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What was the outcome of reaction 'Polycythaemia'? | Successful thrombolysis of normotensive pulmonary embolism with life-threatening hypoxia in a young man with Klinefelter syndrome.
Klinefelter syndrome (KS) affects males born with an additional X chromosome giving the genotype 47XXY classically. This syndrome has primary features of infertility and hypogonadism along with other features including a genetically hypercoagulable state. When associated with other risk factors, KS further increases the risk of venous thromboembolism and could result in life-threatening pulmonary embolism (PE). There should be a lower threshold in suspecting PE as a cause of acute respiratory failure in this patient group and thrombolysis should be considered early in normotensive PE with severe hypoxia for best patient outcomes. Furthermore, clinicians should be cautious in managing testosterone therapy in patients with KS and additional thromboembolic risk factors.
Background
Klinefelter syndrome (KS) is considered to be the most common sex chromosome disorder. An Australian prevalence study had reported a rate of 223 per 100 000 males, with up to 50% of cases remaining undiagnosed.1 Affected males have an additional X chromosome leading to poor development of male secondary sexual characteristics. Other than these phenotypic changes, these patients are more prone to cardiovascular, endocrine and psychiatric disorders.2 KS is also considered to be a genetically hypercoagulable state where affected individuals have been shown to be four times more likely to have venous thromboembolism (VTE).2 The standardised incidence ratio for VTE is reported to be highest before 30 years of age at 12%.3 The current hypothesis for this hypercoagulable state is the presence of increased levels of plasminogen activator inhibitor 1 (PAI-1) in KS, related to obesity and low testosterone levels. Despite this, a study by Zitzmann et al did not demonstrate a change in PAI-1 levels in patients who are treated with testosterone therapy.4 Other hypotheses for the hypercoagulable state seen in this patient group include an increase in factor VIII and IX levels due to the genes coding for these factors being located on the X chromosome. A case series of six KS patients with deep venous thrombosis (DVT) has shown elevated factor VIII levels, but this was not significantly different from a control population with VTE.5
The Pulmonary Embolism International Thrombolysis Study (PEITHO) trial demonstrated that fibrinolytic therapy in patients with intermediate-severity pulmonary embolism (PE) prevented haemodynamic decompensation but increased the risk of major haemorrhage and stroke.6 A third of the patients in the PEITHO trial complained of persisting dyspnoea at 3-month follow-up, but over 80% had only low or intermediate probability of persisting or new-onset pulmonary hypertension at echocardiographic follow-up. Based on these data, the latest guidelines for PE by the European Society of Cardiology do not recommend routine thrombolysis for intermediate-risk PE. On the other hand, a small randomised trial of 83 patients suggested that thrombolysis in submassive PE improved the functional capacity at 3 months compared with anticoagulation alone.7
Here, we report a case of a young man with KS presenting with submassive PE complicated by pneumomediastinum and pneumopericardium with severe hypoxic respiratory failure prompting successful thrombolysis with good functional outcomes.
Case presentation
A young man in his mid-20s with KS presented to the emergency department with fluctuating generalised ill health and worsening shortness of breath for 2 weeks. He had an associated persistent dry cough and mild subjective fevers. He denied any pleuritic chest pain and could not recall any preceding calf tenderness and had no identifiable risk factors for VTE except his father having experienced an unprovoked DVT in the past with a negative thrombophilia screen. The patient had been diagnosed with KS at the age of 18 months with XXYY karyotype while being investigated for developmental delay and has been on testosterone replacement since the age of 15 years with a current testosterone regimen of intramuscular testosterone undecanoate 1000 mg at 3 monthly interval. He was otherwise healthy.
On examination, he was of a lean build with a well-grown beard. He was tachypnoeic (up to 40 breaths/min), tachycardic (up to 140 beats/min), and peripherally and centrally cyanosed. His blood pressure remained stable over 100/60 mm Hg. He had occasional crepitations on bilateral lung fields. His oxygen saturation (SPO2) on room air was 74% and was promptly commenced on a non-rebreather with improvement of SPO2 to 85%.
Investigations
Arterial blood gas performed on admission demonstrated type 1 respiratory failure with PaO2 of 52 mm Hg. ECG showed tachycardia with S1-Q3-T3 pattern. An urgent CT pulmonary angiogram (CTPA) was performed on high suspicion of PE. This demonstrated a completely occluded left main pulmonary artery with a large embolus and another embolus in the right main pulmonary artery extending into the right middle and lower lobe arteries extensively and to the upper lobe arteries to a lesser extent. CTPA further demonstrated pneumomediastinum and pneumopericardium (figure 1). Closer evaluation of his CTPA revealed alveolar rupture leading to pneumomediastinum and pneumopericardium which was attributed to barotrauma from the persistent dry cough.
Figure 1 Bilateral pulmonary embolism with pneumomediastinum and pneumopericardium.
Bedside echocardiogram demonstrated ballooning of the right ventricle, suggestive of significant pulmonary hypertension and his troponin I was elevated at 162 ng/L (<21 ng/L).
Treatment
He was at high risk according to the simplified PE severity index with a 30-day mortality prediction of 8.9%. Due to the high oxygen requirement and severity of clot burden with persistent tachycardia and right ventricular strain, it was decided to thrombolyse him. He received intravenous alteplase 10 mg loading followed by a 90 mg infusion. His saturation improved gradually over a 6-hour period up to 100% on room air. He received therapeutic dose subcutaneous enoxaparin for 7 days following thrombolysis and was changed to oral apixaban 5 mg two times per day for life-long therapy on discharge.
Outcome and follow-up
His testosterone level was 25.4 nmol/L (normal range 10–35 nmol/L). This was 9 weeks after his regular testosterone undecanoate therapy. He was noted to be polycythaemic with a haemoglobin level of 209 g/L and haematocrit of 0.63. The elevated erythropoietin level at 42 mIU/mL (normal range 5–25 mIU/mL) suggests secondary polycythaemia. His haemoglobin level and haematocrit improved to 152 g/L and 0.45, respectively, at the time of discharge. A thrombophilia screen was negative for any secondary causes including JAK2 mutation, antiphospholipid antibodies, anti nuclear antibody, extractable nuclear antigen, vasculitis screening, homocysteine level and prothrombotic gene mutations.
On follow-up at 3 months, he had returned to his baseline functional capacity and his repeat echocardiogram showed complete resolution of right ventricular strain with normal cardiac function. In the long-term management of his testosterone replacement therapy, it was decided to recommence his testosterone only when the serum testosterone level falls below 10 nmol/L.
Discussion
Our patient had multiple risk factors for VTE. KS is known to increase the risk of VTE. He had a family history of unprovoked DVT, although the thrombophilia screening for both him and his father could not identify a hereditary cause. His polycythaemia could have predisposed him to VTE and was likely multifactorial from hypoxia, dehydration and testosterone therapy. The fact that he tolerated an SPO2 down to 74% in the community was remarkable and we postulate that the secondary polycythaemic response may have allowed him to tolerate such severe hypoxia. Although he was not hypotensive, severe hypoxic respiratory failure with signs of right ventricular strain prompted the decision for thrombolysis. Current guidance for PE thrombolysis mostly depends on failed haemodynamics and suggests close monitoring and consideration of rescue thrombolysis for cases like our patient.8 Several researchers have highlighted the need for thrombolysis in severe hypoxic respiratory failure with preserved haemodynamics.9 10 Percutaneous catheter-directed therapy is currently recommended for haemodynamically unstable PE with contraindications for thrombolysis.8 As our patient did not have any contraindications for thrombolysis, this was not considered. Our patient clearly improved with thrombolysis with normalisation of his oxygenation from SPO2 of 74%–100% within hours and his full recovery without any evidence of pulmonary hypertension speaks to the dramatic improvement achieved with this therapy. Polycythaemia is one of the most common side effects of testosterone therapy.11 Regardless of this, a systematic review of six randomised trials and five observational studies failed to show an association between testosterone therapy and thromboembolism.12 Despite this, provided the multiple risk factors our patient had for VTE, it was decided to minimise any risk testosterone-related polycythaemia could cause by targeting his testosterone therapy towards the lower limit of normal.
Learning points
Clinicians should be cognisant about the hypercoagulable state of Klinefelter syndrome, especially when the patient has other risk factors for venous thromboembolism (VTE).
We propose that clinicians use a cautious and closely supervised approach to testosterone replacement therapy in patients with other risk factors for VTE.
Clinicians should be aware of the current limitations for thrombolysis recommendations in pulmonary embolism (PE) which entirely depend on haemodynamic instability, and should carefully explore the need for thrombolysis in normotensive PE with refractory hypoxic respiratory failure on a case-by-case basis, which in our case led to optimum patient outcomes both in the short and long term.
Twitter: @jkndmiththinda
Contributors: NDMJK managed the acute presentation of the case and continues to follow up the case. JG provided Endocrinology input in management. NDMJK did the initial literature review, composed the original draft and prepared the images. JG contributed with literature review and provided critical feedback to the manuscript. All authors contributed to editing and finalising the manuscript and have given final approval to the version submitted and are accountable for the content submitted.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33627349 | 19,038,559 | 2021-02-24 |
What was the outcome of reaction 'Pulmonary embolism'? | Successful thrombolysis of normotensive pulmonary embolism with life-threatening hypoxia in a young man with Klinefelter syndrome.
Klinefelter syndrome (KS) affects males born with an additional X chromosome giving the genotype 47XXY classically. This syndrome has primary features of infertility and hypogonadism along with other features including a genetically hypercoagulable state. When associated with other risk factors, KS further increases the risk of venous thromboembolism and could result in life-threatening pulmonary embolism (PE). There should be a lower threshold in suspecting PE as a cause of acute respiratory failure in this patient group and thrombolysis should be considered early in normotensive PE with severe hypoxia for best patient outcomes. Furthermore, clinicians should be cautious in managing testosterone therapy in patients with KS and additional thromboembolic risk factors.
Background
Klinefelter syndrome (KS) is considered to be the most common sex chromosome disorder. An Australian prevalence study had reported a rate of 223 per 100 000 males, with up to 50% of cases remaining undiagnosed.1 Affected males have an additional X chromosome leading to poor development of male secondary sexual characteristics. Other than these phenotypic changes, these patients are more prone to cardiovascular, endocrine and psychiatric disorders.2 KS is also considered to be a genetically hypercoagulable state where affected individuals have been shown to be four times more likely to have venous thromboembolism (VTE).2 The standardised incidence ratio for VTE is reported to be highest before 30 years of age at 12%.3 The current hypothesis for this hypercoagulable state is the presence of increased levels of plasminogen activator inhibitor 1 (PAI-1) in KS, related to obesity and low testosterone levels. Despite this, a study by Zitzmann et al did not demonstrate a change in PAI-1 levels in patients who are treated with testosterone therapy.4 Other hypotheses for the hypercoagulable state seen in this patient group include an increase in factor VIII and IX levels due to the genes coding for these factors being located on the X chromosome. A case series of six KS patients with deep venous thrombosis (DVT) has shown elevated factor VIII levels, but this was not significantly different from a control population with VTE.5
The Pulmonary Embolism International Thrombolysis Study (PEITHO) trial demonstrated that fibrinolytic therapy in patients with intermediate-severity pulmonary embolism (PE) prevented haemodynamic decompensation but increased the risk of major haemorrhage and stroke.6 A third of the patients in the PEITHO trial complained of persisting dyspnoea at 3-month follow-up, but over 80% had only low or intermediate probability of persisting or new-onset pulmonary hypertension at echocardiographic follow-up. Based on these data, the latest guidelines for PE by the European Society of Cardiology do not recommend routine thrombolysis for intermediate-risk PE. On the other hand, a small randomised trial of 83 patients suggested that thrombolysis in submassive PE improved the functional capacity at 3 months compared with anticoagulation alone.7
Here, we report a case of a young man with KS presenting with submassive PE complicated by pneumomediastinum and pneumopericardium with severe hypoxic respiratory failure prompting successful thrombolysis with good functional outcomes.
Case presentation
A young man in his mid-20s with KS presented to the emergency department with fluctuating generalised ill health and worsening shortness of breath for 2 weeks. He had an associated persistent dry cough and mild subjective fevers. He denied any pleuritic chest pain and could not recall any preceding calf tenderness and had no identifiable risk factors for VTE except his father having experienced an unprovoked DVT in the past with a negative thrombophilia screen. The patient had been diagnosed with KS at the age of 18 months with XXYY karyotype while being investigated for developmental delay and has been on testosterone replacement since the age of 15 years with a current testosterone regimen of intramuscular testosterone undecanoate 1000 mg at 3 monthly interval. He was otherwise healthy.
On examination, he was of a lean build with a well-grown beard. He was tachypnoeic (up to 40 breaths/min), tachycardic (up to 140 beats/min), and peripherally and centrally cyanosed. His blood pressure remained stable over 100/60 mm Hg. He had occasional crepitations on bilateral lung fields. His oxygen saturation (SPO2) on room air was 74% and was promptly commenced on a non-rebreather with improvement of SPO2 to 85%.
Investigations
Arterial blood gas performed on admission demonstrated type 1 respiratory failure with PaO2 of 52 mm Hg. ECG showed tachycardia with S1-Q3-T3 pattern. An urgent CT pulmonary angiogram (CTPA) was performed on high suspicion of PE. This demonstrated a completely occluded left main pulmonary artery with a large embolus and another embolus in the right main pulmonary artery extending into the right middle and lower lobe arteries extensively and to the upper lobe arteries to a lesser extent. CTPA further demonstrated pneumomediastinum and pneumopericardium (figure 1). Closer evaluation of his CTPA revealed alveolar rupture leading to pneumomediastinum and pneumopericardium which was attributed to barotrauma from the persistent dry cough.
Figure 1 Bilateral pulmonary embolism with pneumomediastinum and pneumopericardium.
Bedside echocardiogram demonstrated ballooning of the right ventricle, suggestive of significant pulmonary hypertension and his troponin I was elevated at 162 ng/L (<21 ng/L).
Treatment
He was at high risk according to the simplified PE severity index with a 30-day mortality prediction of 8.9%. Due to the high oxygen requirement and severity of clot burden with persistent tachycardia and right ventricular strain, it was decided to thrombolyse him. He received intravenous alteplase 10 mg loading followed by a 90 mg infusion. His saturation improved gradually over a 6-hour period up to 100% on room air. He received therapeutic dose subcutaneous enoxaparin for 7 days following thrombolysis and was changed to oral apixaban 5 mg two times per day for life-long therapy on discharge.
Outcome and follow-up
His testosterone level was 25.4 nmol/L (normal range 10–35 nmol/L). This was 9 weeks after his regular testosterone undecanoate therapy. He was noted to be polycythaemic with a haemoglobin level of 209 g/L and haematocrit of 0.63. The elevated erythropoietin level at 42 mIU/mL (normal range 5–25 mIU/mL) suggests secondary polycythaemia. His haemoglobin level and haematocrit improved to 152 g/L and 0.45, respectively, at the time of discharge. A thrombophilia screen was negative for any secondary causes including JAK2 mutation, antiphospholipid antibodies, anti nuclear antibody, extractable nuclear antigen, vasculitis screening, homocysteine level and prothrombotic gene mutations.
On follow-up at 3 months, he had returned to his baseline functional capacity and his repeat echocardiogram showed complete resolution of right ventricular strain with normal cardiac function. In the long-term management of his testosterone replacement therapy, it was decided to recommence his testosterone only when the serum testosterone level falls below 10 nmol/L.
Discussion
Our patient had multiple risk factors for VTE. KS is known to increase the risk of VTE. He had a family history of unprovoked DVT, although the thrombophilia screening for both him and his father could not identify a hereditary cause. His polycythaemia could have predisposed him to VTE and was likely multifactorial from hypoxia, dehydration and testosterone therapy. The fact that he tolerated an SPO2 down to 74% in the community was remarkable and we postulate that the secondary polycythaemic response may have allowed him to tolerate such severe hypoxia. Although he was not hypotensive, severe hypoxic respiratory failure with signs of right ventricular strain prompted the decision for thrombolysis. Current guidance for PE thrombolysis mostly depends on failed haemodynamics and suggests close monitoring and consideration of rescue thrombolysis for cases like our patient.8 Several researchers have highlighted the need for thrombolysis in severe hypoxic respiratory failure with preserved haemodynamics.9 10 Percutaneous catheter-directed therapy is currently recommended for haemodynamically unstable PE with contraindications for thrombolysis.8 As our patient did not have any contraindications for thrombolysis, this was not considered. Our patient clearly improved with thrombolysis with normalisation of his oxygenation from SPO2 of 74%–100% within hours and his full recovery without any evidence of pulmonary hypertension speaks to the dramatic improvement achieved with this therapy. Polycythaemia is one of the most common side effects of testosterone therapy.11 Regardless of this, a systematic review of six randomised trials and five observational studies failed to show an association between testosterone therapy and thromboembolism.12 Despite this, provided the multiple risk factors our patient had for VTE, it was decided to minimise any risk testosterone-related polycythaemia could cause by targeting his testosterone therapy towards the lower limit of normal.
Learning points
Clinicians should be cognisant about the hypercoagulable state of Klinefelter syndrome, especially when the patient has other risk factors for venous thromboembolism (VTE).
We propose that clinicians use a cautious and closely supervised approach to testosterone replacement therapy in patients with other risk factors for VTE.
Clinicians should be aware of the current limitations for thrombolysis recommendations in pulmonary embolism (PE) which entirely depend on haemodynamic instability, and should carefully explore the need for thrombolysis in normotensive PE with refractory hypoxic respiratory failure on a case-by-case basis, which in our case led to optimum patient outcomes both in the short and long term.
Twitter: @jkndmiththinda
Contributors: NDMJK managed the acute presentation of the case and continues to follow up the case. JG provided Endocrinology input in management. NDMJK did the initial literature review, composed the original draft and prepared the images. JG contributed with literature review and provided critical feedback to the manuscript. All authors contributed to editing and finalising the manuscript and have given final approval to the version submitted and are accountable for the content submitted.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33627349 | 19,038,559 | 2021-02-24 |
What was the outcome of reaction 'Pulmonary hypertension'? | Successful thrombolysis of normotensive pulmonary embolism with life-threatening hypoxia in a young man with Klinefelter syndrome.
Klinefelter syndrome (KS) affects males born with an additional X chromosome giving the genotype 47XXY classically. This syndrome has primary features of infertility and hypogonadism along with other features including a genetically hypercoagulable state. When associated with other risk factors, KS further increases the risk of venous thromboembolism and could result in life-threatening pulmonary embolism (PE). There should be a lower threshold in suspecting PE as a cause of acute respiratory failure in this patient group and thrombolysis should be considered early in normotensive PE with severe hypoxia for best patient outcomes. Furthermore, clinicians should be cautious in managing testosterone therapy in patients with KS and additional thromboembolic risk factors.
Background
Klinefelter syndrome (KS) is considered to be the most common sex chromosome disorder. An Australian prevalence study had reported a rate of 223 per 100 000 males, with up to 50% of cases remaining undiagnosed.1 Affected males have an additional X chromosome leading to poor development of male secondary sexual characteristics. Other than these phenotypic changes, these patients are more prone to cardiovascular, endocrine and psychiatric disorders.2 KS is also considered to be a genetically hypercoagulable state where affected individuals have been shown to be four times more likely to have venous thromboembolism (VTE).2 The standardised incidence ratio for VTE is reported to be highest before 30 years of age at 12%.3 The current hypothesis for this hypercoagulable state is the presence of increased levels of plasminogen activator inhibitor 1 (PAI-1) in KS, related to obesity and low testosterone levels. Despite this, a study by Zitzmann et al did not demonstrate a change in PAI-1 levels in patients who are treated with testosterone therapy.4 Other hypotheses for the hypercoagulable state seen in this patient group include an increase in factor VIII and IX levels due to the genes coding for these factors being located on the X chromosome. A case series of six KS patients with deep venous thrombosis (DVT) has shown elevated factor VIII levels, but this was not significantly different from a control population with VTE.5
The Pulmonary Embolism International Thrombolysis Study (PEITHO) trial demonstrated that fibrinolytic therapy in patients with intermediate-severity pulmonary embolism (PE) prevented haemodynamic decompensation but increased the risk of major haemorrhage and stroke.6 A third of the patients in the PEITHO trial complained of persisting dyspnoea at 3-month follow-up, but over 80% had only low or intermediate probability of persisting or new-onset pulmonary hypertension at echocardiographic follow-up. Based on these data, the latest guidelines for PE by the European Society of Cardiology do not recommend routine thrombolysis for intermediate-risk PE. On the other hand, a small randomised trial of 83 patients suggested that thrombolysis in submassive PE improved the functional capacity at 3 months compared with anticoagulation alone.7
Here, we report a case of a young man with KS presenting with submassive PE complicated by pneumomediastinum and pneumopericardium with severe hypoxic respiratory failure prompting successful thrombolysis with good functional outcomes.
Case presentation
A young man in his mid-20s with KS presented to the emergency department with fluctuating generalised ill health and worsening shortness of breath for 2 weeks. He had an associated persistent dry cough and mild subjective fevers. He denied any pleuritic chest pain and could not recall any preceding calf tenderness and had no identifiable risk factors for VTE except his father having experienced an unprovoked DVT in the past with a negative thrombophilia screen. The patient had been diagnosed with KS at the age of 18 months with XXYY karyotype while being investigated for developmental delay and has been on testosterone replacement since the age of 15 years with a current testosterone regimen of intramuscular testosterone undecanoate 1000 mg at 3 monthly interval. He was otherwise healthy.
On examination, he was of a lean build with a well-grown beard. He was tachypnoeic (up to 40 breaths/min), tachycardic (up to 140 beats/min), and peripherally and centrally cyanosed. His blood pressure remained stable over 100/60 mm Hg. He had occasional crepitations on bilateral lung fields. His oxygen saturation (SPO2) on room air was 74% and was promptly commenced on a non-rebreather with improvement of SPO2 to 85%.
Investigations
Arterial blood gas performed on admission demonstrated type 1 respiratory failure with PaO2 of 52 mm Hg. ECG showed tachycardia with S1-Q3-T3 pattern. An urgent CT pulmonary angiogram (CTPA) was performed on high suspicion of PE. This demonstrated a completely occluded left main pulmonary artery with a large embolus and another embolus in the right main pulmonary artery extending into the right middle and lower lobe arteries extensively and to the upper lobe arteries to a lesser extent. CTPA further demonstrated pneumomediastinum and pneumopericardium (figure 1). Closer evaluation of his CTPA revealed alveolar rupture leading to pneumomediastinum and pneumopericardium which was attributed to barotrauma from the persistent dry cough.
Figure 1 Bilateral pulmonary embolism with pneumomediastinum and pneumopericardium.
Bedside echocardiogram demonstrated ballooning of the right ventricle, suggestive of significant pulmonary hypertension and his troponin I was elevated at 162 ng/L (<21 ng/L).
Treatment
He was at high risk according to the simplified PE severity index with a 30-day mortality prediction of 8.9%. Due to the high oxygen requirement and severity of clot burden with persistent tachycardia and right ventricular strain, it was decided to thrombolyse him. He received intravenous alteplase 10 mg loading followed by a 90 mg infusion. His saturation improved gradually over a 6-hour period up to 100% on room air. He received therapeutic dose subcutaneous enoxaparin for 7 days following thrombolysis and was changed to oral apixaban 5 mg two times per day for life-long therapy on discharge.
Outcome and follow-up
His testosterone level was 25.4 nmol/L (normal range 10–35 nmol/L). This was 9 weeks after his regular testosterone undecanoate therapy. He was noted to be polycythaemic with a haemoglobin level of 209 g/L and haematocrit of 0.63. The elevated erythropoietin level at 42 mIU/mL (normal range 5–25 mIU/mL) suggests secondary polycythaemia. His haemoglobin level and haematocrit improved to 152 g/L and 0.45, respectively, at the time of discharge. A thrombophilia screen was negative for any secondary causes including JAK2 mutation, antiphospholipid antibodies, anti nuclear antibody, extractable nuclear antigen, vasculitis screening, homocysteine level and prothrombotic gene mutations.
On follow-up at 3 months, he had returned to his baseline functional capacity and his repeat echocardiogram showed complete resolution of right ventricular strain with normal cardiac function. In the long-term management of his testosterone replacement therapy, it was decided to recommence his testosterone only when the serum testosterone level falls below 10 nmol/L.
