reduce AEs and enable to continue axitinib usage.
Acknowledgements
Not applicable.
Availability of data and materials
Data sharing is not applicable to this article, as no datasets were generated or analyzed during the present study.
Authors' contributions
YA contributed to the study concept, design, data collection and writing of the manuscript. YK contributed to data collection and the revision of the manuscript. MH contributed to data collection and the revision of the manuscript. HH contributed to data collection and the revision of the manuscript. KM contributed to data collection, pathological diagnosis and the revision of the manuscript. AH contributed to the study concept, design and the revision of the manuscript. KI contributed to the study concept, design, data collection, writing and the revision of the manuscript, and the supervision of the manuscript. The authenticity of all the raw data was assessed by YA, KM, AH and KI. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Ethical approval was granted from the Ethics Committee of National Defense Medical College.
Patient consent for publication
Written informed consent for the publication of any associated data was obtained from the patient's wife.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Radiological and pathological findings of the primary tumor. (A and B) Contrast-enhanced computed tomography images. A tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected. (C and D) Microscopically, the tumor had papillary architecture. The tumor cells contained abundant eosinophilic cytoplasm with high nuclear grade (Fuhrman nuclear grade 3). The tumor was diagnosed as type 2 papillary RCC. (C) magnification, x100; scale bar, 200 µm. (D) magnification, x400; scale bar, 50 µm. RCC, renal cell carcinoma.
Figure 2 CE-CT images. (A and B) CE-CT images of a (A) lung metastasis (S6) (black arrow) and (B) paracaval lymph node metastases (black arrow) that appeared in 2012. (C) CE-CT of lymph node swellings at the right tracheal bifurcation (white arrow) found in 2013. (D) CE-CT of mediastinal lymph nodes (white arrows) that were swollen again in 2014. CE-CT, Contrast-enhanced computed tomography.
Figure 3 The time course of treatments for the patient with metastatic type 2 papillary renal cell carcinoma. Axi, axitinib; HT, hypertension; IVC, inferior vena cava; LND, lymph node dissection; LNM, lymph node metastasis; RNx, radical nephrectomy; SD, stable disease; SU, sunitinib; TEM, temsirolimus; ZA, zoledronic acid.
Figure 4 CT images during axitinib treatment. (A) CT at axitinib administration. White arrows indicate mediastinal lymph node metastases. (B) CT 7 months after axitinib administration. Lymph node metastases shrunk by using axitinib (partial response, judged by RECIST version 1.1). (C) CT 19 months after axitinib administration. The response was maintained. (D) CT 30 months after axitinib administration. The response was still maintained. (E) Representative bone metastasis (left ilium) at axitinib administration. (F) CT 7 months after axitinib administration. (G) CT 19 months after axitinib administration. (H) CT 30 months after axitinib administration. The bone metastasis in the ilium grew slightly compared with that at axitinib administration (<10%, stable disease, judged by RECIST version 1.1). | AXITINIB, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33732457 | 19,122,950 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease progression'. | Long-term disease control of metastatic type 2 papillary renal cell carcinoma using local treatment and molecular targeted therapy: A case report.
A 46-year-old man underwent right partial nephrectomy for type 2 papillary renal cell carcinoma (PRCC) in 2011. Lung metastasis and lymph node (LN) metastases around the inferior vena cave appeared in 2012. A right radical nephrectomy and extensive LN dissection was performed and the resection of lung metastasis was performed one month after the nephrectomy. Mediastinal LN metastases occurred in 2013, and resection of the affected LNs was performed. Sunitinib and zoledronic acid was started in 2014 because mediastinal LN swelling and multiple bone metastases appeared. Sunitinib treatment was stopped soon after due to adverse events and axitinib treatment was started. Axitinib was effective and the patient had stable disease for 30 months. Adverse events were successfully controlled by dose reduction and periodic drug withdrawal schedules (for example, 5 days on, 2 days off). Axitinib was further continued for 19 months as the metastatic lesions had progressed slowly. Temsirolimus treatment was started in 2019, but it was stopped after three cycles due to interstitial pneumonia. The patient died 80 months after the initial recurrence. Using multidisciplinary treatment, durable disease control was achieved in a patient with metastatic type 2 PRCC.
Introductions
Recently, the prognosis of patients with metastatic renal cell carcinoma (RCC) has been improved by molecular targeted therapies (1) and immune checkpoint inhibitors (2). However, optimal treatment strategies for metastatic non-clear cell RCC (nccRCC) has yet to be established. In previous studies, molecular targeted therapies, especially sunitinib, have shown clinical efficacy for the treatment of metastatic nccRCC (3-7). The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is recommended at present for metastatic nccRCC. In nccRCC papillary renal cell carcinoma (PRCC) is the leading histology (8). PRCC is divided into type 1 and type 2, with type 2 PRCC showing worse prognosis compared with type 1(9). In phase 2 clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, overall survival (OS) of type1 PRCC was 17.8 months, and that of type 2 was 12.4 months (10).
In this report, we present a patient with metastatic type 2 PRCC whose metastatic lesions were controlled for a long time by multidisciplinary treatments including metastasectomies, axitinib, zoledronic acid (ZA), and radiation therapy.
Case report
A 46-year-old man with hematospermia was presented to a urologic clinic in April, 2011. A right renal tumor was found by ultrasound, and the patient was referred to our hospital. The tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected by contrast-enhanced computed tomography (CT) (Fig. 1A and B). A right partial nephrectomy was performed in July, 2011. Pathological diagnosis was type2 PRCC (Fig. 1C and D). A lung metastasis (S6) and paracaval lymph node (LN) metastases appeared in March, 2012 (Fig. 2A and B). After five cycles of temsirolimus, right radical nephrectomy and extensive LN dissection around the inferior vena cava (IVC) and right common iliac vein were performed in June, 2012, and the resection of the lung metastasis was performed one month after the nephrectomy. Then, radiological complete remission was achieved. LN swellings at the right tracheal bifurcation was found by CT in August, 2013 (Fig. 2C). After three cycles of temsirolimus, mediastinal LN dissection was performed in October, 2013. Mediastinal LNs (Fig. 2D) were swollen again, and multiple bone metastases [sternum, right fifth rib, thoracic spine (5-7th vertebrae), left ilium, and right pubis] appeared in 2014. The clinical course of the patient, including local treatments, medical treatments, and treatment-related adverse events are shown in Fig. 3. Sunitinib (37.5 mg/day) and ZA (4 mg/month) were started in June, 2014. Sunitinib was stopped within two weeks because of adverse events (AEs) including fever, malaise, and liver dysfunction. After the patient had recovered from the AEs, axitinib (10 mg/day) was started as a second-line treatment in July, 2014. ZA was continued after the axitinib administration. Because of diarrhea and hoarseness, the treatment schedule of axitinib was changed to a periodic drug withdrawal schedule (5 days-on, 2 days-off) in October, 2014. Next, the daily dose of axitinib was reduced to 8 mg (5 days-on, 2 days-off) to control severe diarrhea in December, 2014. Stereotactic radiation therapy (total 30 Gray, 10 fractions) was performed for bone metastasis at the left ilium in November, 2015 because only the iliac metastasis appeared to be an active lesion among all bone metastases in the bone scintigraphy. The periodic drug withdrawal schedule of axitinib (8 mg/day, 5 days-on, 2 days-off) was changed to the next schedule (8 mg/day, 4 days-on, 3 days-off) due to renal dysfunction and proteinuria in April, 2017. Mediastinal LN metastases and bone metastases was stable for 30 months after the axitinib administration (Fig. 4). Disease progression was confirmed in June, 2017 due to the appearance of multiple small lung metastases. Because the metastatic lesions progressed slowly after the disease progression, axitinib was continued for another 19 months in accordance with the patient's request. The schedule of axitinib was then changed to a third schedule (8 mg/day, 3 days-on, 3 days-off) due to symptoms of anorexia, dyspnea, and muscle pain in April, 2018. Patient was hospitalized due to severe back pain in September, 2018, and palliative radiotherapy was performed for a compression fracture due to metastasis (L1 lumber vertebrae). Axitinib was stopped in October, 2019. Temsirolimus was then administered, but interstitial pneumonia occurred after three cycles of temsirolimus. Although steroid pulse therapy was performed, respiratory and general condition became worse. The patient died in November, 2019. By multidisciplinary treatments including metastasectomy, axitinib, ZA, and radiation therapy, the patient survived for 80 months after the initial recurrence.
Discussion
This patient with metastatic type 2 PRCC could survive 80 months after the initial recurrence by multidisciplinary treatments including metastasectomies, axitinib, ZA, and radiation therapy. Patients with metastatic type 2 PRCC generally have poor prognosis. In a clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median OS in type 2 PRCC was 12.4 months (10). Metastasectomies and axitinib appeared to be especially effective in the present case.
The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is the recommended treatment for metastatic nccRCC, and cabozantinib and everolimus are options. At the beginning of targeted era, mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, was reportedly effective compared with interferon-α for metastatic nccRCC (11). A comparative study between temsirolimus and tyrosine kinase inhibitors (TKIs) in metastatic nccRCC does not exist at present. The superiority of sunitinib compared with everolimus in nccRCC treatment has been reported in two clinical trials (12,13). The ASPEN trial reported that the progression-free survival (PFS) of sunitinib was longer than that of everolimus (12). The ESPN trial reported that both PFS and OS of sunitinib were longer than those of everolimus (13). Among other TKIs, the overall response rate of pazopanib was reportedly 39% in the treatment of metastatic nccRCC (6). There are few studies evaluating the clinical efficacy of systemic therapies in metastatic PRCC. In clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median PFS and OS were 6.6 and 17.8 months in type 1 PRCC, and 5.5 and 12.4 months in type 2, respectively (10). In a Japanese multicenter study evaluating metastatic PRCC in which most PRCC cases (91.4%) were type 2, the prognosis in the era of targeted therapy (OS=22.5 months) was improved compared with that in the cytokine era (OS=6.3 months). PRCC patients treated with TKIs in both first-line and second-line treatments (OS=31.4 months) showed better prognosis than those with mTOR inhibitors in first-line or second-line (OS=12.9 months) (14).
In our case, the second-line use of axitinib was effective and achieved a durable stable disease (SD). There have been few reports in which axitinib showed efficacies for metastatic PRCC (15,16). In our case, AEs were relieved by dose reduction and the setting of periodic drug withdrawal schedules of axitinib, and axitinib could be continued for a long time. The half-life period of axitinib was reportedly short (4.8-5.9 h) (17). Axitinib has a characteristic that AEs can be relieved in a short period because of its short half-life period. Then, axitinib can be started again after the short drug withdrawal period. The risk of regrowth should be low due to the short drug withdrawal. In our previous report of a clear cell RCC patient with metastasis at the paranasal sinus, AEs could be relieved effectively by using periodic drug withdrawal schedules of axitinib and axitinib could be used for more than 30 months (18). Takayama et al also reported a similar RCC case in which intermittent use of axitinib was effective (19).
There is a possibility that prognosis of this patient was improved by metastasectomies. LN metastases around the right common iliac vein and IVC at the time of LN dissection were pathologically confirmed. However, the relapse did not occur in the abdominal and pelvic areas after the extensive LN dissection. This appeared to indicate that LN metastases in the abdominal and the pelvic areas were completely resected by the initial LN dissection. Moreover, the three metastasectomies including the initial LN dissection around the IVC and right iliac vein, the resection of lung metastasis, and the mediastinal LN dissection could delay the timing of TKI administration for two years. Those metastasectomies might contribute to improve the patient's prognosis. In the cytokine era, an efficacy of LN dissection on radical nephrectomy was suggested in PRCC (20). Metastatectomy should be performed appropriately for patients with metastatic PRCC similar to clear cell RCC when radiological complete remission can be achieved by metastasectomy.
Although it is difficult to evaluate the effectiveness of ZA and local radiation therapy in this case, these treatments might present some positive effects for disease control.
We were able to control metastatic lesions of type 2 PRCC for a relatively long term by multidisciplinary treatment. Axitinib was effective and periodic drug withdrawal schedules could reduce AEs and enable to continue axitinib usage.
Acknowledgements
Not applicable.
Availability of data and materials
Data sharing is not applicable to this article, as no datasets were generated or analyzed during the present study.
Authors' contributions
YA contributed to the study concept, design, data collection and writing of the manuscript. YK contributed to data collection and the revision of the manuscript. MH contributed to data collection and the revision of the manuscript. HH contributed to data collection and the revision of the manuscript. KM contributed to data collection, pathological diagnosis and the revision of the manuscript. AH contributed to the study concept, design and the revision of the manuscript. KI contributed to the study concept, design, data collection, writing and the revision of the manuscript, and the supervision of the manuscript. The authenticity of all the raw data was assessed by YA, KM, AH and KI. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Ethical approval was granted from the Ethics Committee of National Defense Medical College.
Patient consent for publication
Written informed consent for the publication of any associated data was obtained from the patient's wife.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Radiological and pathological findings of the primary tumor. (A and B) Contrast-enhanced computed tomography images. A tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected. (C and D) Microscopically, the tumor had papillary architecture. The tumor cells contained abundant eosinophilic cytoplasm with high nuclear grade (Fuhrman nuclear grade 3). The tumor was diagnosed as type 2 papillary RCC. (C) magnification, x100; scale bar, 200 µm. (D) magnification, x400; scale bar, 50 µm. RCC, renal cell carcinoma.
Figure 2 CE-CT images. (A and B) CE-CT images of a (A) lung metastasis (S6) (black arrow) and (B) paracaval lymph node metastases (black arrow) that appeared in 2012. (C) CE-CT of lymph node swellings at the right tracheal bifurcation (white arrow) found in 2013. (D) CE-CT of mediastinal lymph nodes (white arrows) that were swollen again in 2014. CE-CT, Contrast-enhanced computed tomography.
Figure 3 The time course of treatments for the patient with metastatic type 2 papillary renal cell carcinoma. Axi, axitinib; HT, hypertension; IVC, inferior vena cava; LND, lymph node dissection; LNM, lymph node metastasis; RNx, radical nephrectomy; SD, stable disease; SU, sunitinib; TEM, temsirolimus; ZA, zoledronic acid.
Figure 4 CT images during axitinib treatment. (A) CT at axitinib administration. White arrows indicate mediastinal lymph node metastases. (B) CT 7 months after axitinib administration. Lymph node metastases shrunk by using axitinib (partial response, judged by RECIST version 1.1). (C) CT 19 months after axitinib administration. The response was maintained. (D) CT 30 months after axitinib administration. The response was still maintained. (E) Representative bone metastasis (left ilium) at axitinib administration. (F) CT 7 months after axitinib administration. (G) CT 19 months after axitinib administration. (H) CT 30 months after axitinib administration. The bone metastasis in the ilium grew slightly compared with that at axitinib administration (<10%, stable disease, judged by RECIST version 1.1). | SUNITINIB, TEMSIROLIMUS, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33732457 | 19,952,254 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dysphonia'. | Long-term disease control of metastatic type 2 papillary renal cell carcinoma using local treatment and molecular targeted therapy: A case report.
A 46-year-old man underwent right partial nephrectomy for type 2 papillary renal cell carcinoma (PRCC) in 2011. Lung metastasis and lymph node (LN) metastases around the inferior vena cave appeared in 2012. A right radical nephrectomy and extensive LN dissection was performed and the resection of lung metastasis was performed one month after the nephrectomy. Mediastinal LN metastases occurred in 2013, and resection of the affected LNs was performed. Sunitinib and zoledronic acid was started in 2014 because mediastinal LN swelling and multiple bone metastases appeared. Sunitinib treatment was stopped soon after due to adverse events and axitinib treatment was started. Axitinib was effective and the patient had stable disease for 30 months. Adverse events were successfully controlled by dose reduction and periodic drug withdrawal schedules (for example, 5 days on, 2 days off). Axitinib was further continued for 19 months as the metastatic lesions had progressed slowly. Temsirolimus treatment was started in 2019, but it was stopped after three cycles due to interstitial pneumonia. The patient died 80 months after the initial recurrence. Using multidisciplinary treatment, durable disease control was achieved in a patient with metastatic type 2 PRCC.
Introductions
Recently, the prognosis of patients with metastatic renal cell carcinoma (RCC) has been improved by molecular targeted therapies (1) and immune checkpoint inhibitors (2). However, optimal treatment strategies for metastatic non-clear cell RCC (nccRCC) has yet to be established. In previous studies, molecular targeted therapies, especially sunitinib, have shown clinical efficacy for the treatment of metastatic nccRCC (3-7). The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is recommended at present for metastatic nccRCC. In nccRCC papillary renal cell carcinoma (PRCC) is the leading histology (8). PRCC is divided into type 1 and type 2, with type 2 PRCC showing worse prognosis compared with type 1(9). In phase 2 clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, overall survival (OS) of type1 PRCC was 17.8 months, and that of type 2 was 12.4 months (10).
In this report, we present a patient with metastatic type 2 PRCC whose metastatic lesions were controlled for a long time by multidisciplinary treatments including metastasectomies, axitinib, zoledronic acid (ZA), and radiation therapy.
Case report
A 46-year-old man with hematospermia was presented to a urologic clinic in April, 2011. A right renal tumor was found by ultrasound, and the patient was referred to our hospital. The tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected by contrast-enhanced computed tomography (CT) (Fig. 1A and B). A right partial nephrectomy was performed in July, 2011. Pathological diagnosis was type2 PRCC (Fig. 1C and D). A lung metastasis (S6) and paracaval lymph node (LN) metastases appeared in March, 2012 (Fig. 2A and B). After five cycles of temsirolimus, right radical nephrectomy and extensive LN dissection around the inferior vena cava (IVC) and right common iliac vein were performed in June, 2012, and the resection of the lung metastasis was performed one month after the nephrectomy. Then, radiological complete remission was achieved. LN swellings at the right tracheal bifurcation was found by CT in August, 2013 (Fig. 2C). After three cycles of temsirolimus, mediastinal LN dissection was performed in October, 2013. Mediastinal LNs (Fig. 2D) were swollen again, and multiple bone metastases [sternum, right fifth rib, thoracic spine (5-7th vertebrae), left ilium, and right pubis] appeared in 2014. The clinical course of the patient, including local treatments, medical treatments, and treatment-related adverse events are shown in Fig. 3. Sunitinib (37.5 mg/day) and ZA (4 mg/month) were started in June, 2014. Sunitinib was stopped within two weeks because of adverse events (AEs) including fever, malaise, and liver dysfunction. After the patient had recovered from the AEs, axitinib (10 mg/day) was started as a second-line treatment in July, 2014. ZA was continued after the axitinib administration. Because of diarrhea and hoarseness, the treatment schedule of axitinib was changed to a periodic drug withdrawal schedule (5 days-on, 2 days-off) in October, 2014. Next, the daily dose of axitinib was reduced to 8 mg (5 days-on, 2 days-off) to control severe diarrhea in December, 2014. Stereotactic radiation therapy (total 30 Gray, 10 fractions) was performed for bone metastasis at the left ilium in November, 2015 because only the iliac metastasis appeared to be an active lesion among all bone metastases in the bone scintigraphy. The periodic drug withdrawal schedule of axitinib (8 mg/day, 5 days-on, 2 days-off) was changed to the next schedule (8 mg/day, 4 days-on, 3 days-off) due to renal dysfunction and proteinuria in April, 2017. Mediastinal LN metastases and bone metastases was stable for 30 months after the axitinib administration (Fig. 4). Disease progression was confirmed in June, 2017 due to the appearance of multiple small lung metastases. Because the metastatic lesions progressed slowly after the disease progression, axitinib was continued for another 19 months in accordance with the patient's request. The schedule of axitinib was then changed to a third schedule (8 mg/day, 3 days-on, 3 days-off) due to symptoms of anorexia, dyspnea, and muscle pain in April, 2018. Patient was hospitalized due to severe back pain in September, 2018, and palliative radiotherapy was performed for a compression fracture due to metastasis (L1 lumber vertebrae). Axitinib was stopped in October, 2019. Temsirolimus was then administered, but interstitial pneumonia occurred after three cycles of temsirolimus. Although steroid pulse therapy was performed, respiratory and general condition became worse. The patient died in November, 2019. By multidisciplinary treatments including metastasectomy, axitinib, ZA, and radiation therapy, the patient survived for 80 months after the initial recurrence.
Discussion
This patient with metastatic type 2 PRCC could survive 80 months after the initial recurrence by multidisciplinary treatments including metastasectomies, axitinib, ZA, and radiation therapy. Patients with metastatic type 2 PRCC generally have poor prognosis. In a clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median OS in type 2 PRCC was 12.4 months (10). Metastasectomies and axitinib appeared to be especially effective in the present case.
The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is the recommended treatment for metastatic nccRCC, and cabozantinib and everolimus are options. At the beginning of targeted era, mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, was reportedly effective compared with interferon-α for metastatic nccRCC (11). A comparative study between temsirolimus and tyrosine kinase inhibitors (TKIs) in metastatic nccRCC does not exist at present. The superiority of sunitinib compared with everolimus in nccRCC treatment has been reported in two clinical trials (12,13). The ASPEN trial reported that the progression-free survival (PFS) of sunitinib was longer than that of everolimus (12). The ESPN trial reported that both PFS and OS of sunitinib were longer than those of everolimus (13). Among other TKIs, the overall response rate of pazopanib was reportedly 39% in the treatment of metastatic nccRCC (6). There are few studies evaluating the clinical efficacy of systemic therapies in metastatic PRCC. In clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median PFS and OS were 6.6 and 17.8 months in type 1 PRCC, and 5.5 and 12.4 months in type 2, respectively (10). In a Japanese multicenter study evaluating metastatic PRCC in which most PRCC cases (91.4%) were type 2, the prognosis in the era of targeted therapy (OS=22.5 months) was improved compared with that in the cytokine era (OS=6.3 months). PRCC patients treated with TKIs in both first-line and second-line treatments (OS=31.4 months) showed better prognosis than those with mTOR inhibitors in first-line or second-line (OS=12.9 months) (14).
In our case, the second-line use of axitinib was effective and achieved a durable stable disease (SD). There have been few reports in which axitinib showed efficacies for metastatic PRCC (15,16). In our case, AEs were relieved by dose reduction and the setting of periodic drug withdrawal schedules of axitinib, and axitinib could be continued for a long time. The half-life period of axitinib was reportedly short (4.8-5.9 h) (17). Axitinib has a characteristic that AEs can be relieved in a short period because of its short half-life period. Then, axitinib can be started again after the short drug withdrawal period. The risk of regrowth should be low due to the short drug withdrawal. In our previous report of a clear cell RCC patient with metastasis at the paranasal sinus, AEs could be relieved effectively by using periodic drug withdrawal schedules of axitinib and axitinib could be used for more than 30 months (18). Takayama et al also reported a similar RCC case in which intermittent use of axitinib was effective (19).
There is a possibility that prognosis of this patient was improved by metastasectomies. LN metastases around the right common iliac vein and IVC at the time of LN dissection were pathologically confirmed. However, the relapse did not occur in the abdominal and pelvic areas after the extensive LN dissection. This appeared to indicate that LN metastases in the abdominal and the pelvic areas were completely resected by the initial LN dissection. Moreover, the three metastasectomies including the initial LN dissection around the IVC and right iliac vein, the resection of lung metastasis, and the mediastinal LN dissection could delay the timing of TKI administration for two years. Those metastasectomies might contribute to improve the patient's prognosis. In the cytokine era, an efficacy of LN dissection on radical nephrectomy was suggested in PRCC (20). Metastatectomy should be performed appropriately for patients with metastatic PRCC similar to clear cell RCC when radiological complete remission can be achieved by metastasectomy.
Although it is difficult to evaluate the effectiveness of ZA and local radiation therapy in this case, these treatments might present some positive effects for disease control.
We were able to control metastatic lesions of type 2 PRCC for a relatively long term by multidisciplinary treatment. Axitinib was effective and periodic drug withdrawal schedules could reduce AEs and enable to continue axitinib usage.
Acknowledgements
Not applicable.
Availability of data and materials
Data sharing is not applicable to this article, as no datasets were generated or analyzed during the present study.
Authors' contributions
YA contributed to the study concept, design, data collection and writing of the manuscript. YK contributed to data collection and the revision of the manuscript. MH contributed to data collection and the revision of the manuscript. HH contributed to data collection and the revision of the manuscript. KM contributed to data collection, pathological diagnosis and the revision of the manuscript. AH contributed to the study concept, design and the revision of the manuscript. KI contributed to the study concept, design, data collection, writing and the revision of the manuscript, and the supervision of the manuscript. The authenticity of all the raw data was assessed by YA, KM, AH and KI. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Ethical approval was granted from the Ethics Committee of National Defense Medical College.
Patient consent for publication
Written informed consent for the publication of any associated data was obtained from the patient's wife.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Radiological and pathological findings of the primary tumor. (A and B) Contrast-enhanced computed tomography images. A tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected. (C and D) Microscopically, the tumor had papillary architecture. The tumor cells contained abundant eosinophilic cytoplasm with high nuclear grade (Fuhrman nuclear grade 3). The tumor was diagnosed as type 2 papillary RCC. (C) magnification, x100; scale bar, 200 µm. (D) magnification, x400; scale bar, 50 µm. RCC, renal cell carcinoma.
Figure 2 CE-CT images. (A and B) CE-CT images of a (A) lung metastasis (S6) (black arrow) and (B) paracaval lymph node metastases (black arrow) that appeared in 2012. (C) CE-CT of lymph node swellings at the right tracheal bifurcation (white arrow) found in 2013. (D) CE-CT of mediastinal lymph nodes (white arrows) that were swollen again in 2014. CE-CT, Contrast-enhanced computed tomography.
Figure 3 The time course of treatments for the patient with metastatic type 2 papillary renal cell carcinoma. Axi, axitinib; HT, hypertension; IVC, inferior vena cava; LND, lymph node dissection; LNM, lymph node metastasis; RNx, radical nephrectomy; SD, stable disease; SU, sunitinib; TEM, temsirolimus; ZA, zoledronic acid.
Figure 4 CT images during axitinib treatment. (A) CT at axitinib administration. White arrows indicate mediastinal lymph node metastases. (B) CT 7 months after axitinib administration. Lymph node metastases shrunk by using axitinib (partial response, judged by RECIST version 1.1). (C) CT 19 months after axitinib administration. The response was maintained. (D) CT 30 months after axitinib administration. The response was still maintained. (E) Representative bone metastasis (left ilium) at axitinib administration. (F) CT 7 months after axitinib administration. (G) CT 19 months after axitinib administration. (H) CT 30 months after axitinib administration. The bone metastasis in the ilium grew slightly compared with that at axitinib administration (<10%, stable disease, judged by RECIST version 1.1). | AXITINIB, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33732457 | 19,122,950 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dyspnoea'. | Long-term disease control of metastatic type 2 papillary renal cell carcinoma using local treatment and molecular targeted therapy: A case report.
A 46-year-old man underwent right partial nephrectomy for type 2 papillary renal cell carcinoma (PRCC) in 2011. Lung metastasis and lymph node (LN) metastases around the inferior vena cave appeared in 2012. A right radical nephrectomy and extensive LN dissection was performed and the resection of lung metastasis was performed one month after the nephrectomy. Mediastinal LN metastases occurred in 2013, and resection of the affected LNs was performed. Sunitinib and zoledronic acid was started in 2014 because mediastinal LN swelling and multiple bone metastases appeared. Sunitinib treatment was stopped soon after due to adverse events and axitinib treatment was started. Axitinib was effective and the patient had stable disease for 30 months. Adverse events were successfully controlled by dose reduction and periodic drug withdrawal schedules (for example, 5 days on, 2 days off). Axitinib was further continued for 19 months as the metastatic lesions had progressed slowly. Temsirolimus treatment was started in 2019, but it was stopped after three cycles due to interstitial pneumonia. The patient died 80 months after the initial recurrence. Using multidisciplinary treatment, durable disease control was achieved in a patient with metastatic type 2 PRCC.
Introductions
Recently, the prognosis of patients with metastatic renal cell carcinoma (RCC) has been improved by molecular targeted therapies (1) and immune checkpoint inhibitors (2). However, optimal treatment strategies for metastatic non-clear cell RCC (nccRCC) has yet to be established. In previous studies, molecular targeted therapies, especially sunitinib, have shown clinical efficacy for the treatment of metastatic nccRCC (3-7). The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is recommended at present for metastatic nccRCC. In nccRCC papillary renal cell carcinoma (PRCC) is the leading histology (8). PRCC is divided into type 1 and type 2, with type 2 PRCC showing worse prognosis compared with type 1(9). In phase 2 clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, overall survival (OS) of type1 PRCC was 17.8 months, and that of type 2 was 12.4 months (10).
In this report, we present a patient with metastatic type 2 PRCC whose metastatic lesions were controlled for a long time by multidisciplinary treatments including metastasectomies, axitinib, zoledronic acid (ZA), and radiation therapy.