Discussion
Our patient had multiple risk factors for VTE. KS is known to increase the risk of VTE. He had a family history of unprovoked DVT, although the thrombophilia screening for both him and his father could not identify a hereditary cause. His polycythaemia could have predisposed him to VTE and was likely multifactorial from hypoxia, dehydration and testosterone therapy. The fact that he tolerated an SPO2 down to 74% in the community was remarkable and we postulate that the secondary polycythaemic response may have allowed him to tolerate such severe hypoxia. Although he was not hypotensive, severe hypoxic respiratory failure with signs of right ventricular strain prompted the decision for thrombolysis. Current guidance for PE thrombolysis mostly depends on failed haemodynamics and suggests close monitoring and consideration of rescue thrombolysis for cases like our patient.8 Several researchers have highlighted the need for thrombolysis in severe hypoxic respiratory failure with preserved haemodynamics.9 10 Percutaneous catheter-directed therapy is currently recommended for haemodynamically unstable PE with contraindications for thrombolysis.8 As our patient did not have any contraindications for thrombolysis, this was not considered. Our patient clearly improved with thrombolysis with normalisation of his oxygenation from SPO2 of 74%–100% within hours and his full recovery without any evidence of pulmonary hypertension speaks to the dramatic improvement achieved with this therapy. Polycythaemia is one of the most common side effects of testosterone therapy.11 Regardless of this, a systematic review of six randomised trials and five observational studies failed to show an association between testosterone therapy and thromboembolism.12 Despite this, provided the multiple risk factors our patient had for VTE, it was decided to minimise any risk testosterone-related polycythaemia could cause by targeting his testosterone therapy towards the lower limit of normal.
Learning points
Clinicians should be cognisant about the hypercoagulable state of Klinefelter syndrome, especially when the patient has other risk factors for venous thromboembolism (VTE).
We propose that clinicians use a cautious and closely supervised approach to testosterone replacement therapy in patients with other risk factors for VTE.
Clinicians should be aware of the current limitations for thrombolysis recommendations in pulmonary embolism (PE) which entirely depend on haemodynamic instability, and should carefully explore the need for thrombolysis in normotensive PE with refractory hypoxic respiratory failure on a case-by-case basis, which in our case led to optimum patient outcomes both in the short and long term.
Twitter: @jkndmiththinda
Contributors: NDMJK managed the acute presentation of the case and continues to follow up the case. JG provided Endocrinology input in management. NDMJK did the initial literature review, composed the original draft and prepared the images. JG contributed with literature review and provided critical feedback to the manuscript. All authors contributed to editing and finalising the manuscript and have given final approval to the version submitted and are accountable for the content submitted.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33627349 | 19,038,559 | 2021-02-24 |
What was the outcome of reaction 'Respiratory failure'? | Successful thrombolysis of normotensive pulmonary embolism with life-threatening hypoxia in a young man with Klinefelter syndrome.
Klinefelter syndrome (KS) affects males born with an additional X chromosome giving the genotype 47XXY classically. This syndrome has primary features of infertility and hypogonadism along with other features including a genetically hypercoagulable state. When associated with other risk factors, KS further increases the risk of venous thromboembolism and could result in life-threatening pulmonary embolism (PE). There should be a lower threshold in suspecting PE as a cause of acute respiratory failure in this patient group and thrombolysis should be considered early in normotensive PE with severe hypoxia for best patient outcomes. Furthermore, clinicians should be cautious in managing testosterone therapy in patients with KS and additional thromboembolic risk factors.
Background
Klinefelter syndrome (KS) is considered to be the most common sex chromosome disorder. An Australian prevalence study had reported a rate of 223 per 100 000 males, with up to 50% of cases remaining undiagnosed.1 Affected males have an additional X chromosome leading to poor development of male secondary sexual characteristics. Other than these phenotypic changes, these patients are more prone to cardiovascular, endocrine and psychiatric disorders.2 KS is also considered to be a genetically hypercoagulable state where affected individuals have been shown to be four times more likely to have venous thromboembolism (VTE).2 The standardised incidence ratio for VTE is reported to be highest before 30 years of age at 12%.3 The current hypothesis for this hypercoagulable state is the presence of increased levels of plasminogen activator inhibitor 1 (PAI-1) in KS, related to obesity and low testosterone levels. Despite this, a study by Zitzmann et al did not demonstrate a change in PAI-1 levels in patients who are treated with testosterone therapy.4 Other hypotheses for the hypercoagulable state seen in this patient group include an increase in factor VIII and IX levels due to the genes coding for these factors being located on the X chromosome. A case series of six KS patients with deep venous thrombosis (DVT) has shown elevated factor VIII levels, but this was not significantly different from a control population with VTE.5
The Pulmonary Embolism International Thrombolysis Study (PEITHO) trial demonstrated that fibrinolytic therapy in patients with intermediate-severity pulmonary embolism (PE) prevented haemodynamic decompensation but increased the risk of major haemorrhage and stroke.6 A third of the patients in the PEITHO trial complained of persisting dyspnoea at 3-month follow-up, but over 80% had only low or intermediate probability of persisting or new-onset pulmonary hypertension at echocardiographic follow-up. Based on these data, the latest guidelines for PE by the European Society of Cardiology do not recommend routine thrombolysis for intermediate-risk PE. On the other hand, a small randomised trial of 83 patients suggested that thrombolysis in submassive PE improved the functional capacity at 3 months compared with anticoagulation alone.7
Here, we report a case of a young man with KS presenting with submassive PE complicated by pneumomediastinum and pneumopericardium with severe hypoxic respiratory failure prompting successful thrombolysis with good functional outcomes.
Case presentation
A young man in his mid-20s with KS presented to the emergency department with fluctuating generalised ill health and worsening shortness of breath for 2 weeks. He had an associated persistent dry cough and mild subjective fevers. He denied any pleuritic chest pain and could not recall any preceding calf tenderness and had no identifiable risk factors for VTE except his father having experienced an unprovoked DVT in the past with a negative thrombophilia screen. The patient had been diagnosed with KS at the age of 18 months with XXYY karyotype while being investigated for developmental delay and has been on testosterone replacement since the age of 15 years with a current testosterone regimen of intramuscular testosterone undecanoate 1000 mg at 3 monthly interval. He was otherwise healthy.
On examination, he was of a lean build with a well-grown beard. He was tachypnoeic (up to 40 breaths/min), tachycardic (up to 140 beats/min), and peripherally and centrally cyanosed. His blood pressure remained stable over 100/60 mm Hg. He had occasional crepitations on bilateral lung fields. His oxygen saturation (SPO2) on room air was 74% and was promptly commenced on a non-rebreather with improvement of SPO2 to 85%.
Investigations
Arterial blood gas performed on admission demonstrated type 1 respiratory failure with PaO2 of 52 mm Hg. ECG showed tachycardia with S1-Q3-T3 pattern. An urgent CT pulmonary angiogram (CTPA) was performed on high suspicion of PE. This demonstrated a completely occluded left main pulmonary artery with a large embolus and another embolus in the right main pulmonary artery extending into the right middle and lower lobe arteries extensively and to the upper lobe arteries to a lesser extent. CTPA further demonstrated pneumomediastinum and pneumopericardium (figure 1). Closer evaluation of his CTPA revealed alveolar rupture leading to pneumomediastinum and pneumopericardium which was attributed to barotrauma from the persistent dry cough.
Figure 1 Bilateral pulmonary embolism with pneumomediastinum and pneumopericardium.
Bedside echocardiogram demonstrated ballooning of the right ventricle, suggestive of significant pulmonary hypertension and his troponin I was elevated at 162 ng/L (<21 ng/L).
Treatment
He was at high risk according to the simplified PE severity index with a 30-day mortality prediction of 8.9%. Due to the high oxygen requirement and severity of clot burden with persistent tachycardia and right ventricular strain, it was decided to thrombolyse him. He received intravenous alteplase 10 mg loading followed by a 90 mg infusion. His saturation improved gradually over a 6-hour period up to 100% on room air. He received therapeutic dose subcutaneous enoxaparin for 7 days following thrombolysis and was changed to oral apixaban 5 mg two times per day for life-long therapy on discharge.
Outcome and follow-up
His testosterone level was 25.4 nmol/L (normal range 10–35 nmol/L). This was 9 weeks after his regular testosterone undecanoate therapy. He was noted to be polycythaemic with a haemoglobin level of 209 g/L and haematocrit of 0.63. The elevated erythropoietin level at 42 mIU/mL (normal range 5–25 mIU/mL) suggests secondary polycythaemia. His haemoglobin level and haematocrit improved to 152 g/L and 0.45, respectively, at the time of discharge. A thrombophilia screen was negative for any secondary causes including JAK2 mutation, antiphospholipid antibodies, anti nuclear antibody, extractable nuclear antigen, vasculitis screening, homocysteine level and prothrombotic gene mutations.
On follow-up at 3 months, he had returned to his baseline functional capacity and his repeat echocardiogram showed complete resolution of right ventricular strain with normal cardiac function. In the long-term management of his testosterone replacement therapy, it was decided to recommence his testosterone only when the serum testosterone level falls below 10 nmol/L.
Discussion
Our patient had multiple risk factors for VTE. KS is known to increase the risk of VTE. He had a family history of unprovoked DVT, although the thrombophilia screening for both him and his father could not identify a hereditary cause. His polycythaemia could have predisposed him to VTE and was likely multifactorial from hypoxia, dehydration and testosterone therapy. The fact that he tolerated an SPO2 down to 74% in the community was remarkable and we postulate that the secondary polycythaemic response may have allowed him to tolerate such severe hypoxia. Although he was not hypotensive, severe hypoxic respiratory failure with signs of right ventricular strain prompted the decision for thrombolysis. Current guidance for PE thrombolysis mostly depends on failed haemodynamics and suggests close monitoring and consideration of rescue thrombolysis for cases like our patient.8 Several researchers have highlighted the need for thrombolysis in severe hypoxic respiratory failure with preserved haemodynamics.9 10 Percutaneous catheter-directed therapy is currently recommended for haemodynamically unstable PE with contraindications for thrombolysis.8 As our patient did not have any contraindications for thrombolysis, this was not considered. Our patient clearly improved with thrombolysis with normalisation of his oxygenation from SPO2 of 74%–100% within hours and his full recovery without any evidence of pulmonary hypertension speaks to the dramatic improvement achieved with this therapy. Polycythaemia is one of the most common side effects of testosterone therapy.11 Regardless of this, a systematic review of six randomised trials and five observational studies failed to show an association between testosterone therapy and thromboembolism.12 Despite this, provided the multiple risk factors our patient had for VTE, it was decided to minimise any risk testosterone-related polycythaemia could cause by targeting his testosterone therapy towards the lower limit of normal.
Learning points
Clinicians should be cognisant about the hypercoagulable state of Klinefelter syndrome, especially when the patient has other risk factors for venous thromboembolism (VTE).
We propose that clinicians use a cautious and closely supervised approach to testosterone replacement therapy in patients with other risk factors for VTE.
Clinicians should be aware of the current limitations for thrombolysis recommendations in pulmonary embolism (PE) which entirely depend on haemodynamic instability, and should carefully explore the need for thrombolysis in normotensive PE with refractory hypoxic respiratory failure on a case-by-case basis, which in our case led to optimum patient outcomes both in the short and long term.
Twitter: @jkndmiththinda
Contributors: NDMJK managed the acute presentation of the case and continues to follow up the case. JG provided Endocrinology input in management. NDMJK did the initial literature review, composed the original draft and prepared the images. JG contributed with literature review and provided critical feedback to the manuscript. All authors contributed to editing and finalising the manuscript and have given final approval to the version submitted and are accountable for the content submitted.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33627349 | 19,038,559 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cerebral atrophy'. | Atypical Presentation of Pediatric Systemic Lupus Erythematosus Complicated by Cryptococcal Meningitis.
Cryptococcus is an opportunistic fungal pathogen that leads to life-threatening infections. Cryptococcal infections are mainly reported in HIV patients and less commonly encountered in non-HIV immunocompromised host. Cryptococcus neoformans (C. neoformans) is the most common Cryptococcus species causing diseases in humans which can be presented as pulmonary, meningitis, cutaneous, and/or disseminated cryptococcosis. Case Presentation. A 12-year-old female girl from Cairo, Egypt, presented to the pediatric hospital with signs of systemic lupus erythematosus (SLE). She had an aggressive lupus nephritis course for which corticosteroids, mycophenolate mofetil, and cyclophosphamide were prescribed, and the child gradually improved and was discharged. Two months later, the patient exhibited skin lesions involved both in her legs, massive ulcers were developed and extended rapidly through the entire legs followed by deterioration in her conscious level, and signs of meningitis were documented. Cerebrospinal fluid (CSF) examination and microbiological workup were confirmatory for C. neoformans infection, and mental and motor functions were rapidly deteriorated. Treatment with amphotericin B in addition to supportive treatment and close follow-up of the patient's medical condition result in obvious clinical improvement and patient discharge with minimal residual weakness in her legs after almost a one-month duration. After six months, the patient was brought to the emergency department complaining of repeated attacks of seizures, a lumbar puncture was performed, and culture results were again confirmatory for C. neoformans. An intensive course of antifungal therapy was prescribed which was successful, evident by resolution of the signs and symptoms of infection in addition to negative culture results and negative sepsis biomarkers. The child clinically improved, but unfortunately, gradual optic nerve degeneration and brain cell atrophy as a sequel of severe and longstanding cryptococcal infection resulted in her death after almost one year from her first attack.
Cryptococcal infection among non-HIV patients is a rare disease but can result in advanced medical complications which may be fatal. The disease should be suspected to be reliably diagnosed. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening consequences. Amphotericin B can be used effectively in cryptococcosis management in the settings where flucytosine is not available. Signs of cryptococcal meningitis can be manifested again after a period of remission and clinical cure which signifies the latency of Cryptococcus in the central nervous system. The second activation of Cryptococcus after its latency is usually life-threatening and mostly fatal.
1. Background
Immunocompromised individuals including HIV, SLE, and patients on prolonged corticosteroid and immunosuppressant therapy are more prone to various bacterial, viral, and fungal opportunistic infections. One of the most important fatal fungal infections is cryptococcal infection [1–4]. C. neoformans is the most frequent cryptococcal species infect humans, and it is an encapsulated yeast microorganism, which is commonly transmitted through bird feces, plants, dust, soil, and contaminated food [2, 3]. Cryptococcosis can cause disseminated infection reaching to the lungs, central nervous system (CNS), and skin [2, 3, 5]. Dermal manifestations can present in different clinical morphologies including ulcers, acneiform papules, subcutaneous nodules, and rarely, cellulitis [4, 6].
2. Case Presentation
A 12-years-old Egyptian female student presented to Ain Shams University Pediatric Hospital complaining of generalized body edema, frothy urine, and proteinuria (3.7 g/day). The child was diagnosed as nephrotic syndrome, with repeated albumin infusions, and steroid therapy was initiated, but the child was nonresponding; instead, her medical condition deteriorated. Laboratory profile was in concordance with serologically quiescent SLE which included antinuclear antibody titer 1: 1280 finely speckled, elevated rheumatoid factor (RF) of 456 IU/ml (N: 0–20 IU/ml), positive SS-A/Ro > 8.0 and SS-B/La > 8.0 antibodies, anti-beta-2 glycoprotein IgM Ab > 100 U/ml, C-reactive protein (CRP) level 3.9 mg/l (N: 0–5 mg/l), and erythrocyte sedimentation rate (ESR) 51 mm/hour (N: 0–10 mm/hour). The serologic tests that were negative included anti-dsDNA Abs, complement C3 level 154 mg/dl (N: 106–194 mg/dl), complement C4 level 38 mg/dl (N: 19–50 mg/dl), cyclic citrullinated peptide IgG, cryoglobulin, serum immunofixation, Scl-70 scleroderma, Smith, RNP, cardiolipin antibodies, and lupus anticoagulant. Urine studies at the time revealed 3 + proteinuria, no hematuria or pyuria, a creatinine level of 0.93 mg/dl, and eGFR > 60 ml/min/1.73 m2. The diagnosis of SLE with nephrotic presentation was established, upon which the child received a medical regimen for lupus management including corticosteroids, mycophenolate mofetil, and cyclophosphamide which resulted in patient clinical improvement.
Two months later, the child was admitted complaining of poor appetite, nausea and vomiting, tiredness, swollen ankles, and shortness of breath, and deteriorated renal functions were evident in her laboratory profile: creatinine increased to 1.92 mg/dl, 4 + protein on urinalysis, worsening urine protein to creatinine (PC) ratio of 1.9 (N: 0.0–0.1), and 24-hour urine protein of 1170 mg/24 hours (N: 50–150 mg/24 hours). Lupus nephritis grade IV was confirmed. Therefore, the child received intermittent hemodialysis; in addition, the doses of the prescribed immunosuppressant was increased: prednisone (40 mg/day), hydroxychloroquine (6 mg/kg/day), and mycophenolate mofetil (2 g/day). The patient was kept under this protocol; she gradually improved and was discharged. A simplified chart representing the sequence of the disease in the presented case is illustrated in Figure 1.
After two months, the child manifested skin ulcers in her lower extremities which were progressive in course. Drug allergies, insect bites, and family history were excluded. First, these lesions were nonwell-demarcated, erythematous, painful on palpation, nonpruritic with increasing local edema, and bullae formation. A few days later, lesions spread to involve entire her legs up to the groin area, the bullae began to coalescence together, ruptured, and a huge amount of serous discharge was drained from the lesions; no corresponding lesions appeared on the face, trunk, or upper extremities, and fever was not present at first, but with worsening of the lesions, the patient became feverish, hematuric, anemic, and hypotensive with deteriorated general condition; hence, she was admitted for the 2nd time.
At the time of admission, laboratory profile revealed hemoglobin 8.2 g/dL, white blood cell (WBC) count 10,800/mm³, platelet count 129,000 cells/mm³, serum aspartate transaminase (AST) 10 U/L, serum alanine transaminase (ALT) 17 U/L, CRP 12 mg/L, and ESR 60 mm. Upon worsening the skin lesions, bacterial skin infection was suspected; so empirical treatment with amikacin and cefepime was started and the dose of prednisone decreased to 30 mg/day; microbiological cultures revealed no microorganism growth after 48 hours of incubation. Upon suspicion of bacterial cellulitis and due to the lack of improvements of the skin lesions, vancomycin was added to the treatment regimen.
After three days, the patient medical condition deteriorated rapidly. She complained of severe headache, altered memory, continuous agitation, neck rigidity, stiffness, photophobia, and total loss of appetite; so, meningitis was suspected; hence, lumbar puncture was performed, and a CSF sample was sent for cytological examination in addition to culture procedures. The sample was clear colorless on physical inspection (Figure 2)(a), and cell count was 25 cells/HPF.
Direct Gram examination of CSF showed spherical budding encapsulated yeast cells surrounded by translucent hallow around the cells (Figures 2(b) and 2)(c). CSF chemical examination revealed protein level 74 mg/dL (normal range 15–60 mg/dL) and glucose levels 41 mg/dL (normal range 50–80 mg/dL). The sample was cultured on aerobic blood agar, anaerobic blood agar, chocolate, and MacConkey agar; the plates showed delayed growth at the end of the third day (72 hours incubation according to CSF standard operating procedures (SOPs) of our microbiology lab). It was a minute whitish milky colony, which was highly suggestive of fungal infection, confirmed by further subculture, the sample on Sabouraud's dextrose agar (SDA) plates (Figures 2(d)–2(f)). Indian ink stain and positive biochemical reactions were confirmatory for the diagnosis of Cryptococcus infection (Figures 3 and 4). Additionally, antifungal susceptibility testing was performed which was positive for both amphotericin B and flucytosine.
Despite that, the child manifested obvious clinical signs and symptoms of meningitis. Magnetic resonance imaging (MRI) brain with contrast showed findings within normal limits, and blood culture was negative for microbiological growth after 7 days incubation.
Based on the available laboratory results, treatment for disseminated cryptococcosis was initiated immediately upon laboratory notification, prednisone was further decreased to 20 mg/day, and fluconazole was discontinued. Amphotericin B was started at a dose of 0.7 mg/kg/day with an infusion time of 6 hours, since the patient had repeated reactions (fever, chills, and nausea) with a shorter infusion time. Concerning flucytosine, which is indicated as the drug of choice in cryptococcal meningitis treatment, it was not used for treatment of our presented case due to financial aspects and nonavailability in our country, Egypt. Repeated lumber tapping was performed to relieve persistent increased intracranial tension as a consequence of severe meningitis; in addition, plasmapheresis was performed to remove lupus autoantibodies.
The child was subjected for further workup to rule out pneumonia and other organs affection, and for follow up purpose, chest X-ray was ordered, which revealed normal findings, ESR, CRP, complete blood count (CBC), and sepsis marker, neutrophil CD64. These laboratory tests were performed every 3 days on a routine base for monitoring the medical progress which showed dramatic gradual improvement (Table 1 and Figure 5); in conjugation with clinical signs and symptoms improvement evident by regaining her mental and motor skills, besides healing of the leg ulcers, pus draining stopped and swelling disappeared (Figure 6). In this setting, a lumbar puncture was intended to be performed upon this obvious clinical and laboratory improvement preparing the patient to be discharged, but the child refused at her own request and was discharged on her demand after almost 30 days since amphotericin B infusion was first prescribed.
At the time of discharge, the patient had no pulmonary sequelae, but she had residual weakness in her lower limbs. The laboratory results at the time of discharge were hemoglobin 9.2 g/dL, WBC 16.700 cells per mm³, platelet 303.000 cells per mm³, AST 10 U/L, ALT 4 U/L, CRP 6 mg/L, and ESR 53 mm/h. The child was instructed to continue fluconazole (400 mg/day) at home for 8 weeks and then reduced its dose to 200 mg/day for 1 year. And she was weaned gradually from corticosteroid therapy.
One month later, the child was brought to the emergency department complaining of severe headache, projectile vomiting, and blurred vision. She was admitted for the 3rd time. An MRI brain was ordered, and a lumbar puncture was performed urgently to relieve intracranial tension, and for chemical, cytological, and microbiological analyses, all were negative for infection except for CRP slightly positive (12 mg/L). So, lupus flare-up was suspected, and pulse steroid therapy was started, in addition to antifungal (fluconazole) and antibiotic (amikacin and cefepime) coverage. The patient was subjected for plasmapheresis; upon it, she manifested dramatical improvement and discharge. She started to attend the immunotherapy clinic every two weeks for follow up purpose; she did well for 5 months and regained her functions except for difficulty in talking and walking abilities as she could not walk without support; so, the mother was advised to bring her for regular physiotherapy sessions every week.
Five months later, the patient complained of shivering in her legs and hands followed by seizures attacks which were gradually increasing in frequency and duration till her mother brought her to the E/R. She was admitted for the 4th time. Phenytoin was prescribed, initial dose 2.5 mg/kg/dose twice a day and increased gradually to maximum 5 mg/kg/dose twice daily, and intensive work up profile was conducted searching for the cause of the seizures which included electroencephalogram (EEG), MRI brain, full lab evaluation, and CSF chemical analysis and microbiological examination. EEG revealed normal electric impulses without focal activities (Figure 7). MRI brain showed mildly dilated 3rd ventricles, CSF chemistry analysis revealed protein level 82 mg/dL (normal range 15–60 mg/dL), and glucose levels of 35 mg/dL (normal range 50–80 mg/dL). Upon receiving the sample in our microbiology lab, the sample physical criteria were very similar to the previous one, clear colorless, and cell count was 15 cell/cm3. A direct wet film examination was positive for budding yeast cells which were suspected and notified immediately to the pediatric team, and protocol of treatment was decided rapidly. CSF culture results were again confirmatory for C. neoformans.
An intensive course of antifungal therapy was initiated which included amphotericin B (0.7 mg/kg/day) with an infusion time of 6 hours, and fluconazole. Resolution of patient signs and symptoms of infection was clinically evident in addition to negative culture results and improved laboratory sepsis parameters. The child general condition improved, but at this setting, she complained of poor visual acuity. The pediatric team immediately consulted the specialist neurosurgeon, ophthalmologist, and an MRI brain urgently performed which showed evidence of brain cell atrophy with subsequent increased intracranial ventricular sizes and evidence of optic nerve atrophy; the ophthalmologist confirmed bilateral optic nerve degeneration which was more evident on the left side (Figure 8).
After almost one month and, however, signs and symptoms of infection were resolved, cryptococcosis longstanding course with brain cell atrophy as a sequel of cryptococcal meningitis resulted in the child's death after almost one year from her first attack.
3. Discussion and Conclusion
Cryptococcus is an opportunistic fungal pathogen that leads to rare life-threatening infection. Meningoencephalitis and disseminated cryptococcosis are usually common complications reported in immunocompromised hosts [7, 8]. In the presented case, we reported a pediatric systemic lupus erythematosus patient complicated by rapidly disseminating cryptococcal infection which exhibited a latency in the child CNS followed by an attack of infection flare-up which was successfully treated, but slowly progressive brain cell atrophy due to longstanding disease resulted in her death.
Infections and sepsis are major causes of hospitalization, mortality, and morbidity in immunosuppressed patients [9]. Cryptococcosis is one of the fatal fungal infections reported mainly in immunocompromised hosts; however, several reported cases point to its incidence also in immunocompetent patients [10–12]. Cryptococcosis has a low incidence in non-HIV patients, approximately 1 : 100.000 [5, 13]. Patients with SLE are highly susceptible to infections due to the combined effects of their immunosuppressive therapy and the abnormalities of the immune system that the disease itself causes [14]. Concerning our presented case, prolonged corticosteroid therapy and immunosuppressants due to her underlying disease (SLE) were the major risk factors for disseminated cryptococcosis with poor outcomes.
The patient had a progressive renal course complicated by lupus nephritis class IV for which immunosuppressants was given. Lupus nephritis is clinically evident in 50–60% of patients with SLE [15]. Both mycophenolate mofetil and cyclophosphamide were prescribed to our case. Mycophenolate mofetil depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation [16]. While, cyclophosphamide inhibits protein synthesis through DNA and RNA crosslinking [17].
By discussing Cryptococcus as the causative pathogen, C. neoformans is the most common strain causing infections in humans, and it is an encapsulated yeast that has been isolated from chickens' droppings and grows readily in soil contaminated with avian excreta particularly that of pigeons. In humans, it can colonize the upper airway system. Nevertheless, no animal-to-human nor person-to-person respiratory transmission has been documented [9]. Our presented case lived in low socioeconomic and hygienic status, and she denied contact with pigeon or birds. However, the fungus might have been indirectly transmitted via other sources such as vegetables, fruits, and dairy products [8].
C. neoformans generally cause three types of infections: cryptococcal meningitis, pulmonary, and cutaneous cryptococcosis [18]. The dissemination of this disease occurs when at least two noncontiguous sites are affected, which is unusual and mostly observed in HIV patients [4, 19]. In our case, only pulmonary involvement was not present while cutaneous manifestations were the first presenting symptoms followed by cryptococcal meningitis. Some studies support the importance of lumbar puncture in patients with cryptococcosis, even when CNS symptoms are not observed because asymptomatic meningitis is reported to be an early stage of the disease [20].
Systemic lupus erythematosus disease activity index (SLEDAI) was calculated for our presented case in order to be used as a predictor for SLE mortality and as a measure of global disease activity, and it was achieving high values (79) which reflect why the patient underwent into cryptococcal meningitis with poor clinical course. Eventhough, for patients with low SLE activity, the possibility of cryptococcal meningitis should not be underestimated [21].
Skin involvement is a rare presenting symptom of Cryptococcus infection, but it is usually a sign of disseminated disease; it may precede the systemic symptoms even eight months earlier [5, 18]. It is important to stress the rarity and polymorphism of the skin conditions, with the possible development of vesicles or blisters and the potential progression to ulceration [1, 4].
Cryptococcal cellulitis is a rare specific cutaneous manifestation, which was developed in our case. It was initially suspected to be a bacterial infection for which antibiotics were prescribed until its failure and microbiological results confirmed the fungal diagnosis. Although rare, the present case, cryptococcal cellulitis was restricted mainly to the lower body, particularly to the lower extremities, and this was reported in other rare reported cases [1, 2]. Despite that, cryptococcal cellulitis is uncommon and undistinguishable from acute bacterial cellulitis for appearance and presentation [6], but high suspicion especially in a risky patient should be considered.
More than 80% of patients manifested cryptococcal cellulitis and are expected to survive in immunocompetent status when they receive the appropriate antifungal therapy [6]. According to the current guidelines of the American Society of Infectious Diseases for disseminated cryptococcosis management, amphotericin B combined with flucytosine is recommended as the primary therapy, followed by fluconazole as a consolidation therapy [4, 18]. Flucytosine is expensive and was not available in our country; so, it was not considered for the treatment. Instead, it was replaced by the addition of fluconazole to amphotericin B regimen.
Cryptococcal laboratory diagnosis relies on three main methods: latex agglutination test, fungal culture, and direct microscopic examination [22]. In the present case, both the microscopic examination and microbiological cultures were the cornerstone for the diagnosis. C. neoformans was differentiated from other fungal species especially Candida spp. by the characterized morphology in the Gram-stained smear, microbiological culture characters, Indian ink stain positivity, and biochemical reactions.
Indian ink stain was positive in our case. In HIV-positive patients, its sensitivity increases up to 80% due to higher fungal loads in the CSF, while in HIV negative patients, the sensitivity is only 30–50% [8, 23]. CSF culture is considered the gold standard for cryptococcal diagnosis, but it has several diagnostic obstacles as long time is needed for fungus to grow, while time is very critical for management of meningitis cases with evolving lifetime neurological complications [24]. Besides, fungal cultures are not available in all medical facilities and therefore may not be performed. It is also associated with false-negative results, especially in cases with low fungal load, and this may be the attributed cause of negative blood culture result in our case.
Regarding management of cryptococcosis, the prolonged course (6–10 weeks) of IV amphotericin B monotherapy, together with the reduction of chemotherapy to improve immune status, was the main target. Caution was taken while reducing immunosuppressive therapy, since a rapid reduction is reported to be associated with immune reconstitution inflammatory syndrome (IRIS) in some patients [9]. There is evidence that supports the requirement for maintenance therapy with fluconazole administered as indefinite secondary prophylaxis, since the rate of recurrence exceeds 50% after apparently successful treatment [25].
Differential diagnosis of the present case must be addressed which includes besides to what was mentioned, infection versus flare-up attacks in lupus patients; several sepsis markers including CRP increase significantly in SLE patients with concomitant infection but increase only slightly or not at all in patients with a lupus flare without infection [14, 26] which is exactly encountered in our presented case. Additionally, decreased visual acuity due to increased intracranial tension (papilledema) was differentiated from decreased visual acuity due to optic nerve atrophy. For the presented case, papilledema was evident on fundus examination at the time of cryptococcal meningitis first diagnosed, while optic nerve atrophy was evident on fundus examination at the end.
Finally, we highlight the importance of clinicians' awareness about such infection among non-HIV immunocompromised patients including those who are diagnosed with autoimmune diseases. The latency of Cryptococcus should be considered and suspected during the management of such cases which necessitate early recognition and proper management.
For preparing Indian ink-stained film, take two drops from the examined CSF sample directly or a small part of the growing colony from the plate, mix it well with the ink, put a cover slide, and leave the slide for an hour to give a chance for the cells to be settled, and for better contrast view, lower the condenser and reduce the microscopic light and examine the film by using the lens with magnification power (40x). Cryptococcus will be evident as shiny spherical budding in a dark background.
4. Conclusion
Cryptococcal meningitis should be considered as one of the possible diagnoses in a patient with altered sensorium and neck stiffness, especially those who are immunocompromised. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening complications.
Early management of cryptococcal meningitis is associated with better prognosis and lower neurological complications. Despite that, flucytosine is being described as the best antifungal medication for cryptococcal infections. Amphotericin B still gives good results in such cases.
Negative bacterial growth from a skin lesion does not necessitate that it is a sterile lesion; it may be an atypical microorganism or microorganism that needs special media to grow or longer duration to be cultivated. Clinical pathologists should be aware of Cryptococcus laboratory diagnosis and how to differentiate it from Candida spp. Microbiological culture is a confirmatory step for Cryptococcus diagnosis; however, Gram-stained and Indian ink-stained films are rapid and informative diagnostic methods especially in limited resources facilities. The communication between laboratory staff members and treating medical team is very crucial for better clinical judgment specifically in a circumstance where an unusual diagnostic result is released or diagnosing a rare disease.
CSF examination may show low cell count; however, infection presents; this is commonly seen in immunocompromised patients as no adequate inflammation. Cryptococcal infection associated with CNS latency which should to be suspected; hence, meticulous follow-up is an essential step in cryptococcal management. The second activation of cryptococcal latency is usually life-threatening and mostly fatal.
Acknowledgments
The authors would like to thank all members of Immunology Unit-Pediatric Department and Microbiology Unit-Clinical Pathology Department of Ain Shams University Hospital. The authors gratefully acknowledge Professor Dalia Helmy El-Ghoneimy and Professor Malaka Zakaria Amer for their efforts to diagnose and follow up severe medical cases including this presented case and special gratitude to the mother of the child for supporting with detailed medical information and for her medical awareness and patience throughout her daughter's longstanding disease.
Abbreviations
ALT:Alanine transaminase
ANA:Antinuclear antibody
AST:Aspartate transaminase
C. neoformans:
Cryptococcus neoformans
CBC:Complete blood count
CNS:Central nervous system
CRP:C-reactive protein
CSF:Cerebrospinal fluid
DNA:Deoxyribonucleic acid
dsDNA:Double-strand DNA
E.R:Emergency room
EEG:Electroencephalogram
eGFR:Estimated glomerular filtration rate
ESR:Erythrocyte sedimentation rate
HIV:Human immunodeficiency virus
IgG:Immunoglobulin G
IRIS:Immune reconstitution inflammatory syndrome
IV:Intravenous
MPA:Mycophenolic acid
MRI:Magnetic resonance imaging
PC ratio:Protein creatinine ratio
RF:Rheumatoid factor
RNA:Ribonucleic acid
RNP:Ribonucleoprotein antibodies
SDA:Sabouraud's dextrose agar
SLE:Systemic lupus erythematosus
SOPs:Standard operating procedures
WBC:White blood cell.
Data Availability
The data underlying the findings of this research are publicly available.
Ethical Approval
Compliance with ethics guidelines, all procedures followed the ethical standards of the responsible committee on human experimentation (institutional and national).
Consent
Written informed consent for publication of clinical details was obtained from the mother of the patient.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
Authors' Contributions
Heba Ezzat Hashem contributed to acquisition, analysis, and interpretation of data, drafting of paper, conception and design, revision for critical intellectual content, final approval, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Zakaria Hamza Ibrahim involved in revision for critical intellectual content, final approval, and financial support.
Figure 1 A simplified chart representing the sequence of the disease in our case.
Figure 2 (a) Clear colorless CSF sample; other etiological causes of meningitis especially viral meningitis versus fungal meningitis must be differentiated, specifically in the presence of clear colorless CSF samples with low cell count and minimal changes of CSF parameters. (b) Spherical budding yeast in the CSF; it should be differentiated from the elliptical budding yeast cells of Candida spp. which is more commonly encountered during CSF examination as a fungal cause of meningitis. (c) Gram-stained film; direct film from CSF shows spherical budding yeast cells with surrounding translucent haloes due to capsular structure. (d) Blood agar shows small white colonies, after 72 hours of incubation. (e) Sabouraud dextrose agar (SDA) shows pasty colonies that were confirmed to be Cryptococcus neoformans. (f) Gram from culture shows spherical yeast cells with surrounding translucent haloes.
Figure 3 Biochemical reaction; the urease test was positive.
Figure 4
Cryptococcus as shiny spherical budding in a dark background.
Figure 5 Laboratory course of the present case and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation; the patient improved clinically and discharged after almost one month with minimal residual weakness in her lower limbs. The nCD64 test was available in our hospital as a sepsis biomarker, and it was performed for our case for follow-up purposes.
Figure 6 Patient developed extensive skin ulceration with serous oozing from both lower limbs; this image was taken upon her clinical improvement on amphotericin B. The local edema resolved leaving the skin redundant, cracked, and the oozing discharge was first serous-like followed by purulent discharge then pus draining stopped.
Figure 7 EEG at the 4th admission, seizures, and other CNS manifestations in patients who had previous cryptococcal meningitis is very essential to be distinguished; it is due to reactivation of latent infection or due to seizures attributed to other medical causes. For the present case, EEG showed normal electric activates without focal localization.
Figure 8 MRI brain performed at the time of 3rd admission; dilated third ventricles were evident due to brain cell atrophy; at this occasion, signs of increase intracranial tension were negative which excluded it as a cause for cerebral ventricles dilatations.
Table 1 Laboratory course of the present case, and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation.
Hb TLC ANC ALC AMC PLT CRP CD64% CD64 MFI
08/05/2016 10.6 12.2 11.2 0.6 0.4 44 6 98.5 2.87
11/05/2016 9 10.9 9.2 1.1 0.51 81 6 91.5 1.91
15/05/2016 7.7 14.8 12.72 1.57 0.48 209 4 80.1 1.56
22/05/2016 7.2 10 7.6 1.1 0.5 238 4 68.9 1.45
Hb, hemoglobin (g/dl); TLC, total leukocytic count (X109/L); ANC, absolute neutrophil count (X109/L); ALC, absolute lymphocyte count (X109/L); AMC, absolute monocyte count (X109/L); PLT, platelet (X109/L); CRP, C-reactive protein (mg/L); nCD64%, neutrophil CD64%; nCD64MFI, nCD64 mean fluorescence intensity. | CYCLOPHOSPHAMIDE, HYDROXYCHLOROQUINE, MYCOPHENOLIC ACID, PREDNISONE | DrugsGivenReaction | CC BY | 33628263 | 19,588,393 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cerebral ventricle dilatation'. | Atypical Presentation of Pediatric Systemic Lupus Erythematosus Complicated by Cryptococcal Meningitis.
Cryptococcus is an opportunistic fungal pathogen that leads to life-threatening infections. Cryptococcal infections are mainly reported in HIV patients and less commonly encountered in non-HIV immunocompromised host. Cryptococcus neoformans (C. neoformans) is the most common Cryptococcus species causing diseases in humans which can be presented as pulmonary, meningitis, cutaneous, and/or disseminated cryptococcosis. Case Presentation. A 12-year-old female girl from Cairo, Egypt, presented to the pediatric hospital with signs of systemic lupus erythematosus (SLE). She had an aggressive lupus nephritis course for which corticosteroids, mycophenolate mofetil, and cyclophosphamide were prescribed, and the child gradually improved and was discharged. Two months later, the patient exhibited skin lesions involved both in her legs, massive ulcers were developed and extended rapidly through the entire legs followed by deterioration in her conscious level, and signs of meningitis were documented. Cerebrospinal fluid (CSF) examination and microbiological workup were confirmatory for C. neoformans infection, and mental and motor functions were rapidly deteriorated. Treatment with amphotericin B in addition to supportive treatment and close follow-up of the patient's medical condition result in obvious clinical improvement and patient discharge with minimal residual weakness in her legs after almost a one-month duration. After six months, the patient was brought to the emergency department complaining of repeated attacks of seizures, a lumbar puncture was performed, and culture results were again confirmatory for C. neoformans. An intensive course of antifungal therapy was prescribed which was successful, evident by resolution of the signs and symptoms of infection in addition to negative culture results and negative sepsis biomarkers. The child clinically improved, but unfortunately, gradual optic nerve degeneration and brain cell atrophy as a sequel of severe and longstanding cryptococcal infection resulted in her death after almost one year from her first attack.
Cryptococcal infection among non-HIV patients is a rare disease but can result in advanced medical complications which may be fatal. The disease should be suspected to be reliably diagnosed. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening consequences. Amphotericin B can be used effectively in cryptococcosis management in the settings where flucytosine is not available. Signs of cryptococcal meningitis can be manifested again after a period of remission and clinical cure which signifies the latency of Cryptococcus in the central nervous system. The second activation of Cryptococcus after its latency is usually life-threatening and mostly fatal.
1. Background
Immunocompromised individuals including HIV, SLE, and patients on prolonged corticosteroid and immunosuppressant therapy are more prone to various bacterial, viral, and fungal opportunistic infections. One of the most important fatal fungal infections is cryptococcal infection [1–4]. C. neoformans is the most frequent cryptococcal species infect humans, and it is an encapsulated yeast microorganism, which is commonly transmitted through bird feces, plants, dust, soil, and contaminated food [2, 3]. Cryptococcosis can cause disseminated infection reaching to the lungs, central nervous system (CNS), and skin [2, 3, 5]. Dermal manifestations can present in different clinical morphologies including ulcers, acneiform papules, subcutaneous nodules, and rarely, cellulitis [4, 6].
2. Case Presentation
A 12-years-old Egyptian female student presented to Ain Shams University Pediatric Hospital complaining of generalized body edema, frothy urine, and proteinuria (3.7 g/day). The child was diagnosed as nephrotic syndrome, with repeated albumin infusions, and steroid therapy was initiated, but the child was nonresponding; instead, her medical condition deteriorated. Laboratory profile was in concordance with serologically quiescent SLE which included antinuclear antibody titer 1: 1280 finely speckled, elevated rheumatoid factor (RF) of 456 IU/ml (N: 0–20 IU/ml), positive SS-A/Ro > 8.0 and SS-B/La > 8.0 antibodies, anti-beta-2 glycoprotein IgM Ab > 100 U/ml, C-reactive protein (CRP) level 3.9 mg/l (N: 0–5 mg/l), and erythrocyte sedimentation rate (ESR) 51 mm/hour (N: 0–10 mm/hour). The serologic tests that were negative included anti-dsDNA Abs, complement C3 level 154 mg/dl (N: 106–194 mg/dl), complement C4 level 38 mg/dl (N: 19–50 mg/dl), cyclic citrullinated peptide IgG, cryoglobulin, serum immunofixation, Scl-70 scleroderma, Smith, RNP, cardiolipin antibodies, and lupus anticoagulant. Urine studies at the time revealed 3 + proteinuria, no hematuria or pyuria, a creatinine level of 0.93 mg/dl, and eGFR > 60 ml/min/1.73 m2. The diagnosis of SLE with nephrotic presentation was established, upon which the child received a medical regimen for lupus management including corticosteroids, mycophenolate mofetil, and cyclophosphamide which resulted in patient clinical improvement.
Two months later, the child was admitted complaining of poor appetite, nausea and vomiting, tiredness, swollen ankles, and shortness of breath, and deteriorated renal functions were evident in her laboratory profile: creatinine increased to 1.92 mg/dl, 4 + protein on urinalysis, worsening urine protein to creatinine (PC) ratio of 1.9 (N: 0.0–0.1), and 24-hour urine protein of 1170 mg/24 hours (N: 50–150 mg/24 hours). Lupus nephritis grade IV was confirmed. Therefore, the child received intermittent hemodialysis; in addition, the doses of the prescribed immunosuppressant was increased: prednisone (40 mg/day), hydroxychloroquine (6 mg/kg/day), and mycophenolate mofetil (2 g/day). The patient was kept under this protocol; she gradually improved and was discharged. A simplified chart representing the sequence of the disease in the presented case is illustrated in Figure 1.
After two months, the child manifested skin ulcers in her lower extremities which were progressive in course. Drug allergies, insect bites, and family history were excluded. First, these lesions were nonwell-demarcated, erythematous, painful on palpation, nonpruritic with increasing local edema, and bullae formation. A few days later, lesions spread to involve entire her legs up to the groin area, the bullae began to coalescence together, ruptured, and a huge amount of serous discharge was drained from the lesions; no corresponding lesions appeared on the face, trunk, or upper extremities, and fever was not present at first, but with worsening of the lesions, the patient became feverish, hematuric, anemic, and hypotensive with deteriorated general condition; hence, she was admitted for the 2nd time.
At the time of admission, laboratory profile revealed hemoglobin 8.2 g/dL, white blood cell (WBC) count 10,800/mm³, platelet count 129,000 cells/mm³, serum aspartate transaminase (AST) 10 U/L, serum alanine transaminase (ALT) 17 U/L, CRP 12 mg/L, and ESR 60 mm. Upon worsening the skin lesions, bacterial skin infection was suspected; so empirical treatment with amikacin and cefepime was started and the dose of prednisone decreased to 30 mg/day; microbiological cultures revealed no microorganism growth after 48 hours of incubation. Upon suspicion of bacterial cellulitis and due to the lack of improvements of the skin lesions, vancomycin was added to the treatment regimen.
After three days, the patient medical condition deteriorated rapidly. She complained of severe headache, altered memory, continuous agitation, neck rigidity, stiffness, photophobia, and total loss of appetite; so, meningitis was suspected; hence, lumbar puncture was performed, and a CSF sample was sent for cytological examination in addition to culture procedures. The sample was clear colorless on physical inspection (Figure 2)(a), and cell count was 25 cells/HPF.
Direct Gram examination of CSF showed spherical budding encapsulated yeast cells surrounded by translucent hallow around the cells (Figures 2(b) and 2)(c). CSF chemical examination revealed protein level 74 mg/dL (normal range 15–60 mg/dL) and glucose levels 41 mg/dL (normal range 50–80 mg/dL). The sample was cultured on aerobic blood agar, anaerobic blood agar, chocolate, and MacConkey agar; the plates showed delayed growth at the end of the third day (72 hours incubation according to CSF standard operating procedures (SOPs) of our microbiology lab). It was a minute whitish milky colony, which was highly suggestive of fungal infection, confirmed by further subculture, the sample on Sabouraud's dextrose agar (SDA) plates (Figures 2(d)–2(f)). Indian ink stain and positive biochemical reactions were confirmatory for the diagnosis of Cryptococcus infection (Figures 3 and 4). Additionally, antifungal susceptibility testing was performed which was positive for both amphotericin B and flucytosine.
Despite that, the child manifested obvious clinical signs and symptoms of meningitis. Magnetic resonance imaging (MRI) brain with contrast showed findings within normal limits, and blood culture was negative for microbiological growth after 7 days incubation.
Based on the available laboratory results, treatment for disseminated cryptococcosis was initiated immediately upon laboratory notification, prednisone was further decreased to 20 mg/day, and fluconazole was discontinued. Amphotericin B was started at a dose of 0.7 mg/kg/day with an infusion time of 6 hours, since the patient had repeated reactions (fever, chills, and nausea) with a shorter infusion time. Concerning flucytosine, which is indicated as the drug of choice in cryptococcal meningitis treatment, it was not used for treatment of our presented case due to financial aspects and nonavailability in our country, Egypt. Repeated lumber tapping was performed to relieve persistent increased intracranial tension as a consequence of severe meningitis; in addition, plasmapheresis was performed to remove lupus autoantibodies.
The child was subjected for further workup to rule out pneumonia and other organs affection, and for follow up purpose, chest X-ray was ordered, which revealed normal findings, ESR, CRP, complete blood count (CBC), and sepsis marker, neutrophil CD64. These laboratory tests were performed every 3 days on a routine base for monitoring the medical progress which showed dramatic gradual improvement (Table 1 and Figure 5); in conjugation with clinical signs and symptoms improvement evident by regaining her mental and motor skills, besides healing of the leg ulcers, pus draining stopped and swelling disappeared (Figure 6). In this setting, a lumbar puncture was intended to be performed upon this obvious clinical and laboratory improvement preparing the patient to be discharged, but the child refused at her own request and was discharged on her demand after almost 30 days since amphotericin B infusion was first prescribed.
At the time of discharge, the patient had no pulmonary sequelae, but she had residual weakness in her lower limbs. The laboratory results at the time of discharge were hemoglobin 9.2 g/dL, WBC 16.700 cells per mm³, platelet 303.000 cells per mm³, AST 10 U/L, ALT 4 U/L, CRP 6 mg/L, and ESR 53 mm/h. The child was instructed to continue fluconazole (400 mg/day) at home for 8 weeks and then reduced its dose to 200 mg/day for 1 year. And she was weaned gradually from corticosteroid therapy.
One month later, the child was brought to the emergency department complaining of severe headache, projectile vomiting, and blurred vision. She was admitted for the 3rd time. An MRI brain was ordered, and a lumbar puncture was performed urgently to relieve intracranial tension, and for chemical, cytological, and microbiological analyses, all were negative for infection except for CRP slightly positive (12 mg/L). So, lupus flare-up was suspected, and pulse steroid therapy was started, in addition to antifungal (fluconazole) and antibiotic (amikacin and cefepime) coverage. The patient was subjected for plasmapheresis; upon it, she manifested dramatical improvement and discharge. She started to attend the immunotherapy clinic every two weeks for follow up purpose; she did well for 5 months and regained her functions except for difficulty in talking and walking abilities as she could not walk without support; so, the mother was advised to bring her for regular physiotherapy sessions every week.
Five months later, the patient complained of shivering in her legs and hands followed by seizures attacks which were gradually increasing in frequency and duration till her mother brought her to the E/R. She was admitted for the 4th time. Phenytoin was prescribed, initial dose 2.5 mg/kg/dose twice a day and increased gradually to maximum 5 mg/kg/dose twice daily, and intensive work up profile was conducted searching for the cause of the seizures which included electroencephalogram (EEG), MRI brain, full lab evaluation, and CSF chemical analysis and microbiological examination. EEG revealed normal electric impulses without focal activities (Figure 7). MRI brain showed mildly dilated 3rd ventricles, CSF chemistry analysis revealed protein level 82 mg/dL (normal range 15–60 mg/dL), and glucose levels of 35 mg/dL (normal range 50–80 mg/dL). Upon receiving the sample in our microbiology lab, the sample physical criteria were very similar to the previous one, clear colorless, and cell count was 15 cell/cm3. A direct wet film examination was positive for budding yeast cells which were suspected and notified immediately to the pediatric team, and protocol of treatment was decided rapidly. CSF culture results were again confirmatory for C. neoformans.