Case report
A 46-year-old man with hematospermia was presented to a urologic clinic in April, 2011. A right renal tumor was found by ultrasound, and the patient was referred to our hospital. The tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected by contrast-enhanced computed tomography (CT) (Fig. 1A and B). A right partial nephrectomy was performed in July, 2011. Pathological diagnosis was type2 PRCC (Fig. 1C and D). A lung metastasis (S6) and paracaval lymph node (LN) metastases appeared in March, 2012 (Fig. 2A and B). After five cycles of temsirolimus, right radical nephrectomy and extensive LN dissection around the inferior vena cava (IVC) and right common iliac vein were performed in June, 2012, and the resection of the lung metastasis was performed one month after the nephrectomy. Then, radiological complete remission was achieved. LN swellings at the right tracheal bifurcation was found by CT in August, 2013 (Fig. 2C). After three cycles of temsirolimus, mediastinal LN dissection was performed in October, 2013. Mediastinal LNs (Fig. 2D) were swollen again, and multiple bone metastases [sternum, right fifth rib, thoracic spine (5-7th vertebrae), left ilium, and right pubis] appeared in 2014. The clinical course of the patient, including local treatments, medical treatments, and treatment-related adverse events are shown in Fig. 3. Sunitinib (37.5 mg/day) and ZA (4 mg/month) were started in June, 2014. Sunitinib was stopped within two weeks because of adverse events (AEs) including fever, malaise, and liver dysfunction. After the patient had recovered from the AEs, axitinib (10 mg/day) was started as a second-line treatment in July, 2014. ZA was continued after the axitinib administration. Because of diarrhea and hoarseness, the treatment schedule of axitinib was changed to a periodic drug withdrawal schedule (5 days-on, 2 days-off) in October, 2014. Next, the daily dose of axitinib was reduced to 8 mg (5 days-on, 2 days-off) to control severe diarrhea in December, 2014. Stereotactic radiation therapy (total 30 Gray, 10 fractions) was performed for bone metastasis at the left ilium in November, 2015 because only the iliac metastasis appeared to be an active lesion among all bone metastases in the bone scintigraphy. The periodic drug withdrawal schedule of axitinib (8 mg/day, 5 days-on, 2 days-off) was changed to the next schedule (8 mg/day, 4 days-on, 3 days-off) due to renal dysfunction and proteinuria in April, 2017. Mediastinal LN metastases and bone metastases was stable for 30 months after the axitinib administration (Fig. 4). Disease progression was confirmed in June, 2017 due to the appearance of multiple small lung metastases. Because the metastatic lesions progressed slowly after the disease progression, axitinib was continued for another 19 months in accordance with the patient's request. The schedule of axitinib was then changed to a third schedule (8 mg/day, 3 days-on, 3 days-off) due to symptoms of anorexia, dyspnea, and muscle pain in April, 2018. Patient was hospitalized due to severe back pain in September, 2018, and palliative radiotherapy was performed for a compression fracture due to metastasis (L1 lumber vertebrae). Axitinib was stopped in October, 2019. Temsirolimus was then administered, but interstitial pneumonia occurred after three cycles of temsirolimus. Although steroid pulse therapy was performed, respiratory and general condition became worse. The patient died in November, 2019. By multidisciplinary treatments including metastasectomy, axitinib, ZA, and radiation therapy, the patient survived for 80 months after the initial recurrence.
Discussion
This patient with metastatic type 2 PRCC could survive 80 months after the initial recurrence by multidisciplinary treatments including metastasectomies, axitinib, ZA, and radiation therapy. Patients with metastatic type 2 PRCC generally have poor prognosis. In a clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median OS in type 2 PRCC was 12.4 months (10). Metastasectomies and axitinib appeared to be especially effective in the present case.
The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is the recommended treatment for metastatic nccRCC, and cabozantinib and everolimus are options. At the beginning of targeted era, mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, was reportedly effective compared with interferon-α for metastatic nccRCC (11). A comparative study between temsirolimus and tyrosine kinase inhibitors (TKIs) in metastatic nccRCC does not exist at present. The superiority of sunitinib compared with everolimus in nccRCC treatment has been reported in two clinical trials (12,13). The ASPEN trial reported that the progression-free survival (PFS) of sunitinib was longer than that of everolimus (12). The ESPN trial reported that both PFS and OS of sunitinib were longer than those of everolimus (13). Among other TKIs, the overall response rate of pazopanib was reportedly 39% in the treatment of metastatic nccRCC (6). There are few studies evaluating the clinical efficacy of systemic therapies in metastatic PRCC. In clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median PFS and OS were 6.6 and 17.8 months in type 1 PRCC, and 5.5 and 12.4 months in type 2, respectively (10). In a Japanese multicenter study evaluating metastatic PRCC in which most PRCC cases (91.4%) were type 2, the prognosis in the era of targeted therapy (OS=22.5 months) was improved compared with that in the cytokine era (OS=6.3 months). PRCC patients treated with TKIs in both first-line and second-line treatments (OS=31.4 months) showed better prognosis than those with mTOR inhibitors in first-line or second-line (OS=12.9 months) (14).
In our case, the second-line use of axitinib was effective and achieved a durable stable disease (SD). There have been few reports in which axitinib showed efficacies for metastatic PRCC (15,16). In our case, AEs were relieved by dose reduction and the setting of periodic drug withdrawal schedules of axitinib, and axitinib could be continued for a long time. The half-life period of axitinib was reportedly short (4.8-5.9 h) (17). Axitinib has a characteristic that AEs can be relieved in a short period because of its short half-life period. Then, axitinib can be started again after the short drug withdrawal period. The risk of regrowth should be low due to the short drug withdrawal. In our previous report of a clear cell RCC patient with metastasis at the paranasal sinus, AEs could be relieved effectively by using periodic drug withdrawal schedules of axitinib and axitinib could be used for more than 30 months (18). Takayama et al also reported a similar RCC case in which intermittent use of axitinib was effective (19).
There is a possibility that prognosis of this patient was improved by metastasectomies. LN metastases around the right common iliac vein and IVC at the time of LN dissection were pathologically confirmed. However, the relapse did not occur in the abdominal and pelvic areas after the extensive LN dissection. This appeared to indicate that LN metastases in the abdominal and the pelvic areas were completely resected by the initial LN dissection. Moreover, the three metastasectomies including the initial LN dissection around the IVC and right iliac vein, the resection of lung metastasis, and the mediastinal LN dissection could delay the timing of TKI administration for two years. Those metastasectomies might contribute to improve the patient's prognosis. In the cytokine era, an efficacy of LN dissection on radical nephrectomy was suggested in PRCC (20). Metastatectomy should be performed appropriately for patients with metastatic PRCC similar to clear cell RCC when radiological complete remission can be achieved by metastasectomy.
Although it is difficult to evaluate the effectiveness of ZA and local radiation therapy in this case, these treatments might present some positive effects for disease control.
We were able to control metastatic lesions of type 2 PRCC for a relatively long term by multidisciplinary treatment. Axitinib was effective and periodic drug withdrawal schedules could reduce AEs and enable to continue axitinib usage.
Acknowledgements
Not applicable.
Availability of data and materials
Data sharing is not applicable to this article, as no datasets were generated or analyzed during the present study.
Authors' contributions
YA contributed to the study concept, design, data collection and writing of the manuscript. YK contributed to data collection and the revision of the manuscript. MH contributed to data collection and the revision of the manuscript. HH contributed to data collection and the revision of the manuscript. KM contributed to data collection, pathological diagnosis and the revision of the manuscript. AH contributed to the study concept, design and the revision of the manuscript. KI contributed to the study concept, design, data collection, writing and the revision of the manuscript, and the supervision of the manuscript. The authenticity of all the raw data was assessed by YA, KM, AH and KI. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Ethical approval was granted from the Ethics Committee of National Defense Medical College.
Patient consent for publication
Written informed consent for the publication of any associated data was obtained from the patient's wife.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Radiological and pathological findings of the primary tumor. (A and B) Contrast-enhanced computed tomography images. A tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected. (C and D) Microscopically, the tumor had papillary architecture. The tumor cells contained abundant eosinophilic cytoplasm with high nuclear grade (Fuhrman nuclear grade 3). The tumor was diagnosed as type 2 papillary RCC. (C) magnification, x100; scale bar, 200 µm. (D) magnification, x400; scale bar, 50 µm. RCC, renal cell carcinoma.
Figure 2 CE-CT images. (A and B) CE-CT images of a (A) lung metastasis (S6) (black arrow) and (B) paracaval lymph node metastases (black arrow) that appeared in 2012. (C) CE-CT of lymph node swellings at the right tracheal bifurcation (white arrow) found in 2013. (D) CE-CT of mediastinal lymph nodes (white arrows) that were swollen again in 2014. CE-CT, Contrast-enhanced computed tomography.
Figure 3 The time course of treatments for the patient with metastatic type 2 papillary renal cell carcinoma. Axi, axitinib; HT, hypertension; IVC, inferior vena cava; LND, lymph node dissection; LNM, lymph node metastasis; RNx, radical nephrectomy; SD, stable disease; SU, sunitinib; TEM, temsirolimus; ZA, zoledronic acid.
Figure 4 CT images during axitinib treatment. (A) CT at axitinib administration. White arrows indicate mediastinal lymph node metastases. (B) CT 7 months after axitinib administration. Lymph node metastases shrunk by using axitinib (partial response, judged by RECIST version 1.1). (C) CT 19 months after axitinib administration. The response was maintained. (D) CT 30 months after axitinib administration. The response was still maintained. (E) Representative bone metastasis (left ilium) at axitinib administration. (F) CT 7 months after axitinib administration. (G) CT 19 months after axitinib administration. (H) CT 30 months after axitinib administration. The bone metastasis in the ilium grew slightly compared with that at axitinib administration (<10%, stable disease, judged by RECIST version 1.1). | AXITINIB, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33732457 | 19,122,950 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypertension'. | Long-term disease control of metastatic type 2 papillary renal cell carcinoma using local treatment and molecular targeted therapy: A case report.
A 46-year-old man underwent right partial nephrectomy for type 2 papillary renal cell carcinoma (PRCC) in 2011. Lung metastasis and lymph node (LN) metastases around the inferior vena cave appeared in 2012. A right radical nephrectomy and extensive LN dissection was performed and the resection of lung metastasis was performed one month after the nephrectomy. Mediastinal LN metastases occurred in 2013, and resection of the affected LNs was performed. Sunitinib and zoledronic acid was started in 2014 because mediastinal LN swelling and multiple bone metastases appeared. Sunitinib treatment was stopped soon after due to adverse events and axitinib treatment was started. Axitinib was effective and the patient had stable disease for 30 months. Adverse events were successfully controlled by dose reduction and periodic drug withdrawal schedules (for example, 5 days on, 2 days off). Axitinib was further continued for 19 months as the metastatic lesions had progressed slowly. Temsirolimus treatment was started in 2019, but it was stopped after three cycles due to interstitial pneumonia. The patient died 80 months after the initial recurrence. Using multidisciplinary treatment, durable disease control was achieved in a patient with metastatic type 2 PRCC.
Introductions
Recently, the prognosis of patients with metastatic renal cell carcinoma (RCC) has been improved by molecular targeted therapies (1) and immune checkpoint inhibitors (2). However, optimal treatment strategies for metastatic non-clear cell RCC (nccRCC) has yet to be established. In previous studies, molecular targeted therapies, especially sunitinib, have shown clinical efficacy for the treatment of metastatic nccRCC (3-7). The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is recommended at present for metastatic nccRCC. In nccRCC papillary renal cell carcinoma (PRCC) is the leading histology (8). PRCC is divided into type 1 and type 2, with type 2 PRCC showing worse prognosis compared with type 1(9). In phase 2 clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, overall survival (OS) of type1 PRCC was 17.8 months, and that of type 2 was 12.4 months (10).
In this report, we present a patient with metastatic type 2 PRCC whose metastatic lesions were controlled for a long time by multidisciplinary treatments including metastasectomies, axitinib, zoledronic acid (ZA), and radiation therapy.
Case report
A 46-year-old man with hematospermia was presented to a urologic clinic in April, 2011. A right renal tumor was found by ultrasound, and the patient was referred to our hospital. The tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected by contrast-enhanced computed tomography (CT) (Fig. 1A and B). A right partial nephrectomy was performed in July, 2011. Pathological diagnosis was type2 PRCC (Fig. 1C and D). A lung metastasis (S6) and paracaval lymph node (LN) metastases appeared in March, 2012 (Fig. 2A and B). After five cycles of temsirolimus, right radical nephrectomy and extensive LN dissection around the inferior vena cava (IVC) and right common iliac vein were performed in June, 2012, and the resection of the lung metastasis was performed one month after the nephrectomy. Then, radiological complete remission was achieved. LN swellings at the right tracheal bifurcation was found by CT in August, 2013 (Fig. 2C). After three cycles of temsirolimus, mediastinal LN dissection was performed in October, 2013. Mediastinal LNs (Fig. 2D) were swollen again, and multiple bone metastases [sternum, right fifth rib, thoracic spine (5-7th vertebrae), left ilium, and right pubis] appeared in 2014. The clinical course of the patient, including local treatments, medical treatments, and treatment-related adverse events are shown in Fig. 3. Sunitinib (37.5 mg/day) and ZA (4 mg/month) were started in June, 2014. Sunitinib was stopped within two weeks because of adverse events (AEs) including fever, malaise, and liver dysfunction. After the patient had recovered from the AEs, axitinib (10 mg/day) was started as a second-line treatment in July, 2014. ZA was continued after the axitinib administration. Because of diarrhea and hoarseness, the treatment schedule of axitinib was changed to a periodic drug withdrawal schedule (5 days-on, 2 days-off) in October, 2014. Next, the daily dose of axitinib was reduced to 8 mg (5 days-on, 2 days-off) to control severe diarrhea in December, 2014. Stereotactic radiation therapy (total 30 Gray, 10 fractions) was performed for bone metastasis at the left ilium in November, 2015 because only the iliac metastasis appeared to be an active lesion among all bone metastases in the bone scintigraphy. The periodic drug withdrawal schedule of axitinib (8 mg/day, 5 days-on, 2 days-off) was changed to the next schedule (8 mg/day, 4 days-on, 3 days-off) due to renal dysfunction and proteinuria in April, 2017. Mediastinal LN metastases and bone metastases was stable for 30 months after the axitinib administration (Fig. 4). Disease progression was confirmed in June, 2017 due to the appearance of multiple small lung metastases. Because the metastatic lesions progressed slowly after the disease progression, axitinib was continued for another 19 months in accordance with the patient's request. The schedule of axitinib was then changed to a third schedule (8 mg/day, 3 days-on, 3 days-off) due to symptoms of anorexia, dyspnea, and muscle pain in April, 2018. Patient was hospitalized due to severe back pain in September, 2018, and palliative radiotherapy was performed for a compression fracture due to metastasis (L1 lumber vertebrae). Axitinib was stopped in October, 2019. Temsirolimus was then administered, but interstitial pneumonia occurred after three cycles of temsirolimus. Although steroid pulse therapy was performed, respiratory and general condition became worse. The patient died in November, 2019. By multidisciplinary treatments including metastasectomy, axitinib, ZA, and radiation therapy, the patient survived for 80 months after the initial recurrence.
Discussion
This patient with metastatic type 2 PRCC could survive 80 months after the initial recurrence by multidisciplinary treatments including metastasectomies, axitinib, ZA, and radiation therapy. Patients with metastatic type 2 PRCC generally have poor prognosis. In a clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median OS in type 2 PRCC was 12.4 months (10). Metastasectomies and axitinib appeared to be especially effective in the present case.
The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is the recommended treatment for metastatic nccRCC, and cabozantinib and everolimus are options. At the beginning of targeted era, mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, was reportedly effective compared with interferon-α for metastatic nccRCC (11). A comparative study between temsirolimus and tyrosine kinase inhibitors (TKIs) in metastatic nccRCC does not exist at present. The superiority of sunitinib compared with everolimus in nccRCC treatment has been reported in two clinical trials (12,13). The ASPEN trial reported that the progression-free survival (PFS) of sunitinib was longer than that of everolimus (12). The ESPN trial reported that both PFS and OS of sunitinib were longer than those of everolimus (13). Among other TKIs, the overall response rate of pazopanib was reportedly 39% in the treatment of metastatic nccRCC (6). There are few studies evaluating the clinical efficacy of systemic therapies in metastatic PRCC. In clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median PFS and OS were 6.6 and 17.8 months in type 1 PRCC, and 5.5 and 12.4 months in type 2, respectively (10). In a Japanese multicenter study evaluating metastatic PRCC in which most PRCC cases (91.4%) were type 2, the prognosis in the era of targeted therapy (OS=22.5 months) was improved compared with that in the cytokine era (OS=6.3 months). PRCC patients treated with TKIs in both first-line and second-line treatments (OS=31.4 months) showed better prognosis than those with mTOR inhibitors in first-line or second-line (OS=12.9 months) (14).
In our case, the second-line use of axitinib was effective and achieved a durable stable disease (SD). There have been few reports in which axitinib showed efficacies for metastatic PRCC (15,16). In our case, AEs were relieved by dose reduction and the setting of periodic drug withdrawal schedules of axitinib, and axitinib could be continued for a long time. The half-life period of axitinib was reportedly short (4.8-5.9 h) (17). Axitinib has a characteristic that AEs can be relieved in a short period because of its short half-life period. Then, axitinib can be started again after the short drug withdrawal period. The risk of regrowth should be low due to the short drug withdrawal. In our previous report of a clear cell RCC patient with metastasis at the paranasal sinus, AEs could be relieved effectively by using periodic drug withdrawal schedules of axitinib and axitinib could be used for more than 30 months (18). Takayama et al also reported a similar RCC case in which intermittent use of axitinib was effective (19).
There is a possibility that prognosis of this patient was improved by metastasectomies. LN metastases around the right common iliac vein and IVC at the time of LN dissection were pathologically confirmed. However, the relapse did not occur in the abdominal and pelvic areas after the extensive LN dissection. This appeared to indicate that LN metastases in the abdominal and the pelvic areas were completely resected by the initial LN dissection. Moreover, the three metastasectomies including the initial LN dissection around the IVC and right iliac vein, the resection of lung metastasis, and the mediastinal LN dissection could delay the timing of TKI administration for two years. Those metastasectomies might contribute to improve the patient's prognosis. In the cytokine era, an efficacy of LN dissection on radical nephrectomy was suggested in PRCC (20). Metastatectomy should be performed appropriately for patients with metastatic PRCC similar to clear cell RCC when radiological complete remission can be achieved by metastasectomy.
Although it is difficult to evaluate the effectiveness of ZA and local radiation therapy in this case, these treatments might present some positive effects for disease control.
We were able to control metastatic lesions of type 2 PRCC for a relatively long term by multidisciplinary treatment. Axitinib was effective and periodic drug withdrawal schedules could reduce AEs and enable to continue axitinib usage.
Acknowledgements
Not applicable.
Availability of data and materials
Data sharing is not applicable to this article, as no datasets were generated or analyzed during the present study.
Authors' contributions
YA contributed to the study concept, design, data collection and writing of the manuscript. YK contributed to data collection and the revision of the manuscript. MH contributed to data collection and the revision of the manuscript. HH contributed to data collection and the revision of the manuscript. KM contributed to data collection, pathological diagnosis and the revision of the manuscript. AH contributed to the study concept, design and the revision of the manuscript. KI contributed to the study concept, design, data collection, writing and the revision of the manuscript, and the supervision of the manuscript. The authenticity of all the raw data was assessed by YA, KM, AH and KI. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Ethical approval was granted from the Ethics Committee of National Defense Medical College.
Patient consent for publication
Written informed consent for the publication of any associated data was obtained from the patient's wife.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Radiological and pathological findings of the primary tumor. (A and B) Contrast-enhanced computed tomography images. A tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected. (C and D) Microscopically, the tumor had papillary architecture. The tumor cells contained abundant eosinophilic cytoplasm with high nuclear grade (Fuhrman nuclear grade 3). The tumor was diagnosed as type 2 papillary RCC. (C) magnification, x100; scale bar, 200 µm. (D) magnification, x400; scale bar, 50 µm. RCC, renal cell carcinoma.
Figure 2 CE-CT images. (A and B) CE-CT images of a (A) lung metastasis (S6) (black arrow) and (B) paracaval lymph node metastases (black arrow) that appeared in 2012. (C) CE-CT of lymph node swellings at the right tracheal bifurcation (white arrow) found in 2013. (D) CE-CT of mediastinal lymph nodes (white arrows) that were swollen again in 2014. CE-CT, Contrast-enhanced computed tomography.
Figure 3 The time course of treatments for the patient with metastatic type 2 papillary renal cell carcinoma. Axi, axitinib; HT, hypertension; IVC, inferior vena cava; LND, lymph node dissection; LNM, lymph node metastasis; RNx, radical nephrectomy; SD, stable disease; SU, sunitinib; TEM, temsirolimus; ZA, zoledronic acid.
Figure 4 CT images during axitinib treatment. (A) CT at axitinib administration. White arrows indicate mediastinal lymph node metastases. (B) CT 7 months after axitinib administration. Lymph node metastases shrunk by using axitinib (partial response, judged by RECIST version 1.1). (C) CT 19 months after axitinib administration. The response was maintained. (D) CT 30 months after axitinib administration. The response was still maintained. (E) Representative bone metastasis (left ilium) at axitinib administration. (F) CT 7 months after axitinib administration. (G) CT 19 months after axitinib administration. (H) CT 30 months after axitinib administration. The bone metastasis in the ilium grew slightly compared with that at axitinib administration (<10%, stable disease, judged by RECIST version 1.1). | AXITINIB, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33732457 | 19,122,950 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Liver disorder'. | Long-term disease control of metastatic type 2 papillary renal cell carcinoma using local treatment and molecular targeted therapy: A case report.
A 46-year-old man underwent right partial nephrectomy for type 2 papillary renal cell carcinoma (PRCC) in 2011. Lung metastasis and lymph node (LN) metastases around the inferior vena cave appeared in 2012. A right radical nephrectomy and extensive LN dissection was performed and the resection of lung metastasis was performed one month after the nephrectomy. Mediastinal LN metastases occurred in 2013, and resection of the affected LNs was performed. Sunitinib and zoledronic acid was started in 2014 because mediastinal LN swelling and multiple bone metastases appeared. Sunitinib treatment was stopped soon after due to adverse events and axitinib treatment was started. Axitinib was effective and the patient had stable disease for 30 months. Adverse events were successfully controlled by dose reduction and periodic drug withdrawal schedules (for example, 5 days on, 2 days off). Axitinib was further continued for 19 months as the metastatic lesions had progressed slowly. Temsirolimus treatment was started in 2019, but it was stopped after three cycles due to interstitial pneumonia. The patient died 80 months after the initial recurrence. Using multidisciplinary treatment, durable disease control was achieved in a patient with metastatic type 2 PRCC.
Introductions
Recently, the prognosis of patients with metastatic renal cell carcinoma (RCC) has been improved by molecular targeted therapies (1) and immune checkpoint inhibitors (2). However, optimal treatment strategies for metastatic non-clear cell RCC (nccRCC) has yet to be established. In previous studies, molecular targeted therapies, especially sunitinib, have shown clinical efficacy for the treatment of metastatic nccRCC (3-7). The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is recommended at present for metastatic nccRCC. In nccRCC papillary renal cell carcinoma (PRCC) is the leading histology (8). PRCC is divided into type 1 and type 2, with type 2 PRCC showing worse prognosis compared with type 1(9). In phase 2 clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, overall survival (OS) of type1 PRCC was 17.8 months, and that of type 2 was 12.4 months (10).
In this report, we present a patient with metastatic type 2 PRCC whose metastatic lesions were controlled for a long time by multidisciplinary treatments including metastasectomies, axitinib, zoledronic acid (ZA), and radiation therapy.
Case report
A 46-year-old man with hematospermia was presented to a urologic clinic in April, 2011. A right renal tumor was found by ultrasound, and the patient was referred to our hospital. The tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected by contrast-enhanced computed tomography (CT) (Fig. 1A and B). A right partial nephrectomy was performed in July, 2011. Pathological diagnosis was type2 PRCC (Fig. 1C and D). A lung metastasis (S6) and paracaval lymph node (LN) metastases appeared in March, 2012 (Fig. 2A and B). After five cycles of temsirolimus, right radical nephrectomy and extensive LN dissection around the inferior vena cava (IVC) and right common iliac vein were performed in June, 2012, and the resection of the lung metastasis was performed one month after the nephrectomy. Then, radiological complete remission was achieved. LN swellings at the right tracheal bifurcation was found by CT in August, 2013 (Fig. 2C). After three cycles of temsirolimus, mediastinal LN dissection was performed in October, 2013. Mediastinal LNs (Fig. 2D) were swollen again, and multiple bone metastases [sternum, right fifth rib, thoracic spine (5-7th vertebrae), left ilium, and right pubis] appeared in 2014. The clinical course of the patient, including local treatments, medical treatments, and treatment-related adverse events are shown in Fig. 3. Sunitinib (37.5 mg/day) and ZA (4 mg/month) were started in June, 2014. Sunitinib was stopped within two weeks because of adverse events (AEs) including fever, malaise, and liver dysfunction. After the patient had recovered from the AEs, axitinib (10 mg/day) was started as a second-line treatment in July, 2014. ZA was continued after the axitinib administration. Because of diarrhea and hoarseness, the treatment schedule of axitinib was changed to a periodic drug withdrawal schedule (5 days-on, 2 days-off) in October, 2014. Next, the daily dose of axitinib was reduced to 8 mg (5 days-on, 2 days-off) to control severe diarrhea in December, 2014. Stereotactic radiation therapy (total 30 Gray, 10 fractions) was performed for bone metastasis at the left ilium in November, 2015 because only the iliac metastasis appeared to be an active lesion among all bone metastases in the bone scintigraphy. The periodic drug withdrawal schedule of axitinib (8 mg/day, 5 days-on, 2 days-off) was changed to the next schedule (8 mg/day, 4 days-on, 3 days-off) due to renal dysfunction and proteinuria in April, 2017. Mediastinal LN metastases and bone metastases was stable for 30 months after the axitinib administration (Fig. 4). Disease progression was confirmed in June, 2017 due to the appearance of multiple small lung metastases. Because the metastatic lesions progressed slowly after the disease progression, axitinib was continued for another 19 months in accordance with the patient's request. The schedule of axitinib was then changed to a third schedule (8 mg/day, 3 days-on, 3 days-off) due to symptoms of anorexia, dyspnea, and muscle pain in April, 2018. Patient was hospitalized due to severe back pain in September, 2018, and palliative radiotherapy was performed for a compression fracture due to metastasis (L1 lumber vertebrae). Axitinib was stopped in October, 2019. Temsirolimus was then administered, but interstitial pneumonia occurred after three cycles of temsirolimus. Although steroid pulse therapy was performed, respiratory and general condition became worse. The patient died in November, 2019. By multidisciplinary treatments including metastasectomy, axitinib, ZA, and radiation therapy, the patient survived for 80 months after the initial recurrence.
Discussion
This patient with metastatic type 2 PRCC could survive 80 months after the initial recurrence by multidisciplinary treatments including metastasectomies, axitinib, ZA, and radiation therapy. Patients with metastatic type 2 PRCC generally have poor prognosis. In a clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median OS in type 2 PRCC was 12.4 months (10). Metastasectomies and axitinib appeared to be especially effective in the present case.
The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is the recommended treatment for metastatic nccRCC, and cabozantinib and everolimus are options. At the beginning of targeted era, mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, was reportedly effective compared with interferon-α for metastatic nccRCC (11). A comparative study between temsirolimus and tyrosine kinase inhibitors (TKIs) in metastatic nccRCC does not exist at present. The superiority of sunitinib compared with everolimus in nccRCC treatment has been reported in two clinical trials (12,13). The ASPEN trial reported that the progression-free survival (PFS) of sunitinib was longer than that of everolimus (12). The ESPN trial reported that both PFS and OS of sunitinib were longer than those of everolimus (13). Among other TKIs, the overall response rate of pazopanib was reportedly 39% in the treatment of metastatic nccRCC (6). There are few studies evaluating the clinical efficacy of systemic therapies in metastatic PRCC. In clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median PFS and OS were 6.6 and 17.8 months in type 1 PRCC, and 5.5 and 12.4 months in type 2, respectively (10). In a Japanese multicenter study evaluating metastatic PRCC in which most PRCC cases (91.4%) were type 2, the prognosis in the era of targeted therapy (OS=22.5 months) was improved compared with that in the cytokine era (OS=6.3 months). PRCC patients treated with TKIs in both first-line and second-line treatments (OS=31.4 months) showed better prognosis than those with mTOR inhibitors in first-line or second-line (OS=12.9 months) (14).
In our case, the second-line use of axitinib was effective and achieved a durable stable disease (SD). There have been few reports in which axitinib showed efficacies for metastatic PRCC (15,16). In our case, AEs were relieved by dose reduction and the setting of periodic drug withdrawal schedules of axitinib, and axitinib could be continued for a long time. The half-life period of axitinib was reportedly short (4.8-5.9 h) (17). Axitinib has a characteristic that AEs can be relieved in a short period because of its short half-life period. Then, axitinib can be started again after the short drug withdrawal period. The risk of regrowth should be low due to the short drug withdrawal. In our previous report of a clear cell RCC patient with metastasis at the paranasal sinus, AEs could be relieved effectively by using periodic drug withdrawal schedules of axitinib and axitinib could be used for more than 30 months (18). Takayama et al also reported a similar RCC case in which intermittent use of axitinib was effective (19).
There is a possibility that prognosis of this patient was improved by metastasectomies. LN metastases around the right common iliac vein and IVC at the time of LN dissection were pathologically confirmed. However, the relapse did not occur in the abdominal and pelvic areas after the extensive LN dissection. This appeared to indicate that LN metastases in the abdominal and the pelvic areas were completely resected by the initial LN dissection. Moreover, the three metastasectomies including the initial LN dissection around the IVC and right iliac vein, the resection of lung metastasis, and the mediastinal LN dissection could delay the timing of TKI administration for two years. Those metastasectomies might contribute to improve the patient's prognosis. In the cytokine era, an efficacy of LN dissection on radical nephrectomy was suggested in PRCC (20). Metastatectomy should be performed appropriately for patients with metastatic PRCC similar to clear cell RCC when radiological complete remission can be achieved by metastasectomy.