An intensive course of antifungal therapy was initiated which included amphotericin B (0.7 mg/kg/day) with an infusion time of 6 hours, and fluconazole. Resolution of patient signs and symptoms of infection was clinically evident in addition to negative culture results and improved laboratory sepsis parameters. The child general condition improved, but at this setting, she complained of poor visual acuity. The pediatric team immediately consulted the specialist neurosurgeon, ophthalmologist, and an MRI brain urgently performed which showed evidence of brain cell atrophy with subsequent increased intracranial ventricular sizes and evidence of optic nerve atrophy; the ophthalmologist confirmed bilateral optic nerve degeneration which was more evident on the left side (Figure 8).
After almost one month and, however, signs and symptoms of infection were resolved, cryptococcosis longstanding course with brain cell atrophy as a sequel of cryptococcal meningitis resulted in the child's death after almost one year from her first attack.
3. Discussion and Conclusion
Cryptococcus is an opportunistic fungal pathogen that leads to rare life-threatening infection. Meningoencephalitis and disseminated cryptococcosis are usually common complications reported in immunocompromised hosts [7, 8]. In the presented case, we reported a pediatric systemic lupus erythematosus patient complicated by rapidly disseminating cryptococcal infection which exhibited a latency in the child CNS followed by an attack of infection flare-up which was successfully treated, but slowly progressive brain cell atrophy due to longstanding disease resulted in her death.
Infections and sepsis are major causes of hospitalization, mortality, and morbidity in immunosuppressed patients [9]. Cryptococcosis is one of the fatal fungal infections reported mainly in immunocompromised hosts; however, several reported cases point to its incidence also in immunocompetent patients [10–12]. Cryptococcosis has a low incidence in non-HIV patients, approximately 1 : 100.000 [5, 13]. Patients with SLE are highly susceptible to infections due to the combined effects of their immunosuppressive therapy and the abnormalities of the immune system that the disease itself causes [14]. Concerning our presented case, prolonged corticosteroid therapy and immunosuppressants due to her underlying disease (SLE) were the major risk factors for disseminated cryptococcosis with poor outcomes.
The patient had a progressive renal course complicated by lupus nephritis class IV for which immunosuppressants was given. Lupus nephritis is clinically evident in 50–60% of patients with SLE [15]. Both mycophenolate mofetil and cyclophosphamide were prescribed to our case. Mycophenolate mofetil depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation [16]. While, cyclophosphamide inhibits protein synthesis through DNA and RNA crosslinking [17].
By discussing Cryptococcus as the causative pathogen, C. neoformans is the most common strain causing infections in humans, and it is an encapsulated yeast that has been isolated from chickens' droppings and grows readily in soil contaminated with avian excreta particularly that of pigeons. In humans, it can colonize the upper airway system. Nevertheless, no animal-to-human nor person-to-person respiratory transmission has been documented [9]. Our presented case lived in low socioeconomic and hygienic status, and she denied contact with pigeon or birds. However, the fungus might have been indirectly transmitted via other sources such as vegetables, fruits, and dairy products [8].
C. neoformans generally cause three types of infections: cryptococcal meningitis, pulmonary, and cutaneous cryptococcosis [18]. The dissemination of this disease occurs when at least two noncontiguous sites are affected, which is unusual and mostly observed in HIV patients [4, 19]. In our case, only pulmonary involvement was not present while cutaneous manifestations were the first presenting symptoms followed by cryptococcal meningitis. Some studies support the importance of lumbar puncture in patients with cryptococcosis, even when CNS symptoms are not observed because asymptomatic meningitis is reported to be an early stage of the disease [20].
Systemic lupus erythematosus disease activity index (SLEDAI) was calculated for our presented case in order to be used as a predictor for SLE mortality and as a measure of global disease activity, and it was achieving high values (79) which reflect why the patient underwent into cryptococcal meningitis with poor clinical course. Eventhough, for patients with low SLE activity, the possibility of cryptococcal meningitis should not be underestimated [21].
Skin involvement is a rare presenting symptom of Cryptococcus infection, but it is usually a sign of disseminated disease; it may precede the systemic symptoms even eight months earlier [5, 18]. It is important to stress the rarity and polymorphism of the skin conditions, with the possible development of vesicles or blisters and the potential progression to ulceration [1, 4].
Cryptococcal cellulitis is a rare specific cutaneous manifestation, which was developed in our case. It was initially suspected to be a bacterial infection for which antibiotics were prescribed until its failure and microbiological results confirmed the fungal diagnosis. Although rare, the present case, cryptococcal cellulitis was restricted mainly to the lower body, particularly to the lower extremities, and this was reported in other rare reported cases [1, 2]. Despite that, cryptococcal cellulitis is uncommon and undistinguishable from acute bacterial cellulitis for appearance and presentation [6], but high suspicion especially in a risky patient should be considered.
More than 80% of patients manifested cryptococcal cellulitis and are expected to survive in immunocompetent status when they receive the appropriate antifungal therapy [6]. According to the current guidelines of the American Society of Infectious Diseases for disseminated cryptococcosis management, amphotericin B combined with flucytosine is recommended as the primary therapy, followed by fluconazole as a consolidation therapy [4, 18]. Flucytosine is expensive and was not available in our country; so, it was not considered for the treatment. Instead, it was replaced by the addition of fluconazole to amphotericin B regimen.
Cryptococcal laboratory diagnosis relies on three main methods: latex agglutination test, fungal culture, and direct microscopic examination [22]. In the present case, both the microscopic examination and microbiological cultures were the cornerstone for the diagnosis. C. neoformans was differentiated from other fungal species especially Candida spp. by the characterized morphology in the Gram-stained smear, microbiological culture characters, Indian ink stain positivity, and biochemical reactions.
Indian ink stain was positive in our case. In HIV-positive patients, its sensitivity increases up to 80% due to higher fungal loads in the CSF, while in HIV negative patients, the sensitivity is only 30–50% [8, 23]. CSF culture is considered the gold standard for cryptococcal diagnosis, but it has several diagnostic obstacles as long time is needed for fungus to grow, while time is very critical for management of meningitis cases with evolving lifetime neurological complications [24]. Besides, fungal cultures are not available in all medical facilities and therefore may not be performed. It is also associated with false-negative results, especially in cases with low fungal load, and this may be the attributed cause of negative blood culture result in our case.
Regarding management of cryptococcosis, the prolonged course (6–10 weeks) of IV amphotericin B monotherapy, together with the reduction of chemotherapy to improve immune status, was the main target. Caution was taken while reducing immunosuppressive therapy, since a rapid reduction is reported to be associated with immune reconstitution inflammatory syndrome (IRIS) in some patients [9]. There is evidence that supports the requirement for maintenance therapy with fluconazole administered as indefinite secondary prophylaxis, since the rate of recurrence exceeds 50% after apparently successful treatment [25].
Differential diagnosis of the present case must be addressed which includes besides to what was mentioned, infection versus flare-up attacks in lupus patients; several sepsis markers including CRP increase significantly in SLE patients with concomitant infection but increase only slightly or not at all in patients with a lupus flare without infection [14, 26] which is exactly encountered in our presented case. Additionally, decreased visual acuity due to increased intracranial tension (papilledema) was differentiated from decreased visual acuity due to optic nerve atrophy. For the presented case, papilledema was evident on fundus examination at the time of cryptococcal meningitis first diagnosed, while optic nerve atrophy was evident on fundus examination at the end.
Finally, we highlight the importance of clinicians' awareness about such infection among non-HIV immunocompromised patients including those who are diagnosed with autoimmune diseases. The latency of Cryptococcus should be considered and suspected during the management of such cases which necessitate early recognition and proper management.
For preparing Indian ink-stained film, take two drops from the examined CSF sample directly or a small part of the growing colony from the plate, mix it well with the ink, put a cover slide, and leave the slide for an hour to give a chance for the cells to be settled, and for better contrast view, lower the condenser and reduce the microscopic light and examine the film by using the lens with magnification power (40x). Cryptococcus will be evident as shiny spherical budding in a dark background.
4. Conclusion
Cryptococcal meningitis should be considered as one of the possible diagnoses in a patient with altered sensorium and neck stiffness, especially those who are immunocompromised. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening complications.
Early management of cryptococcal meningitis is associated with better prognosis and lower neurological complications. Despite that, flucytosine is being described as the best antifungal medication for cryptococcal infections. Amphotericin B still gives good results in such cases.
Negative bacterial growth from a skin lesion does not necessitate that it is a sterile lesion; it may be an atypical microorganism or microorganism that needs special media to grow or longer duration to be cultivated. Clinical pathologists should be aware of Cryptococcus laboratory diagnosis and how to differentiate it from Candida spp. Microbiological culture is a confirmatory step for Cryptococcus diagnosis; however, Gram-stained and Indian ink-stained films are rapid and informative diagnostic methods especially in limited resources facilities. The communication between laboratory staff members and treating medical team is very crucial for better clinical judgment specifically in a circumstance where an unusual diagnostic result is released or diagnosing a rare disease.
CSF examination may show low cell count; however, infection presents; this is commonly seen in immunocompromised patients as no adequate inflammation. Cryptococcal infection associated with CNS latency which should to be suspected; hence, meticulous follow-up is an essential step in cryptococcal management. The second activation of cryptococcal latency is usually life-threatening and mostly fatal.
Acknowledgments
The authors would like to thank all members of Immunology Unit-Pediatric Department and Microbiology Unit-Clinical Pathology Department of Ain Shams University Hospital. The authors gratefully acknowledge Professor Dalia Helmy El-Ghoneimy and Professor Malaka Zakaria Amer for their efforts to diagnose and follow up severe medical cases including this presented case and special gratitude to the mother of the child for supporting with detailed medical information and for her medical awareness and patience throughout her daughter's longstanding disease.
Abbreviations
ALT:Alanine transaminase
ANA:Antinuclear antibody
AST:Aspartate transaminase
C. neoformans:
Cryptococcus neoformans
CBC:Complete blood count
CNS:Central nervous system
CRP:C-reactive protein
CSF:Cerebrospinal fluid
DNA:Deoxyribonucleic acid
dsDNA:Double-strand DNA
E.R:Emergency room
EEG:Electroencephalogram
eGFR:Estimated glomerular filtration rate
ESR:Erythrocyte sedimentation rate
HIV:Human immunodeficiency virus
IgG:Immunoglobulin G
IRIS:Immune reconstitution inflammatory syndrome
IV:Intravenous
MPA:Mycophenolic acid
MRI:Magnetic resonance imaging
PC ratio:Protein creatinine ratio
RF:Rheumatoid factor
RNA:Ribonucleic acid
RNP:Ribonucleoprotein antibodies
SDA:Sabouraud's dextrose agar
SLE:Systemic lupus erythematosus
SOPs:Standard operating procedures
WBC:White blood cell.
Data Availability
The data underlying the findings of this research are publicly available.
Ethical Approval
Compliance with ethics guidelines, all procedures followed the ethical standards of the responsible committee on human experimentation (institutional and national).
Consent
Written informed consent for publication of clinical details was obtained from the mother of the patient.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
Authors' Contributions
Heba Ezzat Hashem contributed to acquisition, analysis, and interpretation of data, drafting of paper, conception and design, revision for critical intellectual content, final approval, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Zakaria Hamza Ibrahim involved in revision for critical intellectual content, final approval, and financial support.
Figure 1 A simplified chart representing the sequence of the disease in our case.
Figure 2 (a) Clear colorless CSF sample; other etiological causes of meningitis especially viral meningitis versus fungal meningitis must be differentiated, specifically in the presence of clear colorless CSF samples with low cell count and minimal changes of CSF parameters. (b) Spherical budding yeast in the CSF; it should be differentiated from the elliptical budding yeast cells of Candida spp. which is more commonly encountered during CSF examination as a fungal cause of meningitis. (c) Gram-stained film; direct film from CSF shows spherical budding yeast cells with surrounding translucent haloes due to capsular structure. (d) Blood agar shows small white colonies, after 72 hours of incubation. (e) Sabouraud dextrose agar (SDA) shows pasty colonies that were confirmed to be Cryptococcus neoformans. (f) Gram from culture shows spherical yeast cells with surrounding translucent haloes.
Figure 3 Biochemical reaction; the urease test was positive.
Figure 4
Cryptococcus as shiny spherical budding in a dark background.
Figure 5 Laboratory course of the present case and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation; the patient improved clinically and discharged after almost one month with minimal residual weakness in her lower limbs. The nCD64 test was available in our hospital as a sepsis biomarker, and it was performed for our case for follow-up purposes.
Figure 6 Patient developed extensive skin ulceration with serous oozing from both lower limbs; this image was taken upon her clinical improvement on amphotericin B. The local edema resolved leaving the skin redundant, cracked, and the oozing discharge was first serous-like followed by purulent discharge then pus draining stopped.
Figure 7 EEG at the 4th admission, seizures, and other CNS manifestations in patients who had previous cryptococcal meningitis is very essential to be distinguished; it is due to reactivation of latent infection or due to seizures attributed to other medical causes. For the present case, EEG showed normal electric activates without focal localization.
Figure 8 MRI brain performed at the time of 3rd admission; dilated third ventricles were evident due to brain cell atrophy; at this occasion, signs of increase intracranial tension were negative which excluded it as a cause for cerebral ventricles dilatations.
Table 1 Laboratory course of the present case, and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation.
Hb TLC ANC ALC AMC PLT CRP CD64% CD64 MFI
08/05/2016 10.6 12.2 11.2 0.6 0.4 44 6 98.5 2.87
11/05/2016 9 10.9 9.2 1.1 0.51 81 6 91.5 1.91
15/05/2016 7.7 14.8 12.72 1.57 0.48 209 4 80.1 1.56
22/05/2016 7.2 10 7.6 1.1 0.5 238 4 68.9 1.45
Hb, hemoglobin (g/dl); TLC, total leukocytic count (X109/L); ANC, absolute neutrophil count (X109/L); ALC, absolute lymphocyte count (X109/L); AMC, absolute monocyte count (X109/L); PLT, platelet (X109/L); CRP, C-reactive protein (mg/L); nCD64%, neutrophil CD64%; nCD64MFI, nCD64 mean fluorescence intensity. | CYCLOPHOSPHAMIDE, HYDROXYCHLOROQUINE, MYCOPHENOLIC ACID, PREDNISONE | DrugsGivenReaction | CC BY | 33628263 | 19,588,393 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cryptococcosis'. | Atypical Presentation of Pediatric Systemic Lupus Erythematosus Complicated by Cryptococcal Meningitis.
Cryptococcus is an opportunistic fungal pathogen that leads to life-threatening infections. Cryptococcal infections are mainly reported in HIV patients and less commonly encountered in non-HIV immunocompromised host. Cryptococcus neoformans (C. neoformans) is the most common Cryptococcus species causing diseases in humans which can be presented as pulmonary, meningitis, cutaneous, and/or disseminated cryptococcosis. Case Presentation. A 12-year-old female girl from Cairo, Egypt, presented to the pediatric hospital with signs of systemic lupus erythematosus (SLE). She had an aggressive lupus nephritis course for which corticosteroids, mycophenolate mofetil, and cyclophosphamide were prescribed, and the child gradually improved and was discharged. Two months later, the patient exhibited skin lesions involved both in her legs, massive ulcers were developed and extended rapidly through the entire legs followed by deterioration in her conscious level, and signs of meningitis were documented. Cerebrospinal fluid (CSF) examination and microbiological workup were confirmatory for C. neoformans infection, and mental and motor functions were rapidly deteriorated. Treatment with amphotericin B in addition to supportive treatment and close follow-up of the patient's medical condition result in obvious clinical improvement and patient discharge with minimal residual weakness in her legs after almost a one-month duration. After six months, the patient was brought to the emergency department complaining of repeated attacks of seizures, a lumbar puncture was performed, and culture results were again confirmatory for C. neoformans. An intensive course of antifungal therapy was prescribed which was successful, evident by resolution of the signs and symptoms of infection in addition to negative culture results and negative sepsis biomarkers. The child clinically improved, but unfortunately, gradual optic nerve degeneration and brain cell atrophy as a sequel of severe and longstanding cryptococcal infection resulted in her death after almost one year from her first attack.
Cryptococcal infection among non-HIV patients is a rare disease but can result in advanced medical complications which may be fatal. The disease should be suspected to be reliably diagnosed. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening consequences. Amphotericin B can be used effectively in cryptococcosis management in the settings where flucytosine is not available. Signs of cryptococcal meningitis can be manifested again after a period of remission and clinical cure which signifies the latency of Cryptococcus in the central nervous system. The second activation of Cryptococcus after its latency is usually life-threatening and mostly fatal.
1. Background
Immunocompromised individuals including HIV, SLE, and patients on prolonged corticosteroid and immunosuppressant therapy are more prone to various bacterial, viral, and fungal opportunistic infections. One of the most important fatal fungal infections is cryptococcal infection [1–4]. C. neoformans is the most frequent cryptococcal species infect humans, and it is an encapsulated yeast microorganism, which is commonly transmitted through bird feces, plants, dust, soil, and contaminated food [2, 3]. Cryptococcosis can cause disseminated infection reaching to the lungs, central nervous system (CNS), and skin [2, 3, 5]. Dermal manifestations can present in different clinical morphologies including ulcers, acneiform papules, subcutaneous nodules, and rarely, cellulitis [4, 6].
2. Case Presentation
A 12-years-old Egyptian female student presented to Ain Shams University Pediatric Hospital complaining of generalized body edema, frothy urine, and proteinuria (3.7 g/day). The child was diagnosed as nephrotic syndrome, with repeated albumin infusions, and steroid therapy was initiated, but the child was nonresponding; instead, her medical condition deteriorated. Laboratory profile was in concordance with serologically quiescent SLE which included antinuclear antibody titer 1: 1280 finely speckled, elevated rheumatoid factor (RF) of 456 IU/ml (N: 0–20 IU/ml), positive SS-A/Ro > 8.0 and SS-B/La > 8.0 antibodies, anti-beta-2 glycoprotein IgM Ab > 100 U/ml, C-reactive protein (CRP) level 3.9 mg/l (N: 0–5 mg/l), and erythrocyte sedimentation rate (ESR) 51 mm/hour (N: 0–10 mm/hour). The serologic tests that were negative included anti-dsDNA Abs, complement C3 level 154 mg/dl (N: 106–194 mg/dl), complement C4 level 38 mg/dl (N: 19–50 mg/dl), cyclic citrullinated peptide IgG, cryoglobulin, serum immunofixation, Scl-70 scleroderma, Smith, RNP, cardiolipin antibodies, and lupus anticoagulant. Urine studies at the time revealed 3 + proteinuria, no hematuria or pyuria, a creatinine level of 0.93 mg/dl, and eGFR > 60 ml/min/1.73 m2. The diagnosis of SLE with nephrotic presentation was established, upon which the child received a medical regimen for lupus management including corticosteroids, mycophenolate mofetil, and cyclophosphamide which resulted in patient clinical improvement.
Two months later, the child was admitted complaining of poor appetite, nausea and vomiting, tiredness, swollen ankles, and shortness of breath, and deteriorated renal functions were evident in her laboratory profile: creatinine increased to 1.92 mg/dl, 4 + protein on urinalysis, worsening urine protein to creatinine (PC) ratio of 1.9 (N: 0.0–0.1), and 24-hour urine protein of 1170 mg/24 hours (N: 50–150 mg/24 hours). Lupus nephritis grade IV was confirmed. Therefore, the child received intermittent hemodialysis; in addition, the doses of the prescribed immunosuppressant was increased: prednisone (40 mg/day), hydroxychloroquine (6 mg/kg/day), and mycophenolate mofetil (2 g/day). The patient was kept under this protocol; she gradually improved and was discharged. A simplified chart representing the sequence of the disease in the presented case is illustrated in Figure 1.
After two months, the child manifested skin ulcers in her lower extremities which were progressive in course. Drug allergies, insect bites, and family history were excluded. First, these lesions were nonwell-demarcated, erythematous, painful on palpation, nonpruritic with increasing local edema, and bullae formation. A few days later, lesions spread to involve entire her legs up to the groin area, the bullae began to coalescence together, ruptured, and a huge amount of serous discharge was drained from the lesions; no corresponding lesions appeared on the face, trunk, or upper extremities, and fever was not present at first, but with worsening of the lesions, the patient became feverish, hematuric, anemic, and hypotensive with deteriorated general condition; hence, she was admitted for the 2nd time.
At the time of admission, laboratory profile revealed hemoglobin 8.2 g/dL, white blood cell (WBC) count 10,800/mm³, platelet count 129,000 cells/mm³, serum aspartate transaminase (AST) 10 U/L, serum alanine transaminase (ALT) 17 U/L, CRP 12 mg/L, and ESR 60 mm. Upon worsening the skin lesions, bacterial skin infection was suspected; so empirical treatment with amikacin and cefepime was started and the dose of prednisone decreased to 30 mg/day; microbiological cultures revealed no microorganism growth after 48 hours of incubation. Upon suspicion of bacterial cellulitis and due to the lack of improvements of the skin lesions, vancomycin was added to the treatment regimen.
After three days, the patient medical condition deteriorated rapidly. She complained of severe headache, altered memory, continuous agitation, neck rigidity, stiffness, photophobia, and total loss of appetite; so, meningitis was suspected; hence, lumbar puncture was performed, and a CSF sample was sent for cytological examination in addition to culture procedures. The sample was clear colorless on physical inspection (Figure 2)(a), and cell count was 25 cells/HPF.
Direct Gram examination of CSF showed spherical budding encapsulated yeast cells surrounded by translucent hallow around the cells (Figures 2(b) and 2)(c). CSF chemical examination revealed protein level 74 mg/dL (normal range 15–60 mg/dL) and glucose levels 41 mg/dL (normal range 50–80 mg/dL). The sample was cultured on aerobic blood agar, anaerobic blood agar, chocolate, and MacConkey agar; the plates showed delayed growth at the end of the third day (72 hours incubation according to CSF standard operating procedures (SOPs) of our microbiology lab). It was a minute whitish milky colony, which was highly suggestive of fungal infection, confirmed by further subculture, the sample on Sabouraud's dextrose agar (SDA) plates (Figures 2(d)–2(f)). Indian ink stain and positive biochemical reactions were confirmatory for the diagnosis of Cryptococcus infection (Figures 3 and 4). Additionally, antifungal susceptibility testing was performed which was positive for both amphotericin B and flucytosine.
Despite that, the child manifested obvious clinical signs and symptoms of meningitis. Magnetic resonance imaging (MRI) brain with contrast showed findings within normal limits, and blood culture was negative for microbiological growth after 7 days incubation.
Based on the available laboratory results, treatment for disseminated cryptococcosis was initiated immediately upon laboratory notification, prednisone was further decreased to 20 mg/day, and fluconazole was discontinued. Amphotericin B was started at a dose of 0.7 mg/kg/day with an infusion time of 6 hours, since the patient had repeated reactions (fever, chills, and nausea) with a shorter infusion time. Concerning flucytosine, which is indicated as the drug of choice in cryptococcal meningitis treatment, it was not used for treatment of our presented case due to financial aspects and nonavailability in our country, Egypt. Repeated lumber tapping was performed to relieve persistent increased intracranial tension as a consequence of severe meningitis; in addition, plasmapheresis was performed to remove lupus autoantibodies.
The child was subjected for further workup to rule out pneumonia and other organs affection, and for follow up purpose, chest X-ray was ordered, which revealed normal findings, ESR, CRP, complete blood count (CBC), and sepsis marker, neutrophil CD64. These laboratory tests were performed every 3 days on a routine base for monitoring the medical progress which showed dramatic gradual improvement (Table 1 and Figure 5); in conjugation with clinical signs and symptoms improvement evident by regaining her mental and motor skills, besides healing of the leg ulcers, pus draining stopped and swelling disappeared (Figure 6). In this setting, a lumbar puncture was intended to be performed upon this obvious clinical and laboratory improvement preparing the patient to be discharged, but the child refused at her own request and was discharged on her demand after almost 30 days since amphotericin B infusion was first prescribed.
At the time of discharge, the patient had no pulmonary sequelae, but she had residual weakness in her lower limbs. The laboratory results at the time of discharge were hemoglobin 9.2 g/dL, WBC 16.700 cells per mm³, platelet 303.000 cells per mm³, AST 10 U/L, ALT 4 U/L, CRP 6 mg/L, and ESR 53 mm/h. The child was instructed to continue fluconazole (400 mg/day) at home for 8 weeks and then reduced its dose to 200 mg/day for 1 year. And she was weaned gradually from corticosteroid therapy.
One month later, the child was brought to the emergency department complaining of severe headache, projectile vomiting, and blurred vision. She was admitted for the 3rd time. An MRI brain was ordered, and a lumbar puncture was performed urgently to relieve intracranial tension, and for chemical, cytological, and microbiological analyses, all were negative for infection except for CRP slightly positive (12 mg/L). So, lupus flare-up was suspected, and pulse steroid therapy was started, in addition to antifungal (fluconazole) and antibiotic (amikacin and cefepime) coverage. The patient was subjected for plasmapheresis; upon it, she manifested dramatical improvement and discharge. She started to attend the immunotherapy clinic every two weeks for follow up purpose; she did well for 5 months and regained her functions except for difficulty in talking and walking abilities as she could not walk without support; so, the mother was advised to bring her for regular physiotherapy sessions every week.