Although it is difficult to evaluate the effectiveness of ZA and local radiation therapy in this case, these treatments might present some positive effects for disease control.
We were able to control metastatic lesions of type 2 PRCC for a relatively long term by multidisciplinary treatment. Axitinib was effective and periodic drug withdrawal schedules could reduce AEs and enable to continue axitinib usage.
Acknowledgements
Not applicable.
Availability of data and materials
Data sharing is not applicable to this article, as no datasets were generated or analyzed during the present study.
Authors' contributions
YA contributed to the study concept, design, data collection and writing of the manuscript. YK contributed to data collection and the revision of the manuscript. MH contributed to data collection and the revision of the manuscript. HH contributed to data collection and the revision of the manuscript. KM contributed to data collection, pathological diagnosis and the revision of the manuscript. AH contributed to the study concept, design and the revision of the manuscript. KI contributed to the study concept, design, data collection, writing and the revision of the manuscript, and the supervision of the manuscript. The authenticity of all the raw data was assessed by YA, KM, AH and KI. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Ethical approval was granted from the Ethics Committee of National Defense Medical College.
Patient consent for publication
Written informed consent for the publication of any associated data was obtained from the patient's wife.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Radiological and pathological findings of the primary tumor. (A and B) Contrast-enhanced computed tomography images. A tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected. (C and D) Microscopically, the tumor had papillary architecture. The tumor cells contained abundant eosinophilic cytoplasm with high nuclear grade (Fuhrman nuclear grade 3). The tumor was diagnosed as type 2 papillary RCC. (C) magnification, x100; scale bar, 200 µm. (D) magnification, x400; scale bar, 50 µm. RCC, renal cell carcinoma.
Figure 2 CE-CT images. (A and B) CE-CT images of a (A) lung metastasis (S6) (black arrow) and (B) paracaval lymph node metastases (black arrow) that appeared in 2012. (C) CE-CT of lymph node swellings at the right tracheal bifurcation (white arrow) found in 2013. (D) CE-CT of mediastinal lymph nodes (white arrows) that were swollen again in 2014. CE-CT, Contrast-enhanced computed tomography.
Figure 3 The time course of treatments for the patient with metastatic type 2 papillary renal cell carcinoma. Axi, axitinib; HT, hypertension; IVC, inferior vena cava; LND, lymph node dissection; LNM, lymph node metastasis; RNx, radical nephrectomy; SD, stable disease; SU, sunitinib; TEM, temsirolimus; ZA, zoledronic acid.
Figure 4 CT images during axitinib treatment. (A) CT at axitinib administration. White arrows indicate mediastinal lymph node metastases. (B) CT 7 months after axitinib administration. Lymph node metastases shrunk by using axitinib (partial response, judged by RECIST version 1.1). (C) CT 19 months after axitinib administration. The response was maintained. (D) CT 30 months after axitinib administration. The response was still maintained. (E) Representative bone metastasis (left ilium) at axitinib administration. (F) CT 7 months after axitinib administration. (G) CT 19 months after axitinib administration. (H) CT 30 months after axitinib administration. The bone metastasis in the ilium grew slightly compared with that at axitinib administration (<10%, stable disease, judged by RECIST version 1.1). | SUNITINIB, TEMSIROLIMUS, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33732457 | 19,952,254 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Malaise'. | Long-term disease control of metastatic type 2 papillary renal cell carcinoma using local treatment and molecular targeted therapy: A case report.
A 46-year-old man underwent right partial nephrectomy for type 2 papillary renal cell carcinoma (PRCC) in 2011. Lung metastasis and lymph node (LN) metastases around the inferior vena cave appeared in 2012. A right radical nephrectomy and extensive LN dissection was performed and the resection of lung metastasis was performed one month after the nephrectomy. Mediastinal LN metastases occurred in 2013, and resection of the affected LNs was performed. Sunitinib and zoledronic acid was started in 2014 because mediastinal LN swelling and multiple bone metastases appeared. Sunitinib treatment was stopped soon after due to adverse events and axitinib treatment was started. Axitinib was effective and the patient had stable disease for 30 months. Adverse events were successfully controlled by dose reduction and periodic drug withdrawal schedules (for example, 5 days on, 2 days off). Axitinib was further continued for 19 months as the metastatic lesions had progressed slowly. Temsirolimus treatment was started in 2019, but it was stopped after three cycles due to interstitial pneumonia. The patient died 80 months after the initial recurrence. Using multidisciplinary treatment, durable disease control was achieved in a patient with metastatic type 2 PRCC.
Introductions
Recently, the prognosis of patients with metastatic renal cell carcinoma (RCC) has been improved by molecular targeted therapies (1) and immune checkpoint inhibitors (2). However, optimal treatment strategies for metastatic non-clear cell RCC (nccRCC) has yet to be established. In previous studies, molecular targeted therapies, especially sunitinib, have shown clinical efficacy for the treatment of metastatic nccRCC (3-7). The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is recommended at present for metastatic nccRCC. In nccRCC papillary renal cell carcinoma (PRCC) is the leading histology (8). PRCC is divided into type 1 and type 2, with type 2 PRCC showing worse prognosis compared with type 1(9). In phase 2 clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, overall survival (OS) of type1 PRCC was 17.8 months, and that of type 2 was 12.4 months (10).
In this report, we present a patient with metastatic type 2 PRCC whose metastatic lesions were controlled for a long time by multidisciplinary treatments including metastasectomies, axitinib, zoledronic acid (ZA), and radiation therapy.
Case report
A 46-year-old man with hematospermia was presented to a urologic clinic in April, 2011. A right renal tumor was found by ultrasound, and the patient was referred to our hospital. The tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected by contrast-enhanced computed tomography (CT) (Fig. 1A and B). A right partial nephrectomy was performed in July, 2011. Pathological diagnosis was type2 PRCC (Fig. 1C and D). A lung metastasis (S6) and paracaval lymph node (LN) metastases appeared in March, 2012 (Fig. 2A and B). After five cycles of temsirolimus, right radical nephrectomy and extensive LN dissection around the inferior vena cava (IVC) and right common iliac vein were performed in June, 2012, and the resection of the lung metastasis was performed one month after the nephrectomy. Then, radiological complete remission was achieved. LN swellings at the right tracheal bifurcation was found by CT in August, 2013 (Fig. 2C). After three cycles of temsirolimus, mediastinal LN dissection was performed in October, 2013. Mediastinal LNs (Fig. 2D) were swollen again, and multiple bone metastases [sternum, right fifth rib, thoracic spine (5-7th vertebrae), left ilium, and right pubis] appeared in 2014. The clinical course of the patient, including local treatments, medical treatments, and treatment-related adverse events are shown in Fig. 3. Sunitinib (37.5 mg/day) and ZA (4 mg/month) were started in June, 2014. Sunitinib was stopped within two weeks because of adverse events (AEs) including fever, malaise, and liver dysfunction. After the patient had recovered from the AEs, axitinib (10 mg/day) was started as a second-line treatment in July, 2014. ZA was continued after the axitinib administration. Because of diarrhea and hoarseness, the treatment schedule of axitinib was changed to a periodic drug withdrawal schedule (5 days-on, 2 days-off) in October, 2014. Next, the daily dose of axitinib was reduced to 8 mg (5 days-on, 2 days-off) to control severe diarrhea in December, 2014. Stereotactic radiation therapy (total 30 Gray, 10 fractions) was performed for bone metastasis at the left ilium in November, 2015 because only the iliac metastasis appeared to be an active lesion among all bone metastases in the bone scintigraphy. The periodic drug withdrawal schedule of axitinib (8 mg/day, 5 days-on, 2 days-off) was changed to the next schedule (8 mg/day, 4 days-on, 3 days-off) due to renal dysfunction and proteinuria in April, 2017. Mediastinal LN metastases and bone metastases was stable for 30 months after the axitinib administration (Fig. 4). Disease progression was confirmed in June, 2017 due to the appearance of multiple small lung metastases. Because the metastatic lesions progressed slowly after the disease progression, axitinib was continued for another 19 months in accordance with the patient's request. The schedule of axitinib was then changed to a third schedule (8 mg/day, 3 days-on, 3 days-off) due to symptoms of anorexia, dyspnea, and muscle pain in April, 2018. Patient was hospitalized due to severe back pain in September, 2018, and palliative radiotherapy was performed for a compression fracture due to metastasis (L1 lumber vertebrae). Axitinib was stopped in October, 2019. Temsirolimus was then administered, but interstitial pneumonia occurred after three cycles of temsirolimus. Although steroid pulse therapy was performed, respiratory and general condition became worse. The patient died in November, 2019. By multidisciplinary treatments including metastasectomy, axitinib, ZA, and radiation therapy, the patient survived for 80 months after the initial recurrence.
Discussion
This patient with metastatic type 2 PRCC could survive 80 months after the initial recurrence by multidisciplinary treatments including metastasectomies, axitinib, ZA, and radiation therapy. Patients with metastatic type 2 PRCC generally have poor prognosis. In a clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median OS in type 2 PRCC was 12.4 months (10). Metastasectomies and axitinib appeared to be especially effective in the present case.
The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is the recommended treatment for metastatic nccRCC, and cabozantinib and everolimus are options. At the beginning of targeted era, mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, was reportedly effective compared with interferon-α for metastatic nccRCC (11). A comparative study between temsirolimus and tyrosine kinase inhibitors (TKIs) in metastatic nccRCC does not exist at present. The superiority of sunitinib compared with everolimus in nccRCC treatment has been reported in two clinical trials (12,13). The ASPEN trial reported that the progression-free survival (PFS) of sunitinib was longer than that of everolimus (12). The ESPN trial reported that both PFS and OS of sunitinib were longer than those of everolimus (13). Among other TKIs, the overall response rate of pazopanib was reportedly 39% in the treatment of metastatic nccRCC (6). There are few studies evaluating the clinical efficacy of systemic therapies in metastatic PRCC. In clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median PFS and OS were 6.6 and 17.8 months in type 1 PRCC, and 5.5 and 12.4 months in type 2, respectively (10). In a Japanese multicenter study evaluating metastatic PRCC in which most PRCC cases (91.4%) were type 2, the prognosis in the era of targeted therapy (OS=22.5 months) was improved compared with that in the cytokine era (OS=6.3 months). PRCC patients treated with TKIs in both first-line and second-line treatments (OS=31.4 months) showed better prognosis than those with mTOR inhibitors in first-line or second-line (OS=12.9 months) (14).
In our case, the second-line use of axitinib was effective and achieved a durable stable disease (SD). There have been few reports in which axitinib showed efficacies for metastatic PRCC (15,16). In our case, AEs were relieved by dose reduction and the setting of periodic drug withdrawal schedules of axitinib, and axitinib could be continued for a long time. The half-life period of axitinib was reportedly short (4.8-5.9 h) (17). Axitinib has a characteristic that AEs can be relieved in a short period because of its short half-life period. Then, axitinib can be started again after the short drug withdrawal period. The risk of regrowth should be low due to the short drug withdrawal. In our previous report of a clear cell RCC patient with metastasis at the paranasal sinus, AEs could be relieved effectively by using periodic drug withdrawal schedules of axitinib and axitinib could be used for more than 30 months (18). Takayama et al also reported a similar RCC case in which intermittent use of axitinib was effective (19).
There is a possibility that prognosis of this patient was improved by metastasectomies. LN metastases around the right common iliac vein and IVC at the time of LN dissection were pathologically confirmed. However, the relapse did not occur in the abdominal and pelvic areas after the extensive LN dissection. This appeared to indicate that LN metastases in the abdominal and the pelvic areas were completely resected by the initial LN dissection. Moreover, the three metastasectomies including the initial LN dissection around the IVC and right iliac vein, the resection of lung metastasis, and the mediastinal LN dissection could delay the timing of TKI administration for two years. Those metastasectomies might contribute to improve the patient's prognosis. In the cytokine era, an efficacy of LN dissection on radical nephrectomy was suggested in PRCC (20). Metastatectomy should be performed appropriately for patients with metastatic PRCC similar to clear cell RCC when radiological complete remission can be achieved by metastasectomy.
Although it is difficult to evaluate the effectiveness of ZA and local radiation therapy in this case, these treatments might present some positive effects for disease control.
We were able to control metastatic lesions of type 2 PRCC for a relatively long term by multidisciplinary treatment. Axitinib was effective and periodic drug withdrawal schedules could reduce AEs and enable to continue axitinib usage.
Acknowledgements
Not applicable.
Availability of data and materials
Data sharing is not applicable to this article, as no datasets were generated or analyzed during the present study.
Authors' contributions
YA contributed to the study concept, design, data collection and writing of the manuscript. YK contributed to data collection and the revision of the manuscript. MH contributed to data collection and the revision of the manuscript. HH contributed to data collection and the revision of the manuscript. KM contributed to data collection, pathological diagnosis and the revision of the manuscript. AH contributed to the study concept, design and the revision of the manuscript. KI contributed to the study concept, design, data collection, writing and the revision of the manuscript, and the supervision of the manuscript. The authenticity of all the raw data was assessed by YA, KM, AH and KI. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Ethical approval was granted from the Ethics Committee of National Defense Medical College.
Patient consent for publication
Written informed consent for the publication of any associated data was obtained from the patient's wife.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Radiological and pathological findings of the primary tumor. (A and B) Contrast-enhanced computed tomography images. A tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected. (C and D) Microscopically, the tumor had papillary architecture. The tumor cells contained abundant eosinophilic cytoplasm with high nuclear grade (Fuhrman nuclear grade 3). The tumor was diagnosed as type 2 papillary RCC. (C) magnification, x100; scale bar, 200 µm. (D) magnification, x400; scale bar, 50 µm. RCC, renal cell carcinoma.
Figure 2 CE-CT images. (A and B) CE-CT images of a (A) lung metastasis (S6) (black arrow) and (B) paracaval lymph node metastases (black arrow) that appeared in 2012. (C) CE-CT of lymph node swellings at the right tracheal bifurcation (white arrow) found in 2013. (D) CE-CT of mediastinal lymph nodes (white arrows) that were swollen again in 2014. CE-CT, Contrast-enhanced computed tomography.
Figure 3 The time course of treatments for the patient with metastatic type 2 papillary renal cell carcinoma. Axi, axitinib; HT, hypertension; IVC, inferior vena cava; LND, lymph node dissection; LNM, lymph node metastasis; RNx, radical nephrectomy; SD, stable disease; SU, sunitinib; TEM, temsirolimus; ZA, zoledronic acid.
Figure 4 CT images during axitinib treatment. (A) CT at axitinib administration. White arrows indicate mediastinal lymph node metastases. (B) CT 7 months after axitinib administration. Lymph node metastases shrunk by using axitinib (partial response, judged by RECIST version 1.1). (C) CT 19 months after axitinib administration. The response was maintained. (D) CT 30 months after axitinib administration. The response was still maintained. (E) Representative bone metastasis (left ilium) at axitinib administration. (F) CT 7 months after axitinib administration. (G) CT 19 months after axitinib administration. (H) CT 30 months after axitinib administration. The bone metastasis in the ilium grew slightly compared with that at axitinib administration (<10%, stable disease, judged by RECIST version 1.1). | SUNITINIB, TEMSIROLIMUS, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33732457 | 19,952,254 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myalgia'. | Long-term disease control of metastatic type 2 papillary renal cell carcinoma using local treatment and molecular targeted therapy: A case report.
A 46-year-old man underwent right partial nephrectomy for type 2 papillary renal cell carcinoma (PRCC) in 2011. Lung metastasis and lymph node (LN) metastases around the inferior vena cave appeared in 2012. A right radical nephrectomy and extensive LN dissection was performed and the resection of lung metastasis was performed one month after the nephrectomy. Mediastinal LN metastases occurred in 2013, and resection of the affected LNs was performed. Sunitinib and zoledronic acid was started in 2014 because mediastinal LN swelling and multiple bone metastases appeared. Sunitinib treatment was stopped soon after due to adverse events and axitinib treatment was started. Axitinib was effective and the patient had stable disease for 30 months. Adverse events were successfully controlled by dose reduction and periodic drug withdrawal schedules (for example, 5 days on, 2 days off). Axitinib was further continued for 19 months as the metastatic lesions had progressed slowly. Temsirolimus treatment was started in 2019, but it was stopped after three cycles due to interstitial pneumonia. The patient died 80 months after the initial recurrence. Using multidisciplinary treatment, durable disease control was achieved in a patient with metastatic type 2 PRCC.
Introductions
Recently, the prognosis of patients with metastatic renal cell carcinoma (RCC) has been improved by molecular targeted therapies (1) and immune checkpoint inhibitors (2). However, optimal treatment strategies for metastatic non-clear cell RCC (nccRCC) has yet to be established. In previous studies, molecular targeted therapies, especially sunitinib, have shown clinical efficacy for the treatment of metastatic nccRCC (3-7). The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is recommended at present for metastatic nccRCC. In nccRCC papillary renal cell carcinoma (PRCC) is the leading histology (8). PRCC is divided into type 1 and type 2, with type 2 PRCC showing worse prognosis compared with type 1(9). In phase 2 clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, overall survival (OS) of type1 PRCC was 17.8 months, and that of type 2 was 12.4 months (10).
In this report, we present a patient with metastatic type 2 PRCC whose metastatic lesions were controlled for a long time by multidisciplinary treatments including metastasectomies, axitinib, zoledronic acid (ZA), and radiation therapy.
Case report
A 46-year-old man with hematospermia was presented to a urologic clinic in April, 2011. A right renal tumor was found by ultrasound, and the patient was referred to our hospital. The tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected by contrast-enhanced computed tomography (CT) (Fig. 1A and B). A right partial nephrectomy was performed in July, 2011. Pathological diagnosis was type2 PRCC (Fig. 1C and D). A lung metastasis (S6) and paracaval lymph node (LN) metastases appeared in March, 2012 (Fig. 2A and B). After five cycles of temsirolimus, right radical nephrectomy and extensive LN dissection around the inferior vena cava (IVC) and right common iliac vein were performed in June, 2012, and the resection of the lung metastasis was performed one month after the nephrectomy. Then, radiological complete remission was achieved. LN swellings at the right tracheal bifurcation was found by CT in August, 2013 (Fig. 2C). After three cycles of temsirolimus, mediastinal LN dissection was performed in October, 2013. Mediastinal LNs (Fig. 2D) were swollen again, and multiple bone metastases [sternum, right fifth rib, thoracic spine (5-7th vertebrae), left ilium, and right pubis] appeared in 2014. The clinical course of the patient, including local treatments, medical treatments, and treatment-related adverse events are shown in Fig. 3. Sunitinib (37.5 mg/day) and ZA (4 mg/month) were started in June, 2014. Sunitinib was stopped within two weeks because of adverse events (AEs) including fever, malaise, and liver dysfunction. After the patient had recovered from the AEs, axitinib (10 mg/day) was started as a second-line treatment in July, 2014. ZA was continued after the axitinib administration. Because of diarrhea and hoarseness, the treatment schedule of axitinib was changed to a periodic drug withdrawal schedule (5 days-on, 2 days-off) in October, 2014. Next, the daily dose of axitinib was reduced to 8 mg (5 days-on, 2 days-off) to control severe diarrhea in December, 2014. Stereotactic radiation therapy (total 30 Gray, 10 fractions) was performed for bone metastasis at the left ilium in November, 2015 because only the iliac metastasis appeared to be an active lesion among all bone metastases in the bone scintigraphy. The periodic drug withdrawal schedule of axitinib (8 mg/day, 5 days-on, 2 days-off) was changed to the next schedule (8 mg/day, 4 days-on, 3 days-off) due to renal dysfunction and proteinuria in April, 2017. Mediastinal LN metastases and bone metastases was stable for 30 months after the axitinib administration (Fig. 4). Disease progression was confirmed in June, 2017 due to the appearance of multiple small lung metastases. Because the metastatic lesions progressed slowly after the disease progression, axitinib was continued for another 19 months in accordance with the patient's request. The schedule of axitinib was then changed to a third schedule (8 mg/day, 3 days-on, 3 days-off) due to symptoms of anorexia, dyspnea, and muscle pain in April, 2018. Patient was hospitalized due to severe back pain in September, 2018, and palliative radiotherapy was performed for a compression fracture due to metastasis (L1 lumber vertebrae). Axitinib was stopped in October, 2019. Temsirolimus was then administered, but interstitial pneumonia occurred after three cycles of temsirolimus. Although steroid pulse therapy was performed, respiratory and general condition became worse. The patient died in November, 2019. By multidisciplinary treatments including metastasectomy, axitinib, ZA, and radiation therapy, the patient survived for 80 months after the initial recurrence.
Discussion
This patient with metastatic type 2 PRCC could survive 80 months after the initial recurrence by multidisciplinary treatments including metastasectomies, axitinib, ZA, and radiation therapy. Patients with metastatic type 2 PRCC generally have poor prognosis. In a clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median OS in type 2 PRCC was 12.4 months (10). Metastasectomies and axitinib appeared to be especially effective in the present case.
The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is the recommended treatment for metastatic nccRCC, and cabozantinib and everolimus are options. At the beginning of targeted era, mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, was reportedly effective compared with interferon-α for metastatic nccRCC (11). A comparative study between temsirolimus and tyrosine kinase inhibitors (TKIs) in metastatic nccRCC does not exist at present. The superiority of sunitinib compared with everolimus in nccRCC treatment has been reported in two clinical trials (12,13). The ASPEN trial reported that the progression-free survival (PFS) of sunitinib was longer than that of everolimus (12). The ESPN trial reported that both PFS and OS of sunitinib were longer than those of everolimus (13). Among other TKIs, the overall response rate of pazopanib was reportedly 39% in the treatment of metastatic nccRCC (6). There are few studies evaluating the clinical efficacy of systemic therapies in metastatic PRCC. In clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median PFS and OS were 6.6 and 17.8 months in type 1 PRCC, and 5.5 and 12.4 months in type 2, respectively (10). In a Japanese multicenter study evaluating metastatic PRCC in which most PRCC cases (91.4%) were type 2, the prognosis in the era of targeted therapy (OS=22.5 months) was improved compared with that in the cytokine era (OS=6.3 months). PRCC patients treated with TKIs in both first-line and second-line treatments (OS=31.4 months) showed better prognosis than those with mTOR inhibitors in first-line or second-line (OS=12.9 months) (14).
In our case, the second-line use of axitinib was effective and achieved a durable stable disease (SD). There have been few reports in which axitinib showed efficacies for metastatic PRCC (15,16). In our case, AEs were relieved by dose reduction and the setting of periodic drug withdrawal schedules of axitinib, and axitinib could be continued for a long time. The half-life period of axitinib was reportedly short (4.8-5.9 h) (17). Axitinib has a characteristic that AEs can be relieved in a short period because of its short half-life period. Then, axitinib can be started again after the short drug withdrawal period. The risk of regrowth should be low due to the short drug withdrawal. In our previous report of a clear cell RCC patient with metastasis at the paranasal sinus, AEs could be relieved effectively by using periodic drug withdrawal schedules of axitinib and axitinib could be used for more than 30 months (18). Takayama et al also reported a similar RCC case in which intermittent use of axitinib was effective (19).
There is a possibility that prognosis of this patient was improved by metastasectomies. LN metastases around the right common iliac vein and IVC at the time of LN dissection were pathologically confirmed. However, the relapse did not occur in the abdominal and pelvic areas after the extensive LN dissection. This appeared to indicate that LN metastases in the abdominal and the pelvic areas were completely resected by the initial LN dissection. Moreover, the three metastasectomies including the initial LN dissection around the IVC and right iliac vein, the resection of lung metastasis, and the mediastinal LN dissection could delay the timing of TKI administration for two years. Those metastasectomies might contribute to improve the patient's prognosis. In the cytokine era, an efficacy of LN dissection on radical nephrectomy was suggested in PRCC (20). Metastatectomy should be performed appropriately for patients with metastatic PRCC similar to clear cell RCC when radiological complete remission can be achieved by metastasectomy.
Although it is difficult to evaluate the effectiveness of ZA and local radiation therapy in this case, these treatments might present some positive effects for disease control.
We were able to control metastatic lesions of type 2 PRCC for a relatively long term by multidisciplinary treatment. Axitinib was effective and periodic drug withdrawal schedules could reduce AEs and enable to continue axitinib usage.
Acknowledgements
Not applicable.
Availability of data and materials
Data sharing is not applicable to this article, as no datasets were generated or analyzed during the present study.
Authors' contributions
YA contributed to the study concept, design, data collection and writing of the manuscript. YK contributed to data collection and the revision of the manuscript. MH contributed to data collection and the revision of the manuscript. HH contributed to data collection and the revision of the manuscript. KM contributed to data collection, pathological diagnosis and the revision of the manuscript. AH contributed to the study concept, design and the revision of the manuscript. KI contributed to the study concept, design, data collection, writing and the revision of the manuscript, and the supervision of the manuscript. The authenticity of all the raw data was assessed by YA, KM, AH and KI. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Ethical approval was granted from the Ethics Committee of National Defense Medical College.
Patient consent for publication
Written informed consent for the publication of any associated data was obtained from the patient's wife.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Radiological and pathological findings of the primary tumor. (A and B) Contrast-enhanced computed tomography images. A tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected. (C and D) Microscopically, the tumor had papillary architecture. The tumor cells contained abundant eosinophilic cytoplasm with high nuclear grade (Fuhrman nuclear grade 3). The tumor was diagnosed as type 2 papillary RCC. (C) magnification, x100; scale bar, 200 µm. (D) magnification, x400; scale bar, 50 µm. RCC, renal cell carcinoma.
Figure 2 CE-CT images. (A and B) CE-CT images of a (A) lung metastasis (S6) (black arrow) and (B) paracaval lymph node metastases (black arrow) that appeared in 2012. (C) CE-CT of lymph node swellings at the right tracheal bifurcation (white arrow) found in 2013. (D) CE-CT of mediastinal lymph nodes (white arrows) that were swollen again in 2014. CE-CT, Contrast-enhanced computed tomography.
Figure 3 The time course of treatments for the patient with metastatic type 2 papillary renal cell carcinoma. Axi, axitinib; HT, hypertension; IVC, inferior vena cava; LND, lymph node dissection; LNM, lymph node metastasis; RNx, radical nephrectomy; SD, stable disease; SU, sunitinib; TEM, temsirolimus; ZA, zoledronic acid.
Figure 4 CT images during axitinib treatment. (A) CT at axitinib administration. White arrows indicate mediastinal lymph node metastases. (B) CT 7 months after axitinib administration. Lymph node metastases shrunk by using axitinib (partial response, judged by RECIST version 1.1). (C) CT 19 months after axitinib administration. The response was maintained. (D) CT 30 months after axitinib administration. The response was still maintained. (E) Representative bone metastasis (left ilium) at axitinib administration. (F) CT 7 months after axitinib administration. (G) CT 19 months after axitinib administration. (H) CT 30 months after axitinib administration. The bone metastasis in the ilium grew slightly compared with that at axitinib administration (<10%, stable disease, judged by RECIST version 1.1). | AXITINIB, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33732457 | 19,122,950 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Proteinuria'. | Long-term disease control of metastatic type 2 papillary renal cell carcinoma using local treatment and molecular targeted therapy: A case report.
A 46-year-old man underwent right partial nephrectomy for type 2 papillary renal cell carcinoma (PRCC) in 2011. Lung metastasis and lymph node (LN) metastases around the inferior vena cave appeared in 2012. A right radical nephrectomy and extensive LN dissection was performed and the resection of lung metastasis was performed one month after the nephrectomy. Mediastinal LN metastases occurred in 2013, and resection of the affected LNs was performed. Sunitinib and zoledronic acid was started in 2014 because mediastinal LN swelling and multiple bone metastases appeared. Sunitinib treatment was stopped soon after due to adverse events and axitinib treatment was started. Axitinib was effective and the patient had stable disease for 30 months. Adverse events were successfully controlled by dose reduction and periodic drug withdrawal schedules (for example, 5 days on, 2 days off). Axitinib was further continued for 19 months as the metastatic lesions had progressed slowly. Temsirolimus treatment was started in 2019, but it was stopped after three cycles due to interstitial pneumonia. The patient died 80 months after the initial recurrence. Using multidisciplinary treatment, durable disease control was achieved in a patient with metastatic type 2 PRCC.
Introductions
Recently, the prognosis of patients with metastatic renal cell carcinoma (RCC) has been improved by molecular targeted therapies (1) and immune checkpoint inhibitors (2). However, optimal treatment strategies for metastatic non-clear cell RCC (nccRCC) has yet to be established. In previous studies, molecular targeted therapies, especially sunitinib, have shown clinical efficacy for the treatment of metastatic nccRCC (3-7). The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is recommended at present for metastatic nccRCC. In nccRCC papillary renal cell carcinoma (PRCC) is the leading histology (8). PRCC is divided into type 1 and type 2, with type 2 PRCC showing worse prognosis compared with type 1(9). In phase 2 clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, overall survival (OS) of type1 PRCC was 17.8 months, and that of type 2 was 12.4 months (10).
In this report, we present a patient with metastatic type 2 PRCC whose metastatic lesions were controlled for a long time by multidisciplinary treatments including metastasectomies, axitinib, zoledronic acid (ZA), and radiation therapy.
Case report
A 46-year-old man with hematospermia was presented to a urologic clinic in April, 2011. A right renal tumor was found by ultrasound, and the patient was referred to our hospital. The tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected by contrast-enhanced computed tomography (CT) (Fig. 1A and B). A right partial nephrectomy was performed in July, 2011. Pathological diagnosis was type2 PRCC (Fig. 1C and D). A lung metastasis (S6) and paracaval lymph node (LN) metastases appeared in March, 2012 (Fig. 2A and B). After five cycles of temsirolimus, right radical nephrectomy and extensive LN dissection around the inferior vena cava (IVC) and right common iliac vein were performed in June, 2012, and the resection of the lung metastasis was performed one month after the nephrectomy. Then, radiological complete remission was achieved. LN swellings at the right tracheal bifurcation was found by CT in August, 2013 (Fig. 2C). After three cycles of temsirolimus, mediastinal LN dissection was performed in October, 2013. Mediastinal LNs (Fig. 2D) were swollen again, and multiple bone metastases [sternum, right fifth rib, thoracic spine (5-7th vertebrae), left ilium, and right pubis] appeared in 2014. The clinical course of the patient, including local treatments, medical treatments, and treatment-related adverse events are shown in Fig. 3. Sunitinib (37.5 mg/day) and ZA (4 mg/month) were started in June, 2014. Sunitinib was stopped within two weeks because of adverse events (AEs) including fever, malaise, and liver dysfunction. After the patient had recovered from the AEs, axitinib (10 mg/day) was started as a second-line treatment in July, 2014. ZA was continued after the axitinib administration. Because of diarrhea and hoarseness, the treatment schedule of axitinib was changed to a periodic drug withdrawal schedule (5 days-on, 2 days-off) in October, 2014. Next, the daily dose of axitinib was reduced to 8 mg (5 days-on, 2 days-off) to control severe diarrhea in December, 2014. Stereotactic radiation therapy (total 30 Gray, 10 fractions) was performed for bone metastasis at the left ilium in November, 2015 because only the iliac metastasis appeared to be an active lesion among all bone metastases in the bone scintigraphy. The periodic drug withdrawal schedule of axitinib (8 mg/day, 5 days-on, 2 days-off) was changed to the next schedule (8 mg/day, 4 days-on, 3 days-off) due to renal dysfunction and proteinuria in April, 2017. Mediastinal LN metastases and bone metastases was stable for 30 months after the axitinib administration (Fig. 4). Disease progression was confirmed in June, 2017 due to the appearance of multiple small lung metastases. Because the metastatic lesions progressed slowly after the disease progression, axitinib was continued for another 19 months in accordance with the patient's request. The schedule of axitinib was then changed to a third schedule (8 mg/day, 3 days-on, 3 days-off) due to symptoms of anorexia, dyspnea, and muscle pain in April, 2018. Patient was hospitalized due to severe back pain in September, 2018, and palliative radiotherapy was performed for a compression fracture due to metastasis (L1 lumber vertebrae). Axitinib was stopped in October, 2019. Temsirolimus was then administered, but interstitial pneumonia occurred after three cycles of temsirolimus. Although steroid pulse therapy was performed, respiratory and general condition became worse. The patient died in November, 2019. By multidisciplinary treatments including metastasectomy, axitinib, ZA, and radiation therapy, the patient survived for 80 months after the initial recurrence.
Discussion
This patient with metastatic type 2 PRCC could survive 80 months after the initial recurrence by multidisciplinary treatments including metastasectomies, axitinib, ZA, and radiation therapy. Patients with metastatic type 2 PRCC generally have poor prognosis. In a clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median OS in type 2 PRCC was 12.4 months (10). Metastasectomies and axitinib appeared to be especially effective in the present case.
The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is the recommended treatment for metastatic nccRCC, and cabozantinib and everolimus are options. At the beginning of targeted era, mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, was reportedly effective compared with interferon-α for metastatic nccRCC (11). A comparative study between temsirolimus and tyrosine kinase inhibitors (TKIs) in metastatic nccRCC does not exist at present. The superiority of sunitinib compared with everolimus in nccRCC treatment has been reported in two clinical trials (12,13). The ASPEN trial reported that the progression-free survival (PFS) of sunitinib was longer than that of everolimus (12). The ESPN trial reported that both PFS and OS of sunitinib were longer than those of everolimus (13). Among other TKIs, the overall response rate of pazopanib was reportedly 39% in the treatment of metastatic nccRCC (6). There are few studies evaluating the clinical efficacy of systemic therapies in metastatic PRCC. In clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median PFS and OS were 6.6 and 17.8 months in type 1 PRCC, and 5.5 and 12.4 months in type 2, respectively (10). In a Japanese multicenter study evaluating metastatic PRCC in which most PRCC cases (91.4%) were type 2, the prognosis in the era of targeted therapy (OS=22.5 months) was improved compared with that in the cytokine era (OS=6.3 months). PRCC patients treated with TKIs in both first-line and second-line treatments (OS=31.4 months) showed better prognosis than those with mTOR inhibitors in first-line or second-line (OS=12.9 months) (14).
In our case, the second-line use of axitinib was effective and achieved a durable stable disease (SD). There have been few reports in which axitinib showed efficacies for metastatic PRCC (15,16). In our case, AEs were relieved by dose reduction and the setting of periodic drug withdrawal schedules of axitinib, and axitinib could be continued for a long time. The half-life period of axitinib was reportedly short (4.8-5.9 h) (17). Axitinib has a characteristic that AEs can be relieved in a short period because of its short half-life period. Then, axitinib can be started again after the short drug withdrawal period. The risk of regrowth should be low due to the short drug withdrawal. In our previous report of a clear cell RCC patient with metastasis at the paranasal sinus, AEs could be relieved effectively by using periodic drug withdrawal schedules of axitinib and axitinib could be used for more than 30 months (18). Takayama et al also reported a similar RCC case in which intermittent use of axitinib was effective (19).
There is a possibility that prognosis of this patient was improved by metastasectomies. LN metastases around the right common iliac vein and IVC at the time of LN dissection were pathologically confirmed. However, the relapse did not occur in the abdominal and pelvic areas after the extensive LN dissection. This appeared to indicate that LN metastases in the abdominal and the pelvic areas were completely resected by the initial LN dissection. Moreover, the three metastasectomies including the initial LN dissection around the IVC and right iliac vein, the resection of lung metastasis, and the mediastinal LN dissection could delay the timing of TKI administration for two years. Those metastasectomies might contribute to improve the patient's prognosis. In the cytokine era, an efficacy of LN dissection on radical nephrectomy was suggested in PRCC (20). Metastatectomy should be performed appropriately for patients with metastatic PRCC similar to clear cell RCC when radiological complete remission can be achieved by metastasectomy.
Although it is difficult to evaluate the effectiveness of ZA and local radiation therapy in this case, these treatments might present some positive effects for disease control.
We were able to control metastatic lesions of type 2 PRCC for a relatively long term by multidisciplinary treatment. Axitinib was effective and periodic drug withdrawal schedules could reduce AEs and enable to continue axitinib usage.
Acknowledgements
Not applicable.
Availability of data and materials
Data sharing is not applicable to this article, as no datasets were generated or analyzed during the present study.
Authors' contributions
YA contributed to the study concept, design, data collection and writing of the manuscript. YK contributed to data collection and the revision of the manuscript. MH contributed to data collection and the revision of the manuscript. HH contributed to data collection and the revision of the manuscript. KM contributed to data collection, pathological diagnosis and the revision of the manuscript. AH contributed to the study concept, design and the revision of the manuscript. KI contributed to the study concept, design, data collection, writing and the revision of the manuscript, and the supervision of the manuscript. The authenticity of all the raw data was assessed by YA, KM, AH and KI. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Ethical approval was granted from the Ethics Committee of National Defense Medical College.
Patient consent for publication
Written informed consent for the publication of any associated data was obtained from the patient's wife.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Radiological and pathological findings of the primary tumor. (A and B) Contrast-enhanced computed tomography images. A tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected. (C and D) Microscopically, the tumor had papillary architecture. The tumor cells contained abundant eosinophilic cytoplasm with high nuclear grade (Fuhrman nuclear grade 3). The tumor was diagnosed as type 2 papillary RCC. (C) magnification, x100; scale bar, 200 µm. (D) magnification, x400; scale bar, 50 µm. RCC, renal cell carcinoma.
Figure 2 CE-CT images. (A and B) CE-CT images of a (A) lung metastasis (S6) (black arrow) and (B) paracaval lymph node metastases (black arrow) that appeared in 2012. (C) CE-CT of lymph node swellings at the right tracheal bifurcation (white arrow) found in 2013. (D) CE-CT of mediastinal lymph nodes (white arrows) that were swollen again in 2014. CE-CT, Contrast-enhanced computed tomography.
Figure 3 The time course of treatments for the patient with metastatic type 2 papillary renal cell carcinoma. Axi, axitinib; HT, hypertension; IVC, inferior vena cava; LND, lymph node dissection; LNM, lymph node metastasis; RNx, radical nephrectomy; SD, stable disease; SU, sunitinib; TEM, temsirolimus; ZA, zoledronic acid.
Figure 4 CT images during axitinib treatment. (A) CT at axitinib administration. White arrows indicate mediastinal lymph node metastases. (B) CT 7 months after axitinib administration. Lymph node metastases shrunk by using axitinib (partial response, judged by RECIST version 1.1). (C) CT 19 months after axitinib administration. The response was maintained. (D) CT 30 months after axitinib administration. The response was still maintained. (E) Representative bone metastasis (left ilium) at axitinib administration. (F) CT 7 months after axitinib administration. (G) CT 19 months after axitinib administration. (H) CT 30 months after axitinib administration. The bone metastasis in the ilium grew slightly compared with that at axitinib administration (<10%, stable disease, judged by RECIST version 1.1). | AXITINIB, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33732457 | 19,122,950 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pyrexia'. | Long-term disease control of metastatic type 2 papillary renal cell carcinoma using local treatment and molecular targeted therapy: A case report.
A 46-year-old man underwent right partial nephrectomy for type 2 papillary renal cell carcinoma (PRCC) in 2011. Lung metastasis and lymph node (LN) metastases around the inferior vena cave appeared in 2012. A right radical nephrectomy and extensive LN dissection was performed and the resection of lung metastasis was performed one month after the nephrectomy. Mediastinal LN metastases occurred in 2013, and resection of the affected LNs was performed. Sunitinib and zoledronic acid was started in 2014 because mediastinal LN swelling and multiple bone metastases appeared. Sunitinib treatment was stopped soon after due to adverse events and axitinib treatment was started. Axitinib was effective and the patient had stable disease for 30 months. Adverse events were successfully controlled by dose reduction and periodic drug withdrawal schedules (for example, 5 days on, 2 days off). Axitinib was further continued for 19 months as the metastatic lesions had progressed slowly. Temsirolimus treatment was started in 2019, but it was stopped after three cycles due to interstitial pneumonia. The patient died 80 months after the initial recurrence. Using multidisciplinary treatment, durable disease control was achieved in a patient with metastatic type 2 PRCC.
Introductions
Recently, the prognosis of patients with metastatic renal cell carcinoma (RCC) has been improved by molecular targeted therapies (1) and immune checkpoint inhibitors (2). However, optimal treatment strategies for metastatic non-clear cell RCC (nccRCC) has yet to be established. In previous studies, molecular targeted therapies, especially sunitinib, have shown clinical efficacy for the treatment of metastatic nccRCC (3-7). The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is recommended at present for metastatic nccRCC. In nccRCC papillary renal cell carcinoma (PRCC) is the leading histology (8). PRCC is divided into type 1 and type 2, with type 2 PRCC showing worse prognosis compared with type 1(9). In phase 2 clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, overall survival (OS) of type1 PRCC was 17.8 months, and that of type 2 was 12.4 months (10).
In this report, we present a patient with metastatic type 2 PRCC whose metastatic lesions were controlled for a long time by multidisciplinary treatments including metastasectomies, axitinib, zoledronic acid (ZA), and radiation therapy.
Case report
A 46-year-old man with hematospermia was presented to a urologic clinic in April, 2011. A right renal tumor was found by ultrasound, and the patient was referred to our hospital. The tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected by contrast-enhanced computed tomography (CT) (Fig. 1A and B). A right partial nephrectomy was performed in July, 2011. Pathological diagnosis was type2 PRCC (Fig. 1C and D). A lung metastasis (S6) and paracaval lymph node (LN) metastases appeared in March, 2012 (Fig. 2A and B). After five cycles of temsirolimus, right radical nephrectomy and extensive LN dissection around the inferior vena cava (IVC) and right common iliac vein were performed in June, 2012, and the resection of the lung metastasis was performed one month after the nephrectomy. Then, radiological complete remission was achieved. LN swellings at the right tracheal bifurcation was found by CT in August, 2013 (Fig. 2C). After three cycles of temsirolimus, mediastinal LN dissection was performed in October, 2013. Mediastinal LNs (Fig. 2D) were swollen again, and multiple bone metastases [sternum, right fifth rib, thoracic spine (5-7th vertebrae), left ilium, and right pubis] appeared in 2014. The clinical course of the patient, including local treatments, medical treatments, and treatment-related adverse events are shown in Fig. 3. Sunitinib (37.5 mg/day) and ZA (4 mg/month) were started in June, 2014. Sunitinib was stopped within two weeks because of adverse events (AEs) including fever, malaise, and liver dysfunction. After the patient had recovered from the AEs, axitinib (10 mg/day) was started as a second-line treatment in July, 2014. ZA was continued after the axitinib administration. Because of diarrhea and hoarseness, the treatment schedule of axitinib was changed to a periodic drug withdrawal schedule (5 days-on, 2 days-off) in October, 2014. Next, the daily dose of axitinib was reduced to 8 mg (5 days-on, 2 days-off) to control severe diarrhea in December, 2014. Stereotactic radiation therapy (total 30 Gray, 10 fractions) was performed for bone metastasis at the left ilium in November, 2015 because only the iliac metastasis appeared to be an active lesion among all bone metastases in the bone scintigraphy. The periodic drug withdrawal schedule of axitinib (8 mg/day, 5 days-on, 2 days-off) was changed to the next schedule (8 mg/day, 4 days-on, 3 days-off) due to renal dysfunction and proteinuria in April, 2017. Mediastinal LN metastases and bone metastases was stable for 30 months after the axitinib administration (Fig. 4). Disease progression was confirmed in June, 2017 due to the appearance of multiple small lung metastases. Because the metastatic lesions progressed slowly after the disease progression, axitinib was continued for another 19 months in accordance with the patient's request. The schedule of axitinib was then changed to a third schedule (8 mg/day, 3 days-on, 3 days-off) due to symptoms of anorexia, dyspnea, and muscle pain in April, 2018. Patient was hospitalized due to severe back pain in September, 2018, and palliative radiotherapy was performed for a compression fracture due to metastasis (L1 lumber vertebrae). Axitinib was stopped in October, 2019. Temsirolimus was then administered, but interstitial pneumonia occurred after three cycles of temsirolimus. Although steroid pulse therapy was performed, respiratory and general condition became worse. The patient died in November, 2019. By multidisciplinary treatments including metastasectomy, axitinib, ZA, and radiation therapy, the patient survived for 80 months after the initial recurrence.
Discussion
This patient with metastatic type 2 PRCC could survive 80 months after the initial recurrence by multidisciplinary treatments including metastasectomies, axitinib, ZA, and radiation therapy. Patients with metastatic type 2 PRCC generally have poor prognosis. In a clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median OS in type 2 PRCC was 12.4 months (10). Metastasectomies and axitinib appeared to be especially effective in the present case.
The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is the recommended treatment for metastatic nccRCC, and cabozantinib and everolimus are options. At the beginning of targeted era, mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, was reportedly effective compared with interferon-α for metastatic nccRCC (11). A comparative study between temsirolimus and tyrosine kinase inhibitors (TKIs) in metastatic nccRCC does not exist at present. The superiority of sunitinib compared with everolimus in nccRCC treatment has been reported in two clinical trials (12,13). The ASPEN trial reported that the progression-free survival (PFS) of sunitinib was longer than that of everolimus (12). The ESPN trial reported that both PFS and OS of sunitinib were longer than those of everolimus (13). Among other TKIs, the overall response rate of pazopanib was reportedly 39% in the treatment of metastatic nccRCC (6). There are few studies evaluating the clinical efficacy of systemic therapies in metastatic PRCC. In clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median PFS and OS were 6.6 and 17.8 months in type 1 PRCC, and 5.5 and 12.4 months in type 2, respectively (10). In a Japanese multicenter study evaluating metastatic PRCC in which most PRCC cases (91.4%) were type 2, the prognosis in the era of targeted therapy (OS=22.5 months) was improved compared with that in the cytokine era (OS=6.3 months). PRCC patients treated with TKIs in both first-line and second-line treatments (OS=31.4 months) showed better prognosis than those with mTOR inhibitors in first-line or second-line (OS=12.9 months) (14).
In our case, the second-line use of axitinib was effective and achieved a durable stable disease (SD). There have been few reports in which axitinib showed efficacies for metastatic PRCC (15,16). In our case, AEs were relieved by dose reduction and the setting of periodic drug withdrawal schedules of axitinib, and axitinib could be continued for a long time. The half-life period of axitinib was reportedly short (4.8-5.9 h) (17). Axitinib has a characteristic that AEs can be relieved in a short period because of its short half-life period. Then, axitinib can be started again after the short drug withdrawal period. The risk of regrowth should be low due to the short drug withdrawal. In our previous report of a clear cell RCC patient with metastasis at the paranasal sinus, AEs could be relieved effectively by using periodic drug withdrawal schedules of axitinib and axitinib could be used for more than 30 months (18). Takayama et al also reported a similar RCC case in which intermittent use of axitinib was effective (19).
There is a possibility that prognosis of this patient was improved by metastasectomies. LN metastases around the right common iliac vein and IVC at the time of LN dissection were pathologically confirmed. However, the relapse did not occur in the abdominal and pelvic areas after the extensive LN dissection. This appeared to indicate that LN metastases in the abdominal and the pelvic areas were completely resected by the initial LN dissection. Moreover, the three metastasectomies including the initial LN dissection around the IVC and right iliac vein, the resection of lung metastasis, and the mediastinal LN dissection could delay the timing of TKI administration for two years. Those metastasectomies might contribute to improve the patient's prognosis. In the cytokine era, an efficacy of LN dissection on radical nephrectomy was suggested in PRCC (20). Metastatectomy should be performed appropriately for patients with metastatic PRCC similar to clear cell RCC when radiological complete remission can be achieved by metastasectomy.
Although it is difficult to evaluate the effectiveness of ZA and local radiation therapy in this case, these treatments might present some positive effects for disease control.
We were able to control metastatic lesions of type 2 PRCC for a relatively long term by multidisciplinary treatment. Axitinib was effective and periodic drug withdrawal schedules could reduce AEs and enable to continue axitinib usage.
Acknowledgements
Not applicable.
Availability of data and materials
Data sharing is not applicable to this article, as no datasets were generated or analyzed during the present study.
Authors' contributions
YA contributed to the study concept, design, data collection and writing of the manuscript. YK contributed to data collection and the revision of the manuscript. MH contributed to data collection and the revision of the manuscript. HH contributed to data collection and the revision of the manuscript. KM contributed to data collection, pathological diagnosis and the revision of the manuscript. AH contributed to the study concept, design and the revision of the manuscript. KI contributed to the study concept, design, data collection, writing and the revision of the manuscript, and the supervision of the manuscript. The authenticity of all the raw data was assessed by YA, KM, AH and KI. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Ethical approval was granted from the Ethics Committee of National Defense Medical College.
Patient consent for publication
Written informed consent for the publication of any associated data was obtained from the patient's wife.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Radiological and pathological findings of the primary tumor. (A and B) Contrast-enhanced computed tomography images. A tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected. (C and D) Microscopically, the tumor had papillary architecture. The tumor cells contained abundant eosinophilic cytoplasm with high nuclear grade (Fuhrman nuclear grade 3). The tumor was diagnosed as type 2 papillary RCC. (C) magnification, x100; scale bar, 200 µm. (D) magnification, x400; scale bar, 50 µm. RCC, renal cell carcinoma.
Figure 2 CE-CT images. (A and B) CE-CT images of a (A) lung metastasis (S6) (black arrow) and (B) paracaval lymph node metastases (black arrow) that appeared in 2012. (C) CE-CT of lymph node swellings at the right tracheal bifurcation (white arrow) found in 2013. (D) CE-CT of mediastinal lymph nodes (white arrows) that were swollen again in 2014. CE-CT, Contrast-enhanced computed tomography.
Figure 3 The time course of treatments for the patient with metastatic type 2 papillary renal cell carcinoma. Axi, axitinib; HT, hypertension; IVC, inferior vena cava; LND, lymph node dissection; LNM, lymph node metastasis; RNx, radical nephrectomy; SD, stable disease; SU, sunitinib; TEM, temsirolimus; ZA, zoledronic acid.
Figure 4 CT images during axitinib treatment. (A) CT at axitinib administration. White arrows indicate mediastinal lymph node metastases. (B) CT 7 months after axitinib administration. Lymph node metastases shrunk by using axitinib (partial response, judged by RECIST version 1.1). (C) CT 19 months after axitinib administration. The response was maintained. (D) CT 30 months after axitinib administration. The response was still maintained. (E) Representative bone metastasis (left ilium) at axitinib administration. (F) CT 7 months after axitinib administration. (G) CT 19 months after axitinib administration. (H) CT 30 months after axitinib administration. The bone metastasis in the ilium grew slightly compared with that at axitinib administration (<10%, stable disease, judged by RECIST version 1.1). | SUNITINIB, TEMSIROLIMUS, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33732457 | 19,952,254 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Renal impairment'. | Long-term disease control of metastatic type 2 papillary renal cell carcinoma using local treatment and molecular targeted therapy: A case report.
A 46-year-old man underwent right partial nephrectomy for type 2 papillary renal cell carcinoma (PRCC) in 2011. Lung metastasis and lymph node (LN) metastases around the inferior vena cave appeared in 2012. A right radical nephrectomy and extensive LN dissection was performed and the resection of lung metastasis was performed one month after the nephrectomy. Mediastinal LN metastases occurred in 2013, and resection of the affected LNs was performed. Sunitinib and zoledronic acid was started in 2014 because mediastinal LN swelling and multiple bone metastases appeared. Sunitinib treatment was stopped soon after due to adverse events and axitinib treatment was started. Axitinib was effective and the patient had stable disease for 30 months. Adverse events were successfully controlled by dose reduction and periodic drug withdrawal schedules (for example, 5 days on, 2 days off). Axitinib was further continued for 19 months as the metastatic lesions had progressed slowly. Temsirolimus treatment was started in 2019, but it was stopped after three cycles due to interstitial pneumonia. The patient died 80 months after the initial recurrence. Using multidisciplinary treatment, durable disease control was achieved in a patient with metastatic type 2 PRCC.
Introductions
Recently, the prognosis of patients with metastatic renal cell carcinoma (RCC) has been improved by molecular targeted therapies (1) and immune checkpoint inhibitors (2). However, optimal treatment strategies for metastatic non-clear cell RCC (nccRCC) has yet to be established. In previous studies, molecular targeted therapies, especially sunitinib, have shown clinical efficacy for the treatment of metastatic nccRCC (3-7). The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is recommended at present for metastatic nccRCC. In nccRCC papillary renal cell carcinoma (PRCC) is the leading histology (8). PRCC is divided into type 1 and type 2, with type 2 PRCC showing worse prognosis compared with type 1(9). In phase 2 clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, overall survival (OS) of type1 PRCC was 17.8 months, and that of type 2 was 12.4 months (10).
In this report, we present a patient with metastatic type 2 PRCC whose metastatic lesions were controlled for a long time by multidisciplinary treatments including metastasectomies, axitinib, zoledronic acid (ZA), and radiation therapy.
Case report
A 46-year-old man with hematospermia was presented to a urologic clinic in April, 2011. A right renal tumor was found by ultrasound, and the patient was referred to our hospital. The tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected by contrast-enhanced computed tomography (CT) (Fig. 1A and B). A right partial nephrectomy was performed in July, 2011. Pathological diagnosis was type2 PRCC (Fig. 1C and D). A lung metastasis (S6) and paracaval lymph node (LN) metastases appeared in March, 2012 (Fig. 2A and B). After five cycles of temsirolimus, right radical nephrectomy and extensive LN dissection around the inferior vena cava (IVC) and right common iliac vein were performed in June, 2012, and the resection of the lung metastasis was performed one month after the nephrectomy. Then, radiological complete remission was achieved. LN swellings at the right tracheal bifurcation was found by CT in August, 2013 (Fig. 2C). After three cycles of temsirolimus, mediastinal LN dissection was performed in October, 2013. Mediastinal LNs (Fig. 2D) were swollen again, and multiple bone metastases [sternum, right fifth rib, thoracic spine (5-7th vertebrae), left ilium, and right pubis] appeared in 2014. The clinical course of the patient, including local treatments, medical treatments, and treatment-related adverse events are shown in Fig. 3. Sunitinib (37.5 mg/day) and ZA (4 mg/month) were started in June, 2014. Sunitinib was stopped within two weeks because of adverse events (AEs) including fever, malaise, and liver dysfunction. After the patient had recovered from the AEs, axitinib (10 mg/day) was started as a second-line treatment in July, 2014. ZA was continued after the axitinib administration. Because of diarrhea and hoarseness, the treatment schedule of axitinib was changed to a periodic drug withdrawal schedule (5 days-on, 2 days-off) in October, 2014. Next, the daily dose of axitinib was reduced to 8 mg (5 days-on, 2 days-off) to control severe diarrhea in December, 2014. Stereotactic radiation therapy (total 30 Gray, 10 fractions) was performed for bone metastasis at the left ilium in November, 2015 because only the iliac metastasis appeared to be an active lesion among all bone metastases in the bone scintigraphy. The periodic drug withdrawal schedule of axitinib (8 mg/day, 5 days-on, 2 days-off) was changed to the next schedule (8 mg/day, 4 days-on, 3 days-off) due to renal dysfunction and proteinuria in April, 2017. Mediastinal LN metastases and bone metastases was stable for 30 months after the axitinib administration (Fig. 4). Disease progression was confirmed in June, 2017 due to the appearance of multiple small lung metastases. Because the metastatic lesions progressed slowly after the disease progression, axitinib was continued for another 19 months in accordance with the patient's request. The schedule of axitinib was then changed to a third schedule (8 mg/day, 3 days-on, 3 days-off) due to symptoms of anorexia, dyspnea, and muscle pain in April, 2018. Patient was hospitalized due to severe back pain in September, 2018, and palliative radiotherapy was performed for a compression fracture due to metastasis (L1 lumber vertebrae). Axitinib was stopped in October, 2019. Temsirolimus was then administered, but interstitial pneumonia occurred after three cycles of temsirolimus. Although steroid pulse therapy was performed, respiratory and general condition became worse. The patient died in November, 2019. By multidisciplinary treatments including metastasectomy, axitinib, ZA, and radiation therapy, the patient survived for 80 months after the initial recurrence.
Discussion
This patient with metastatic type 2 PRCC could survive 80 months after the initial recurrence by multidisciplinary treatments including metastasectomies, axitinib, ZA, and radiation therapy. Patients with metastatic type 2 PRCC generally have poor prognosis. In a clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median OS in type 2 PRCC was 12.4 months (10). Metastasectomies and axitinib appeared to be especially effective in the present case.
The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is the recommended treatment for metastatic nccRCC, and cabozantinib and everolimus are options. At the beginning of targeted era, mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, was reportedly effective compared with interferon-α for metastatic nccRCC (11). A comparative study between temsirolimus and tyrosine kinase inhibitors (TKIs) in metastatic nccRCC does not exist at present. The superiority of sunitinib compared with everolimus in nccRCC treatment has been reported in two clinical trials (12,13). The ASPEN trial reported that the progression-free survival (PFS) of sunitinib was longer than that of everolimus (12). The ESPN trial reported that both PFS and OS of sunitinib were longer than those of everolimus (13). Among other TKIs, the overall response rate of pazopanib was reportedly 39% in the treatment of metastatic nccRCC (6). There are few studies evaluating the clinical efficacy of systemic therapies in metastatic PRCC. In clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median PFS and OS were 6.6 and 17.8 months in type 1 PRCC, and 5.5 and 12.4 months in type 2, respectively (10). In a Japanese multicenter study evaluating metastatic PRCC in which most PRCC cases (91.4%) were type 2, the prognosis in the era of targeted therapy (OS=22.5 months) was improved compared with that in the cytokine era (OS=6.3 months). PRCC patients treated with TKIs in both first-line and second-line treatments (OS=31.4 months) showed better prognosis than those with mTOR inhibitors in first-line or second-line (OS=12.9 months) (14).
In our case, the second-line use of axitinib was effective and achieved a durable stable disease (SD). There have been few reports in which axitinib showed efficacies for metastatic PRCC (15,16). In our case, AEs were relieved by dose reduction and the setting of periodic drug withdrawal schedules of axitinib, and axitinib could be continued for a long time. The half-life period of axitinib was reportedly short (4.8-5.9 h) (17). Axitinib has a characteristic that AEs can be relieved in a short period because of its short half-life period. Then, axitinib can be started again after the short drug withdrawal period. The risk of regrowth should be low due to the short drug withdrawal. In our previous report of a clear cell RCC patient with metastasis at the paranasal sinus, AEs could be relieved effectively by using periodic drug withdrawal schedules of axitinib and axitinib could be used for more than 30 months (18). Takayama et al also reported a similar RCC case in which intermittent use of axitinib was effective (19).