Five months later, the patient complained of shivering in her legs and hands followed by seizures attacks which were gradually increasing in frequency and duration till her mother brought her to the E/R. She was admitted for the 4th time. Phenytoin was prescribed, initial dose 2.5 mg/kg/dose twice a day and increased gradually to maximum 5 mg/kg/dose twice daily, and intensive work up profile was conducted searching for the cause of the seizures which included electroencephalogram (EEG), MRI brain, full lab evaluation, and CSF chemical analysis and microbiological examination. EEG revealed normal electric impulses without focal activities (Figure 7). MRI brain showed mildly dilated 3rd ventricles, CSF chemistry analysis revealed protein level 82 mg/dL (normal range 15–60 mg/dL), and glucose levels of 35 mg/dL (normal range 50–80 mg/dL). Upon receiving the sample in our microbiology lab, the sample physical criteria were very similar to the previous one, clear colorless, and cell count was 15 cell/cm3. A direct wet film examination was positive for budding yeast cells which were suspected and notified immediately to the pediatric team, and protocol of treatment was decided rapidly. CSF culture results were again confirmatory for C. neoformans.
An intensive course of antifungal therapy was initiated which included amphotericin B (0.7 mg/kg/day) with an infusion time of 6 hours, and fluconazole. Resolution of patient signs and symptoms of infection was clinically evident in addition to negative culture results and improved laboratory sepsis parameters. The child general condition improved, but at this setting, she complained of poor visual acuity. The pediatric team immediately consulted the specialist neurosurgeon, ophthalmologist, and an MRI brain urgently performed which showed evidence of brain cell atrophy with subsequent increased intracranial ventricular sizes and evidence of optic nerve atrophy; the ophthalmologist confirmed bilateral optic nerve degeneration which was more evident on the left side (Figure 8).
After almost one month and, however, signs and symptoms of infection were resolved, cryptococcosis longstanding course with brain cell atrophy as a sequel of cryptococcal meningitis resulted in the child's death after almost one year from her first attack.
3. Discussion and Conclusion
Cryptococcus is an opportunistic fungal pathogen that leads to rare life-threatening infection. Meningoencephalitis and disseminated cryptococcosis are usually common complications reported in immunocompromised hosts [7, 8]. In the presented case, we reported a pediatric systemic lupus erythematosus patient complicated by rapidly disseminating cryptococcal infection which exhibited a latency in the child CNS followed by an attack of infection flare-up which was successfully treated, but slowly progressive brain cell atrophy due to longstanding disease resulted in her death.
Infections and sepsis are major causes of hospitalization, mortality, and morbidity in immunosuppressed patients [9]. Cryptococcosis is one of the fatal fungal infections reported mainly in immunocompromised hosts; however, several reported cases point to its incidence also in immunocompetent patients [10–12]. Cryptococcosis has a low incidence in non-HIV patients, approximately 1 : 100.000 [5, 13]. Patients with SLE are highly susceptible to infections due to the combined effects of their immunosuppressive therapy and the abnormalities of the immune system that the disease itself causes [14]. Concerning our presented case, prolonged corticosteroid therapy and immunosuppressants due to her underlying disease (SLE) were the major risk factors for disseminated cryptococcosis with poor outcomes.
The patient had a progressive renal course complicated by lupus nephritis class IV for which immunosuppressants was given. Lupus nephritis is clinically evident in 50–60% of patients with SLE [15]. Both mycophenolate mofetil and cyclophosphamide were prescribed to our case. Mycophenolate mofetil depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation [16]. While, cyclophosphamide inhibits protein synthesis through DNA and RNA crosslinking [17].
By discussing Cryptococcus as the causative pathogen, C. neoformans is the most common strain causing infections in humans, and it is an encapsulated yeast that has been isolated from chickens' droppings and grows readily in soil contaminated with avian excreta particularly that of pigeons. In humans, it can colonize the upper airway system. Nevertheless, no animal-to-human nor person-to-person respiratory transmission has been documented [9]. Our presented case lived in low socioeconomic and hygienic status, and she denied contact with pigeon or birds. However, the fungus might have been indirectly transmitted via other sources such as vegetables, fruits, and dairy products [8].
C. neoformans generally cause three types of infections: cryptococcal meningitis, pulmonary, and cutaneous cryptococcosis [18]. The dissemination of this disease occurs when at least two noncontiguous sites are affected, which is unusual and mostly observed in HIV patients [4, 19]. In our case, only pulmonary involvement was not present while cutaneous manifestations were the first presenting symptoms followed by cryptococcal meningitis. Some studies support the importance of lumbar puncture in patients with cryptococcosis, even when CNS symptoms are not observed because asymptomatic meningitis is reported to be an early stage of the disease [20].
Systemic lupus erythematosus disease activity index (SLEDAI) was calculated for our presented case in order to be used as a predictor for SLE mortality and as a measure of global disease activity, and it was achieving high values (79) which reflect why the patient underwent into cryptococcal meningitis with poor clinical course. Eventhough, for patients with low SLE activity, the possibility of cryptococcal meningitis should not be underestimated [21].
Skin involvement is a rare presenting symptom of Cryptococcus infection, but it is usually a sign of disseminated disease; it may precede the systemic symptoms even eight months earlier [5, 18]. It is important to stress the rarity and polymorphism of the skin conditions, with the possible development of vesicles or blisters and the potential progression to ulceration [1, 4].
Cryptococcal cellulitis is a rare specific cutaneous manifestation, which was developed in our case. It was initially suspected to be a bacterial infection for which antibiotics were prescribed until its failure and microbiological results confirmed the fungal diagnosis. Although rare, the present case, cryptococcal cellulitis was restricted mainly to the lower body, particularly to the lower extremities, and this was reported in other rare reported cases [1, 2]. Despite that, cryptococcal cellulitis is uncommon and undistinguishable from acute bacterial cellulitis for appearance and presentation [6], but high suspicion especially in a risky patient should be considered.
More than 80% of patients manifested cryptococcal cellulitis and are expected to survive in immunocompetent status when they receive the appropriate antifungal therapy [6]. According to the current guidelines of the American Society of Infectious Diseases for disseminated cryptococcosis management, amphotericin B combined with flucytosine is recommended as the primary therapy, followed by fluconazole as a consolidation therapy [4, 18]. Flucytosine is expensive and was not available in our country; so, it was not considered for the treatment. Instead, it was replaced by the addition of fluconazole to amphotericin B regimen.
Cryptococcal laboratory diagnosis relies on three main methods: latex agglutination test, fungal culture, and direct microscopic examination [22]. In the present case, both the microscopic examination and microbiological cultures were the cornerstone for the diagnosis. C. neoformans was differentiated from other fungal species especially Candida spp. by the characterized morphology in the Gram-stained smear, microbiological culture characters, Indian ink stain positivity, and biochemical reactions.
Indian ink stain was positive in our case. In HIV-positive patients, its sensitivity increases up to 80% due to higher fungal loads in the CSF, while in HIV negative patients, the sensitivity is only 30–50% [8, 23]. CSF culture is considered the gold standard for cryptococcal diagnosis, but it has several diagnostic obstacles as long time is needed for fungus to grow, while time is very critical for management of meningitis cases with evolving lifetime neurological complications [24]. Besides, fungal cultures are not available in all medical facilities and therefore may not be performed. It is also associated with false-negative results, especially in cases with low fungal load, and this may be the attributed cause of negative blood culture result in our case.
Regarding management of cryptococcosis, the prolonged course (6–10 weeks) of IV amphotericin B monotherapy, together with the reduction of chemotherapy to improve immune status, was the main target. Caution was taken while reducing immunosuppressive therapy, since a rapid reduction is reported to be associated with immune reconstitution inflammatory syndrome (IRIS) in some patients [9]. There is evidence that supports the requirement for maintenance therapy with fluconazole administered as indefinite secondary prophylaxis, since the rate of recurrence exceeds 50% after apparently successful treatment [25].
Differential diagnosis of the present case must be addressed which includes besides to what was mentioned, infection versus flare-up attacks in lupus patients; several sepsis markers including CRP increase significantly in SLE patients with concomitant infection but increase only slightly or not at all in patients with a lupus flare without infection [14, 26] which is exactly encountered in our presented case. Additionally, decreased visual acuity due to increased intracranial tension (papilledema) was differentiated from decreased visual acuity due to optic nerve atrophy. For the presented case, papilledema was evident on fundus examination at the time of cryptococcal meningitis first diagnosed, while optic nerve atrophy was evident on fundus examination at the end.
Finally, we highlight the importance of clinicians' awareness about such infection among non-HIV immunocompromised patients including those who are diagnosed with autoimmune diseases. The latency of Cryptococcus should be considered and suspected during the management of such cases which necessitate early recognition and proper management.
For preparing Indian ink-stained film, take two drops from the examined CSF sample directly or a small part of the growing colony from the plate, mix it well with the ink, put a cover slide, and leave the slide for an hour to give a chance for the cells to be settled, and for better contrast view, lower the condenser and reduce the microscopic light and examine the film by using the lens with magnification power (40x). Cryptococcus will be evident as shiny spherical budding in a dark background.
4. Conclusion
Cryptococcal meningitis should be considered as one of the possible diagnoses in a patient with altered sensorium and neck stiffness, especially those who are immunocompromised. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening complications.
Early management of cryptococcal meningitis is associated with better prognosis and lower neurological complications. Despite that, flucytosine is being described as the best antifungal medication for cryptococcal infections. Amphotericin B still gives good results in such cases.
Negative bacterial growth from a skin lesion does not necessitate that it is a sterile lesion; it may be an atypical microorganism or microorganism that needs special media to grow or longer duration to be cultivated. Clinical pathologists should be aware of Cryptococcus laboratory diagnosis and how to differentiate it from Candida spp. Microbiological culture is a confirmatory step for Cryptococcus diagnosis; however, Gram-stained and Indian ink-stained films are rapid and informative diagnostic methods especially in limited resources facilities. The communication between laboratory staff members and treating medical team is very crucial for better clinical judgment specifically in a circumstance where an unusual diagnostic result is released or diagnosing a rare disease.
CSF examination may show low cell count; however, infection presents; this is commonly seen in immunocompromised patients as no adequate inflammation. Cryptococcal infection associated with CNS latency which should to be suspected; hence, meticulous follow-up is an essential step in cryptococcal management. The second activation of cryptococcal latency is usually life-threatening and mostly fatal.
Acknowledgments
The authors would like to thank all members of Immunology Unit-Pediatric Department and Microbiology Unit-Clinical Pathology Department of Ain Shams University Hospital. The authors gratefully acknowledge Professor Dalia Helmy El-Ghoneimy and Professor Malaka Zakaria Amer for their efforts to diagnose and follow up severe medical cases including this presented case and special gratitude to the mother of the child for supporting with detailed medical information and for her medical awareness and patience throughout her daughter's longstanding disease.
Abbreviations
ALT:Alanine transaminase
ANA:Antinuclear antibody
AST:Aspartate transaminase
C. neoformans:
Cryptococcus neoformans
CBC:Complete blood count
CNS:Central nervous system
CRP:C-reactive protein
CSF:Cerebrospinal fluid
DNA:Deoxyribonucleic acid
dsDNA:Double-strand DNA
E.R:Emergency room
EEG:Electroencephalogram
eGFR:Estimated glomerular filtration rate
ESR:Erythrocyte sedimentation rate
HIV:Human immunodeficiency virus
IgG:Immunoglobulin G
IRIS:Immune reconstitution inflammatory syndrome
IV:Intravenous
MPA:Mycophenolic acid
MRI:Magnetic resonance imaging
PC ratio:Protein creatinine ratio
RF:Rheumatoid factor
RNA:Ribonucleic acid
RNP:Ribonucleoprotein antibodies
SDA:Sabouraud's dextrose agar
SLE:Systemic lupus erythematosus
SOPs:Standard operating procedures
WBC:White blood cell.
Data Availability
The data underlying the findings of this research are publicly available.
Ethical Approval
Compliance with ethics guidelines, all procedures followed the ethical standards of the responsible committee on human experimentation (institutional and national).
Consent
Written informed consent for publication of clinical details was obtained from the mother of the patient.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
Authors' Contributions
Heba Ezzat Hashem contributed to acquisition, analysis, and interpretation of data, drafting of paper, conception and design, revision for critical intellectual content, final approval, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Zakaria Hamza Ibrahim involved in revision for critical intellectual content, final approval, and financial support.
Figure 1 A simplified chart representing the sequence of the disease in our case.
Figure 2 (a) Clear colorless CSF sample; other etiological causes of meningitis especially viral meningitis versus fungal meningitis must be differentiated, specifically in the presence of clear colorless CSF samples with low cell count and minimal changes of CSF parameters. (b) Spherical budding yeast in the CSF; it should be differentiated from the elliptical budding yeast cells of Candida spp. which is more commonly encountered during CSF examination as a fungal cause of meningitis. (c) Gram-stained film; direct film from CSF shows spherical budding yeast cells with surrounding translucent haloes due to capsular structure. (d) Blood agar shows small white colonies, after 72 hours of incubation. (e) Sabouraud dextrose agar (SDA) shows pasty colonies that were confirmed to be Cryptococcus neoformans. (f) Gram from culture shows spherical yeast cells with surrounding translucent haloes.
Figure 3 Biochemical reaction; the urease test was positive.
Figure 4
Cryptococcus as shiny spherical budding in a dark background.
Figure 5 Laboratory course of the present case and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation; the patient improved clinically and discharged after almost one month with minimal residual weakness in her lower limbs. The nCD64 test was available in our hospital as a sepsis biomarker, and it was performed for our case for follow-up purposes.
Figure 6 Patient developed extensive skin ulceration with serous oozing from both lower limbs; this image was taken upon her clinical improvement on amphotericin B. The local edema resolved leaving the skin redundant, cracked, and the oozing discharge was first serous-like followed by purulent discharge then pus draining stopped.
Figure 7 EEG at the 4th admission, seizures, and other CNS manifestations in patients who had previous cryptococcal meningitis is very essential to be distinguished; it is due to reactivation of latent infection or due to seizures attributed to other medical causes. For the present case, EEG showed normal electric activates without focal localization.
Figure 8 MRI brain performed at the time of 3rd admission; dilated third ventricles were evident due to brain cell atrophy; at this occasion, signs of increase intracranial tension were negative which excluded it as a cause for cerebral ventricles dilatations.
Table 1 Laboratory course of the present case, and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation.
Hb TLC ANC ALC AMC PLT CRP CD64% CD64 MFI
08/05/2016 10.6 12.2 11.2 0.6 0.4 44 6 98.5 2.87
11/05/2016 9 10.9 9.2 1.1 0.51 81 6 91.5 1.91
15/05/2016 7.7 14.8 12.72 1.57 0.48 209 4 80.1 1.56
22/05/2016 7.2 10 7.6 1.1 0.5 238 4 68.9 1.45
Hb, hemoglobin (g/dl); TLC, total leukocytic count (X109/L); ANC, absolute neutrophil count (X109/L); ALC, absolute lymphocyte count (X109/L); AMC, absolute monocyte count (X109/L); PLT, platelet (X109/L); CRP, C-reactive protein (mg/L); nCD64%, neutrophil CD64%; nCD64MFI, nCD64 mean fluorescence intensity. | CYCLOPHOSPHAMIDE, HYDROXYCHLOROQUINE, MYCOPHENOLIC ACID, PREDNISONE | DrugsGivenReaction | CC BY | 33628263 | 19,588,393 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Atypical Presentation of Pediatric Systemic Lupus Erythematosus Complicated by Cryptococcal Meningitis.
Cryptococcus is an opportunistic fungal pathogen that leads to life-threatening infections. Cryptococcal infections are mainly reported in HIV patients and less commonly encountered in non-HIV immunocompromised host. Cryptococcus neoformans (C. neoformans) is the most common Cryptococcus species causing diseases in humans which can be presented as pulmonary, meningitis, cutaneous, and/or disseminated cryptococcosis. Case Presentation. A 12-year-old female girl from Cairo, Egypt, presented to the pediatric hospital with signs of systemic lupus erythematosus (SLE). She had an aggressive lupus nephritis course for which corticosteroids, mycophenolate mofetil, and cyclophosphamide were prescribed, and the child gradually improved and was discharged. Two months later, the patient exhibited skin lesions involved both in her legs, massive ulcers were developed and extended rapidly through the entire legs followed by deterioration in her conscious level, and signs of meningitis were documented. Cerebrospinal fluid (CSF) examination and microbiological workup were confirmatory for C. neoformans infection, and mental and motor functions were rapidly deteriorated. Treatment with amphotericin B in addition to supportive treatment and close follow-up of the patient's medical condition result in obvious clinical improvement and patient discharge with minimal residual weakness in her legs after almost a one-month duration. After six months, the patient was brought to the emergency department complaining of repeated attacks of seizures, a lumbar puncture was performed, and culture results were again confirmatory for C. neoformans. An intensive course of antifungal therapy was prescribed which was successful, evident by resolution of the signs and symptoms of infection in addition to negative culture results and negative sepsis biomarkers. The child clinically improved, but unfortunately, gradual optic nerve degeneration and brain cell atrophy as a sequel of severe and longstanding cryptococcal infection resulted in her death after almost one year from her first attack.
Cryptococcal infection among non-HIV patients is a rare disease but can result in advanced medical complications which may be fatal. The disease should be suspected to be reliably diagnosed. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening consequences. Amphotericin B can be used effectively in cryptococcosis management in the settings where flucytosine is not available. Signs of cryptococcal meningitis can be manifested again after a period of remission and clinical cure which signifies the latency of Cryptococcus in the central nervous system. The second activation of Cryptococcus after its latency is usually life-threatening and mostly fatal.
1. Background
Immunocompromised individuals including HIV, SLE, and patients on prolonged corticosteroid and immunosuppressant therapy are more prone to various bacterial, viral, and fungal opportunistic infections. One of the most important fatal fungal infections is cryptococcal infection [1–4]. C. neoformans is the most frequent cryptococcal species infect humans, and it is an encapsulated yeast microorganism, which is commonly transmitted through bird feces, plants, dust, soil, and contaminated food [2, 3]. Cryptococcosis can cause disseminated infection reaching to the lungs, central nervous system (CNS), and skin [2, 3, 5]. Dermal manifestations can present in different clinical morphologies including ulcers, acneiform papules, subcutaneous nodules, and rarely, cellulitis [4, 6].
2. Case Presentation
A 12-years-old Egyptian female student presented to Ain Shams University Pediatric Hospital complaining of generalized body edema, frothy urine, and proteinuria (3.7 g/day). The child was diagnosed as nephrotic syndrome, with repeated albumin infusions, and steroid therapy was initiated, but the child was nonresponding; instead, her medical condition deteriorated. Laboratory profile was in concordance with serologically quiescent SLE which included antinuclear antibody titer 1: 1280 finely speckled, elevated rheumatoid factor (RF) of 456 IU/ml (N: 0–20 IU/ml), positive SS-A/Ro > 8.0 and SS-B/La > 8.0 antibodies, anti-beta-2 glycoprotein IgM Ab > 100 U/ml, C-reactive protein (CRP) level 3.9 mg/l (N: 0–5 mg/l), and erythrocyte sedimentation rate (ESR) 51 mm/hour (N: 0–10 mm/hour). The serologic tests that were negative included anti-dsDNA Abs, complement C3 level 154 mg/dl (N: 106–194 mg/dl), complement C4 level 38 mg/dl (N: 19–50 mg/dl), cyclic citrullinated peptide IgG, cryoglobulin, serum immunofixation, Scl-70 scleroderma, Smith, RNP, cardiolipin antibodies, and lupus anticoagulant. Urine studies at the time revealed 3 + proteinuria, no hematuria or pyuria, a creatinine level of 0.93 mg/dl, and eGFR > 60 ml/min/1.73 m2. The diagnosis of SLE with nephrotic presentation was established, upon which the child received a medical regimen for lupus management including corticosteroids, mycophenolate mofetil, and cyclophosphamide which resulted in patient clinical improvement.
Two months later, the child was admitted complaining of poor appetite, nausea and vomiting, tiredness, swollen ankles, and shortness of breath, and deteriorated renal functions were evident in her laboratory profile: creatinine increased to 1.92 mg/dl, 4 + protein on urinalysis, worsening urine protein to creatinine (PC) ratio of 1.9 (N: 0.0–0.1), and 24-hour urine protein of 1170 mg/24 hours (N: 50–150 mg/24 hours). Lupus nephritis grade IV was confirmed. Therefore, the child received intermittent hemodialysis; in addition, the doses of the prescribed immunosuppressant was increased: prednisone (40 mg/day), hydroxychloroquine (6 mg/kg/day), and mycophenolate mofetil (2 g/day). The patient was kept under this protocol; she gradually improved and was discharged. A simplified chart representing the sequence of the disease in the presented case is illustrated in Figure 1.
After two months, the child manifested skin ulcers in her lower extremities which were progressive in course. Drug allergies, insect bites, and family history were excluded. First, these lesions were nonwell-demarcated, erythematous, painful on palpation, nonpruritic with increasing local edema, and bullae formation. A few days later, lesions spread to involve entire her legs up to the groin area, the bullae began to coalescence together, ruptured, and a huge amount of serous discharge was drained from the lesions; no corresponding lesions appeared on the face, trunk, or upper extremities, and fever was not present at first, but with worsening of the lesions, the patient became feverish, hematuric, anemic, and hypotensive with deteriorated general condition; hence, she was admitted for the 2nd time.
At the time of admission, laboratory profile revealed hemoglobin 8.2 g/dL, white blood cell (WBC) count 10,800/mm³, platelet count 129,000 cells/mm³, serum aspartate transaminase (AST) 10 U/L, serum alanine transaminase (ALT) 17 U/L, CRP 12 mg/L, and ESR 60 mm. Upon worsening the skin lesions, bacterial skin infection was suspected; so empirical treatment with amikacin and cefepime was started and the dose of prednisone decreased to 30 mg/day; microbiological cultures revealed no microorganism growth after 48 hours of incubation. Upon suspicion of bacterial cellulitis and due to the lack of improvements of the skin lesions, vancomycin was added to the treatment regimen.
After three days, the patient medical condition deteriorated rapidly. She complained of severe headache, altered memory, continuous agitation, neck rigidity, stiffness, photophobia, and total loss of appetite; so, meningitis was suspected; hence, lumbar puncture was performed, and a CSF sample was sent for cytological examination in addition to culture procedures. The sample was clear colorless on physical inspection (Figure 2)(a), and cell count was 25 cells/HPF.
Direct Gram examination of CSF showed spherical budding encapsulated yeast cells surrounded by translucent hallow around the cells (Figures 2(b) and 2)(c). CSF chemical examination revealed protein level 74 mg/dL (normal range 15–60 mg/dL) and glucose levels 41 mg/dL (normal range 50–80 mg/dL). The sample was cultured on aerobic blood agar, anaerobic blood agar, chocolate, and MacConkey agar; the plates showed delayed growth at the end of the third day (72 hours incubation according to CSF standard operating procedures (SOPs) of our microbiology lab). It was a minute whitish milky colony, which was highly suggestive of fungal infection, confirmed by further subculture, the sample on Sabouraud's dextrose agar (SDA) plates (Figures 2(d)–2(f)). Indian ink stain and positive biochemical reactions were confirmatory for the diagnosis of Cryptococcus infection (Figures 3 and 4). Additionally, antifungal susceptibility testing was performed which was positive for both amphotericin B and flucytosine.
Despite that, the child manifested obvious clinical signs and symptoms of meningitis. Magnetic resonance imaging (MRI) brain with contrast showed findings within normal limits, and blood culture was negative for microbiological growth after 7 days incubation.
Based on the available laboratory results, treatment for disseminated cryptococcosis was initiated immediately upon laboratory notification, prednisone was further decreased to 20 mg/day, and fluconazole was discontinued. Amphotericin B was started at a dose of 0.7 mg/kg/day with an infusion time of 6 hours, since the patient had repeated reactions (fever, chills, and nausea) with a shorter infusion time. Concerning flucytosine, which is indicated as the drug of choice in cryptococcal meningitis treatment, it was not used for treatment of our presented case due to financial aspects and nonavailability in our country, Egypt. Repeated lumber tapping was performed to relieve persistent increased intracranial tension as a consequence of severe meningitis; in addition, plasmapheresis was performed to remove lupus autoantibodies.
The child was subjected for further workup to rule out pneumonia and other organs affection, and for follow up purpose, chest X-ray was ordered, which revealed normal findings, ESR, CRP, complete blood count (CBC), and sepsis marker, neutrophil CD64. These laboratory tests were performed every 3 days on a routine base for monitoring the medical progress which showed dramatic gradual improvement (Table 1 and Figure 5); in conjugation with clinical signs and symptoms improvement evident by regaining her mental and motor skills, besides healing of the leg ulcers, pus draining stopped and swelling disappeared (Figure 6). In this setting, a lumbar puncture was intended to be performed upon this obvious clinical and laboratory improvement preparing the patient to be discharged, but the child refused at her own request and was discharged on her demand after almost 30 days since amphotericin B infusion was first prescribed.