There is a possibility that prognosis of this patient was improved by metastasectomies. LN metastases around the right common iliac vein and IVC at the time of LN dissection were pathologically confirmed. However, the relapse did not occur in the abdominal and pelvic areas after the extensive LN dissection. This appeared to indicate that LN metastases in the abdominal and the pelvic areas were completely resected by the initial LN dissection. Moreover, the three metastasectomies including the initial LN dissection around the IVC and right iliac vein, the resection of lung metastasis, and the mediastinal LN dissection could delay the timing of TKI administration for two years. Those metastasectomies might contribute to improve the patient's prognosis. In the cytokine era, an efficacy of LN dissection on radical nephrectomy was suggested in PRCC (20). Metastatectomy should be performed appropriately for patients with metastatic PRCC similar to clear cell RCC when radiological complete remission can be achieved by metastasectomy.
Although it is difficult to evaluate the effectiveness of ZA and local radiation therapy in this case, these treatments might present some positive effects for disease control.
We were able to control metastatic lesions of type 2 PRCC for a relatively long term by multidisciplinary treatment. Axitinib was effective and periodic drug withdrawal schedules could reduce AEs and enable to continue axitinib usage.
Acknowledgements
Not applicable.
Availability of data and materials
Data sharing is not applicable to this article, as no datasets were generated or analyzed during the present study.
Authors' contributions
YA contributed to the study concept, design, data collection and writing of the manuscript. YK contributed to data collection and the revision of the manuscript. MH contributed to data collection and the revision of the manuscript. HH contributed to data collection and the revision of the manuscript. KM contributed to data collection, pathological diagnosis and the revision of the manuscript. AH contributed to the study concept, design and the revision of the manuscript. KI contributed to the study concept, design, data collection, writing and the revision of the manuscript, and the supervision of the manuscript. The authenticity of all the raw data was assessed by YA, KM, AH and KI. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Ethical approval was granted from the Ethics Committee of National Defense Medical College.
Patient consent for publication
Written informed consent for the publication of any associated data was obtained from the patient's wife.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Radiological and pathological findings of the primary tumor. (A and B) Contrast-enhanced computed tomography images. A tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected. (C and D) Microscopically, the tumor had papillary architecture. The tumor cells contained abundant eosinophilic cytoplasm with high nuclear grade (Fuhrman nuclear grade 3). The tumor was diagnosed as type 2 papillary RCC. (C) magnification, x100; scale bar, 200 µm. (D) magnification, x400; scale bar, 50 µm. RCC, renal cell carcinoma.
Figure 2 CE-CT images. (A and B) CE-CT images of a (A) lung metastasis (S6) (black arrow) and (B) paracaval lymph node metastases (black arrow) that appeared in 2012. (C) CE-CT of lymph node swellings at the right tracheal bifurcation (white arrow) found in 2013. (D) CE-CT of mediastinal lymph nodes (white arrows) that were swollen again in 2014. CE-CT, Contrast-enhanced computed tomography.
Figure 3 The time course of treatments for the patient with metastatic type 2 papillary renal cell carcinoma. Axi, axitinib; HT, hypertension; IVC, inferior vena cava; LND, lymph node dissection; LNM, lymph node metastasis; RNx, radical nephrectomy; SD, stable disease; SU, sunitinib; TEM, temsirolimus; ZA, zoledronic acid.
Figure 4 CT images during axitinib treatment. (A) CT at axitinib administration. White arrows indicate mediastinal lymph node metastases. (B) CT 7 months after axitinib administration. Lymph node metastases shrunk by using axitinib (partial response, judged by RECIST version 1.1). (C) CT 19 months after axitinib administration. The response was maintained. (D) CT 30 months after axitinib administration. The response was still maintained. (E) Representative bone metastasis (left ilium) at axitinib administration. (F) CT 7 months after axitinib administration. (G) CT 19 months after axitinib administration. (H) CT 30 months after axitinib administration. The bone metastasis in the ilium grew slightly compared with that at axitinib administration (<10%, stable disease, judged by RECIST version 1.1). | AXITINIB, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33732457 | 19,122,950 | 2021-04 |
What was the outcome of reaction 'Liver disorder'? | Long-term disease control of metastatic type 2 papillary renal cell carcinoma using local treatment and molecular targeted therapy: A case report.
A 46-year-old man underwent right partial nephrectomy for type 2 papillary renal cell carcinoma (PRCC) in 2011. Lung metastasis and lymph node (LN) metastases around the inferior vena cave appeared in 2012. A right radical nephrectomy and extensive LN dissection was performed and the resection of lung metastasis was performed one month after the nephrectomy. Mediastinal LN metastases occurred in 2013, and resection of the affected LNs was performed. Sunitinib and zoledronic acid was started in 2014 because mediastinal LN swelling and multiple bone metastases appeared. Sunitinib treatment was stopped soon after due to adverse events and axitinib treatment was started. Axitinib was effective and the patient had stable disease for 30 months. Adverse events were successfully controlled by dose reduction and periodic drug withdrawal schedules (for example, 5 days on, 2 days off). Axitinib was further continued for 19 months as the metastatic lesions had progressed slowly. Temsirolimus treatment was started in 2019, but it was stopped after three cycles due to interstitial pneumonia. The patient died 80 months after the initial recurrence. Using multidisciplinary treatment, durable disease control was achieved in a patient with metastatic type 2 PRCC.
Introductions
Recently, the prognosis of patients with metastatic renal cell carcinoma (RCC) has been improved by molecular targeted therapies (1) and immune checkpoint inhibitors (2). However, optimal treatment strategies for metastatic non-clear cell RCC (nccRCC) has yet to be established. In previous studies, molecular targeted therapies, especially sunitinib, have shown clinical efficacy for the treatment of metastatic nccRCC (3-7). The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is recommended at present for metastatic nccRCC. In nccRCC papillary renal cell carcinoma (PRCC) is the leading histology (8). PRCC is divided into type 1 and type 2, with type 2 PRCC showing worse prognosis compared with type 1(9). In phase 2 clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, overall survival (OS) of type1 PRCC was 17.8 months, and that of type 2 was 12.4 months (10).
In this report, we present a patient with metastatic type 2 PRCC whose metastatic lesions were controlled for a long time by multidisciplinary treatments including metastasectomies, axitinib, zoledronic acid (ZA), and radiation therapy.
Case report
A 46-year-old man with hematospermia was presented to a urologic clinic in April, 2011. A right renal tumor was found by ultrasound, and the patient was referred to our hospital. The tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected by contrast-enhanced computed tomography (CT) (Fig. 1A and B). A right partial nephrectomy was performed in July, 2011. Pathological diagnosis was type2 PRCC (Fig. 1C and D). A lung metastasis (S6) and paracaval lymph node (LN) metastases appeared in March, 2012 (Fig. 2A and B). After five cycles of temsirolimus, right radical nephrectomy and extensive LN dissection around the inferior vena cava (IVC) and right common iliac vein were performed in June, 2012, and the resection of the lung metastasis was performed one month after the nephrectomy. Then, radiological complete remission was achieved. LN swellings at the right tracheal bifurcation was found by CT in August, 2013 (Fig. 2C). After three cycles of temsirolimus, mediastinal LN dissection was performed in October, 2013. Mediastinal LNs (Fig. 2D) were swollen again, and multiple bone metastases [sternum, right fifth rib, thoracic spine (5-7th vertebrae), left ilium, and right pubis] appeared in 2014. The clinical course of the patient, including local treatments, medical treatments, and treatment-related adverse events are shown in Fig. 3. Sunitinib (37.5 mg/day) and ZA (4 mg/month) were started in June, 2014. Sunitinib was stopped within two weeks because of adverse events (AEs) including fever, malaise, and liver dysfunction. After the patient had recovered from the AEs, axitinib (10 mg/day) was started as a second-line treatment in July, 2014. ZA was continued after the axitinib administration. Because of diarrhea and hoarseness, the treatment schedule of axitinib was changed to a periodic drug withdrawal schedule (5 days-on, 2 days-off) in October, 2014. Next, the daily dose of axitinib was reduced to 8 mg (5 days-on, 2 days-off) to control severe diarrhea in December, 2014. Stereotactic radiation therapy (total 30 Gray, 10 fractions) was performed for bone metastasis at the left ilium in November, 2015 because only the iliac metastasis appeared to be an active lesion among all bone metastases in the bone scintigraphy. The periodic drug withdrawal schedule of axitinib (8 mg/day, 5 days-on, 2 days-off) was changed to the next schedule (8 mg/day, 4 days-on, 3 days-off) due to renal dysfunction and proteinuria in April, 2017. Mediastinal LN metastases and bone metastases was stable for 30 months after the axitinib administration (Fig. 4). Disease progression was confirmed in June, 2017 due to the appearance of multiple small lung metastases. Because the metastatic lesions progressed slowly after the disease progression, axitinib was continued for another 19 months in accordance with the patient's request. The schedule of axitinib was then changed to a third schedule (8 mg/day, 3 days-on, 3 days-off) due to symptoms of anorexia, dyspnea, and muscle pain in April, 2018. Patient was hospitalized due to severe back pain in September, 2018, and palliative radiotherapy was performed for a compression fracture due to metastasis (L1 lumber vertebrae). Axitinib was stopped in October, 2019. Temsirolimus was then administered, but interstitial pneumonia occurred after three cycles of temsirolimus. Although steroid pulse therapy was performed, respiratory and general condition became worse. The patient died in November, 2019. By multidisciplinary treatments including metastasectomy, axitinib, ZA, and radiation therapy, the patient survived for 80 months after the initial recurrence.
Discussion
This patient with metastatic type 2 PRCC could survive 80 months after the initial recurrence by multidisciplinary treatments including metastasectomies, axitinib, ZA, and radiation therapy. Patients with metastatic type 2 PRCC generally have poor prognosis. In a clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median OS in type 2 PRCC was 12.4 months (10). Metastasectomies and axitinib appeared to be especially effective in the present case.
The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is the recommended treatment for metastatic nccRCC, and cabozantinib and everolimus are options. At the beginning of targeted era, mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, was reportedly effective compared with interferon-α for metastatic nccRCC (11). A comparative study between temsirolimus and tyrosine kinase inhibitors (TKIs) in metastatic nccRCC does not exist at present. The superiority of sunitinib compared with everolimus in nccRCC treatment has been reported in two clinical trials (12,13). The ASPEN trial reported that the progression-free survival (PFS) of sunitinib was longer than that of everolimus (12). The ESPN trial reported that both PFS and OS of sunitinib were longer than those of everolimus (13). Among other TKIs, the overall response rate of pazopanib was reportedly 39% in the treatment of metastatic nccRCC (6). There are few studies evaluating the clinical efficacy of systemic therapies in metastatic PRCC. In clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median PFS and OS were 6.6 and 17.8 months in type 1 PRCC, and 5.5 and 12.4 months in type 2, respectively (10). In a Japanese multicenter study evaluating metastatic PRCC in which most PRCC cases (91.4%) were type 2, the prognosis in the era of targeted therapy (OS=22.5 months) was improved compared with that in the cytokine era (OS=6.3 months). PRCC patients treated with TKIs in both first-line and second-line treatments (OS=31.4 months) showed better prognosis than those with mTOR inhibitors in first-line or second-line (OS=12.9 months) (14).
In our case, the second-line use of axitinib was effective and achieved a durable stable disease (SD). There have been few reports in which axitinib showed efficacies for metastatic PRCC (15,16). In our case, AEs were relieved by dose reduction and the setting of periodic drug withdrawal schedules of axitinib, and axitinib could be continued for a long time. The half-life period of axitinib was reportedly short (4.8-5.9 h) (17). Axitinib has a characteristic that AEs can be relieved in a short period because of its short half-life period. Then, axitinib can be started again after the short drug withdrawal period. The risk of regrowth should be low due to the short drug withdrawal. In our previous report of a clear cell RCC patient with metastasis at the paranasal sinus, AEs could be relieved effectively by using periodic drug withdrawal schedules of axitinib and axitinib could be used for more than 30 months (18). Takayama et al also reported a similar RCC case in which intermittent use of axitinib was effective (19).
There is a possibility that prognosis of this patient was improved by metastasectomies. LN metastases around the right common iliac vein and IVC at the time of LN dissection were pathologically confirmed. However, the relapse did not occur in the abdominal and pelvic areas after the extensive LN dissection. This appeared to indicate that LN metastases in the abdominal and the pelvic areas were completely resected by the initial LN dissection. Moreover, the three metastasectomies including the initial LN dissection around the IVC and right iliac vein, the resection of lung metastasis, and the mediastinal LN dissection could delay the timing of TKI administration for two years. Those metastasectomies might contribute to improve the patient's prognosis. In the cytokine era, an efficacy of LN dissection on radical nephrectomy was suggested in PRCC (20). Metastatectomy should be performed appropriately for patients with metastatic PRCC similar to clear cell RCC when radiological complete remission can be achieved by metastasectomy.
Although it is difficult to evaluate the effectiveness of ZA and local radiation therapy in this case, these treatments might present some positive effects for disease control.
We were able to control metastatic lesions of type 2 PRCC for a relatively long term by multidisciplinary treatment. Axitinib was effective and periodic drug withdrawal schedules could reduce AEs and enable to continue axitinib usage.
Acknowledgements
Not applicable.
Availability of data and materials
Data sharing is not applicable to this article, as no datasets were generated or analyzed during the present study.
Authors' contributions
YA contributed to the study concept, design, data collection and writing of the manuscript. YK contributed to data collection and the revision of the manuscript. MH contributed to data collection and the revision of the manuscript. HH contributed to data collection and the revision of the manuscript. KM contributed to data collection, pathological diagnosis and the revision of the manuscript. AH contributed to the study concept, design and the revision of the manuscript. KI contributed to the study concept, design, data collection, writing and the revision of the manuscript, and the supervision of the manuscript. The authenticity of all the raw data was assessed by YA, KM, AH and KI. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Ethical approval was granted from the Ethics Committee of National Defense Medical College.
Patient consent for publication
Written informed consent for the publication of any associated data was obtained from the patient's wife.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Radiological and pathological findings of the primary tumor. (A and B) Contrast-enhanced computed tomography images. A tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected. (C and D) Microscopically, the tumor had papillary architecture. The tumor cells contained abundant eosinophilic cytoplasm with high nuclear grade (Fuhrman nuclear grade 3). The tumor was diagnosed as type 2 papillary RCC. (C) magnification, x100; scale bar, 200 µm. (D) magnification, x400; scale bar, 50 µm. RCC, renal cell carcinoma.
Figure 2 CE-CT images. (A and B) CE-CT images of a (A) lung metastasis (S6) (black arrow) and (B) paracaval lymph node metastases (black arrow) that appeared in 2012. (C) CE-CT of lymph node swellings at the right tracheal bifurcation (white arrow) found in 2013. (D) CE-CT of mediastinal lymph nodes (white arrows) that were swollen again in 2014. CE-CT, Contrast-enhanced computed tomography.
Figure 3 The time course of treatments for the patient with metastatic type 2 papillary renal cell carcinoma. Axi, axitinib; HT, hypertension; IVC, inferior vena cava; LND, lymph node dissection; LNM, lymph node metastasis; RNx, radical nephrectomy; SD, stable disease; SU, sunitinib; TEM, temsirolimus; ZA, zoledronic acid.
Figure 4 CT images during axitinib treatment. (A) CT at axitinib administration. White arrows indicate mediastinal lymph node metastases. (B) CT 7 months after axitinib administration. Lymph node metastases shrunk by using axitinib (partial response, judged by RECIST version 1.1). (C) CT 19 months after axitinib administration. The response was maintained. (D) CT 30 months after axitinib administration. The response was still maintained. (E) Representative bone metastasis (left ilium) at axitinib administration. (F) CT 7 months after axitinib administration. (G) CT 19 months after axitinib administration. (H) CT 30 months after axitinib administration. The bone metastasis in the ilium grew slightly compared with that at axitinib administration (<10%, stable disease, judged by RECIST version 1.1). | Recovered | ReactionOutcome | CC BY-NC-ND | 33732457 | 19,952,254 | 2021-04 |
What was the outcome of reaction 'Malaise'? | Long-term disease control of metastatic type 2 papillary renal cell carcinoma using local treatment and molecular targeted therapy: A case report.
A 46-year-old man underwent right partial nephrectomy for type 2 papillary renal cell carcinoma (PRCC) in 2011. Lung metastasis and lymph node (LN) metastases around the inferior vena cave appeared in 2012. A right radical nephrectomy and extensive LN dissection was performed and the resection of lung metastasis was performed one month after the nephrectomy. Mediastinal LN metastases occurred in 2013, and resection of the affected LNs was performed. Sunitinib and zoledronic acid was started in 2014 because mediastinal LN swelling and multiple bone metastases appeared. Sunitinib treatment was stopped soon after due to adverse events and axitinib treatment was started. Axitinib was effective and the patient had stable disease for 30 months. Adverse events were successfully controlled by dose reduction and periodic drug withdrawal schedules (for example, 5 days on, 2 days off). Axitinib was further continued for 19 months as the metastatic lesions had progressed slowly. Temsirolimus treatment was started in 2019, but it was stopped after three cycles due to interstitial pneumonia. The patient died 80 months after the initial recurrence. Using multidisciplinary treatment, durable disease control was achieved in a patient with metastatic type 2 PRCC.
Introductions
Recently, the prognosis of patients with metastatic renal cell carcinoma (RCC) has been improved by molecular targeted therapies (1) and immune checkpoint inhibitors (2). However, optimal treatment strategies for metastatic non-clear cell RCC (nccRCC) has yet to be established. In previous studies, molecular targeted therapies, especially sunitinib, have shown clinical efficacy for the treatment of metastatic nccRCC (3-7). The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is recommended at present for metastatic nccRCC. In nccRCC papillary renal cell carcinoma (PRCC) is the leading histology (8). PRCC is divided into type 1 and type 2, with type 2 PRCC showing worse prognosis compared with type 1(9). In phase 2 clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, overall survival (OS) of type1 PRCC was 17.8 months, and that of type 2 was 12.4 months (10).
In this report, we present a patient with metastatic type 2 PRCC whose metastatic lesions were controlled for a long time by multidisciplinary treatments including metastasectomies, axitinib, zoledronic acid (ZA), and radiation therapy.
Case report
A 46-year-old man with hematospermia was presented to a urologic clinic in April, 2011. A right renal tumor was found by ultrasound, and the patient was referred to our hospital. The tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected by contrast-enhanced computed tomography (CT) (Fig. 1A and B). A right partial nephrectomy was performed in July, 2011. Pathological diagnosis was type2 PRCC (Fig. 1C and D). A lung metastasis (S6) and paracaval lymph node (LN) metastases appeared in March, 2012 (Fig. 2A and B). After five cycles of temsirolimus, right radical nephrectomy and extensive LN dissection around the inferior vena cava (IVC) and right common iliac vein were performed in June, 2012, and the resection of the lung metastasis was performed one month after the nephrectomy. Then, radiological complete remission was achieved. LN swellings at the right tracheal bifurcation was found by CT in August, 2013 (Fig. 2C). After three cycles of temsirolimus, mediastinal LN dissection was performed in October, 2013. Mediastinal LNs (Fig. 2D) were swollen again, and multiple bone metastases [sternum, right fifth rib, thoracic spine (5-7th vertebrae), left ilium, and right pubis] appeared in 2014. The clinical course of the patient, including local treatments, medical treatments, and treatment-related adverse events are shown in Fig. 3. Sunitinib (37.5 mg/day) and ZA (4 mg/month) were started in June, 2014. Sunitinib was stopped within two weeks because of adverse events (AEs) including fever, malaise, and liver dysfunction. After the patient had recovered from the AEs, axitinib (10 mg/day) was started as a second-line treatment in July, 2014. ZA was continued after the axitinib administration. Because of diarrhea and hoarseness, the treatment schedule of axitinib was changed to a periodic drug withdrawal schedule (5 days-on, 2 days-off) in October, 2014. Next, the daily dose of axitinib was reduced to 8 mg (5 days-on, 2 days-off) to control severe diarrhea in December, 2014. Stereotactic radiation therapy (total 30 Gray, 10 fractions) was performed for bone metastasis at the left ilium in November, 2015 because only the iliac metastasis appeared to be an active lesion among all bone metastases in the bone scintigraphy. The periodic drug withdrawal schedule of axitinib (8 mg/day, 5 days-on, 2 days-off) was changed to the next schedule (8 mg/day, 4 days-on, 3 days-off) due to renal dysfunction and proteinuria in April, 2017. Mediastinal LN metastases and bone metastases was stable for 30 months after the axitinib administration (Fig. 4). Disease progression was confirmed in June, 2017 due to the appearance of multiple small lung metastases. Because the metastatic lesions progressed slowly after the disease progression, axitinib was continued for another 19 months in accordance with the patient's request. The schedule of axitinib was then changed to a third schedule (8 mg/day, 3 days-on, 3 days-off) due to symptoms of anorexia, dyspnea, and muscle pain in April, 2018. Patient was hospitalized due to severe back pain in September, 2018, and palliative radiotherapy was performed for a compression fracture due to metastasis (L1 lumber vertebrae). Axitinib was stopped in October, 2019. Temsirolimus was then administered, but interstitial pneumonia occurred after three cycles of temsirolimus. Although steroid pulse therapy was performed, respiratory and general condition became worse. The patient died in November, 2019. By multidisciplinary treatments including metastasectomy, axitinib, ZA, and radiation therapy, the patient survived for 80 months after the initial recurrence.
Discussion
This patient with metastatic type 2 PRCC could survive 80 months after the initial recurrence by multidisciplinary treatments including metastasectomies, axitinib, ZA, and radiation therapy. Patients with metastatic type 2 PRCC generally have poor prognosis. In a clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median OS in type 2 PRCC was 12.4 months (10). Metastasectomies and axitinib appeared to be especially effective in the present case.
The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is the recommended treatment for metastatic nccRCC, and cabozantinib and everolimus are options. At the beginning of targeted era, mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, was reportedly effective compared with interferon-α for metastatic nccRCC (11). A comparative study between temsirolimus and tyrosine kinase inhibitors (TKIs) in metastatic nccRCC does not exist at present. The superiority of sunitinib compared with everolimus in nccRCC treatment has been reported in two clinical trials (12,13). The ASPEN trial reported that the progression-free survival (PFS) of sunitinib was longer than that of everolimus (12). The ESPN trial reported that both PFS and OS of sunitinib were longer than those of everolimus (13). Among other TKIs, the overall response rate of pazopanib was reportedly 39% in the treatment of metastatic nccRCC (6). There are few studies evaluating the clinical efficacy of systemic therapies in metastatic PRCC. In clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median PFS and OS were 6.6 and 17.8 months in type 1 PRCC, and 5.5 and 12.4 months in type 2, respectively (10). In a Japanese multicenter study evaluating metastatic PRCC in which most PRCC cases (91.4%) were type 2, the prognosis in the era of targeted therapy (OS=22.5 months) was improved compared with that in the cytokine era (OS=6.3 months). PRCC patients treated with TKIs in both first-line and second-line treatments (OS=31.4 months) showed better prognosis than those with mTOR inhibitors in first-line or second-line (OS=12.9 months) (14).
In our case, the second-line use of axitinib was effective and achieved a durable stable disease (SD). There have been few reports in which axitinib showed efficacies for metastatic PRCC (15,16). In our case, AEs were relieved by dose reduction and the setting of periodic drug withdrawal schedules of axitinib, and axitinib could be continued for a long time. The half-life period of axitinib was reportedly short (4.8-5.9 h) (17). Axitinib has a characteristic that AEs can be relieved in a short period because of its short half-life period. Then, axitinib can be started again after the short drug withdrawal period. The risk of regrowth should be low due to the short drug withdrawal. In our previous report of a clear cell RCC patient with metastasis at the paranasal sinus, AEs could be relieved effectively by using periodic drug withdrawal schedules of axitinib and axitinib could be used for more than 30 months (18). Takayama et al also reported a similar RCC case in which intermittent use of axitinib was effective (19).
There is a possibility that prognosis of this patient was improved by metastasectomies. LN metastases around the right common iliac vein and IVC at the time of LN dissection were pathologically confirmed. However, the relapse did not occur in the abdominal and pelvic areas after the extensive LN dissection. This appeared to indicate that LN metastases in the abdominal and the pelvic areas were completely resected by the initial LN dissection. Moreover, the three metastasectomies including the initial LN dissection around the IVC and right iliac vein, the resection of lung metastasis, and the mediastinal LN dissection could delay the timing of TKI administration for two years. Those metastasectomies might contribute to improve the patient's prognosis. In the cytokine era, an efficacy of LN dissection on radical nephrectomy was suggested in PRCC (20). Metastatectomy should be performed appropriately for patients with metastatic PRCC similar to clear cell RCC when radiological complete remission can be achieved by metastasectomy.
Although it is difficult to evaluate the effectiveness of ZA and local radiation therapy in this case, these treatments might present some positive effects for disease control.
We were able to control metastatic lesions of type 2 PRCC for a relatively long term by multidisciplinary treatment. Axitinib was effective and periodic drug withdrawal schedules could reduce AEs and enable to continue axitinib usage.
Acknowledgements
Not applicable.
Availability of data and materials
Data sharing is not applicable to this article, as no datasets were generated or analyzed during the present study.
Authors' contributions
YA contributed to the study concept, design, data collection and writing of the manuscript. YK contributed to data collection and the revision of the manuscript. MH contributed to data collection and the revision of the manuscript. HH contributed to data collection and the revision of the manuscript. KM contributed to data collection, pathological diagnosis and the revision of the manuscript. AH contributed to the study concept, design and the revision of the manuscript. KI contributed to the study concept, design, data collection, writing and the revision of the manuscript, and the supervision of the manuscript. The authenticity of all the raw data was assessed by YA, KM, AH and KI. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Ethical approval was granted from the Ethics Committee of National Defense Medical College.
Patient consent for publication
Written informed consent for the publication of any associated data was obtained from the patient's wife.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Radiological and pathological findings of the primary tumor. (A and B) Contrast-enhanced computed tomography images. A tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected. (C and D) Microscopically, the tumor had papillary architecture. The tumor cells contained abundant eosinophilic cytoplasm with high nuclear grade (Fuhrman nuclear grade 3). The tumor was diagnosed as type 2 papillary RCC. (C) magnification, x100; scale bar, 200 µm. (D) magnification, x400; scale bar, 50 µm. RCC, renal cell carcinoma.
Figure 2 CE-CT images. (A and B) CE-CT images of a (A) lung metastasis (S6) (black arrow) and (B) paracaval lymph node metastases (black arrow) that appeared in 2012. (C) CE-CT of lymph node swellings at the right tracheal bifurcation (white arrow) found in 2013. (D) CE-CT of mediastinal lymph nodes (white arrows) that were swollen again in 2014. CE-CT, Contrast-enhanced computed tomography.
Figure 3 The time course of treatments for the patient with metastatic type 2 papillary renal cell carcinoma. Axi, axitinib; HT, hypertension; IVC, inferior vena cava; LND, lymph node dissection; LNM, lymph node metastasis; RNx, radical nephrectomy; SD, stable disease; SU, sunitinib; TEM, temsirolimus; ZA, zoledronic acid.
Figure 4 CT images during axitinib treatment. (A) CT at axitinib administration. White arrows indicate mediastinal lymph node metastases. (B) CT 7 months after axitinib administration. Lymph node metastases shrunk by using axitinib (partial response, judged by RECIST version 1.1). (C) CT 19 months after axitinib administration. The response was maintained. (D) CT 30 months after axitinib administration. The response was still maintained. (E) Representative bone metastasis (left ilium) at axitinib administration. (F) CT 7 months after axitinib administration. (G) CT 19 months after axitinib administration. (H) CT 30 months after axitinib administration. The bone metastasis in the ilium grew slightly compared with that at axitinib administration (<10%, stable disease, judged by RECIST version 1.1). | Recovered | ReactionOutcome | CC BY-NC-ND | 33732457 | 19,952,254 | 2021-04 |
What was the outcome of reaction 'Pyrexia'? | Long-term disease control of metastatic type 2 papillary renal cell carcinoma using local treatment and molecular targeted therapy: A case report.
A 46-year-old man underwent right partial nephrectomy for type 2 papillary renal cell carcinoma (PRCC) in 2011. Lung metastasis and lymph node (LN) metastases around the inferior vena cave appeared in 2012. A right radical nephrectomy and extensive LN dissection was performed and the resection of lung metastasis was performed one month after the nephrectomy. Mediastinal LN metastases occurred in 2013, and resection of the affected LNs was performed. Sunitinib and zoledronic acid was started in 2014 because mediastinal LN swelling and multiple bone metastases appeared. Sunitinib treatment was stopped soon after due to adverse events and axitinib treatment was started. Axitinib was effective and the patient had stable disease for 30 months. Adverse events were successfully controlled by dose reduction and periodic drug withdrawal schedules (for example, 5 days on, 2 days off). Axitinib was further continued for 19 months as the metastatic lesions had progressed slowly. Temsirolimus treatment was started in 2019, but it was stopped after three cycles due to interstitial pneumonia. The patient died 80 months after the initial recurrence. Using multidisciplinary treatment, durable disease control was achieved in a patient with metastatic type 2 PRCC.
Introductions
Recently, the prognosis of patients with metastatic renal cell carcinoma (RCC) has been improved by molecular targeted therapies (1) and immune checkpoint inhibitors (2). However, optimal treatment strategies for metastatic non-clear cell RCC (nccRCC) has yet to be established. In previous studies, molecular targeted therapies, especially sunitinib, have shown clinical efficacy for the treatment of metastatic nccRCC (3-7). The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is recommended at present for metastatic nccRCC. In nccRCC papillary renal cell carcinoma (PRCC) is the leading histology (8). PRCC is divided into type 1 and type 2, with type 2 PRCC showing worse prognosis compared with type 1(9). In phase 2 clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, overall survival (OS) of type1 PRCC was 17.8 months, and that of type 2 was 12.4 months (10).
In this report, we present a patient with metastatic type 2 PRCC whose metastatic lesions were controlled for a long time by multidisciplinary treatments including metastasectomies, axitinib, zoledronic acid (ZA), and radiation therapy.
Case report
A 46-year-old man with hematospermia was presented to a urologic clinic in April, 2011. A right renal tumor was found by ultrasound, and the patient was referred to our hospital. The tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected by contrast-enhanced computed tomography (CT) (Fig. 1A and B). A right partial nephrectomy was performed in July, 2011. Pathological diagnosis was type2 PRCC (Fig. 1C and D). A lung metastasis (S6) and paracaval lymph node (LN) metastases appeared in March, 2012 (Fig. 2A and B). After five cycles of temsirolimus, right radical nephrectomy and extensive LN dissection around the inferior vena cava (IVC) and right common iliac vein were performed in June, 2012, and the resection of the lung metastasis was performed one month after the nephrectomy. Then, radiological complete remission was achieved. LN swellings at the right tracheal bifurcation was found by CT in August, 2013 (Fig. 2C). After three cycles of temsirolimus, mediastinal LN dissection was performed in October, 2013. Mediastinal LNs (Fig. 2D) were swollen again, and multiple bone metastases [sternum, right fifth rib, thoracic spine (5-7th vertebrae), left ilium, and right pubis] appeared in 2014. The clinical course of the patient, including local treatments, medical treatments, and treatment-related adverse events are shown in Fig. 3. Sunitinib (37.5 mg/day) and ZA (4 mg/month) were started in June, 2014. Sunitinib was stopped within two weeks because of adverse events (AEs) including fever, malaise, and liver dysfunction. After the patient had recovered from the AEs, axitinib (10 mg/day) was started as a second-line treatment in July, 2014. ZA was continued after the axitinib administration. Because of diarrhea and hoarseness, the treatment schedule of axitinib was changed to a periodic drug withdrawal schedule (5 days-on, 2 days-off) in October, 2014. Next, the daily dose of axitinib was reduced to 8 mg (5 days-on, 2 days-off) to control severe diarrhea in December, 2014. Stereotactic radiation therapy (total 30 Gray, 10 fractions) was performed for bone metastasis at the left ilium in November, 2015 because only the iliac metastasis appeared to be an active lesion among all bone metastases in the bone scintigraphy. The periodic drug withdrawal schedule of axitinib (8 mg/day, 5 days-on, 2 days-off) was changed to the next schedule (8 mg/day, 4 days-on, 3 days-off) due to renal dysfunction and proteinuria in April, 2017. Mediastinal LN metastases and bone metastases was stable for 30 months after the axitinib administration (Fig. 4). Disease progression was confirmed in June, 2017 due to the appearance of multiple small lung metastases. Because the metastatic lesions progressed slowly after the disease progression, axitinib was continued for another 19 months in accordance with the patient's request. The schedule of axitinib was then changed to a third schedule (8 mg/day, 3 days-on, 3 days-off) due to symptoms of anorexia, dyspnea, and muscle pain in April, 2018. Patient was hospitalized due to severe back pain in September, 2018, and palliative radiotherapy was performed for a compression fracture due to metastasis (L1 lumber vertebrae). Axitinib was stopped in October, 2019. Temsirolimus was then administered, but interstitial pneumonia occurred after three cycles of temsirolimus. Although steroid pulse therapy was performed, respiratory and general condition became worse. The patient died in November, 2019. By multidisciplinary treatments including metastasectomy, axitinib, ZA, and radiation therapy, the patient survived for 80 months after the initial recurrence.
Discussion
This patient with metastatic type 2 PRCC could survive 80 months after the initial recurrence by multidisciplinary treatments including metastasectomies, axitinib, ZA, and radiation therapy. Patients with metastatic type 2 PRCC generally have poor prognosis. In a clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median OS in type 2 PRCC was 12.4 months (10). Metastasectomies and axitinib appeared to be especially effective in the present case.
The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is the recommended treatment for metastatic nccRCC, and cabozantinib and everolimus are options. At the beginning of targeted era, mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, was reportedly effective compared with interferon-α for metastatic nccRCC (11). A comparative study between temsirolimus and tyrosine kinase inhibitors (TKIs) in metastatic nccRCC does not exist at present. The superiority of sunitinib compared with everolimus in nccRCC treatment has been reported in two clinical trials (12,13). The ASPEN trial reported that the progression-free survival (PFS) of sunitinib was longer than that of everolimus (12). The ESPN trial reported that both PFS and OS of sunitinib were longer than those of everolimus (13). Among other TKIs, the overall response rate of pazopanib was reportedly 39% in the treatment of metastatic nccRCC (6). There are few studies evaluating the clinical efficacy of systemic therapies in metastatic PRCC. In clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median PFS and OS were 6.6 and 17.8 months in type 1 PRCC, and 5.5 and 12.4 months in type 2, respectively (10). In a Japanese multicenter study evaluating metastatic PRCC in which most PRCC cases (91.4%) were type 2, the prognosis in the era of targeted therapy (OS=22.5 months) was improved compared with that in the cytokine era (OS=6.3 months). PRCC patients treated with TKIs in both first-line and second-line treatments (OS=31.4 months) showed better prognosis than those with mTOR inhibitors in first-line or second-line (OS=12.9 months) (14).
In our case, the second-line use of axitinib was effective and achieved a durable stable disease (SD). There have been few reports in which axitinib showed efficacies for metastatic PRCC (15,16). In our case, AEs were relieved by dose reduction and the setting of periodic drug withdrawal schedules of axitinib, and axitinib could be continued for a long time. The half-life period of axitinib was reportedly short (4.8-5.9 h) (17). Axitinib has a characteristic that AEs can be relieved in a short period because of its short half-life period. Then, axitinib can be started again after the short drug withdrawal period. The risk of regrowth should be low due to the short drug withdrawal. In our previous report of a clear cell RCC patient with metastasis at the paranasal sinus, AEs could be relieved effectively by using periodic drug withdrawal schedules of axitinib and axitinib could be used for more than 30 months (18). Takayama et al also reported a similar RCC case in which intermittent use of axitinib was effective (19).
There is a possibility that prognosis of this patient was improved by metastasectomies. LN metastases around the right common iliac vein and IVC at the time of LN dissection were pathologically confirmed. However, the relapse did not occur in the abdominal and pelvic areas after the extensive LN dissection. This appeared to indicate that LN metastases in the abdominal and the pelvic areas were completely resected by the initial LN dissection. Moreover, the three metastasectomies including the initial LN dissection around the IVC and right iliac vein, the resection of lung metastasis, and the mediastinal LN dissection could delay the timing of TKI administration for two years. Those metastasectomies might contribute to improve the patient's prognosis. In the cytokine era, an efficacy of LN dissection on radical nephrectomy was suggested in PRCC (20). Metastatectomy should be performed appropriately for patients with metastatic PRCC similar to clear cell RCC when radiological complete remission can be achieved by metastasectomy.
Although it is difficult to evaluate the effectiveness of ZA and local radiation therapy in this case, these treatments might present some positive effects for disease control.
We were able to control metastatic lesions of type 2 PRCC for a relatively long term by multidisciplinary treatment. Axitinib was effective and periodic drug withdrawal schedules could reduce AEs and enable to continue axitinib usage.
Acknowledgements
Not applicable.
Availability of data and materials
Data sharing is not applicable to this article, as no datasets were generated or analyzed during the present study.
Authors' contributions
YA contributed to the study concept, design, data collection and writing of the manuscript. YK contributed to data collection and the revision of the manuscript. MH contributed to data collection and the revision of the manuscript. HH contributed to data collection and the revision of the manuscript. KM contributed to data collection, pathological diagnosis and the revision of the manuscript. AH contributed to the study concept, design and the revision of the manuscript. KI contributed to the study concept, design, data collection, writing and the revision of the manuscript, and the supervision of the manuscript. The authenticity of all the raw data was assessed by YA, KM, AH and KI. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Ethical approval was granted from the Ethics Committee of National Defense Medical College.
Patient consent for publication
Written informed consent for the publication of any associated data was obtained from the patient's wife.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Radiological and pathological findings of the primary tumor. (A and B) Contrast-enhanced computed tomography images. A tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected. (C and D) Microscopically, the tumor had papillary architecture. The tumor cells contained abundant eosinophilic cytoplasm with high nuclear grade (Fuhrman nuclear grade 3). The tumor was diagnosed as type 2 papillary RCC. (C) magnification, x100; scale bar, 200 µm. (D) magnification, x400; scale bar, 50 µm. RCC, renal cell carcinoma.
Figure 2 CE-CT images. (A and B) CE-CT images of a (A) lung metastasis (S6) (black arrow) and (B) paracaval lymph node metastases (black arrow) that appeared in 2012. (C) CE-CT of lymph node swellings at the right tracheal bifurcation (white arrow) found in 2013. (D) CE-CT of mediastinal lymph nodes (white arrows) that were swollen again in 2014. CE-CT, Contrast-enhanced computed tomography.
Figure 3 The time course of treatments for the patient with metastatic type 2 papillary renal cell carcinoma. Axi, axitinib; HT, hypertension; IVC, inferior vena cava; LND, lymph node dissection; LNM, lymph node metastasis; RNx, radical nephrectomy; SD, stable disease; SU, sunitinib; TEM, temsirolimus; ZA, zoledronic acid.
Figure 4 CT images during axitinib treatment. (A) CT at axitinib administration. White arrows indicate mediastinal lymph node metastases. (B) CT 7 months after axitinib administration. Lymph node metastases shrunk by using axitinib (partial response, judged by RECIST version 1.1). (C) CT 19 months after axitinib administration. The response was maintained. (D) CT 30 months after axitinib administration. The response was still maintained. (E) Representative bone metastasis (left ilium) at axitinib administration. (F) CT 7 months after axitinib administration. (G) CT 19 months after axitinib administration. (H) CT 30 months after axitinib administration. The bone metastasis in the ilium grew slightly compared with that at axitinib administration (<10%, stable disease, judged by RECIST version 1.1). | Recovered | ReactionOutcome | CC BY-NC-ND | 33732457 | 19,952,254 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute respiratory distress syndrome'. | Multimodality treatment in immunocompromised patients with severe COVID-19: the role of IL-6 inhibitor, intravenous immunoglobulin, and haemoperfusion.
Cytokine release syndrome (CRS) is known to be associated with severe coronavirus disease 2019 (COVID-19). Multiple anti-inflammatory therapies such as tocilizumab, corticosteroids, intravenous immunoglobulin (IVIG), and haemoadsorption or haemoperfusion have been used to combat this life-threatening condition. However, immunocompromised hosts are often omitted from research studies, and knowledge on the clinical efficacy of these therapies in immunocompromised patients is therefore limited. We report two cases of immunocompromised patients with severe COVID-19-related CRS requiring mechanical ventilation who were treated with multimodality treatment consisting of tocilizumab, IVIG, and haemoperfusion. Within 48 h, both patients showed clinical improvement with PaO2:FiO2 ratio and haemodynamic stability. Both survived to discharge. There were no adverse events following these therapies. In conclusion, combined therapeutic modalities, possibly tailored to individual inflammatory profiles, are promising treatment for severe COVID-19 infection in the immunocompromised host. Timely administration of adjunctive therapies that alleviate overwhelming inflammation may provide the best outcome.
Introduction
In December 2019, a cluster of unexplained pneumonia cases were initially diagnosed in Wuhan, the capital of Hubei province, China. A new beta‐coronavirus, now named severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), was identified as the cause of coronavirus disease 2019 (COVID‐19). Two months after the index case of COVID‐19 pneumonia in Wuhan, the disease outbreak of COVID‐19 acute respiratory disease resulted in more than 70,000 confirmed cases and 2718 deaths officially reported in mainland China. On 30 January 2020, WHO declared a Public Health Emergency of International Concern regarding the outbreak of COVID‐19 in China. The pandemic has since infected more than 90 million people resulting in over 2 million deaths worldwide.
Among COVID‐19 patients, clinical symptoms may range from mild upper respiratory tract symptoms to severe acute respiratory distress syndrome (ARDS), with some progressing to multiorgan failure [1]. Initial retrospective studies in China reported that patients requiring intensive care unit (ICU) admission had elevated inflammatory cytokines and chemokines in serum compared to those not requiring ICU admission which suggest that cytokine release syndrome (CRS) might play an important role in the pathogenesis of severe COVID‐19 infection [2]. Furthermore, interleukin (IL)‐6 was also found to be elevated in severe COVID‐19 infection which is suspected to be driven by viral infection; therefore, IL‐6 receptor blockade may potentially be an effective treatment for this resulting overwhelming inflammation. Treatment for COVID‐19 pneumonia has been focused on both eradicating the virus itself as well as diminishing the inflammatory response from cytokine storms, which is believed to be responsible for multiorgan failure in patients infected with COVID‐19.
While established protocols for patients with severe disease are currently available, immunocompromised patients are often omitted from clinical studies. As a result, the efficacy of adjunctive treatment in immunocompromised patients is commonly extrapolated from studies in normal hosts. Clinical experience in immunocompromised hosts is limited to case reports and case series. In addition to standard treatment, intravenous immunoglobulin (IVIG), haemoadsorption, and tocilizumab would be potential therapies in those with severe disease and may be even more beneficial in patients who are immunocompromised.
We report two immunocompromised patients with severe COVID‐19 pneumonia who successfully underwent multimodality treatment with tocilizumab, IVIG, and haemoperfusion as adjunctive therapies. Evidence on anti‐inflammatory therapies as adjunctive treatment for severe COVID‐19‐related CRS is also reviewed.
Case Report
We, herein, reported two patients with severe COVID‐19 pneumonia who were treated with favipiravir‐based regimen combined with other antimicrobial agents. Multimodality treatment with tocilizumab, IVIG, and haemoperfusion was used as adjunctive therapy. Both patients were on mechanical ventilation using lung protective ventilation strategies, sedation, and neuromuscular blocking agent. Mode of oxygen therapy, laboratory data, and adjunctive treatments given in each patient were summarized in time sequence as shown in Figures 1 and 2.
Figure 1 Summary of mode of oxygen therapy and adjunctive treatments given in each patient in time sequence.
Figure 2 Laboratory investigations of each patient in time sequence.
Case 1
A 58‐year‐old woman with a known history of HIV infection, diabetes, and dyslipidaemia was presented. Her last CD4 count was 700 cell/mm3 with good virological suppression. She had fever, cough, and myalgia for six days prior to admission. The real‐time reverse transcriptase‐polymerase chain reaction (RT‐PCR) from her nasopharyngeal and throat swab was positive for SARS‐CoV‐2. No pulmonary opacity was shown in her initial chest X‐ray (Fig. 3). Favipiravir, hydroxychloroquine (HCQ), and darunavir/ritonavir (DRV/r) were administered.
Figure 3 Chest radiographs on initial presentation, on the day before each adjunctive therapy, and on discharge date.
On day 6 of admission, she developed dyspnoea with SpO2 (peripheral capillary oxygen saturation, on ambient air) of 93%. Her follow‐up chest X‐ray showed multifocal patchy opacity in both middle and lower lung zones. Haemoculture was identified as Acinetobactor baumannii. Her clinical condition rapidly progressed to ARDS on the same day which required invasive mechanical ventilation (PaO2:FiO2 ratio was 260). Repeat RT‐PCR for SARS‐CoV‐2 was still positive with cycle threshold (ct) of 20. COVID‐19‐induced CRS and co‐infection with A. baumannii septicaemia were thought to be responsible for clinical deterioration. Two sessions of polymyxin B haemoperfusion (PMX‐HP) were performed on days 6 and 7 of admission. Ampicillin‐sulbactam, colistin, and sulperazone were also given empirically which later de‐escalated to ceftazidime.
After the second session of haemoperfusion, her body temperature returned to normal but became hypotensive. Echocardiography revealed a cardiac ejection fraction of 30% and apical wall hypokinesia consistent with stress‐induced cardiomyopathy. The patient was started on norepinephrine and dobutamine for combination septic and cardiogenic shock. Inflammatory markers were elevated: IL‐6 was 1091 pg/mL, ferritin was 3316 ng/mL, hs‐CRP was 228 mg/L, D‐dimer was 2174 ng/mL, and lactate dehydrogenase (LDH) was 492 U/L. Her chest X‐ray showed progression to diffuse bilateral ground‐glass and patchy opacity (Fig. 3). A single dose of tocilizumab (400 mg) was administered intravenously. Her clinical status was improved significantly after haemoperfusion followed by tocilizumab. Vasopressors were weaned off and PaO2:FiO2 ratio was increased to 500 within 48 h of tocilizumab administration. She remained on invasive mechanical ventilation for another five days and was successfully extubated on day 12 of admission. She was discharged from the hospital with a total length of stay of 22 days. The time to negative RT‐PCR for SARS‐CoV‐2 was 15 days after admission.
Case 2
A 69‐year‐old man, partially dependent on most activity of daily living, with a known history of relapse multiple myeloma (MM) IgG kappa stage II presented with spinal cord compression at the level of T3–T7 receiving laminectomy and fusion surgery, triple vessel disease, diabetes, and hypertension. He presented at emergency room with dyspnoea and myalgia for one week. His vital signs were body temperature (BT) 37.4°C, respiratory rate (RR) 30/min, blood pressure 60/40 mmHg, and SpO2 (on ambient air) 64%. On admission (seventh day of symptom onset), he was mechanically ventilated due to hypoxaemic respiratory failure. The RT‐PCR for SARS‐CoV‐2 was detected from nasopharyngeal swab and tracheal suction. The initial chest X‐ray showed bilateral patchy opacity (Fig. 3). Favipiravir, HCQ, azithromycin, and ceftriaxone were administered afterwards. His haemodynamic stability was maintained by norepinephrine. Fludrocortisone was concomitantly administered with a high suspicion of autonomic dysreflexia as the history of spinal cord compression.
On day 2 of admission, due to worsening of his haemodynamic stability and oxygenation (PaO2:FiO2 ratio of 130), we decided to initiate PMX‐HP for two consecutive days (days 2 and 3 of admission). The level of endotoxin activity assay (EAA) before haemoperfusion was 0.58 U. On day 4 (11th day of symptom onset), he still had haemodynamic instability and worsening hypoxaemia requiring higher dose of norepinephrine and FiO2 (PaO2:FiO2 ratio of 143). Laboratory results showed elevation of the inflammatory markers: IL‐6 was 426.2 pg/mL, ferritin was 190.5 ng/mL, hs‐CRP was 225 mg/L, D‐dimer was 7979 ng/mL, and LDH was 321 U/L. The sputum culture was identified as Klebsiella pneumoniae. Single dose of tocilizumab (400 mg) and piperacillin‐tazobactam was administered. Nevertheless, the patient's condition did not improve including haemodynamic instability and persistent low PaO2:FiO2 ratio; 25 mg of IVIG (Flebogamma®, Grifols, DKSH, Spain) was administered for four consecutive days (days 6–9 of admission). Eventually, the PaO2:FiO2 ratio was increased to 180–230 and norepinephrine could be weaned off on day 13. His clinical condition was complicated with secondary bacterial cellulitis which was managed by antibiotic. However, he could be successfully extubated with a total 31 days of mechanical ventilation and discharged with a total length of stay of 45 days. The time to negative RT‐PCR for SARS‐CoV‐2 was 21 days.
Discussion
CRS‐related ARDS and secondary haemophagocytic lymphohistiocytosis (sHLH) are two distinct constellation of symptoms which are believed to attribute to the high mortality rate among COVID‐19 patients with respiratory failure [3, 4, 5]. CRS has previously been observed following chimeric antigen receptor (CAR) T‐cell therapy and therapeutic antibodies administration but has also been seen in certain viral infections such as SARS‐CoV‐1 and now in SARS‐CoV‐2. In addition, the characteristics of hyperinflammation reported in severe COVID‐19 infection also resemble sHLH triggered by other viral infections [2]. However, the clinical syndrome of these two entities might be indistinguishable. Early detection of hyperinflammatory state and selection of life‐saving therapies should be done to prevent clinical deterioration in severe COVID‐19 patients.
In our critical cases of COVID‐19, both were immunocompromised patients with hypoxaemic respiratory failure requiring invasive mechanical ventilation. At the time of the first wave of the pandemic in Thailand, there were limited clinical data available for the treatment of severe COVID‐19. Aiming to prevent clinical deterioration in patients with CRS, tocilizumab, IVIG, haemoperfusion, and corticosteroids had been introduced as part of treatment in our centre. Dhakal et al. reported the overall mortality rate of 57% from the case series of MM patients infected with COVID‐19 and none of them received tocilizumab [6]. Up to now, additional data on the clinical efficacy of these therapeutic modalities used for coronaviruses were published, particularly COVID‐19 infection. These adjunctive treatments will be discussed and reviewed.
Tocilizumab
The upregulation of cytokines and chemokines, IL‐6, is thought to be a major step in the immunopathogenesis of COVID‐19‐related ARDS. Inhibition of IL‐6 should therefore theoretically be effective in suppressing overwhelming inflammation found in COVID‐19 [7]. Tocilizumab is a humanized anti‐IL‐6 receptor which is Food and Drug Administration (FDA)‐approved for use in rheumatoid arthritis, CAR T‐cell‐induced CRS, and various other rheumatological conditions. Off‐label use of tocilizumab in severe COVID‐19 infection was found to be effective in the treatment of COVID‐19 patients [8].
In critically ill patients infected with COVID‐19, remarkable improvement of respiratory parameters and return of body temperature to normal were observed after tocilizumab treatment [9, 10, 11]. Another observational study of combination of low‐dose methylprednisolone and tocilizumab was conducted in 15 patients at a single centre in China. Patients who achieved normalization of IL‐6 levels with tocilizumab and methylprednisolone had clinical stabilizations rather than disease progression [12]. In contrast, some retrospective case–control study failed to demonstrate the mortality benefit of using tocilizumab in severe COVID‐19 patients [13, 14]. Of note, another non‐randomized observational study using intravenous or subcutaneous tocilizumab in severe or critical COVID‐19 patients showed significantly higher survival rates compared to patients not receiving tocilizumab [15, 16]. Recently, the preliminary result of randomized controlled COVACTA trial and BACC bay trial showed disappointing result of tocilizumab that failed to improve the patient mortality or intubation in moderately severe non‐intubated COVID‐19 [17, 18]. However, a lower primary outcome event rate of intubation and death may have limited the treatment effect of tocilizumab in this study. In contrast, sarilumab, another IL‐6 inhibitor, did show a trend towards decreased mortality in a recent randomized controlled study in critically ill patients [19]. It remains to be seen whether IL‐6 inhibitors may be of use in our most critical patients.
In addition, in a case of extremely high level of IL‐6, repeated dose of tocilizumab is suggested [12]. The prospective study in Italy also reported that two to three doses of tocilizumab (800 mg), 12–24 h apart, may be an effective treatment in COVID‐19 pneumonia‐related hyperinflammatory syndrome [11]. However, as our immunocompromised cases with worsening CRS despite receiving single dose of tocilizumab, the IL‐6 level in the second case was still high (Fig. 2). Given the risk of its immunomodulatory effect, we believed that the risks of repeated dose might outweigh benefits in our cases. Furthermore, the clinical efficacy of tocilizumab in immunocompromised patients was reported in one case of MM patient who was successfully treated with tocilizumab as well as a case series in kidney transplant recipients [20, 21]. Other than case reports and series, there are no controlled trials on the use of IL‐6 inhibitors in immunocompromised hosts with COVID‐19. Hence, the risk–benefit profile of using tocilizumab in such cases should be carefully considered.
Intravenous immunoglobulin
Data on the immunomodulatory effects of IVIG have been shown to regulate multiple steps in complex network of immune systems depending on the immunopathogenesis of those diseases. Fc receptor‐mediated effect, regulation of T cells, regulation of B cells and antibodies, activation of complements, cytokines neutralization and inhibition of downstream mediator gene transcription, toxin scavenging, and regulation of apoptosis were demonstrated to be the responsible immunomodulatory pathways [22, 23, 24]. However, immunoglobulin was prepared from the plasma of a donor who had high titres of neutralizing activities against a specific organism, so‐called hyperimmune IVIG (H‐IVIG). Both IVIG and H‐IVIG have always been introduced to be part of the treatment regimen or prevention of the emerging infectious diseases.
The efficacy of IVIG or H‐IVIG in viral infection had been investigated and found to be of potential benefit in specified viral subgroups. During the pandemic of 2009 influenza A(H1N1), the early use of H‐IVIG within five days of symptom onset was associated with lower viral load. However, the survival benefit of H‐IVIG with neutralizing activities against H1N1 strain over normal IVIG without its neutralizing activities remains unclear [25]. Furthermore, H‐IVIG using high‐titre anti‐influenza plasma also failed to show survival benefit in treating hospitalized patients infected with influenza A or B compared to placebo [26].
The published studies of IVIG in treating SARS‐CoV infection were also inconclusive due to the retrospective nature of the study. IVIG may be effective in selected SARS‐CoV patients with leukopenia and/or thrombocytopenia, radiological progression of the chest radiography, or haemophagocytic syndrome [27, 28]. However, none of the studies failed to demonstrate its efficacy over other therapy, such as ribavirin and corticosteroids. There is also lack of evidence to prove the efficacy of IVIG in Middle East respiratory syndrome coronavirus (MERS‐CoV) patients. Experimental studies on animal model of human polyclonal immunoglobulin (G) antibodies, derived from transchromosomic bovines, demonstrated high neutralizing antibody titres in vitro and reduced MERS‐CoV titres in animal model [29]. Some retrospective studies reported the clinical outcome of IVIG in a subgroup of patients, but a large clinical trial is still required to demonstrate its efficacy [30]. Recently published studies of currently marketed IVIG (Gamunex®‐C, Grifols, DKSH, Spain and Flebogamma dual inactivation and filtration (DIF)) were demonstrated to have positive reactivity against MERS‐CoV, SARS‐CoV, and SARS‐CoV‐2 in vitro [31], although the effect of enhancing viral clearance in vivo is still lacking.
On the other hand, the efficacy of IVIG is not limited to those neutralizing activities but is also used to ameliorate the immune response in CRS. As for evidence in MERS‐CoV and SARS‐CoV, IVIG is another promising therapy exhibiting clinical benefits in selected patient with clinically suspected CRS [27, 32]. There is substantial evidence to prove the efficacy of polyvalent IVIG in COVID‐19 patients. The clinical outcomes of critically ill COVID‐19 patients who received IVIG as part of the therapy were reported in the large cohort study, so its efficacy could not be concluded [33]. However, one retrospective study analysed that the clinical outcomes of IVIG in severe COVID‐19 pneumonia as an adjunctive therapy initiated within 48 h of ICU admission could reduce the use of mechanical ventilation, length of stay in hospital and ICU, and also 28‐day mortality [34]. A recent observational report of COVID‐19 patients, given five days of high dose of IVIG (0.3–0.5 g/kg/day), had also been shown to be effective in preventing clinical deterioration and intubation [35, 36]. Moreover, a multicentre retrospective cohort study in China also could not address the overall survival benefit of IVIG but found that, in critical patients who use high dose IVIG (>15 g/day) it could significantly reduce 28‐ and 60‐day mortality (P = 0.002 and P < 0.0001, respectively). Early initiation of IVIG within seven days of admission could also reduce 60‐day mortality, total in‐hospital stay, and total course of disease, and increase survival time [37].
To the best of our knowledge, polyvalent IVIG is another rescue therapy in COVID‐19‐related CRS regarding its anti‐inflammatory effects as mentioned above. In our cases, IVIG was also prescribed as a part of adjunctive therapies. However, appropriate timing, doses, and preparation of IVIG remain unclear and require well‐designed study to support their benefits. Therefore, administration of IVIG should be considered only in severe COVID‐19 with CRS as its efficacy has not been well elicited from previous study. Convalescent plasma or H‐IVIG may be an attractive additional treatment in severe COVID‐19 infection. Nevertheless, protocols for collection, preparation, and administration in real‐world practice are diverse and extremely challenging.
Haemoperfusion
There are limited data on the use of haemoadsorption for the treatment of COVID 19 specifically. However, several extracorporeal blood purification systems (e.g. CytoSorb, CytoSorbents Corporation, Monmouth Junction, NJ, USA and oXiris, GAMBRO Industries, France) that are designed theoretically for adsorption of endogenous pathogenic mediators and pro‐inflammatory cytokines have been temporarily approved by the FDA under Emergency Use Authorization (EUA) programme for compassionate use in patients with severe COVID‐19 infection.