At the time of discharge, the patient had no pulmonary sequelae, but she had residual weakness in her lower limbs. The laboratory results at the time of discharge were hemoglobin 9.2 g/dL, WBC 16.700 cells per mm³, platelet 303.000 cells per mm³, AST 10 U/L, ALT 4 U/L, CRP 6 mg/L, and ESR 53 mm/h. The child was instructed to continue fluconazole (400 mg/day) at home for 8 weeks and then reduced its dose to 200 mg/day for 1 year. And she was weaned gradually from corticosteroid therapy.
One month later, the child was brought to the emergency department complaining of severe headache, projectile vomiting, and blurred vision. She was admitted for the 3rd time. An MRI brain was ordered, and a lumbar puncture was performed urgently to relieve intracranial tension, and for chemical, cytological, and microbiological analyses, all were negative for infection except for CRP slightly positive (12 mg/L). So, lupus flare-up was suspected, and pulse steroid therapy was started, in addition to antifungal (fluconazole) and antibiotic (amikacin and cefepime) coverage. The patient was subjected for plasmapheresis; upon it, she manifested dramatical improvement and discharge. She started to attend the immunotherapy clinic every two weeks for follow up purpose; she did well for 5 months and regained her functions except for difficulty in talking and walking abilities as she could not walk without support; so, the mother was advised to bring her for regular physiotherapy sessions every week.
Five months later, the patient complained of shivering in her legs and hands followed by seizures attacks which were gradually increasing in frequency and duration till her mother brought her to the E/R. She was admitted for the 4th time. Phenytoin was prescribed, initial dose 2.5 mg/kg/dose twice a day and increased gradually to maximum 5 mg/kg/dose twice daily, and intensive work up profile was conducted searching for the cause of the seizures which included electroencephalogram (EEG), MRI brain, full lab evaluation, and CSF chemical analysis and microbiological examination. EEG revealed normal electric impulses without focal activities (Figure 7). MRI brain showed mildly dilated 3rd ventricles, CSF chemistry analysis revealed protein level 82 mg/dL (normal range 15–60 mg/dL), and glucose levels of 35 mg/dL (normal range 50–80 mg/dL). Upon receiving the sample in our microbiology lab, the sample physical criteria were very similar to the previous one, clear colorless, and cell count was 15 cell/cm3. A direct wet film examination was positive for budding yeast cells which were suspected and notified immediately to the pediatric team, and protocol of treatment was decided rapidly. CSF culture results were again confirmatory for C. neoformans.
An intensive course of antifungal therapy was initiated which included amphotericin B (0.7 mg/kg/day) with an infusion time of 6 hours, and fluconazole. Resolution of patient signs and symptoms of infection was clinically evident in addition to negative culture results and improved laboratory sepsis parameters. The child general condition improved, but at this setting, she complained of poor visual acuity. The pediatric team immediately consulted the specialist neurosurgeon, ophthalmologist, and an MRI brain urgently performed which showed evidence of brain cell atrophy with subsequent increased intracranial ventricular sizes and evidence of optic nerve atrophy; the ophthalmologist confirmed bilateral optic nerve degeneration which was more evident on the left side (Figure 8).
After almost one month and, however, signs and symptoms of infection were resolved, cryptococcosis longstanding course with brain cell atrophy as a sequel of cryptococcal meningitis resulted in the child's death after almost one year from her first attack.
3. Discussion and Conclusion
Cryptococcus is an opportunistic fungal pathogen that leads to rare life-threatening infection. Meningoencephalitis and disseminated cryptococcosis are usually common complications reported in immunocompromised hosts [7, 8]. In the presented case, we reported a pediatric systemic lupus erythematosus patient complicated by rapidly disseminating cryptococcal infection which exhibited a latency in the child CNS followed by an attack of infection flare-up which was successfully treated, but slowly progressive brain cell atrophy due to longstanding disease resulted in her death.
Infections and sepsis are major causes of hospitalization, mortality, and morbidity in immunosuppressed patients [9]. Cryptococcosis is one of the fatal fungal infections reported mainly in immunocompromised hosts; however, several reported cases point to its incidence also in immunocompetent patients [10–12]. Cryptococcosis has a low incidence in non-HIV patients, approximately 1 : 100.000 [5, 13]. Patients with SLE are highly susceptible to infections due to the combined effects of their immunosuppressive therapy and the abnormalities of the immune system that the disease itself causes [14]. Concerning our presented case, prolonged corticosteroid therapy and immunosuppressants due to her underlying disease (SLE) were the major risk factors for disseminated cryptococcosis with poor outcomes.
The patient had a progressive renal course complicated by lupus nephritis class IV for which immunosuppressants was given. Lupus nephritis is clinically evident in 50–60% of patients with SLE [15]. Both mycophenolate mofetil and cyclophosphamide were prescribed to our case. Mycophenolate mofetil depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation [16]. While, cyclophosphamide inhibits protein synthesis through DNA and RNA crosslinking [17].
By discussing Cryptococcus as the causative pathogen, C. neoformans is the most common strain causing infections in humans, and it is an encapsulated yeast that has been isolated from chickens' droppings and grows readily in soil contaminated with avian excreta particularly that of pigeons. In humans, it can colonize the upper airway system. Nevertheless, no animal-to-human nor person-to-person respiratory transmission has been documented [9]. Our presented case lived in low socioeconomic and hygienic status, and she denied contact with pigeon or birds. However, the fungus might have been indirectly transmitted via other sources such as vegetables, fruits, and dairy products [8].
C. neoformans generally cause three types of infections: cryptococcal meningitis, pulmonary, and cutaneous cryptococcosis [18]. The dissemination of this disease occurs when at least two noncontiguous sites are affected, which is unusual and mostly observed in HIV patients [4, 19]. In our case, only pulmonary involvement was not present while cutaneous manifestations were the first presenting symptoms followed by cryptococcal meningitis. Some studies support the importance of lumbar puncture in patients with cryptococcosis, even when CNS symptoms are not observed because asymptomatic meningitis is reported to be an early stage of the disease [20].
Systemic lupus erythematosus disease activity index (SLEDAI) was calculated for our presented case in order to be used as a predictor for SLE mortality and as a measure of global disease activity, and it was achieving high values (79) which reflect why the patient underwent into cryptococcal meningitis with poor clinical course. Eventhough, for patients with low SLE activity, the possibility of cryptococcal meningitis should not be underestimated [21].
Skin involvement is a rare presenting symptom of Cryptococcus infection, but it is usually a sign of disseminated disease; it may precede the systemic symptoms even eight months earlier [5, 18]. It is important to stress the rarity and polymorphism of the skin conditions, with the possible development of vesicles or blisters and the potential progression to ulceration [1, 4].
Cryptococcal cellulitis is a rare specific cutaneous manifestation, which was developed in our case. It was initially suspected to be a bacterial infection for which antibiotics were prescribed until its failure and microbiological results confirmed the fungal diagnosis. Although rare, the present case, cryptococcal cellulitis was restricted mainly to the lower body, particularly to the lower extremities, and this was reported in other rare reported cases [1, 2]. Despite that, cryptococcal cellulitis is uncommon and undistinguishable from acute bacterial cellulitis for appearance and presentation [6], but high suspicion especially in a risky patient should be considered.
More than 80% of patients manifested cryptococcal cellulitis and are expected to survive in immunocompetent status when they receive the appropriate antifungal therapy [6]. According to the current guidelines of the American Society of Infectious Diseases for disseminated cryptococcosis management, amphotericin B combined with flucytosine is recommended as the primary therapy, followed by fluconazole as a consolidation therapy [4, 18]. Flucytosine is expensive and was not available in our country; so, it was not considered for the treatment. Instead, it was replaced by the addition of fluconazole to amphotericin B regimen.
Cryptococcal laboratory diagnosis relies on three main methods: latex agglutination test, fungal culture, and direct microscopic examination [22]. In the present case, both the microscopic examination and microbiological cultures were the cornerstone for the diagnosis. C. neoformans was differentiated from other fungal species especially Candida spp. by the characterized morphology in the Gram-stained smear, microbiological culture characters, Indian ink stain positivity, and biochemical reactions.
Indian ink stain was positive in our case. In HIV-positive patients, its sensitivity increases up to 80% due to higher fungal loads in the CSF, while in HIV negative patients, the sensitivity is only 30–50% [8, 23]. CSF culture is considered the gold standard for cryptococcal diagnosis, but it has several diagnostic obstacles as long time is needed for fungus to grow, while time is very critical for management of meningitis cases with evolving lifetime neurological complications [24]. Besides, fungal cultures are not available in all medical facilities and therefore may not be performed. It is also associated with false-negative results, especially in cases with low fungal load, and this may be the attributed cause of negative blood culture result in our case.
Regarding management of cryptococcosis, the prolonged course (6–10 weeks) of IV amphotericin B monotherapy, together with the reduction of chemotherapy to improve immune status, was the main target. Caution was taken while reducing immunosuppressive therapy, since a rapid reduction is reported to be associated with immune reconstitution inflammatory syndrome (IRIS) in some patients [9]. There is evidence that supports the requirement for maintenance therapy with fluconazole administered as indefinite secondary prophylaxis, since the rate of recurrence exceeds 50% after apparently successful treatment [25].
Differential diagnosis of the present case must be addressed which includes besides to what was mentioned, infection versus flare-up attacks in lupus patients; several sepsis markers including CRP increase significantly in SLE patients with concomitant infection but increase only slightly or not at all in patients with a lupus flare without infection [14, 26] which is exactly encountered in our presented case. Additionally, decreased visual acuity due to increased intracranial tension (papilledema) was differentiated from decreased visual acuity due to optic nerve atrophy. For the presented case, papilledema was evident on fundus examination at the time of cryptococcal meningitis first diagnosed, while optic nerve atrophy was evident on fundus examination at the end.
Finally, we highlight the importance of clinicians' awareness about such infection among non-HIV immunocompromised patients including those who are diagnosed with autoimmune diseases. The latency of Cryptococcus should be considered and suspected during the management of such cases which necessitate early recognition and proper management.
For preparing Indian ink-stained film, take two drops from the examined CSF sample directly or a small part of the growing colony from the plate, mix it well with the ink, put a cover slide, and leave the slide for an hour to give a chance for the cells to be settled, and for better contrast view, lower the condenser and reduce the microscopic light and examine the film by using the lens with magnification power (40x). Cryptococcus will be evident as shiny spherical budding in a dark background.
4. Conclusion
Cryptococcal meningitis should be considered as one of the possible diagnoses in a patient with altered sensorium and neck stiffness, especially those who are immunocompromised. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening complications.
Early management of cryptococcal meningitis is associated with better prognosis and lower neurological complications. Despite that, flucytosine is being described as the best antifungal medication for cryptococcal infections. Amphotericin B still gives good results in such cases.
Negative bacterial growth from a skin lesion does not necessitate that it is a sterile lesion; it may be an atypical microorganism or microorganism that needs special media to grow or longer duration to be cultivated. Clinical pathologists should be aware of Cryptococcus laboratory diagnosis and how to differentiate it from Candida spp. Microbiological culture is a confirmatory step for Cryptococcus diagnosis; however, Gram-stained and Indian ink-stained films are rapid and informative diagnostic methods especially in limited resources facilities. The communication between laboratory staff members and treating medical team is very crucial for better clinical judgment specifically in a circumstance where an unusual diagnostic result is released or diagnosing a rare disease.
CSF examination may show low cell count; however, infection presents; this is commonly seen in immunocompromised patients as no adequate inflammation. Cryptococcal infection associated with CNS latency which should to be suspected; hence, meticulous follow-up is an essential step in cryptococcal management. The second activation of cryptococcal latency is usually life-threatening and mostly fatal.
Acknowledgments
The authors would like to thank all members of Immunology Unit-Pediatric Department and Microbiology Unit-Clinical Pathology Department of Ain Shams University Hospital. The authors gratefully acknowledge Professor Dalia Helmy El-Ghoneimy and Professor Malaka Zakaria Amer for their efforts to diagnose and follow up severe medical cases including this presented case and special gratitude to the mother of the child for supporting with detailed medical information and for her medical awareness and patience throughout her daughter's longstanding disease.
Abbreviations
ALT:Alanine transaminase
ANA:Antinuclear antibody
AST:Aspartate transaminase
C. neoformans:
Cryptococcus neoformans
CBC:Complete blood count
CNS:Central nervous system
CRP:C-reactive protein
CSF:Cerebrospinal fluid
DNA:Deoxyribonucleic acid
dsDNA:Double-strand DNA
E.R:Emergency room
EEG:Electroencephalogram
eGFR:Estimated glomerular filtration rate
ESR:Erythrocyte sedimentation rate
HIV:Human immunodeficiency virus
IgG:Immunoglobulin G
IRIS:Immune reconstitution inflammatory syndrome
IV:Intravenous
MPA:Mycophenolic acid
MRI:Magnetic resonance imaging
PC ratio:Protein creatinine ratio
RF:Rheumatoid factor
RNA:Ribonucleic acid
RNP:Ribonucleoprotein antibodies
SDA:Sabouraud's dextrose agar
SLE:Systemic lupus erythematosus
SOPs:Standard operating procedures
WBC:White blood cell.
Data Availability
The data underlying the findings of this research are publicly available.
Ethical Approval
Compliance with ethics guidelines, all procedures followed the ethical standards of the responsible committee on human experimentation (institutional and national).
Consent
Written informed consent for publication of clinical details was obtained from the mother of the patient.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
Authors' Contributions
Heba Ezzat Hashem contributed to acquisition, analysis, and interpretation of data, drafting of paper, conception and design, revision for critical intellectual content, final approval, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Zakaria Hamza Ibrahim involved in revision for critical intellectual content, final approval, and financial support.
Figure 1 A simplified chart representing the sequence of the disease in our case.
Figure 2 (a) Clear colorless CSF sample; other etiological causes of meningitis especially viral meningitis versus fungal meningitis must be differentiated, specifically in the presence of clear colorless CSF samples with low cell count and minimal changes of CSF parameters. (b) Spherical budding yeast in the CSF; it should be differentiated from the elliptical budding yeast cells of Candida spp. which is more commonly encountered during CSF examination as a fungal cause of meningitis. (c) Gram-stained film; direct film from CSF shows spherical budding yeast cells with surrounding translucent haloes due to capsular structure. (d) Blood agar shows small white colonies, after 72 hours of incubation. (e) Sabouraud dextrose agar (SDA) shows pasty colonies that were confirmed to be Cryptococcus neoformans. (f) Gram from culture shows spherical yeast cells with surrounding translucent haloes.
Figure 3 Biochemical reaction; the urease test was positive.
Figure 4
Cryptococcus as shiny spherical budding in a dark background.
Figure 5 Laboratory course of the present case and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation; the patient improved clinically and discharged after almost one month with minimal residual weakness in her lower limbs. The nCD64 test was available in our hospital as a sepsis biomarker, and it was performed for our case for follow-up purposes.
Figure 6 Patient developed extensive skin ulceration with serous oozing from both lower limbs; this image was taken upon her clinical improvement on amphotericin B. The local edema resolved leaving the skin redundant, cracked, and the oozing discharge was first serous-like followed by purulent discharge then pus draining stopped.
Figure 7 EEG at the 4th admission, seizures, and other CNS manifestations in patients who had previous cryptococcal meningitis is very essential to be distinguished; it is due to reactivation of latent infection or due to seizures attributed to other medical causes. For the present case, EEG showed normal electric activates without focal localization.
Figure 8 MRI brain performed at the time of 3rd admission; dilated third ventricles were evident due to brain cell atrophy; at this occasion, signs of increase intracranial tension were negative which excluded it as a cause for cerebral ventricles dilatations.
Table 1 Laboratory course of the present case, and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation.
Hb TLC ANC ALC AMC PLT CRP CD64% CD64 MFI
08/05/2016 10.6 12.2 11.2 0.6 0.4 44 6 98.5 2.87
11/05/2016 9 10.9 9.2 1.1 0.51 81 6 91.5 1.91
15/05/2016 7.7 14.8 12.72 1.57 0.48 209 4 80.1 1.56
22/05/2016 7.2 10 7.6 1.1 0.5 238 4 68.9 1.45
Hb, hemoglobin (g/dl); TLC, total leukocytic count (X109/L); ANC, absolute neutrophil count (X109/L); ALC, absolute lymphocyte count (X109/L); AMC, absolute monocyte count (X109/L); PLT, platelet (X109/L); CRP, C-reactive protein (mg/L); nCD64%, neutrophil CD64%; nCD64MFI, nCD64 mean fluorescence intensity. | AMIKACIN, CEFEPIME HYDROCHLORIDE, CYCLOPHOSPHAMIDE, FLUCONAZOLE, HYDROXYCHLOROQUINE, MYCOPHENOLATE MOFETIL, PREDNISONE, VANCOMYCIN | DrugsGivenReaction | CC BY | 33628263 | 19,565,138 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Infection'. | Atypical Presentation of Pediatric Systemic Lupus Erythematosus Complicated by Cryptococcal Meningitis.
Cryptococcus is an opportunistic fungal pathogen that leads to life-threatening infections. Cryptococcal infections are mainly reported in HIV patients and less commonly encountered in non-HIV immunocompromised host. Cryptococcus neoformans (C. neoformans) is the most common Cryptococcus species causing diseases in humans which can be presented as pulmonary, meningitis, cutaneous, and/or disseminated cryptococcosis. Case Presentation. A 12-year-old female girl from Cairo, Egypt, presented to the pediatric hospital with signs of systemic lupus erythematosus (SLE). She had an aggressive lupus nephritis course for which corticosteroids, mycophenolate mofetil, and cyclophosphamide were prescribed, and the child gradually improved and was discharged. Two months later, the patient exhibited skin lesions involved both in her legs, massive ulcers were developed and extended rapidly through the entire legs followed by deterioration in her conscious level, and signs of meningitis were documented. Cerebrospinal fluid (CSF) examination and microbiological workup were confirmatory for C. neoformans infection, and mental and motor functions were rapidly deteriorated. Treatment with amphotericin B in addition to supportive treatment and close follow-up of the patient's medical condition result in obvious clinical improvement and patient discharge with minimal residual weakness in her legs after almost a one-month duration. After six months, the patient was brought to the emergency department complaining of repeated attacks of seizures, a lumbar puncture was performed, and culture results were again confirmatory for C. neoformans. An intensive course of antifungal therapy was prescribed which was successful, evident by resolution of the signs and symptoms of infection in addition to negative culture results and negative sepsis biomarkers. The child clinically improved, but unfortunately, gradual optic nerve degeneration and brain cell atrophy as a sequel of severe and longstanding cryptococcal infection resulted in her death after almost one year from her first attack.
Cryptococcal infection among non-HIV patients is a rare disease but can result in advanced medical complications which may be fatal. The disease should be suspected to be reliably diagnosed. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening consequences. Amphotericin B can be used effectively in cryptococcosis management in the settings where flucytosine is not available. Signs of cryptococcal meningitis can be manifested again after a period of remission and clinical cure which signifies the latency of Cryptococcus in the central nervous system. The second activation of Cryptococcus after its latency is usually life-threatening and mostly fatal.
1. Background
Immunocompromised individuals including HIV, SLE, and patients on prolonged corticosteroid and immunosuppressant therapy are more prone to various bacterial, viral, and fungal opportunistic infections. One of the most important fatal fungal infections is cryptococcal infection [1–4]. C. neoformans is the most frequent cryptococcal species infect humans, and it is an encapsulated yeast microorganism, which is commonly transmitted through bird feces, plants, dust, soil, and contaminated food [2, 3]. Cryptococcosis can cause disseminated infection reaching to the lungs, central nervous system (CNS), and skin [2, 3, 5]. Dermal manifestations can present in different clinical morphologies including ulcers, acneiform papules, subcutaneous nodules, and rarely, cellulitis [4, 6].
2. Case Presentation
A 12-years-old Egyptian female student presented to Ain Shams University Pediatric Hospital complaining of generalized body edema, frothy urine, and proteinuria (3.7 g/day). The child was diagnosed as nephrotic syndrome, with repeated albumin infusions, and steroid therapy was initiated, but the child was nonresponding; instead, her medical condition deteriorated. Laboratory profile was in concordance with serologically quiescent SLE which included antinuclear antibody titer 1: 1280 finely speckled, elevated rheumatoid factor (RF) of 456 IU/ml (N: 0–20 IU/ml), positive SS-A/Ro > 8.0 and SS-B/La > 8.0 antibodies, anti-beta-2 glycoprotein IgM Ab > 100 U/ml, C-reactive protein (CRP) level 3.9 mg/l (N: 0–5 mg/l), and erythrocyte sedimentation rate (ESR) 51 mm/hour (N: 0–10 mm/hour). The serologic tests that were negative included anti-dsDNA Abs, complement C3 level 154 mg/dl (N: 106–194 mg/dl), complement C4 level 38 mg/dl (N: 19–50 mg/dl), cyclic citrullinated peptide IgG, cryoglobulin, serum immunofixation, Scl-70 scleroderma, Smith, RNP, cardiolipin antibodies, and lupus anticoagulant. Urine studies at the time revealed 3 + proteinuria, no hematuria or pyuria, a creatinine level of 0.93 mg/dl, and eGFR > 60 ml/min/1.73 m2. The diagnosis of SLE with nephrotic presentation was established, upon which the child received a medical regimen for lupus management including corticosteroids, mycophenolate mofetil, and cyclophosphamide which resulted in patient clinical improvement.
Two months later, the child was admitted complaining of poor appetite, nausea and vomiting, tiredness, swollen ankles, and shortness of breath, and deteriorated renal functions were evident in her laboratory profile: creatinine increased to 1.92 mg/dl, 4 + protein on urinalysis, worsening urine protein to creatinine (PC) ratio of 1.9 (N: 0.0–0.1), and 24-hour urine protein of 1170 mg/24 hours (N: 50–150 mg/24 hours). Lupus nephritis grade IV was confirmed. Therefore, the child received intermittent hemodialysis; in addition, the doses of the prescribed immunosuppressant was increased: prednisone (40 mg/day), hydroxychloroquine (6 mg/kg/day), and mycophenolate mofetil (2 g/day). The patient was kept under this protocol; she gradually improved and was discharged. A simplified chart representing the sequence of the disease in the presented case is illustrated in Figure 1.
After two months, the child manifested skin ulcers in her lower extremities which were progressive in course. Drug allergies, insect bites, and family history were excluded. First, these lesions were nonwell-demarcated, erythematous, painful on palpation, nonpruritic with increasing local edema, and bullae formation. A few days later, lesions spread to involve entire her legs up to the groin area, the bullae began to coalescence together, ruptured, and a huge amount of serous discharge was drained from the lesions; no corresponding lesions appeared on the face, trunk, or upper extremities, and fever was not present at first, but with worsening of the lesions, the patient became feverish, hematuric, anemic, and hypotensive with deteriorated general condition; hence, she was admitted for the 2nd time.
At the time of admission, laboratory profile revealed hemoglobin 8.2 g/dL, white blood cell (WBC) count 10,800/mm³, platelet count 129,000 cells/mm³, serum aspartate transaminase (AST) 10 U/L, serum alanine transaminase (ALT) 17 U/L, CRP 12 mg/L, and ESR 60 mm. Upon worsening the skin lesions, bacterial skin infection was suspected; so empirical treatment with amikacin and cefepime was started and the dose of prednisone decreased to 30 mg/day; microbiological cultures revealed no microorganism growth after 48 hours of incubation. Upon suspicion of bacterial cellulitis and due to the lack of improvements of the skin lesions, vancomycin was added to the treatment regimen.
After three days, the patient medical condition deteriorated rapidly. She complained of severe headache, altered memory, continuous agitation, neck rigidity, stiffness, photophobia, and total loss of appetite; so, meningitis was suspected; hence, lumbar puncture was performed, and a CSF sample was sent for cytological examination in addition to culture procedures. The sample was clear colorless on physical inspection (Figure 2)(a), and cell count was 25 cells/HPF.
Direct Gram examination of CSF showed spherical budding encapsulated yeast cells surrounded by translucent hallow around the cells (Figures 2(b) and 2)(c). CSF chemical examination revealed protein level 74 mg/dL (normal range 15–60 mg/dL) and glucose levels 41 mg/dL (normal range 50–80 mg/dL). The sample was cultured on aerobic blood agar, anaerobic blood agar, chocolate, and MacConkey agar; the plates showed delayed growth at the end of the third day (72 hours incubation according to CSF standard operating procedures (SOPs) of our microbiology lab). It was a minute whitish milky colony, which was highly suggestive of fungal infection, confirmed by further subculture, the sample on Sabouraud's dextrose agar (SDA) plates (Figures 2(d)–2(f)). Indian ink stain and positive biochemical reactions were confirmatory for the diagnosis of Cryptococcus infection (Figures 3 and 4). Additionally, antifungal susceptibility testing was performed which was positive for both amphotericin B and flucytosine.