In our cases, PMX‐HP was used based on the high level of EAA, of which intermediate to high level (more than 0.4 U) could demonstrate endotoxaemia and be associated with worse clinical outcomes [38]. Concomitant bacterial infections were reported as described previously and might be related with high EAA level in our cases. Sirivongrangson et al. reported endotoxaemia and circulating bacterial DNA in COVID‐19 pneumonia that was proposed to result from secondary bacterial translocation, which could contribute to cytokine storm and multiorgan failure [39]. The clinical efficacy of PMX‐HP had been demonstrated by case series from EUPHAS2 registry which was associated with haemodynamic improvement and organ function recovery in COVID‐19 patients with a history of septic shock from secondary bacterial infection [40]. Moreover, Ishiwari et al. also reported a successful treatment of PMX‐HP in a case of COVID‐19‐associated hypercytokinaemia‐induced severe respiratory failure who had been treated with methylprednisolone (1 g) for three days [41]. However, the clinical benefit of using haemoadsorption and haemoperfusion in COVID‐19 patients and pilot studies remains debatable. As presented here, the haemoperfusion combined with other life‐saving therapies was shown to be effective in COVID‐19‐related CRS. Therefore, we believe that using these extracorporeal therapies are of potential theoretical benefit and should be reserved in severe cases that do not respond to standard‐of‐care treatment, particularly dexamethasone.
To summarize, several novel adjunctive therapies have been shown to mediate the inflammatory response in critically ill patients. Based on previous data and clinical experience with other coronaviruses, IVIG, convalescent plasma, corticosteroids, and tocilizumab are potential treatments to combat the unusually aggressive inflammatory response that is mostly associated with detrimental outcomes for COVID‐19 patients. As our patients demonstrated, multimodality treatments may be effective in critical COVID‐19 patients. We demonstrate here that IL‐6 inhibitors, IVIG, and haemoadsorption can be used safely in selected immunocompromised hosts. Many confounding factors such as severity of disease, co‐morbid conditions, and co‐infections may potentially obfuscate the effects of tocilizumab in combination with other adjuvant treatments. However, we do believe that the multiple pathways of the pathogenesis of COVID‐19 should warrant multimodality treatment rather than a single agent inhibiting one single pathway. Using multiple adjuvant treatments attacking the various mechanisms of inflammation may potentially lead to better outcomes for our most critical patients.
In conclusion, we suggest that timely administration of adjunctive therapies aiming to alleviate inflammation in critically ill COVID‐19‐infected patients, whose laboratory parameters suggest severe hyperinflammation, may influence the mortality outcome. No single therapy has been proven to defeat CRS in its entirety. Combined therapeutic modalities, possibly tailored to individual inflammatory profiles, should be considered in these complex patients and may produce better outcomes, as shown here.
Disclosure Statements
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
This study was approved by the Faculty of Medicine, Chulalongkorn University (IRB 348/63).
At the time this report was accepted for publication, the authors declared that the patients in this report had not been included in any previously published report on COVID‐19 that they had authored.
Author Contribution Statement
Conceptualization: Nophol Leelayuwatanakul, Monvasi Pachinburavan. Methodology: Nophol Leelayuwatanakul, Monvasi Pachinburavan. Formal analysis: Nophol Leelayuwatanakul, Vorawut Thanthitaweewat, Sarita Thawanaphong, Watsamon Jantarabenjakul. Investigation: Nophol Leelayuwatanakul, Vorawut Thanthitaweewat, Sarita Thawanaphong, Watsamon Jantarabenjakul. Resources: Nophol Leelayuwatanakul, Napplika Kongpolprom, Thitiwat Sriprasart, Vorakamol Phoophiboon, Vorawut Thanthitaweewat, Sarita Thawanaphong, Worawan Sirichana, Naricha Chirakalwasan, Kamon Kawkitinarong, Chanchai Sittipunt, Opass Putcharoen, Leilani Paitoonpong, Gompol Suwanpimolkul, Watsamon Jantarabenjakul, Nattachai Srisawat, Monvasi Pachinburavan. Data curation: Nophol Leelayuwatanakul, Vorawut Thanthitaweewat, Sarita Thawanaphong, Watsamon Jantarabenjakul. Writing—original draft preparation: Nophol Leelayuwatanakul. Writing—review and editing: Monvasi Pachinburavan. Visualization: Napplika Kongpolprom, Thitiwat Sriprasart, Vorakamol Phoophiboon, Vorawut Thanthitaweewat, Sarita Thawanaphong, Worawan Sirichana, Naricha Chirakalwasan, Kamon Kawkitinarong, Chanchai Sittipunt, Opass Putcharoen, Leilani Paitoonpong, Gompol Suwanpimolkul, Watsamon Jantarabenjakul, Nattachai Srisawat, Supervision: Monvasi Pachinburavan. Project administration: Nophol Leelayuwatanakul, Monvasi Pachinburavan. All authors have read and agreed to the published version of the manuscript.
Acknowledgments
We would like to acknowledge all patients, their families, and healthcare workers involved in the diagnosis, treatment, and follow‐up of patients in King Chulalongkorn Memorial Hospital (KCMH). We thank our residents, fellows, and attendings from the Thai Red Cross Emerging Infectious Diseases (TRC‐EID) Clinical Center and Department of Medicine who were involved in taking care of all COVID‐19 critical patients. We also thank KCMH and the Thai Ministry of Public Health for their provision of tocilizumab and favipiravir for patient care. | DARUNAVIR\RITONAVIR, FAVIPIRAVIR, HYDROXYCHLOROQUINE | DrugsGivenReaction | CC BY | 33732466 | 19,181,917 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Multimodality treatment in immunocompromised patients with severe COVID-19: the role of IL-6 inhibitor, intravenous immunoglobulin, and haemoperfusion.
Cytokine release syndrome (CRS) is known to be associated with severe coronavirus disease 2019 (COVID-19). Multiple anti-inflammatory therapies such as tocilizumab, corticosteroids, intravenous immunoglobulin (IVIG), and haemoadsorption or haemoperfusion have been used to combat this life-threatening condition. However, immunocompromised hosts are often omitted from research studies, and knowledge on the clinical efficacy of these therapies in immunocompromised patients is therefore limited. We report two cases of immunocompromised patients with severe COVID-19-related CRS requiring mechanical ventilation who were treated with multimodality treatment consisting of tocilizumab, IVIG, and haemoperfusion. Within 48 h, both patients showed clinical improvement with PaO2:FiO2 ratio and haemodynamic stability. Both survived to discharge. There were no adverse events following these therapies. In conclusion, combined therapeutic modalities, possibly tailored to individual inflammatory profiles, are promising treatment for severe COVID-19 infection in the immunocompromised host. Timely administration of adjunctive therapies that alleviate overwhelming inflammation may provide the best outcome.
Introduction
In December 2019, a cluster of unexplained pneumonia cases were initially diagnosed in Wuhan, the capital of Hubei province, China. A new beta‐coronavirus, now named severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), was identified as the cause of coronavirus disease 2019 (COVID‐19). Two months after the index case of COVID‐19 pneumonia in Wuhan, the disease outbreak of COVID‐19 acute respiratory disease resulted in more than 70,000 confirmed cases and 2718 deaths officially reported in mainland China. On 30 January 2020, WHO declared a Public Health Emergency of International Concern regarding the outbreak of COVID‐19 in China. The pandemic has since infected more than 90 million people resulting in over 2 million deaths worldwide.
Among COVID‐19 patients, clinical symptoms may range from mild upper respiratory tract symptoms to severe acute respiratory distress syndrome (ARDS), with some progressing to multiorgan failure [1]. Initial retrospective studies in China reported that patients requiring intensive care unit (ICU) admission had elevated inflammatory cytokines and chemokines in serum compared to those not requiring ICU admission which suggest that cytokine release syndrome (CRS) might play an important role in the pathogenesis of severe COVID‐19 infection [2]. Furthermore, interleukin (IL)‐6 was also found to be elevated in severe COVID‐19 infection which is suspected to be driven by viral infection; therefore, IL‐6 receptor blockade may potentially be an effective treatment for this resulting overwhelming inflammation. Treatment for COVID‐19 pneumonia has been focused on both eradicating the virus itself as well as diminishing the inflammatory response from cytokine storms, which is believed to be responsible for multiorgan failure in patients infected with COVID‐19.
While established protocols for patients with severe disease are currently available, immunocompromised patients are often omitted from clinical studies. As a result, the efficacy of adjunctive treatment in immunocompromised patients is commonly extrapolated from studies in normal hosts. Clinical experience in immunocompromised hosts is limited to case reports and case series. In addition to standard treatment, intravenous immunoglobulin (IVIG), haemoadsorption, and tocilizumab would be potential therapies in those with severe disease and may be even more beneficial in patients who are immunocompromised.
We report two immunocompromised patients with severe COVID‐19 pneumonia who successfully underwent multimodality treatment with tocilizumab, IVIG, and haemoperfusion as adjunctive therapies. Evidence on anti‐inflammatory therapies as adjunctive treatment for severe COVID‐19‐related CRS is also reviewed.
Case Report
We, herein, reported two patients with severe COVID‐19 pneumonia who were treated with favipiravir‐based regimen combined with other antimicrobial agents. Multimodality treatment with tocilizumab, IVIG, and haemoperfusion was used as adjunctive therapy. Both patients were on mechanical ventilation using lung protective ventilation strategies, sedation, and neuromuscular blocking agent. Mode of oxygen therapy, laboratory data, and adjunctive treatments given in each patient were summarized in time sequence as shown in Figures 1 and 2.
Figure 1 Summary of mode of oxygen therapy and adjunctive treatments given in each patient in time sequence.
Figure 2 Laboratory investigations of each patient in time sequence.
Case 1
A 58‐year‐old woman with a known history of HIV infection, diabetes, and dyslipidaemia was presented. Her last CD4 count was 700 cell/mm3 with good virological suppression. She had fever, cough, and myalgia for six days prior to admission. The real‐time reverse transcriptase‐polymerase chain reaction (RT‐PCR) from her nasopharyngeal and throat swab was positive for SARS‐CoV‐2. No pulmonary opacity was shown in her initial chest X‐ray (Fig. 3). Favipiravir, hydroxychloroquine (HCQ), and darunavir/ritonavir (DRV/r) were administered.
Figure 3 Chest radiographs on initial presentation, on the day before each adjunctive therapy, and on discharge date.
On day 6 of admission, she developed dyspnoea with SpO2 (peripheral capillary oxygen saturation, on ambient air) of 93%. Her follow‐up chest X‐ray showed multifocal patchy opacity in both middle and lower lung zones. Haemoculture was identified as Acinetobactor baumannii. Her clinical condition rapidly progressed to ARDS on the same day which required invasive mechanical ventilation (PaO2:FiO2 ratio was 260). Repeat RT‐PCR for SARS‐CoV‐2 was still positive with cycle threshold (ct) of 20. COVID‐19‐induced CRS and co‐infection with A. baumannii septicaemia were thought to be responsible for clinical deterioration. Two sessions of polymyxin B haemoperfusion (PMX‐HP) were performed on days 6 and 7 of admission. Ampicillin‐sulbactam, colistin, and sulperazone were also given empirically which later de‐escalated to ceftazidime.
After the second session of haemoperfusion, her body temperature returned to normal but became hypotensive. Echocardiography revealed a cardiac ejection fraction of 30% and apical wall hypokinesia consistent with stress‐induced cardiomyopathy. The patient was started on norepinephrine and dobutamine for combination septic and cardiogenic shock. Inflammatory markers were elevated: IL‐6 was 1091 pg/mL, ferritin was 3316 ng/mL, hs‐CRP was 228 mg/L, D‐dimer was 2174 ng/mL, and lactate dehydrogenase (LDH) was 492 U/L. Her chest X‐ray showed progression to diffuse bilateral ground‐glass and patchy opacity (Fig. 3). A single dose of tocilizumab (400 mg) was administered intravenously. Her clinical status was improved significantly after haemoperfusion followed by tocilizumab. Vasopressors were weaned off and PaO2:FiO2 ratio was increased to 500 within 48 h of tocilizumab administration. She remained on invasive mechanical ventilation for another five days and was successfully extubated on day 12 of admission. She was discharged from the hospital with a total length of stay of 22 days. The time to negative RT‐PCR for SARS‐CoV‐2 was 15 days after admission.
Case 2
A 69‐year‐old man, partially dependent on most activity of daily living, with a known history of relapse multiple myeloma (MM) IgG kappa stage II presented with spinal cord compression at the level of T3–T7 receiving laminectomy and fusion surgery, triple vessel disease, diabetes, and hypertension. He presented at emergency room with dyspnoea and myalgia for one week. His vital signs were body temperature (BT) 37.4°C, respiratory rate (RR) 30/min, blood pressure 60/40 mmHg, and SpO2 (on ambient air) 64%. On admission (seventh day of symptom onset), he was mechanically ventilated due to hypoxaemic respiratory failure. The RT‐PCR for SARS‐CoV‐2 was detected from nasopharyngeal swab and tracheal suction. The initial chest X‐ray showed bilateral patchy opacity (Fig. 3). Favipiravir, HCQ, azithromycin, and ceftriaxone were administered afterwards. His haemodynamic stability was maintained by norepinephrine. Fludrocortisone was concomitantly administered with a high suspicion of autonomic dysreflexia as the history of spinal cord compression.
On day 2 of admission, due to worsening of his haemodynamic stability and oxygenation (PaO2:FiO2 ratio of 130), we decided to initiate PMX‐HP for two consecutive days (days 2 and 3 of admission). The level of endotoxin activity assay (EAA) before haemoperfusion was 0.58 U. On day 4 (11th day of symptom onset), he still had haemodynamic instability and worsening hypoxaemia requiring higher dose of norepinephrine and FiO2 (PaO2:FiO2 ratio of 143). Laboratory results showed elevation of the inflammatory markers: IL‐6 was 426.2 pg/mL, ferritin was 190.5 ng/mL, hs‐CRP was 225 mg/L, D‐dimer was 7979 ng/mL, and LDH was 321 U/L. The sputum culture was identified as Klebsiella pneumoniae. Single dose of tocilizumab (400 mg) and piperacillin‐tazobactam was administered. Nevertheless, the patient's condition did not improve including haemodynamic instability and persistent low PaO2:FiO2 ratio; 25 mg of IVIG (Flebogamma®, Grifols, DKSH, Spain) was administered for four consecutive days (days 6–9 of admission). Eventually, the PaO2:FiO2 ratio was increased to 180–230 and norepinephrine could be weaned off on day 13. His clinical condition was complicated with secondary bacterial cellulitis which was managed by antibiotic. However, he could be successfully extubated with a total 31 days of mechanical ventilation and discharged with a total length of stay of 45 days. The time to negative RT‐PCR for SARS‐CoV‐2 was 21 days.
Discussion
CRS‐related ARDS and secondary haemophagocytic lymphohistiocytosis (sHLH) are two distinct constellation of symptoms which are believed to attribute to the high mortality rate among COVID‐19 patients with respiratory failure [3, 4, 5]. CRS has previously been observed following chimeric antigen receptor (CAR) T‐cell therapy and therapeutic antibodies administration but has also been seen in certain viral infections such as SARS‐CoV‐1 and now in SARS‐CoV‐2. In addition, the characteristics of hyperinflammation reported in severe COVID‐19 infection also resemble sHLH triggered by other viral infections [2]. However, the clinical syndrome of these two entities might be indistinguishable. Early detection of hyperinflammatory state and selection of life‐saving therapies should be done to prevent clinical deterioration in severe COVID‐19 patients.
In our critical cases of COVID‐19, both were immunocompromised patients with hypoxaemic respiratory failure requiring invasive mechanical ventilation. At the time of the first wave of the pandemic in Thailand, there were limited clinical data available for the treatment of severe COVID‐19. Aiming to prevent clinical deterioration in patients with CRS, tocilizumab, IVIG, haemoperfusion, and corticosteroids had been introduced as part of treatment in our centre. Dhakal et al. reported the overall mortality rate of 57% from the case series of MM patients infected with COVID‐19 and none of them received tocilizumab [6]. Up to now, additional data on the clinical efficacy of these therapeutic modalities used for coronaviruses were published, particularly COVID‐19 infection. These adjunctive treatments will be discussed and reviewed.
Tocilizumab
The upregulation of cytokines and chemokines, IL‐6, is thought to be a major step in the immunopathogenesis of COVID‐19‐related ARDS. Inhibition of IL‐6 should therefore theoretically be effective in suppressing overwhelming inflammation found in COVID‐19 [7]. Tocilizumab is a humanized anti‐IL‐6 receptor which is Food and Drug Administration (FDA)‐approved for use in rheumatoid arthritis, CAR T‐cell‐induced CRS, and various other rheumatological conditions. Off‐label use of tocilizumab in severe COVID‐19 infection was found to be effective in the treatment of COVID‐19 patients [8].
In critically ill patients infected with COVID‐19, remarkable improvement of respiratory parameters and return of body temperature to normal were observed after tocilizumab treatment [9, 10, 11]. Another observational study of combination of low‐dose methylprednisolone and tocilizumab was conducted in 15 patients at a single centre in China. Patients who achieved normalization of IL‐6 levels with tocilizumab and methylprednisolone had clinical stabilizations rather than disease progression [12]. In contrast, some retrospective case–control study failed to demonstrate the mortality benefit of using tocilizumab in severe COVID‐19 patients [13, 14]. Of note, another non‐randomized observational study using intravenous or subcutaneous tocilizumab in severe or critical COVID‐19 patients showed significantly higher survival rates compared to patients not receiving tocilizumab [15, 16]. Recently, the preliminary result of randomized controlled COVACTA trial and BACC bay trial showed disappointing result of tocilizumab that failed to improve the patient mortality or intubation in moderately severe non‐intubated COVID‐19 [17, 18]. However, a lower primary outcome event rate of intubation and death may have limited the treatment effect of tocilizumab in this study. In contrast, sarilumab, another IL‐6 inhibitor, did show a trend towards decreased mortality in a recent randomized controlled study in critically ill patients [19]. It remains to be seen whether IL‐6 inhibitors may be of use in our most critical patients.
In addition, in a case of extremely high level of IL‐6, repeated dose of tocilizumab is suggested [12]. The prospective study in Italy also reported that two to three doses of tocilizumab (800 mg), 12–24 h apart, may be an effective treatment in COVID‐19 pneumonia‐related hyperinflammatory syndrome [11]. However, as our immunocompromised cases with worsening CRS despite receiving single dose of tocilizumab, the IL‐6 level in the second case was still high (Fig. 2). Given the risk of its immunomodulatory effect, we believed that the risks of repeated dose might outweigh benefits in our cases. Furthermore, the clinical efficacy of tocilizumab in immunocompromised patients was reported in one case of MM patient who was successfully treated with tocilizumab as well as a case series in kidney transplant recipients [20, 21]. Other than case reports and series, there are no controlled trials on the use of IL‐6 inhibitors in immunocompromised hosts with COVID‐19. Hence, the risk–benefit profile of using tocilizumab in such cases should be carefully considered.
Intravenous immunoglobulin
Data on the immunomodulatory effects of IVIG have been shown to regulate multiple steps in complex network of immune systems depending on the immunopathogenesis of those diseases. Fc receptor‐mediated effect, regulation of T cells, regulation of B cells and antibodies, activation of complements, cytokines neutralization and inhibition of downstream mediator gene transcription, toxin scavenging, and regulation of apoptosis were demonstrated to be the responsible immunomodulatory pathways [22, 23, 24]. However, immunoglobulin was prepared from the plasma of a donor who had high titres of neutralizing activities against a specific organism, so‐called hyperimmune IVIG (H‐IVIG). Both IVIG and H‐IVIG have always been introduced to be part of the treatment regimen or prevention of the emerging infectious diseases.
The efficacy of IVIG or H‐IVIG in viral infection had been investigated and found to be of potential benefit in specified viral subgroups. During the pandemic of 2009 influenza A(H1N1), the early use of H‐IVIG within five days of symptom onset was associated with lower viral load. However, the survival benefit of H‐IVIG with neutralizing activities against H1N1 strain over normal IVIG without its neutralizing activities remains unclear [25]. Furthermore, H‐IVIG using high‐titre anti‐influenza plasma also failed to show survival benefit in treating hospitalized patients infected with influenza A or B compared to placebo [26].
The published studies of IVIG in treating SARS‐CoV infection were also inconclusive due to the retrospective nature of the study. IVIG may be effective in selected SARS‐CoV patients with leukopenia and/or thrombocytopenia, radiological progression of the chest radiography, or haemophagocytic syndrome [27, 28]. However, none of the studies failed to demonstrate its efficacy over other therapy, such as ribavirin and corticosteroids. There is also lack of evidence to prove the efficacy of IVIG in Middle East respiratory syndrome coronavirus (MERS‐CoV) patients. Experimental studies on animal model of human polyclonal immunoglobulin (G) antibodies, derived from transchromosomic bovines, demonstrated high neutralizing antibody titres in vitro and reduced MERS‐CoV titres in animal model [29]. Some retrospective studies reported the clinical outcome of IVIG in a subgroup of patients, but a large clinical trial is still required to demonstrate its efficacy [30]. Recently published studies of currently marketed IVIG (Gamunex®‐C, Grifols, DKSH, Spain and Flebogamma dual inactivation and filtration (DIF)) were demonstrated to have positive reactivity against MERS‐CoV, SARS‐CoV, and SARS‐CoV‐2 in vitro [31], although the effect of enhancing viral clearance in vivo is still lacking.
On the other hand, the efficacy of IVIG is not limited to those neutralizing activities but is also used to ameliorate the immune response in CRS. As for evidence in MERS‐CoV and SARS‐CoV, IVIG is another promising therapy exhibiting clinical benefits in selected patient with clinically suspected CRS [27, 32]. There is substantial evidence to prove the efficacy of polyvalent IVIG in COVID‐19 patients. The clinical outcomes of critically ill COVID‐19 patients who received IVIG as part of the therapy were reported in the large cohort study, so its efficacy could not be concluded [33]. However, one retrospective study analysed that the clinical outcomes of IVIG in severe COVID‐19 pneumonia as an adjunctive therapy initiated within 48 h of ICU admission could reduce the use of mechanical ventilation, length of stay in hospital and ICU, and also 28‐day mortality [34]. A recent observational report of COVID‐19 patients, given five days of high dose of IVIG (0.3–0.5 g/kg/day), had also been shown to be effective in preventing clinical deterioration and intubation [35, 36]. Moreover, a multicentre retrospective cohort study in China also could not address the overall survival benefit of IVIG but found that, in critical patients who use high dose IVIG (>15 g/day) it could significantly reduce 28‐ and 60‐day mortality (P = 0.002 and P < 0.0001, respectively). Early initiation of IVIG within seven days of admission could also reduce 60‐day mortality, total in‐hospital stay, and total course of disease, and increase survival time [37].
To the best of our knowledge, polyvalent IVIG is another rescue therapy in COVID‐19‐related CRS regarding its anti‐inflammatory effects as mentioned above. In our cases, IVIG was also prescribed as a part of adjunctive therapies. However, appropriate timing, doses, and preparation of IVIG remain unclear and require well‐designed study to support their benefits. Therefore, administration of IVIG should be considered only in severe COVID‐19 with CRS as its efficacy has not been well elicited from previous study. Convalescent plasma or H‐IVIG may be an attractive additional treatment in severe COVID‐19 infection. Nevertheless, protocols for collection, preparation, and administration in real‐world practice are diverse and extremely challenging.
Haemoperfusion
There are limited data on the use of haemoadsorption for the treatment of COVID 19 specifically. However, several extracorporeal blood purification systems (e.g. CytoSorb, CytoSorbents Corporation, Monmouth Junction, NJ, USA and oXiris, GAMBRO Industries, France) that are designed theoretically for adsorption of endogenous pathogenic mediators and pro‐inflammatory cytokines have been temporarily approved by the FDA under Emergency Use Authorization (EUA) programme for compassionate use in patients with severe COVID‐19 infection.
In our cases, PMX‐HP was used based on the high level of EAA, of which intermediate to high level (more than 0.4 U) could demonstrate endotoxaemia and be associated with worse clinical outcomes [38]. Concomitant bacterial infections were reported as described previously and might be related with high EAA level in our cases. Sirivongrangson et al. reported endotoxaemia and circulating bacterial DNA in COVID‐19 pneumonia that was proposed to result from secondary bacterial translocation, which could contribute to cytokine storm and multiorgan failure [39]. The clinical efficacy of PMX‐HP had been demonstrated by case series from EUPHAS2 registry which was associated with haemodynamic improvement and organ function recovery in COVID‐19 patients with a history of septic shock from secondary bacterial infection [40]. Moreover, Ishiwari et al. also reported a successful treatment of PMX‐HP in a case of COVID‐19‐associated hypercytokinaemia‐induced severe respiratory failure who had been treated with methylprednisolone (1 g) for three days [41]. However, the clinical benefit of using haemoadsorption and haemoperfusion in COVID‐19 patients and pilot studies remains debatable. As presented here, the haemoperfusion combined with other life‐saving therapies was shown to be effective in COVID‐19‐related CRS. Therefore, we believe that using these extracorporeal therapies are of potential theoretical benefit and should be reserved in severe cases that do not respond to standard‐of‐care treatment, particularly dexamethasone.
To summarize, several novel adjunctive therapies have been shown to mediate the inflammatory response in critically ill patients. Based on previous data and clinical experience with other coronaviruses, IVIG, convalescent plasma, corticosteroids, and tocilizumab are potential treatments to combat the unusually aggressive inflammatory response that is mostly associated with detrimental outcomes for COVID‐19 patients. As our patients demonstrated, multimodality treatments may be effective in critical COVID‐19 patients. We demonstrate here that IL‐6 inhibitors, IVIG, and haemoadsorption can be used safely in selected immunocompromised hosts. Many confounding factors such as severity of disease, co‐morbid conditions, and co‐infections may potentially obfuscate the effects of tocilizumab in combination with other adjuvant treatments. However, we do believe that the multiple pathways of the pathogenesis of COVID‐19 should warrant multimodality treatment rather than a single agent inhibiting one single pathway. Using multiple adjuvant treatments attacking the various mechanisms of inflammation may potentially lead to better outcomes for our most critical patients.
In conclusion, we suggest that timely administration of adjunctive therapies aiming to alleviate inflammation in critically ill COVID‐19‐infected patients, whose laboratory parameters suggest severe hyperinflammation, may influence the mortality outcome. No single therapy has been proven to defeat CRS in its entirety. Combined therapeutic modalities, possibly tailored to individual inflammatory profiles, should be considered in these complex patients and may produce better outcomes, as shown here.
Disclosure Statements
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
This study was approved by the Faculty of Medicine, Chulalongkorn University (IRB 348/63).
At the time this report was accepted for publication, the authors declared that the patients in this report had not been included in any previously published report on COVID‐19 that they had authored.
Author Contribution Statement
Conceptualization: Nophol Leelayuwatanakul, Monvasi Pachinburavan. Methodology: Nophol Leelayuwatanakul, Monvasi Pachinburavan. Formal analysis: Nophol Leelayuwatanakul, Vorawut Thanthitaweewat, Sarita Thawanaphong, Watsamon Jantarabenjakul. Investigation: Nophol Leelayuwatanakul, Vorawut Thanthitaweewat, Sarita Thawanaphong, Watsamon Jantarabenjakul. Resources: Nophol Leelayuwatanakul, Napplika Kongpolprom, Thitiwat Sriprasart, Vorakamol Phoophiboon, Vorawut Thanthitaweewat, Sarita Thawanaphong, Worawan Sirichana, Naricha Chirakalwasan, Kamon Kawkitinarong, Chanchai Sittipunt, Opass Putcharoen, Leilani Paitoonpong, Gompol Suwanpimolkul, Watsamon Jantarabenjakul, Nattachai Srisawat, Monvasi Pachinburavan. Data curation: Nophol Leelayuwatanakul, Vorawut Thanthitaweewat, Sarita Thawanaphong, Watsamon Jantarabenjakul. Writing—original draft preparation: Nophol Leelayuwatanakul. Writing—review and editing: Monvasi Pachinburavan. Visualization: Napplika Kongpolprom, Thitiwat Sriprasart, Vorakamol Phoophiboon, Vorawut Thanthitaweewat, Sarita Thawanaphong, Worawan Sirichana, Naricha Chirakalwasan, Kamon Kawkitinarong, Chanchai Sittipunt, Opass Putcharoen, Leilani Paitoonpong, Gompol Suwanpimolkul, Watsamon Jantarabenjakul, Nattachai Srisawat, Supervision: Monvasi Pachinburavan. Project administration: Nophol Leelayuwatanakul, Monvasi Pachinburavan. All authors have read and agreed to the published version of the manuscript.
Acknowledgments
We would like to acknowledge all patients, their families, and healthcare workers involved in the diagnosis, treatment, and follow‐up of patients in King Chulalongkorn Memorial Hospital (KCMH). We thank our residents, fellows, and attendings from the Thai Red Cross Emerging Infectious Diseases (TRC‐EID) Clinical Center and Department of Medicine who were involved in taking care of all COVID‐19 critical patients. We also thank KCMH and the Thai Ministry of Public Health for their provision of tocilizumab and favipiravir for patient care. | AZITHROMYCIN ANHYDROUS, CEFTRIAXONE, FAVIPIRAVIR, HYDROXYCHLOROQUINE | DrugsGivenReaction | CC BY | 33732466 | 19,181,918 | 2021-04 |
What was the outcome of reaction 'Acute respiratory distress syndrome'? | Multimodality treatment in immunocompromised patients with severe COVID-19: the role of IL-6 inhibitor, intravenous immunoglobulin, and haemoperfusion.