Despite that, the child manifested obvious clinical signs and symptoms of meningitis. Magnetic resonance imaging (MRI) brain with contrast showed findings within normal limits, and blood culture was negative for microbiological growth after 7 days incubation.
Based on the available laboratory results, treatment for disseminated cryptococcosis was initiated immediately upon laboratory notification, prednisone was further decreased to 20 mg/day, and fluconazole was discontinued. Amphotericin B was started at a dose of 0.7 mg/kg/day with an infusion time of 6 hours, since the patient had repeated reactions (fever, chills, and nausea) with a shorter infusion time. Concerning flucytosine, which is indicated as the drug of choice in cryptococcal meningitis treatment, it was not used for treatment of our presented case due to financial aspects and nonavailability in our country, Egypt. Repeated lumber tapping was performed to relieve persistent increased intracranial tension as a consequence of severe meningitis; in addition, plasmapheresis was performed to remove lupus autoantibodies.
The child was subjected for further workup to rule out pneumonia and other organs affection, and for follow up purpose, chest X-ray was ordered, which revealed normal findings, ESR, CRP, complete blood count (CBC), and sepsis marker, neutrophil CD64. These laboratory tests were performed every 3 days on a routine base for monitoring the medical progress which showed dramatic gradual improvement (Table 1 and Figure 5); in conjugation with clinical signs and symptoms improvement evident by regaining her mental and motor skills, besides healing of the leg ulcers, pus draining stopped and swelling disappeared (Figure 6). In this setting, a lumbar puncture was intended to be performed upon this obvious clinical and laboratory improvement preparing the patient to be discharged, but the child refused at her own request and was discharged on her demand after almost 30 days since amphotericin B infusion was first prescribed.
At the time of discharge, the patient had no pulmonary sequelae, but she had residual weakness in her lower limbs. The laboratory results at the time of discharge were hemoglobin 9.2 g/dL, WBC 16.700 cells per mm³, platelet 303.000 cells per mm³, AST 10 U/L, ALT 4 U/L, CRP 6 mg/L, and ESR 53 mm/h. The child was instructed to continue fluconazole (400 mg/day) at home for 8 weeks and then reduced its dose to 200 mg/day for 1 year. And she was weaned gradually from corticosteroid therapy.
One month later, the child was brought to the emergency department complaining of severe headache, projectile vomiting, and blurred vision. She was admitted for the 3rd time. An MRI brain was ordered, and a lumbar puncture was performed urgently to relieve intracranial tension, and for chemical, cytological, and microbiological analyses, all were negative for infection except for CRP slightly positive (12 mg/L). So, lupus flare-up was suspected, and pulse steroid therapy was started, in addition to antifungal (fluconazole) and antibiotic (amikacin and cefepime) coverage. The patient was subjected for plasmapheresis; upon it, she manifested dramatical improvement and discharge. She started to attend the immunotherapy clinic every two weeks for follow up purpose; she did well for 5 months and regained her functions except for difficulty in talking and walking abilities as she could not walk without support; so, the mother was advised to bring her for regular physiotherapy sessions every week.
Five months later, the patient complained of shivering in her legs and hands followed by seizures attacks which were gradually increasing in frequency and duration till her mother brought her to the E/R. She was admitted for the 4th time. Phenytoin was prescribed, initial dose 2.5 mg/kg/dose twice a day and increased gradually to maximum 5 mg/kg/dose twice daily, and intensive work up profile was conducted searching for the cause of the seizures which included electroencephalogram (EEG), MRI brain, full lab evaluation, and CSF chemical analysis and microbiological examination. EEG revealed normal electric impulses without focal activities (Figure 7). MRI brain showed mildly dilated 3rd ventricles, CSF chemistry analysis revealed protein level 82 mg/dL (normal range 15–60 mg/dL), and glucose levels of 35 mg/dL (normal range 50–80 mg/dL). Upon receiving the sample in our microbiology lab, the sample physical criteria were very similar to the previous one, clear colorless, and cell count was 15 cell/cm3. A direct wet film examination was positive for budding yeast cells which were suspected and notified immediately to the pediatric team, and protocol of treatment was decided rapidly. CSF culture results were again confirmatory for C. neoformans.
An intensive course of antifungal therapy was initiated which included amphotericin B (0.7 mg/kg/day) with an infusion time of 6 hours, and fluconazole. Resolution of patient signs and symptoms of infection was clinically evident in addition to negative culture results and improved laboratory sepsis parameters. The child general condition improved, but at this setting, she complained of poor visual acuity. The pediatric team immediately consulted the specialist neurosurgeon, ophthalmologist, and an MRI brain urgently performed which showed evidence of brain cell atrophy with subsequent increased intracranial ventricular sizes and evidence of optic nerve atrophy; the ophthalmologist confirmed bilateral optic nerve degeneration which was more evident on the left side (Figure 8).
After almost one month and, however, signs and symptoms of infection were resolved, cryptococcosis longstanding course with brain cell atrophy as a sequel of cryptococcal meningitis resulted in the child's death after almost one year from her first attack.
3. Discussion and Conclusion
Cryptococcus is an opportunistic fungal pathogen that leads to rare life-threatening infection. Meningoencephalitis and disseminated cryptococcosis are usually common complications reported in immunocompromised hosts [7, 8]. In the presented case, we reported a pediatric systemic lupus erythematosus patient complicated by rapidly disseminating cryptococcal infection which exhibited a latency in the child CNS followed by an attack of infection flare-up which was successfully treated, but slowly progressive brain cell atrophy due to longstanding disease resulted in her death.
Infections and sepsis are major causes of hospitalization, mortality, and morbidity in immunosuppressed patients [9]. Cryptococcosis is one of the fatal fungal infections reported mainly in immunocompromised hosts; however, several reported cases point to its incidence also in immunocompetent patients [10–12]. Cryptococcosis has a low incidence in non-HIV patients, approximately 1 : 100.000 [5, 13]. Patients with SLE are highly susceptible to infections due to the combined effects of their immunosuppressive therapy and the abnormalities of the immune system that the disease itself causes [14]. Concerning our presented case, prolonged corticosteroid therapy and immunosuppressants due to her underlying disease (SLE) were the major risk factors for disseminated cryptococcosis with poor outcomes.
The patient had a progressive renal course complicated by lupus nephritis class IV for which immunosuppressants was given. Lupus nephritis is clinically evident in 50–60% of patients with SLE [15]. Both mycophenolate mofetil and cyclophosphamide were prescribed to our case. Mycophenolate mofetil depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation [16]. While, cyclophosphamide inhibits protein synthesis through DNA and RNA crosslinking [17].
By discussing Cryptococcus as the causative pathogen, C. neoformans is the most common strain causing infections in humans, and it is an encapsulated yeast that has been isolated from chickens' droppings and grows readily in soil contaminated with avian excreta particularly that of pigeons. In humans, it can colonize the upper airway system. Nevertheless, no animal-to-human nor person-to-person respiratory transmission has been documented [9]. Our presented case lived in low socioeconomic and hygienic status, and she denied contact with pigeon or birds. However, the fungus might have been indirectly transmitted via other sources such as vegetables, fruits, and dairy products [8].
C. neoformans generally cause three types of infections: cryptococcal meningitis, pulmonary, and cutaneous cryptococcosis [18]. The dissemination of this disease occurs when at least two noncontiguous sites are affected, which is unusual and mostly observed in HIV patients [4, 19]. In our case, only pulmonary involvement was not present while cutaneous manifestations were the first presenting symptoms followed by cryptococcal meningitis. Some studies support the importance of lumbar puncture in patients with cryptococcosis, even when CNS symptoms are not observed because asymptomatic meningitis is reported to be an early stage of the disease [20].
Systemic lupus erythematosus disease activity index (SLEDAI) was calculated for our presented case in order to be used as a predictor for SLE mortality and as a measure of global disease activity, and it was achieving high values (79) which reflect why the patient underwent into cryptococcal meningitis with poor clinical course. Eventhough, for patients with low SLE activity, the possibility of cryptococcal meningitis should not be underestimated [21].
Skin involvement is a rare presenting symptom of Cryptococcus infection, but it is usually a sign of disseminated disease; it may precede the systemic symptoms even eight months earlier [5, 18]. It is important to stress the rarity and polymorphism of the skin conditions, with the possible development of vesicles or blisters and the potential progression to ulceration [1, 4].
Cryptococcal cellulitis is a rare specific cutaneous manifestation, which was developed in our case. It was initially suspected to be a bacterial infection for which antibiotics were prescribed until its failure and microbiological results confirmed the fungal diagnosis. Although rare, the present case, cryptococcal cellulitis was restricted mainly to the lower body, particularly to the lower extremities, and this was reported in other rare reported cases [1, 2]. Despite that, cryptococcal cellulitis is uncommon and undistinguishable from acute bacterial cellulitis for appearance and presentation [6], but high suspicion especially in a risky patient should be considered.
More than 80% of patients manifested cryptococcal cellulitis and are expected to survive in immunocompetent status when they receive the appropriate antifungal therapy [6]. According to the current guidelines of the American Society of Infectious Diseases for disseminated cryptococcosis management, amphotericin B combined with flucytosine is recommended as the primary therapy, followed by fluconazole as a consolidation therapy [4, 18]. Flucytosine is expensive and was not available in our country; so, it was not considered for the treatment. Instead, it was replaced by the addition of fluconazole to amphotericin B regimen.
Cryptococcal laboratory diagnosis relies on three main methods: latex agglutination test, fungal culture, and direct microscopic examination [22]. In the present case, both the microscopic examination and microbiological cultures were the cornerstone for the diagnosis. C. neoformans was differentiated from other fungal species especially Candida spp. by the characterized morphology in the Gram-stained smear, microbiological culture characters, Indian ink stain positivity, and biochemical reactions.
Indian ink stain was positive in our case. In HIV-positive patients, its sensitivity increases up to 80% due to higher fungal loads in the CSF, while in HIV negative patients, the sensitivity is only 30–50% [8, 23]. CSF culture is considered the gold standard for cryptococcal diagnosis, but it has several diagnostic obstacles as long time is needed for fungus to grow, while time is very critical for management of meningitis cases with evolving lifetime neurological complications [24]. Besides, fungal cultures are not available in all medical facilities and therefore may not be performed. It is also associated with false-negative results, especially in cases with low fungal load, and this may be the attributed cause of negative blood culture result in our case.
Regarding management of cryptococcosis, the prolonged course (6–10 weeks) of IV amphotericin B monotherapy, together with the reduction of chemotherapy to improve immune status, was the main target. Caution was taken while reducing immunosuppressive therapy, since a rapid reduction is reported to be associated with immune reconstitution inflammatory syndrome (IRIS) in some patients [9]. There is evidence that supports the requirement for maintenance therapy with fluconazole administered as indefinite secondary prophylaxis, since the rate of recurrence exceeds 50% after apparently successful treatment [25].
Differential diagnosis of the present case must be addressed which includes besides to what was mentioned, infection versus flare-up attacks in lupus patients; several sepsis markers including CRP increase significantly in SLE patients with concomitant infection but increase only slightly or not at all in patients with a lupus flare without infection [14, 26] which is exactly encountered in our presented case. Additionally, decreased visual acuity due to increased intracranial tension (papilledema) was differentiated from decreased visual acuity due to optic nerve atrophy. For the presented case, papilledema was evident on fundus examination at the time of cryptococcal meningitis first diagnosed, while optic nerve atrophy was evident on fundus examination at the end.
Finally, we highlight the importance of clinicians' awareness about such infection among non-HIV immunocompromised patients including those who are diagnosed with autoimmune diseases. The latency of Cryptococcus should be considered and suspected during the management of such cases which necessitate early recognition and proper management.
For preparing Indian ink-stained film, take two drops from the examined CSF sample directly or a small part of the growing colony from the plate, mix it well with the ink, put a cover slide, and leave the slide for an hour to give a chance for the cells to be settled, and for better contrast view, lower the condenser and reduce the microscopic light and examine the film by using the lens with magnification power (40x). Cryptococcus will be evident as shiny spherical budding in a dark background.
4. Conclusion
Cryptococcal meningitis should be considered as one of the possible diagnoses in a patient with altered sensorium and neck stiffness, especially those who are immunocompromised. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening complications.
Early management of cryptococcal meningitis is associated with better prognosis and lower neurological complications. Despite that, flucytosine is being described as the best antifungal medication for cryptococcal infections. Amphotericin B still gives good results in such cases.
Negative bacterial growth from a skin lesion does not necessitate that it is a sterile lesion; it may be an atypical microorganism or microorganism that needs special media to grow or longer duration to be cultivated. Clinical pathologists should be aware of Cryptococcus laboratory diagnosis and how to differentiate it from Candida spp. Microbiological culture is a confirmatory step for Cryptococcus diagnosis; however, Gram-stained and Indian ink-stained films are rapid and informative diagnostic methods especially in limited resources facilities. The communication between laboratory staff members and treating medical team is very crucial for better clinical judgment specifically in a circumstance where an unusual diagnostic result is released or diagnosing a rare disease.
CSF examination may show low cell count; however, infection presents; this is commonly seen in immunocompromised patients as no adequate inflammation. Cryptococcal infection associated with CNS latency which should to be suspected; hence, meticulous follow-up is an essential step in cryptococcal management. The second activation of cryptococcal latency is usually life-threatening and mostly fatal.
Acknowledgments
The authors would like to thank all members of Immunology Unit-Pediatric Department and Microbiology Unit-Clinical Pathology Department of Ain Shams University Hospital. The authors gratefully acknowledge Professor Dalia Helmy El-Ghoneimy and Professor Malaka Zakaria Amer for their efforts to diagnose and follow up severe medical cases including this presented case and special gratitude to the mother of the child for supporting with detailed medical information and for her medical awareness and patience throughout her daughter's longstanding disease.
Abbreviations
ALT:Alanine transaminase
ANA:Antinuclear antibody
AST:Aspartate transaminase
C. neoformans:
Cryptococcus neoformans
CBC:Complete blood count
CNS:Central nervous system
CRP:C-reactive protein
CSF:Cerebrospinal fluid
DNA:Deoxyribonucleic acid
dsDNA:Double-strand DNA
E.R:Emergency room
EEG:Electroencephalogram
eGFR:Estimated glomerular filtration rate
ESR:Erythrocyte sedimentation rate
HIV:Human immunodeficiency virus
IgG:Immunoglobulin G
IRIS:Immune reconstitution inflammatory syndrome
IV:Intravenous
MPA:Mycophenolic acid
MRI:Magnetic resonance imaging
PC ratio:Protein creatinine ratio
RF:Rheumatoid factor
RNA:Ribonucleic acid
RNP:Ribonucleoprotein antibodies
SDA:Sabouraud's dextrose agar
SLE:Systemic lupus erythematosus
SOPs:Standard operating procedures
WBC:White blood cell.
Data Availability
The data underlying the findings of this research are publicly available.
Ethical Approval
Compliance with ethics guidelines, all procedures followed the ethical standards of the responsible committee on human experimentation (institutional and national).
Consent
Written informed consent for publication of clinical details was obtained from the mother of the patient.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
Authors' Contributions
Heba Ezzat Hashem contributed to acquisition, analysis, and interpretation of data, drafting of paper, conception and design, revision for critical intellectual content, final approval, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Zakaria Hamza Ibrahim involved in revision for critical intellectual content, final approval, and financial support.
Figure 1 A simplified chart representing the sequence of the disease in our case.
Figure 2 (a) Clear colorless CSF sample; other etiological causes of meningitis especially viral meningitis versus fungal meningitis must be differentiated, specifically in the presence of clear colorless CSF samples with low cell count and minimal changes of CSF parameters. (b) Spherical budding yeast in the CSF; it should be differentiated from the elliptical budding yeast cells of Candida spp. which is more commonly encountered during CSF examination as a fungal cause of meningitis. (c) Gram-stained film; direct film from CSF shows spherical budding yeast cells with surrounding translucent haloes due to capsular structure. (d) Blood agar shows small white colonies, after 72 hours of incubation. (e) Sabouraud dextrose agar (SDA) shows pasty colonies that were confirmed to be Cryptococcus neoformans. (f) Gram from culture shows spherical yeast cells with surrounding translucent haloes.
Figure 3 Biochemical reaction; the urease test was positive.
Figure 4
Cryptococcus as shiny spherical budding in a dark background.
Figure 5 Laboratory course of the present case and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation; the patient improved clinically and discharged after almost one month with minimal residual weakness in her lower limbs. The nCD64 test was available in our hospital as a sepsis biomarker, and it was performed for our case for follow-up purposes.
Figure 6 Patient developed extensive skin ulceration with serous oozing from both lower limbs; this image was taken upon her clinical improvement on amphotericin B. The local edema resolved leaving the skin redundant, cracked, and the oozing discharge was first serous-like followed by purulent discharge then pus draining stopped.
Figure 7 EEG at the 4th admission, seizures, and other CNS manifestations in patients who had previous cryptococcal meningitis is very essential to be distinguished; it is due to reactivation of latent infection or due to seizures attributed to other medical causes. For the present case, EEG showed normal electric activates without focal localization.
Figure 8 MRI brain performed at the time of 3rd admission; dilated third ventricles were evident due to brain cell atrophy; at this occasion, signs of increase intracranial tension were negative which excluded it as a cause for cerebral ventricles dilatations.
Table 1 Laboratory course of the present case, and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation.
Hb TLC ANC ALC AMC PLT CRP CD64% CD64 MFI
08/05/2016 10.6 12.2 11.2 0.6 0.4 44 6 98.5 2.87
11/05/2016 9 10.9 9.2 1.1 0.51 81 6 91.5 1.91
15/05/2016 7.7 14.8 12.72 1.57 0.48 209 4 80.1 1.56
22/05/2016 7.2 10 7.6 1.1 0.5 238 4 68.9 1.45
Hb, hemoglobin (g/dl); TLC, total leukocytic count (X109/L); ANC, absolute neutrophil count (X109/L); ALC, absolute lymphocyte count (X109/L); AMC, absolute monocyte count (X109/L); PLT, platelet (X109/L); CRP, C-reactive protein (mg/L); nCD64%, neutrophil CD64%; nCD64MFI, nCD64 mean fluorescence intensity. | CYCLOPHOSPHAMIDE, HYDROXYCHLOROQUINE, MYCOPHENOLIC ACID, PREDNISONE | DrugsGivenReaction | CC BY | 33628263 | 19,588,393 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Intracranial pressure increased'. | Atypical Presentation of Pediatric Systemic Lupus Erythematosus Complicated by Cryptococcal Meningitis.
Cryptococcus is an opportunistic fungal pathogen that leads to life-threatening infections. Cryptococcal infections are mainly reported in HIV patients and less commonly encountered in non-HIV immunocompromised host. Cryptococcus neoformans (C. neoformans) is the most common Cryptococcus species causing diseases in humans which can be presented as pulmonary, meningitis, cutaneous, and/or disseminated cryptococcosis. Case Presentation. A 12-year-old female girl from Cairo, Egypt, presented to the pediatric hospital with signs of systemic lupus erythematosus (SLE). She had an aggressive lupus nephritis course for which corticosteroids, mycophenolate mofetil, and cyclophosphamide were prescribed, and the child gradually improved and was discharged. Two months later, the patient exhibited skin lesions involved both in her legs, massive ulcers were developed and extended rapidly through the entire legs followed by deterioration in her conscious level, and signs of meningitis were documented. Cerebrospinal fluid (CSF) examination and microbiological workup were confirmatory for C. neoformans infection, and mental and motor functions were rapidly deteriorated. Treatment with amphotericin B in addition to supportive treatment and close follow-up of the patient's medical condition result in obvious clinical improvement and patient discharge with minimal residual weakness in her legs after almost a one-month duration. After six months, the patient was brought to the emergency department complaining of repeated attacks of seizures, a lumbar puncture was performed, and culture results were again confirmatory for C. neoformans. An intensive course of antifungal therapy was prescribed which was successful, evident by resolution of the signs and symptoms of infection in addition to negative culture results and negative sepsis biomarkers. The child clinically improved, but unfortunately, gradual optic nerve degeneration and brain cell atrophy as a sequel of severe and longstanding cryptococcal infection resulted in her death after almost one year from her first attack.
Cryptococcal infection among non-HIV patients is a rare disease but can result in advanced medical complications which may be fatal. The disease should be suspected to be reliably diagnosed. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening consequences. Amphotericin B can be used effectively in cryptococcosis management in the settings where flucytosine is not available. Signs of cryptococcal meningitis can be manifested again after a period of remission and clinical cure which signifies the latency of Cryptococcus in the central nervous system. The second activation of Cryptococcus after its latency is usually life-threatening and mostly fatal.
1. Background
Immunocompromised individuals including HIV, SLE, and patients on prolonged corticosteroid and immunosuppressant therapy are more prone to various bacterial, viral, and fungal opportunistic infections. One of the most important fatal fungal infections is cryptococcal infection [1–4]. C. neoformans is the most frequent cryptococcal species infect humans, and it is an encapsulated yeast microorganism, which is commonly transmitted through bird feces, plants, dust, soil, and contaminated food [2, 3]. Cryptococcosis can cause disseminated infection reaching to the lungs, central nervous system (CNS), and skin [2, 3, 5]. Dermal manifestations can present in different clinical morphologies including ulcers, acneiform papules, subcutaneous nodules, and rarely, cellulitis [4, 6].
2. Case Presentation
A 12-years-old Egyptian female student presented to Ain Shams University Pediatric Hospital complaining of generalized body edema, frothy urine, and proteinuria (3.7 g/day). The child was diagnosed as nephrotic syndrome, with repeated albumin infusions, and steroid therapy was initiated, but the child was nonresponding; instead, her medical condition deteriorated. Laboratory profile was in concordance with serologically quiescent SLE which included antinuclear antibody titer 1: 1280 finely speckled, elevated rheumatoid factor (RF) of 456 IU/ml (N: 0–20 IU/ml), positive SS-A/Ro > 8.0 and SS-B/La > 8.0 antibodies, anti-beta-2 glycoprotein IgM Ab > 100 U/ml, C-reactive protein (CRP) level 3.9 mg/l (N: 0–5 mg/l), and erythrocyte sedimentation rate (ESR) 51 mm/hour (N: 0–10 mm/hour). The serologic tests that were negative included anti-dsDNA Abs, complement C3 level 154 mg/dl (N: 106–194 mg/dl), complement C4 level 38 mg/dl (N: 19–50 mg/dl), cyclic citrullinated peptide IgG, cryoglobulin, serum immunofixation, Scl-70 scleroderma, Smith, RNP, cardiolipin antibodies, and lupus anticoagulant. Urine studies at the time revealed 3 + proteinuria, no hematuria or pyuria, a creatinine level of 0.93 mg/dl, and eGFR > 60 ml/min/1.73 m2. The diagnosis of SLE with nephrotic presentation was established, upon which the child received a medical regimen for lupus management including corticosteroids, mycophenolate mofetil, and cyclophosphamide which resulted in patient clinical improvement.
Two months later, the child was admitted complaining of poor appetite, nausea and vomiting, tiredness, swollen ankles, and shortness of breath, and deteriorated renal functions were evident in her laboratory profile: creatinine increased to 1.92 mg/dl, 4 + protein on urinalysis, worsening urine protein to creatinine (PC) ratio of 1.9 (N: 0.0–0.1), and 24-hour urine protein of 1170 mg/24 hours (N: 50–150 mg/24 hours). Lupus nephritis grade IV was confirmed. Therefore, the child received intermittent hemodialysis; in addition, the doses of the prescribed immunosuppressant was increased: prednisone (40 mg/day), hydroxychloroquine (6 mg/kg/day), and mycophenolate mofetil (2 g/day). The patient was kept under this protocol; she gradually improved and was discharged. A simplified chart representing the sequence of the disease in the presented case is illustrated in Figure 1.
After two months, the child manifested skin ulcers in her lower extremities which were progressive in course. Drug allergies, insect bites, and family history were excluded. First, these lesions were nonwell-demarcated, erythematous, painful on palpation, nonpruritic with increasing local edema, and bullae formation. A few days later, lesions spread to involve entire her legs up to the groin area, the bullae began to coalescence together, ruptured, and a huge amount of serous discharge was drained from the lesions; no corresponding lesions appeared on the face, trunk, or upper extremities, and fever was not present at first, but with worsening of the lesions, the patient became feverish, hematuric, anemic, and hypotensive with deteriorated general condition; hence, she was admitted for the 2nd time.