Cytokine release syndrome (CRS) is known to be associated with severe coronavirus disease 2019 (COVID-19). Multiple anti-inflammatory therapies such as tocilizumab, corticosteroids, intravenous immunoglobulin (IVIG), and haemoadsorption or haemoperfusion have been used to combat this life-threatening condition. However, immunocompromised hosts are often omitted from research studies, and knowledge on the clinical efficacy of these therapies in immunocompromised patients is therefore limited. We report two cases of immunocompromised patients with severe COVID-19-related CRS requiring mechanical ventilation who were treated with multimodality treatment consisting of tocilizumab, IVIG, and haemoperfusion. Within 48 h, both patients showed clinical improvement with PaO2:FiO2 ratio and haemodynamic stability. Both survived to discharge. There were no adverse events following these therapies. In conclusion, combined therapeutic modalities, possibly tailored to individual inflammatory profiles, are promising treatment for severe COVID-19 infection in the immunocompromised host. Timely administration of adjunctive therapies that alleviate overwhelming inflammation may provide the best outcome.
Introduction
In December 2019, a cluster of unexplained pneumonia cases were initially diagnosed in Wuhan, the capital of Hubei province, China. A new beta‐coronavirus, now named severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), was identified as the cause of coronavirus disease 2019 (COVID‐19). Two months after the index case of COVID‐19 pneumonia in Wuhan, the disease outbreak of COVID‐19 acute respiratory disease resulted in more than 70,000 confirmed cases and 2718 deaths officially reported in mainland China. On 30 January 2020, WHO declared a Public Health Emergency of International Concern regarding the outbreak of COVID‐19 in China. The pandemic has since infected more than 90 million people resulting in over 2 million deaths worldwide.
Among COVID‐19 patients, clinical symptoms may range from mild upper respiratory tract symptoms to severe acute respiratory distress syndrome (ARDS), with some progressing to multiorgan failure [1]. Initial retrospective studies in China reported that patients requiring intensive care unit (ICU) admission had elevated inflammatory cytokines and chemokines in serum compared to those not requiring ICU admission which suggest that cytokine release syndrome (CRS) might play an important role in the pathogenesis of severe COVID‐19 infection [2]. Furthermore, interleukin (IL)‐6 was also found to be elevated in severe COVID‐19 infection which is suspected to be driven by viral infection; therefore, IL‐6 receptor blockade may potentially be an effective treatment for this resulting overwhelming inflammation. Treatment for COVID‐19 pneumonia has been focused on both eradicating the virus itself as well as diminishing the inflammatory response from cytokine storms, which is believed to be responsible for multiorgan failure in patients infected with COVID‐19.
While established protocols for patients with severe disease are currently available, immunocompromised patients are often omitted from clinical studies. As a result, the efficacy of adjunctive treatment in immunocompromised patients is commonly extrapolated from studies in normal hosts. Clinical experience in immunocompromised hosts is limited to case reports and case series. In addition to standard treatment, intravenous immunoglobulin (IVIG), haemoadsorption, and tocilizumab would be potential therapies in those with severe disease and may be even more beneficial in patients who are immunocompromised.
We report two immunocompromised patients with severe COVID‐19 pneumonia who successfully underwent multimodality treatment with tocilizumab, IVIG, and haemoperfusion as adjunctive therapies. Evidence on anti‐inflammatory therapies as adjunctive treatment for severe COVID‐19‐related CRS is also reviewed.
Case Report
We, herein, reported two patients with severe COVID‐19 pneumonia who were treated with favipiravir‐based regimen combined with other antimicrobial agents. Multimodality treatment with tocilizumab, IVIG, and haemoperfusion was used as adjunctive therapy. Both patients were on mechanical ventilation using lung protective ventilation strategies, sedation, and neuromuscular blocking agent. Mode of oxygen therapy, laboratory data, and adjunctive treatments given in each patient were summarized in time sequence as shown in Figures 1 and 2.
Figure 1 Summary of mode of oxygen therapy and adjunctive treatments given in each patient in time sequence.
Figure 2 Laboratory investigations of each patient in time sequence.
Case 1
A 58‐year‐old woman with a known history of HIV infection, diabetes, and dyslipidaemia was presented. Her last CD4 count was 700 cell/mm3 with good virological suppression. She had fever, cough, and myalgia for six days prior to admission. The real‐time reverse transcriptase‐polymerase chain reaction (RT‐PCR) from her nasopharyngeal and throat swab was positive for SARS‐CoV‐2. No pulmonary opacity was shown in her initial chest X‐ray (Fig. 3). Favipiravir, hydroxychloroquine (HCQ), and darunavir/ritonavir (DRV/r) were administered.
Figure 3 Chest radiographs on initial presentation, on the day before each adjunctive therapy, and on discharge date.
On day 6 of admission, she developed dyspnoea with SpO2 (peripheral capillary oxygen saturation, on ambient air) of 93%. Her follow‐up chest X‐ray showed multifocal patchy opacity in both middle and lower lung zones. Haemoculture was identified as Acinetobactor baumannii. Her clinical condition rapidly progressed to ARDS on the same day which required invasive mechanical ventilation (PaO2:FiO2 ratio was 260). Repeat RT‐PCR for SARS‐CoV‐2 was still positive with cycle threshold (ct) of 20. COVID‐19‐induced CRS and co‐infection with A. baumannii septicaemia were thought to be responsible for clinical deterioration. Two sessions of polymyxin B haemoperfusion (PMX‐HP) were performed on days 6 and 7 of admission. Ampicillin‐sulbactam, colistin, and sulperazone were also given empirically which later de‐escalated to ceftazidime.
After the second session of haemoperfusion, her body temperature returned to normal but became hypotensive. Echocardiography revealed a cardiac ejection fraction of 30% and apical wall hypokinesia consistent with stress‐induced cardiomyopathy. The patient was started on norepinephrine and dobutamine for combination septic and cardiogenic shock. Inflammatory markers were elevated: IL‐6 was 1091 pg/mL, ferritin was 3316 ng/mL, hs‐CRP was 228 mg/L, D‐dimer was 2174 ng/mL, and lactate dehydrogenase (LDH) was 492 U/L. Her chest X‐ray showed progression to diffuse bilateral ground‐glass and patchy opacity (Fig. 3). A single dose of tocilizumab (400 mg) was administered intravenously. Her clinical status was improved significantly after haemoperfusion followed by tocilizumab. Vasopressors were weaned off and PaO2:FiO2 ratio was increased to 500 within 48 h of tocilizumab administration. She remained on invasive mechanical ventilation for another five days and was successfully extubated on day 12 of admission. She was discharged from the hospital with a total length of stay of 22 days. The time to negative RT‐PCR for SARS‐CoV‐2 was 15 days after admission.
Case 2
A 69‐year‐old man, partially dependent on most activity of daily living, with a known history of relapse multiple myeloma (MM) IgG kappa stage II presented with spinal cord compression at the level of T3–T7 receiving laminectomy and fusion surgery, triple vessel disease, diabetes, and hypertension. He presented at emergency room with dyspnoea and myalgia for one week. His vital signs were body temperature (BT) 37.4°C, respiratory rate (RR) 30/min, blood pressure 60/40 mmHg, and SpO2 (on ambient air) 64%. On admission (seventh day of symptom onset), he was mechanically ventilated due to hypoxaemic respiratory failure. The RT‐PCR for SARS‐CoV‐2 was detected from nasopharyngeal swab and tracheal suction. The initial chest X‐ray showed bilateral patchy opacity (Fig. 3). Favipiravir, HCQ, azithromycin, and ceftriaxone were administered afterwards. His haemodynamic stability was maintained by norepinephrine. Fludrocortisone was concomitantly administered with a high suspicion of autonomic dysreflexia as the history of spinal cord compression.
On day 2 of admission, due to worsening of his haemodynamic stability and oxygenation (PaO2:FiO2 ratio of 130), we decided to initiate PMX‐HP for two consecutive days (days 2 and 3 of admission). The level of endotoxin activity assay (EAA) before haemoperfusion was 0.58 U. On day 4 (11th day of symptom onset), he still had haemodynamic instability and worsening hypoxaemia requiring higher dose of norepinephrine and FiO2 (PaO2:FiO2 ratio of 143). Laboratory results showed elevation of the inflammatory markers: IL‐6 was 426.2 pg/mL, ferritin was 190.5 ng/mL, hs‐CRP was 225 mg/L, D‐dimer was 7979 ng/mL, and LDH was 321 U/L. The sputum culture was identified as Klebsiella pneumoniae. Single dose of tocilizumab (400 mg) and piperacillin‐tazobactam was administered. Nevertheless, the patient's condition did not improve including haemodynamic instability and persistent low PaO2:FiO2 ratio; 25 mg of IVIG (Flebogamma®, Grifols, DKSH, Spain) was administered for four consecutive days (days 6–9 of admission). Eventually, the PaO2:FiO2 ratio was increased to 180–230 and norepinephrine could be weaned off on day 13. His clinical condition was complicated with secondary bacterial cellulitis which was managed by antibiotic. However, he could be successfully extubated with a total 31 days of mechanical ventilation and discharged with a total length of stay of 45 days. The time to negative RT‐PCR for SARS‐CoV‐2 was 21 days.
Discussion
CRS‐related ARDS and secondary haemophagocytic lymphohistiocytosis (sHLH) are two distinct constellation of symptoms which are believed to attribute to the high mortality rate among COVID‐19 patients with respiratory failure [3, 4, 5]. CRS has previously been observed following chimeric antigen receptor (CAR) T‐cell therapy and therapeutic antibodies administration but has also been seen in certain viral infections such as SARS‐CoV‐1 and now in SARS‐CoV‐2. In addition, the characteristics of hyperinflammation reported in severe COVID‐19 infection also resemble sHLH triggered by other viral infections [2]. However, the clinical syndrome of these two entities might be indistinguishable. Early detection of hyperinflammatory state and selection of life‐saving therapies should be done to prevent clinical deterioration in severe COVID‐19 patients.
In our critical cases of COVID‐19, both were immunocompromised patients with hypoxaemic respiratory failure requiring invasive mechanical ventilation. At the time of the first wave of the pandemic in Thailand, there were limited clinical data available for the treatment of severe COVID‐19. Aiming to prevent clinical deterioration in patients with CRS, tocilizumab, IVIG, haemoperfusion, and corticosteroids had been introduced as part of treatment in our centre. Dhakal et al. reported the overall mortality rate of 57% from the case series of MM patients infected with COVID‐19 and none of them received tocilizumab [6]. Up to now, additional data on the clinical efficacy of these therapeutic modalities used for coronaviruses were published, particularly COVID‐19 infection. These adjunctive treatments will be discussed and reviewed.
Tocilizumab
The upregulation of cytokines and chemokines, IL‐6, is thought to be a major step in the immunopathogenesis of COVID‐19‐related ARDS. Inhibition of IL‐6 should therefore theoretically be effective in suppressing overwhelming inflammation found in COVID‐19 [7]. Tocilizumab is a humanized anti‐IL‐6 receptor which is Food and Drug Administration (FDA)‐approved for use in rheumatoid arthritis, CAR T‐cell‐induced CRS, and various other rheumatological conditions. Off‐label use of tocilizumab in severe COVID‐19 infection was found to be effective in the treatment of COVID‐19 patients [8].
In critically ill patients infected with COVID‐19, remarkable improvement of respiratory parameters and return of body temperature to normal were observed after tocilizumab treatment [9, 10, 11]. Another observational study of combination of low‐dose methylprednisolone and tocilizumab was conducted in 15 patients at a single centre in China. Patients who achieved normalization of IL‐6 levels with tocilizumab and methylprednisolone had clinical stabilizations rather than disease progression [12]. In contrast, some retrospective case–control study failed to demonstrate the mortality benefit of using tocilizumab in severe COVID‐19 patients [13, 14]. Of note, another non‐randomized observational study using intravenous or subcutaneous tocilizumab in severe or critical COVID‐19 patients showed significantly higher survival rates compared to patients not receiving tocilizumab [15, 16]. Recently, the preliminary result of randomized controlled COVACTA trial and BACC bay trial showed disappointing result of tocilizumab that failed to improve the patient mortality or intubation in moderately severe non‐intubated COVID‐19 [17, 18]. However, a lower primary outcome event rate of intubation and death may have limited the treatment effect of tocilizumab in this study. In contrast, sarilumab, another IL‐6 inhibitor, did show a trend towards decreased mortality in a recent randomized controlled study in critically ill patients [19]. It remains to be seen whether IL‐6 inhibitors may be of use in our most critical patients.
In addition, in a case of extremely high level of IL‐6, repeated dose of tocilizumab is suggested [12]. The prospective study in Italy also reported that two to three doses of tocilizumab (800 mg), 12–24 h apart, may be an effective treatment in COVID‐19 pneumonia‐related hyperinflammatory syndrome [11]. However, as our immunocompromised cases with worsening CRS despite receiving single dose of tocilizumab, the IL‐6 level in the second case was still high (Fig. 2). Given the risk of its immunomodulatory effect, we believed that the risks of repeated dose might outweigh benefits in our cases. Furthermore, the clinical efficacy of tocilizumab in immunocompromised patients was reported in one case of MM patient who was successfully treated with tocilizumab as well as a case series in kidney transplant recipients [20, 21]. Other than case reports and series, there are no controlled trials on the use of IL‐6 inhibitors in immunocompromised hosts with COVID‐19. Hence, the risk–benefit profile of using tocilizumab in such cases should be carefully considered.
Intravenous immunoglobulin
Data on the immunomodulatory effects of IVIG have been shown to regulate multiple steps in complex network of immune systems depending on the immunopathogenesis of those diseases. Fc receptor‐mediated effect, regulation of T cells, regulation of B cells and antibodies, activation of complements, cytokines neutralization and inhibition of downstream mediator gene transcription, toxin scavenging, and regulation of apoptosis were demonstrated to be the responsible immunomodulatory pathways [22, 23, 24]. However, immunoglobulin was prepared from the plasma of a donor who had high titres of neutralizing activities against a specific organism, so‐called hyperimmune IVIG (H‐IVIG). Both IVIG and H‐IVIG have always been introduced to be part of the treatment regimen or prevention of the emerging infectious diseases.
The efficacy of IVIG or H‐IVIG in viral infection had been investigated and found to be of potential benefit in specified viral subgroups. During the pandemic of 2009 influenza A(H1N1), the early use of H‐IVIG within five days of symptom onset was associated with lower viral load. However, the survival benefit of H‐IVIG with neutralizing activities against H1N1 strain over normal IVIG without its neutralizing activities remains unclear [25]. Furthermore, H‐IVIG using high‐titre anti‐influenza plasma also failed to show survival benefit in treating hospitalized patients infected with influenza A or B compared to placebo [26].
The published studies of IVIG in treating SARS‐CoV infection were also inconclusive due to the retrospective nature of the study. IVIG may be effective in selected SARS‐CoV patients with leukopenia and/or thrombocytopenia, radiological progression of the chest radiography, or haemophagocytic syndrome [27, 28]. However, none of the studies failed to demonstrate its efficacy over other therapy, such as ribavirin and corticosteroids. There is also lack of evidence to prove the efficacy of IVIG in Middle East respiratory syndrome coronavirus (MERS‐CoV) patients. Experimental studies on animal model of human polyclonal immunoglobulin (G) antibodies, derived from transchromosomic bovines, demonstrated high neutralizing antibody titres in vitro and reduced MERS‐CoV titres in animal model [29]. Some retrospective studies reported the clinical outcome of IVIG in a subgroup of patients, but a large clinical trial is still required to demonstrate its efficacy [30]. Recently published studies of currently marketed IVIG (Gamunex®‐C, Grifols, DKSH, Spain and Flebogamma dual inactivation and filtration (DIF)) were demonstrated to have positive reactivity against MERS‐CoV, SARS‐CoV, and SARS‐CoV‐2 in vitro [31], although the effect of enhancing viral clearance in vivo is still lacking.
On the other hand, the efficacy of IVIG is not limited to those neutralizing activities but is also used to ameliorate the immune response in CRS. As for evidence in MERS‐CoV and SARS‐CoV, IVIG is another promising therapy exhibiting clinical benefits in selected patient with clinically suspected CRS [27, 32]. There is substantial evidence to prove the efficacy of polyvalent IVIG in COVID‐19 patients. The clinical outcomes of critically ill COVID‐19 patients who received IVIG as part of the therapy were reported in the large cohort study, so its efficacy could not be concluded [33]. However, one retrospective study analysed that the clinical outcomes of IVIG in severe COVID‐19 pneumonia as an adjunctive therapy initiated within 48 h of ICU admission could reduce the use of mechanical ventilation, length of stay in hospital and ICU, and also 28‐day mortality [34]. A recent observational report of COVID‐19 patients, given five days of high dose of IVIG (0.3–0.5 g/kg/day), had also been shown to be effective in preventing clinical deterioration and intubation [35, 36]. Moreover, a multicentre retrospective cohort study in China also could not address the overall survival benefit of IVIG but found that, in critical patients who use high dose IVIG (>15 g/day) it could significantly reduce 28‐ and 60‐day mortality (P = 0.002 and P < 0.0001, respectively). Early initiation of IVIG within seven days of admission could also reduce 60‐day mortality, total in‐hospital stay, and total course of disease, and increase survival time [37].
To the best of our knowledge, polyvalent IVIG is another rescue therapy in COVID‐19‐related CRS regarding its anti‐inflammatory effects as mentioned above. In our cases, IVIG was also prescribed as a part of adjunctive therapies. However, appropriate timing, doses, and preparation of IVIG remain unclear and require well‐designed study to support their benefits. Therefore, administration of IVIG should be considered only in severe COVID‐19 with CRS as its efficacy has not been well elicited from previous study. Convalescent plasma or H‐IVIG may be an attractive additional treatment in severe COVID‐19 infection. Nevertheless, protocols for collection, preparation, and administration in real‐world practice are diverse and extremely challenging.
Haemoperfusion
There are limited data on the use of haemoadsorption for the treatment of COVID 19 specifically. However, several extracorporeal blood purification systems (e.g. CytoSorb, CytoSorbents Corporation, Monmouth Junction, NJ, USA and oXiris, GAMBRO Industries, France) that are designed theoretically for adsorption of endogenous pathogenic mediators and pro‐inflammatory cytokines have been temporarily approved by the FDA under Emergency Use Authorization (EUA) programme for compassionate use in patients with severe COVID‐19 infection.
In our cases, PMX‐HP was used based on the high level of EAA, of which intermediate to high level (more than 0.4 U) could demonstrate endotoxaemia and be associated with worse clinical outcomes [38]. Concomitant bacterial infections were reported as described previously and might be related with high EAA level in our cases. Sirivongrangson et al. reported endotoxaemia and circulating bacterial DNA in COVID‐19 pneumonia that was proposed to result from secondary bacterial translocation, which could contribute to cytokine storm and multiorgan failure [39]. The clinical efficacy of PMX‐HP had been demonstrated by case series from EUPHAS2 registry which was associated with haemodynamic improvement and organ function recovery in COVID‐19 patients with a history of septic shock from secondary bacterial infection [40]. Moreover, Ishiwari et al. also reported a successful treatment of PMX‐HP in a case of COVID‐19‐associated hypercytokinaemia‐induced severe respiratory failure who had been treated with methylprednisolone (1 g) for three days [41]. However, the clinical benefit of using haemoadsorption and haemoperfusion in COVID‐19 patients and pilot studies remains debatable. As presented here, the haemoperfusion combined with other life‐saving therapies was shown to be effective in COVID‐19‐related CRS. Therefore, we believe that using these extracorporeal therapies are of potential theoretical benefit and should be reserved in severe cases that do not respond to standard‐of‐care treatment, particularly dexamethasone.
To summarize, several novel adjunctive therapies have been shown to mediate the inflammatory response in critically ill patients. Based on previous data and clinical experience with other coronaviruses, IVIG, convalescent plasma, corticosteroids, and tocilizumab are potential treatments to combat the unusually aggressive inflammatory response that is mostly associated with detrimental outcomes for COVID‐19 patients. As our patients demonstrated, multimodality treatments may be effective in critical COVID‐19 patients. We demonstrate here that IL‐6 inhibitors, IVIG, and haemoadsorption can be used safely in selected immunocompromised hosts. Many confounding factors such as severity of disease, co‐morbid conditions, and co‐infections may potentially obfuscate the effects of tocilizumab in combination with other adjuvant treatments. However, we do believe that the multiple pathways of the pathogenesis of COVID‐19 should warrant multimodality treatment rather than a single agent inhibiting one single pathway. Using multiple adjuvant treatments attacking the various mechanisms of inflammation may potentially lead to better outcomes for our most critical patients.
In conclusion, we suggest that timely administration of adjunctive therapies aiming to alleviate inflammation in critically ill COVID‐19‐infected patients, whose laboratory parameters suggest severe hyperinflammation, may influence the mortality outcome. No single therapy has been proven to defeat CRS in its entirety. Combined therapeutic modalities, possibly tailored to individual inflammatory profiles, should be considered in these complex patients and may produce better outcomes, as shown here.
Disclosure Statements
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
This study was approved by the Faculty of Medicine, Chulalongkorn University (IRB 348/63).
At the time this report was accepted for publication, the authors declared that the patients in this report had not been included in any previously published report on COVID‐19 that they had authored.
Author Contribution Statement
Conceptualization: Nophol Leelayuwatanakul, Monvasi Pachinburavan. Methodology: Nophol Leelayuwatanakul, Monvasi Pachinburavan. Formal analysis: Nophol Leelayuwatanakul, Vorawut Thanthitaweewat, Sarita Thawanaphong, Watsamon Jantarabenjakul. Investigation: Nophol Leelayuwatanakul, Vorawut Thanthitaweewat, Sarita Thawanaphong, Watsamon Jantarabenjakul. Resources: Nophol Leelayuwatanakul, Napplika Kongpolprom, Thitiwat Sriprasart, Vorakamol Phoophiboon, Vorawut Thanthitaweewat, Sarita Thawanaphong, Worawan Sirichana, Naricha Chirakalwasan, Kamon Kawkitinarong, Chanchai Sittipunt, Opass Putcharoen, Leilani Paitoonpong, Gompol Suwanpimolkul, Watsamon Jantarabenjakul, Nattachai Srisawat, Monvasi Pachinburavan. Data curation: Nophol Leelayuwatanakul, Vorawut Thanthitaweewat, Sarita Thawanaphong, Watsamon Jantarabenjakul. Writing—original draft preparation: Nophol Leelayuwatanakul. Writing—review and editing: Monvasi Pachinburavan. Visualization: Napplika Kongpolprom, Thitiwat Sriprasart, Vorakamol Phoophiboon, Vorawut Thanthitaweewat, Sarita Thawanaphong, Worawan Sirichana, Naricha Chirakalwasan, Kamon Kawkitinarong, Chanchai Sittipunt, Opass Putcharoen, Leilani Paitoonpong, Gompol Suwanpimolkul, Watsamon Jantarabenjakul, Nattachai Srisawat, Supervision: Monvasi Pachinburavan. Project administration: Nophol Leelayuwatanakul, Monvasi Pachinburavan. All authors have read and agreed to the published version of the manuscript.
Acknowledgments
We would like to acknowledge all patients, their families, and healthcare workers involved in the diagnosis, treatment, and follow‐up of patients in King Chulalongkorn Memorial Hospital (KCMH). We thank our residents, fellows, and attendings from the Thai Red Cross Emerging Infectious Diseases (TRC‐EID) Clinical Center and Department of Medicine who were involved in taking care of all COVID‐19 critical patients. We also thank KCMH and the Thai Ministry of Public Health for their provision of tocilizumab and favipiravir for patient care. | Recovered | ReactionOutcome | CC BY | 33732466 | 19,181,917 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood electrolytes abnormal'. | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | DAPSONE, EFAVIRENZ, FLUCONAZOLE, LAMIVUDINE, SULFAMETHOXAZOLE\TRIMETHOPRIM, TENOFOVIR DISOPROXIL FUMARATE | DrugsGivenReaction | CC BY-NC | 33732476 | 19,889,986 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | DAPSONE, EFAVIRENZ, FLUCONAZOLE, LAMIVUDINE, SULFAMETHOXAZOLE\TRIMETHOPRIM, TENOFOVIR DISOPROXIL FUMARATE | DrugsGivenReaction | CC BY-NC | 33732476 | 19,889,986 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cryptosporidiosis infection'. | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | DAPSONE, EFAVIRENZ, FLUCONAZOLE, LAMIVUDINE, SULFAMETHOXAZOLE\TRIMETHOPRIM, TENOFOVIR DISOPROXIL FUMARATE | DrugsGivenReaction | CC BY-NC | 33732476 | 19,889,986 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cytomegalovirus oesophagitis'. | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | DAPSONE, EFAVIRENZ, FLUCONAZOLE, LAMIVUDINE, SULFAMETHOXAZOLE\TRIMETHOPRIM, TENOFOVIR DISOPROXIL FUMARATE | DrugsGivenReaction | CC BY-NC | 33732476 | 19,889,986 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Depression'. | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | ATAZANAVIR\RITONAVIR, AZITHROMYCIN, DAPSONE, EFAVIRENZ\LAMIVUDINE\TENOFOVIR DISOPROXIL FUMARATE, FLUCONAZOLE, LAMIVUDINE, NITAZOXANIDE, ZIDOVUDINE | DrugsGivenReaction | CC BY-NC | 33732476 | 19,903,764 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Electrolyte imbalance'. | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | ATAZANAVIR\RITONAVIR, AZITHROMYCIN, DAPSONE, EFAVIRENZ\LAMIVUDINE\TENOFOVIR DISOPROXIL FUMARATE, FLUCONAZOLE, LAMIVUDINE, NITAZOXANIDE, ZIDOVUDINE | DrugsGivenReaction | CC BY-NC | 33732476 | 19,903,764 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Erythema'. | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | DAPSONE, EFAVIRENZ, FLUCONAZOLE, LAMIVUDINE, SULFAMETHOXAZOLE\TRIMETHOPRIM, TENOFOVIR DISOPROXIL FUMARATE | DrugsGivenReaction | CC BY-NC | 33732476 | 19,889,986 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Oesophageal candidiasis'. | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | DAPSONE, EFAVIRENZ, FLUCONAZOLE, LAMIVUDINE, SULFAMETHOXAZOLE\TRIMETHOPRIM, TENOFOVIR DISOPROXIL FUMARATE | DrugsGivenReaction | CC BY-NC | 33732476 | 19,889,986 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Oral mucosal erythema'. | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | DAPSONE, EFAVIRENZ, FLUCONAZOLE, LAMIVUDINE, SULFAMETHOXAZOLE\TRIMETHOPRIM, TENOFOVIR DISOPROXIL FUMARATE | DrugsGivenReaction | CC BY-NC | 33732476 | 19,889,986 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Punctate keratitis'. | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | DAPSONE, EFAVIRENZ, FLUCONAZOLE, LAMIVUDINE, SULFAMETHOXAZOLE\TRIMETHOPRIM, TENOFOVIR DISOPROXIL FUMARATE | DrugsGivenReaction | CC BY-NC | 33732476 | 19,889,986 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'SJS-TEN overlap'. | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | DAPSONE, EFAVIRENZ, FLUCONAZOLE, LAMIVUDINE, SULFAMETHOXAZOLE\TRIMETHOPRIM, TENOFOVIR DISOPROXIL FUMARATE | DrugsGivenReaction | CC BY-NC | 33732476 | 19,889,986 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Skin lesion'. | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | DAPSONE, EFAVIRENZ, FLUCONAZOLE, LAMIVUDINE, SULFAMETHOXAZOLE\TRIMETHOPRIM, TENOFOVIR DISOPROXIL FUMARATE | DrugsGivenReaction | CC BY-NC | 33732476 | 19,889,986 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Stevens-Johnson syndrome'. | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | SULFAMETHOXAZOLE\TRIMETHOPRIM | DrugsGivenReaction | CC BY-NC | 33732476 | 20,020,604 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapy non-responder'. | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | DAPSONE, EFAVIRENZ, FLUCONAZOLE, LAMIVUDINE, SULFAMETHOXAZOLE\TRIMETHOPRIM, TENOFOVIR DISOPROXIL FUMARATE | DrugsGivenReaction | CC BY-NC | 33732476 | 19,889,986 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Toxic epidermal necrolysis'. | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | SULFAMETHOXAZOLE\TRIMETHOPRIM | DrugsGivenReaction | CC BY-NC | 33732476 | 20,020,604 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Treatment failure'. | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | ATAZANAVIR\RITONAVIR, AZITHROMYCIN, DAPSONE, EFAVIRENZ\LAMIVUDINE\TENOFOVIR DISOPROXIL FUMARATE, FLUCONAZOLE, LAMIVUDINE, NITAZOXANIDE, ZIDOVUDINE | DrugsGivenReaction | CC BY-NC | 33732476 | 19,903,764 | 2021-03 |
What was the administration route of drug 'SULFAMETHOXAZOLE\TRIMETHOPRIM'? | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33732476 | 20,020,604 | 2021-03 |
What was the dosage of drug 'ATAZANAVIR\RITONAVIR'? | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | UNK, SECOND-LINE THERAPY | DrugDosageText | CC BY-NC | 33732476 | 19,903,764 | 2021-03 |
What was the dosage of drug 'AZITHROMYCIN'? | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | UNK, QD (ONCE DAILY) | DrugDosageText | CC BY-NC | 33732476 | 19,903,764 | 2021-03 |
What was the dosage of drug 'EFAVIRENZ\LAMIVUDINE\TENOFOVIR DISOPROXIL FUMARATE'? | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | UNK, FIRST-LINE THERAPY | DrugDosageText | CC BY-NC | 33732476 | 19,903,764 | 2021-03 |
What was the dosage of drug 'LAMIVUDINE'? | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | UNK, SECOND-LINE THERAPY | DrugDosageText | CC BY-NC | 33732476 | 19,903,764 | 2021-03 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.