At the time of admission, laboratory profile revealed hemoglobin 8.2 g/dL, white blood cell (WBC) count 10,800/mm³, platelet count 129,000 cells/mm³, serum aspartate transaminase (AST) 10 U/L, serum alanine transaminase (ALT) 17 U/L, CRP 12 mg/L, and ESR 60 mm. Upon worsening the skin lesions, bacterial skin infection was suspected; so empirical treatment with amikacin and cefepime was started and the dose of prednisone decreased to 30 mg/day; microbiological cultures revealed no microorganism growth after 48 hours of incubation. Upon suspicion of bacterial cellulitis and due to the lack of improvements of the skin lesions, vancomycin was added to the treatment regimen.
After three days, the patient medical condition deteriorated rapidly. She complained of severe headache, altered memory, continuous agitation, neck rigidity, stiffness, photophobia, and total loss of appetite; so, meningitis was suspected; hence, lumbar puncture was performed, and a CSF sample was sent for cytological examination in addition to culture procedures. The sample was clear colorless on physical inspection (Figure 2)(a), and cell count was 25 cells/HPF.
Direct Gram examination of CSF showed spherical budding encapsulated yeast cells surrounded by translucent hallow around the cells (Figures 2(b) and 2)(c). CSF chemical examination revealed protein level 74 mg/dL (normal range 15–60 mg/dL) and glucose levels 41 mg/dL (normal range 50–80 mg/dL). The sample was cultured on aerobic blood agar, anaerobic blood agar, chocolate, and MacConkey agar; the plates showed delayed growth at the end of the third day (72 hours incubation according to CSF standard operating procedures (SOPs) of our microbiology lab). It was a minute whitish milky colony, which was highly suggestive of fungal infection, confirmed by further subculture, the sample on Sabouraud's dextrose agar (SDA) plates (Figures 2(d)–2(f)). Indian ink stain and positive biochemical reactions were confirmatory for the diagnosis of Cryptococcus infection (Figures 3 and 4). Additionally, antifungal susceptibility testing was performed which was positive for both amphotericin B and flucytosine.
Despite that, the child manifested obvious clinical signs and symptoms of meningitis. Magnetic resonance imaging (MRI) brain with contrast showed findings within normal limits, and blood culture was negative for microbiological growth after 7 days incubation.
Based on the available laboratory results, treatment for disseminated cryptococcosis was initiated immediately upon laboratory notification, prednisone was further decreased to 20 mg/day, and fluconazole was discontinued. Amphotericin B was started at a dose of 0.7 mg/kg/day with an infusion time of 6 hours, since the patient had repeated reactions (fever, chills, and nausea) with a shorter infusion time. Concerning flucytosine, which is indicated as the drug of choice in cryptococcal meningitis treatment, it was not used for treatment of our presented case due to financial aspects and nonavailability in our country, Egypt. Repeated lumber tapping was performed to relieve persistent increased intracranial tension as a consequence of severe meningitis; in addition, plasmapheresis was performed to remove lupus autoantibodies.
The child was subjected for further workup to rule out pneumonia and other organs affection, and for follow up purpose, chest X-ray was ordered, which revealed normal findings, ESR, CRP, complete blood count (CBC), and sepsis marker, neutrophil CD64. These laboratory tests were performed every 3 days on a routine base for monitoring the medical progress which showed dramatic gradual improvement (Table 1 and Figure 5); in conjugation with clinical signs and symptoms improvement evident by regaining her mental and motor skills, besides healing of the leg ulcers, pus draining stopped and swelling disappeared (Figure 6). In this setting, a lumbar puncture was intended to be performed upon this obvious clinical and laboratory improvement preparing the patient to be discharged, but the child refused at her own request and was discharged on her demand after almost 30 days since amphotericin B infusion was first prescribed.
At the time of discharge, the patient had no pulmonary sequelae, but she had residual weakness in her lower limbs. The laboratory results at the time of discharge were hemoglobin 9.2 g/dL, WBC 16.700 cells per mm³, platelet 303.000 cells per mm³, AST 10 U/L, ALT 4 U/L, CRP 6 mg/L, and ESR 53 mm/h. The child was instructed to continue fluconazole (400 mg/day) at home for 8 weeks and then reduced its dose to 200 mg/day for 1 year. And she was weaned gradually from corticosteroid therapy.
One month later, the child was brought to the emergency department complaining of severe headache, projectile vomiting, and blurred vision. She was admitted for the 3rd time. An MRI brain was ordered, and a lumbar puncture was performed urgently to relieve intracranial tension, and for chemical, cytological, and microbiological analyses, all were negative for infection except for CRP slightly positive (12 mg/L). So, lupus flare-up was suspected, and pulse steroid therapy was started, in addition to antifungal (fluconazole) and antibiotic (amikacin and cefepime) coverage. The patient was subjected for plasmapheresis; upon it, she manifested dramatical improvement and discharge. She started to attend the immunotherapy clinic every two weeks for follow up purpose; she did well for 5 months and regained her functions except for difficulty in talking and walking abilities as she could not walk without support; so, the mother was advised to bring her for regular physiotherapy sessions every week.
Five months later, the patient complained of shivering in her legs and hands followed by seizures attacks which were gradually increasing in frequency and duration till her mother brought her to the E/R. She was admitted for the 4th time. Phenytoin was prescribed, initial dose 2.5 mg/kg/dose twice a day and increased gradually to maximum 5 mg/kg/dose twice daily, and intensive work up profile was conducted searching for the cause of the seizures which included electroencephalogram (EEG), MRI brain, full lab evaluation, and CSF chemical analysis and microbiological examination. EEG revealed normal electric impulses without focal activities (Figure 7). MRI brain showed mildly dilated 3rd ventricles, CSF chemistry analysis revealed protein level 82 mg/dL (normal range 15–60 mg/dL), and glucose levels of 35 mg/dL (normal range 50–80 mg/dL). Upon receiving the sample in our microbiology lab, the sample physical criteria were very similar to the previous one, clear colorless, and cell count was 15 cell/cm3. A direct wet film examination was positive for budding yeast cells which were suspected and notified immediately to the pediatric team, and protocol of treatment was decided rapidly. CSF culture results were again confirmatory for C. neoformans.
An intensive course of antifungal therapy was initiated which included amphotericin B (0.7 mg/kg/day) with an infusion time of 6 hours, and fluconazole. Resolution of patient signs and symptoms of infection was clinically evident in addition to negative culture results and improved laboratory sepsis parameters. The child general condition improved, but at this setting, she complained of poor visual acuity. The pediatric team immediately consulted the specialist neurosurgeon, ophthalmologist, and an MRI brain urgently performed which showed evidence of brain cell atrophy with subsequent increased intracranial ventricular sizes and evidence of optic nerve atrophy; the ophthalmologist confirmed bilateral optic nerve degeneration which was more evident on the left side (Figure 8).
After almost one month and, however, signs and symptoms of infection were resolved, cryptococcosis longstanding course with brain cell atrophy as a sequel of cryptococcal meningitis resulted in the child's death after almost one year from her first attack.
3. Discussion and Conclusion
Cryptococcus is an opportunistic fungal pathogen that leads to rare life-threatening infection. Meningoencephalitis and disseminated cryptococcosis are usually common complications reported in immunocompromised hosts [7, 8]. In the presented case, we reported a pediatric systemic lupus erythematosus patient complicated by rapidly disseminating cryptococcal infection which exhibited a latency in the child CNS followed by an attack of infection flare-up which was successfully treated, but slowly progressive brain cell atrophy due to longstanding disease resulted in her death.
Infections and sepsis are major causes of hospitalization, mortality, and morbidity in immunosuppressed patients [9]. Cryptococcosis is one of the fatal fungal infections reported mainly in immunocompromised hosts; however, several reported cases point to its incidence also in immunocompetent patients [10–12]. Cryptococcosis has a low incidence in non-HIV patients, approximately 1 : 100.000 [5, 13]. Patients with SLE are highly susceptible to infections due to the combined effects of their immunosuppressive therapy and the abnormalities of the immune system that the disease itself causes [14]. Concerning our presented case, prolonged corticosteroid therapy and immunosuppressants due to her underlying disease (SLE) were the major risk factors for disseminated cryptococcosis with poor outcomes.
The patient had a progressive renal course complicated by lupus nephritis class IV for which immunosuppressants was given. Lupus nephritis is clinically evident in 50–60% of patients with SLE [15]. Both mycophenolate mofetil and cyclophosphamide were prescribed to our case. Mycophenolate mofetil depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation [16]. While, cyclophosphamide inhibits protein synthesis through DNA and RNA crosslinking [17].
By discussing Cryptococcus as the causative pathogen, C. neoformans is the most common strain causing infections in humans, and it is an encapsulated yeast that has been isolated from chickens' droppings and grows readily in soil contaminated with avian excreta particularly that of pigeons. In humans, it can colonize the upper airway system. Nevertheless, no animal-to-human nor person-to-person respiratory transmission has been documented [9]. Our presented case lived in low socioeconomic and hygienic status, and she denied contact with pigeon or birds. However, the fungus might have been indirectly transmitted via other sources such as vegetables, fruits, and dairy products [8].
C. neoformans generally cause three types of infections: cryptococcal meningitis, pulmonary, and cutaneous cryptococcosis [18]. The dissemination of this disease occurs when at least two noncontiguous sites are affected, which is unusual and mostly observed in HIV patients [4, 19]. In our case, only pulmonary involvement was not present while cutaneous manifestations were the first presenting symptoms followed by cryptococcal meningitis. Some studies support the importance of lumbar puncture in patients with cryptococcosis, even when CNS symptoms are not observed because asymptomatic meningitis is reported to be an early stage of the disease [20].
Systemic lupus erythematosus disease activity index (SLEDAI) was calculated for our presented case in order to be used as a predictor for SLE mortality and as a measure of global disease activity, and it was achieving high values (79) which reflect why the patient underwent into cryptococcal meningitis with poor clinical course. Eventhough, for patients with low SLE activity, the possibility of cryptococcal meningitis should not be underestimated [21].
Skin involvement is a rare presenting symptom of Cryptococcus infection, but it is usually a sign of disseminated disease; it may precede the systemic symptoms even eight months earlier [5, 18]. It is important to stress the rarity and polymorphism of the skin conditions, with the possible development of vesicles or blisters and the potential progression to ulceration [1, 4].
Cryptococcal cellulitis is a rare specific cutaneous manifestation, which was developed in our case. It was initially suspected to be a bacterial infection for which antibiotics were prescribed until its failure and microbiological results confirmed the fungal diagnosis. Although rare, the present case, cryptococcal cellulitis was restricted mainly to the lower body, particularly to the lower extremities, and this was reported in other rare reported cases [1, 2]. Despite that, cryptococcal cellulitis is uncommon and undistinguishable from acute bacterial cellulitis for appearance and presentation [6], but high suspicion especially in a risky patient should be considered.
More than 80% of patients manifested cryptococcal cellulitis and are expected to survive in immunocompetent status when they receive the appropriate antifungal therapy [6]. According to the current guidelines of the American Society of Infectious Diseases for disseminated cryptococcosis management, amphotericin B combined with flucytosine is recommended as the primary therapy, followed by fluconazole as a consolidation therapy [4, 18]. Flucytosine is expensive and was not available in our country; so, it was not considered for the treatment. Instead, it was replaced by the addition of fluconazole to amphotericin B regimen.
Cryptococcal laboratory diagnosis relies on three main methods: latex agglutination test, fungal culture, and direct microscopic examination [22]. In the present case, both the microscopic examination and microbiological cultures were the cornerstone for the diagnosis. C. neoformans was differentiated from other fungal species especially Candida spp. by the characterized morphology in the Gram-stained smear, microbiological culture characters, Indian ink stain positivity, and biochemical reactions.
Indian ink stain was positive in our case. In HIV-positive patients, its sensitivity increases up to 80% due to higher fungal loads in the CSF, while in HIV negative patients, the sensitivity is only 30–50% [8, 23]. CSF culture is considered the gold standard for cryptococcal diagnosis, but it has several diagnostic obstacles as long time is needed for fungus to grow, while time is very critical for management of meningitis cases with evolving lifetime neurological complications [24]. Besides, fungal cultures are not available in all medical facilities and therefore may not be performed. It is also associated with false-negative results, especially in cases with low fungal load, and this may be the attributed cause of negative blood culture result in our case.
Regarding management of cryptococcosis, the prolonged course (6–10 weeks) of IV amphotericin B monotherapy, together with the reduction of chemotherapy to improve immune status, was the main target. Caution was taken while reducing immunosuppressive therapy, since a rapid reduction is reported to be associated with immune reconstitution inflammatory syndrome (IRIS) in some patients [9]. There is evidence that supports the requirement for maintenance therapy with fluconazole administered as indefinite secondary prophylaxis, since the rate of recurrence exceeds 50% after apparently successful treatment [25].
Differential diagnosis of the present case must be addressed which includes besides to what was mentioned, infection versus flare-up attacks in lupus patients; several sepsis markers including CRP increase significantly in SLE patients with concomitant infection but increase only slightly or not at all in patients with a lupus flare without infection [14, 26] which is exactly encountered in our presented case. Additionally, decreased visual acuity due to increased intracranial tension (papilledema) was differentiated from decreased visual acuity due to optic nerve atrophy. For the presented case, papilledema was evident on fundus examination at the time of cryptococcal meningitis first diagnosed, while optic nerve atrophy was evident on fundus examination at the end.
Finally, we highlight the importance of clinicians' awareness about such infection among non-HIV immunocompromised patients including those who are diagnosed with autoimmune diseases. The latency of Cryptococcus should be considered and suspected during the management of such cases which necessitate early recognition and proper management.
For preparing Indian ink-stained film, take two drops from the examined CSF sample directly or a small part of the growing colony from the plate, mix it well with the ink, put a cover slide, and leave the slide for an hour to give a chance for the cells to be settled, and for better contrast view, lower the condenser and reduce the microscopic light and examine the film by using the lens with magnification power (40x). Cryptococcus will be evident as shiny spherical budding in a dark background.
4. Conclusion
Cryptococcal meningitis should be considered as one of the possible diagnoses in a patient with altered sensorium and neck stiffness, especially those who are immunocompromised. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening complications.
Early management of cryptococcal meningitis is associated with better prognosis and lower neurological complications. Despite that, flucytosine is being described as the best antifungal medication for cryptococcal infections. Amphotericin B still gives good results in such cases.
Negative bacterial growth from a skin lesion does not necessitate that it is a sterile lesion; it may be an atypical microorganism or microorganism that needs special media to grow or longer duration to be cultivated. Clinical pathologists should be aware of Cryptococcus laboratory diagnosis and how to differentiate it from Candida spp. Microbiological culture is a confirmatory step for Cryptococcus diagnosis; however, Gram-stained and Indian ink-stained films are rapid and informative diagnostic methods especially in limited resources facilities. The communication between laboratory staff members and treating medical team is very crucial for better clinical judgment specifically in a circumstance where an unusual diagnostic result is released or diagnosing a rare disease.
CSF examination may show low cell count; however, infection presents; this is commonly seen in immunocompromised patients as no adequate inflammation. Cryptococcal infection associated with CNS latency which should to be suspected; hence, meticulous follow-up is an essential step in cryptococcal management. The second activation of cryptococcal latency is usually life-threatening and mostly fatal.
Acknowledgments
The authors would like to thank all members of Immunology Unit-Pediatric Department and Microbiology Unit-Clinical Pathology Department of Ain Shams University Hospital. The authors gratefully acknowledge Professor Dalia Helmy El-Ghoneimy and Professor Malaka Zakaria Amer for their efforts to diagnose and follow up severe medical cases including this presented case and special gratitude to the mother of the child for supporting with detailed medical information and for her medical awareness and patience throughout her daughter's longstanding disease.
Abbreviations
ALT:Alanine transaminase
ANA:Antinuclear antibody
AST:Aspartate transaminase
C. neoformans:
Cryptococcus neoformans
CBC:Complete blood count
CNS:Central nervous system
CRP:C-reactive protein
CSF:Cerebrospinal fluid
DNA:Deoxyribonucleic acid
dsDNA:Double-strand DNA
E.R:Emergency room
EEG:Electroencephalogram
eGFR:Estimated glomerular filtration rate
ESR:Erythrocyte sedimentation rate
HIV:Human immunodeficiency virus
IgG:Immunoglobulin G
IRIS:Immune reconstitution inflammatory syndrome
IV:Intravenous
MPA:Mycophenolic acid
MRI:Magnetic resonance imaging
PC ratio:Protein creatinine ratio
RF:Rheumatoid factor
RNA:Ribonucleic acid
RNP:Ribonucleoprotein antibodies
SDA:Sabouraud's dextrose agar
SLE:Systemic lupus erythematosus
SOPs:Standard operating procedures
WBC:White blood cell.
Data Availability
The data underlying the findings of this research are publicly available.
Ethical Approval
Compliance with ethics guidelines, all procedures followed the ethical standards of the responsible committee on human experimentation (institutional and national).
Consent
Written informed consent for publication of clinical details was obtained from the mother of the patient.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
Authors' Contributions
Heba Ezzat Hashem contributed to acquisition, analysis, and interpretation of data, drafting of paper, conception and design, revision for critical intellectual content, final approval, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Zakaria Hamza Ibrahim involved in revision for critical intellectual content, final approval, and financial support.
Figure 1 A simplified chart representing the sequence of the disease in our case.
Figure 2 (a) Clear colorless CSF sample; other etiological causes of meningitis especially viral meningitis versus fungal meningitis must be differentiated, specifically in the presence of clear colorless CSF samples with low cell count and minimal changes of CSF parameters. (b) Spherical budding yeast in the CSF; it should be differentiated from the elliptical budding yeast cells of Candida spp. which is more commonly encountered during CSF examination as a fungal cause of meningitis. (c) Gram-stained film; direct film from CSF shows spherical budding yeast cells with surrounding translucent haloes due to capsular structure. (d) Blood agar shows small white colonies, after 72 hours of incubation. (e) Sabouraud dextrose agar (SDA) shows pasty colonies that were confirmed to be Cryptococcus neoformans. (f) Gram from culture shows spherical yeast cells with surrounding translucent haloes.
Figure 3 Biochemical reaction; the urease test was positive.
Figure 4
Cryptococcus as shiny spherical budding in a dark background.
Figure 5 Laboratory course of the present case and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation; the patient improved clinically and discharged after almost one month with minimal residual weakness in her lower limbs. The nCD64 test was available in our hospital as a sepsis biomarker, and it was performed for our case for follow-up purposes.
Figure 6 Patient developed extensive skin ulceration with serous oozing from both lower limbs; this image was taken upon her clinical improvement on amphotericin B. The local edema resolved leaving the skin redundant, cracked, and the oozing discharge was first serous-like followed by purulent discharge then pus draining stopped.
Figure 7 EEG at the 4th admission, seizures, and other CNS manifestations in patients who had previous cryptococcal meningitis is very essential to be distinguished; it is due to reactivation of latent infection or due to seizures attributed to other medical causes. For the present case, EEG showed normal electric activates without focal localization.
Figure 8 MRI brain performed at the time of 3rd admission; dilated third ventricles were evident due to brain cell atrophy; at this occasion, signs of increase intracranial tension were negative which excluded it as a cause for cerebral ventricles dilatations.
Table 1 Laboratory course of the present case, and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation.
Hb TLC ANC ALC AMC PLT CRP CD64% CD64 MFI
08/05/2016 10.6 12.2 11.2 0.6 0.4 44 6 98.5 2.87
11/05/2016 9 10.9 9.2 1.1 0.51 81 6 91.5 1.91
15/05/2016 7.7 14.8 12.72 1.57 0.48 209 4 80.1 1.56
22/05/2016 7.2 10 7.6 1.1 0.5 238 4 68.9 1.45
Hb, hemoglobin (g/dl); TLC, total leukocytic count (X109/L); ANC, absolute neutrophil count (X109/L); ALC, absolute lymphocyte count (X109/L); AMC, absolute monocyte count (X109/L); PLT, platelet (X109/L); CRP, C-reactive protein (mg/L); nCD64%, neutrophil CD64%; nCD64MFI, nCD64 mean fluorescence intensity. | CYCLOPHOSPHAMIDE, HYDROXYCHLOROQUINE, MYCOPHENOLIC ACID, PREDNISONE | DrugsGivenReaction | CC BY | 33628263 | 19,588,393 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nerve degeneration'. | Atypical Presentation of Pediatric Systemic Lupus Erythematosus Complicated by Cryptococcal Meningitis.
Cryptococcus is an opportunistic fungal pathogen that leads to life-threatening infections. Cryptococcal infections are mainly reported in HIV patients and less commonly encountered in non-HIV immunocompromised host. Cryptococcus neoformans (C. neoformans) is the most common Cryptococcus species causing diseases in humans which can be presented as pulmonary, meningitis, cutaneous, and/or disseminated cryptococcosis. Case Presentation. A 12-year-old female girl from Cairo, Egypt, presented to the pediatric hospital with signs of systemic lupus erythematosus (SLE). She had an aggressive lupus nephritis course for which corticosteroids, mycophenolate mofetil, and cyclophosphamide were prescribed, and the child gradually improved and was discharged. Two months later, the patient exhibited skin lesions involved both in her legs, massive ulcers were developed and extended rapidly through the entire legs followed by deterioration in her conscious level, and signs of meningitis were documented. Cerebrospinal fluid (CSF) examination and microbiological workup were confirmatory for C. neoformans infection, and mental and motor functions were rapidly deteriorated. Treatment with amphotericin B in addition to supportive treatment and close follow-up of the patient's medical condition result in obvious clinical improvement and patient discharge with minimal residual weakness in her legs after almost a one-month duration. After six months, the patient was brought to the emergency department complaining of repeated attacks of seizures, a lumbar puncture was performed, and culture results were again confirmatory for C. neoformans. An intensive course of antifungal therapy was prescribed which was successful, evident by resolution of the signs and symptoms of infection in addition to negative culture results and negative sepsis biomarkers. The child clinically improved, but unfortunately, gradual optic nerve degeneration and brain cell atrophy as a sequel of severe and longstanding cryptococcal infection resulted in her death after almost one year from her first attack.
Cryptococcal infection among non-HIV patients is a rare disease but can result in advanced medical complications which may be fatal. The disease should be suspected to be reliably diagnosed. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening consequences. Amphotericin B can be used effectively in cryptococcosis management in the settings where flucytosine is not available. Signs of cryptococcal meningitis can be manifested again after a period of remission and clinical cure which signifies the latency of Cryptococcus in the central nervous system. The second activation of Cryptococcus after its latency is usually life-threatening and mostly fatal.
1. Background
Immunocompromised individuals including HIV, SLE, and patients on prolonged corticosteroid and immunosuppressant therapy are more prone to various bacterial, viral, and fungal opportunistic infections. One of the most important fatal fungal infections is cryptococcal infection [1–4]. C. neoformans is the most frequent cryptococcal species infect humans, and it is an encapsulated yeast microorganism, which is commonly transmitted through bird feces, plants, dust, soil, and contaminated food [2, 3]. Cryptococcosis can cause disseminated infection reaching to the lungs, central nervous system (CNS), and skin [2, 3, 5]. Dermal manifestations can present in different clinical morphologies including ulcers, acneiform papules, subcutaneous nodules, and rarely, cellulitis [4, 6].
2. Case Presentation
A 12-years-old Egyptian female student presented to Ain Shams University Pediatric Hospital complaining of generalized body edema, frothy urine, and proteinuria (3.7 g/day). The child was diagnosed as nephrotic syndrome, with repeated albumin infusions, and steroid therapy was initiated, but the child was nonresponding; instead, her medical condition deteriorated. Laboratory profile was in concordance with serologically quiescent SLE which included antinuclear antibody titer 1: 1280 finely speckled, elevated rheumatoid factor (RF) of 456 IU/ml (N: 0–20 IU/ml), positive SS-A/Ro > 8.0 and SS-B/La > 8.0 antibodies, anti-beta-2 glycoprotein IgM Ab > 100 U/ml, C-reactive protein (CRP) level 3.9 mg/l (N: 0–5 mg/l), and erythrocyte sedimentation rate (ESR) 51 mm/hour (N: 0–10 mm/hour). The serologic tests that were negative included anti-dsDNA Abs, complement C3 level 154 mg/dl (N: 106–194 mg/dl), complement C4 level 38 mg/dl (N: 19–50 mg/dl), cyclic citrullinated peptide IgG, cryoglobulin, serum immunofixation, Scl-70 scleroderma, Smith, RNP, cardiolipin antibodies, and lupus anticoagulant. Urine studies at the time revealed 3 + proteinuria, no hematuria or pyuria, a creatinine level of 0.93 mg/dl, and eGFR > 60 ml/min/1.73 m2. The diagnosis of SLE with nephrotic presentation was established, upon which the child received a medical regimen for lupus management including corticosteroids, mycophenolate mofetil, and cyclophosphamide which resulted in patient clinical improvement.
Two months later, the child was admitted complaining of poor appetite, nausea and vomiting, tiredness, swollen ankles, and shortness of breath, and deteriorated renal functions were evident in her laboratory profile: creatinine increased to 1.92 mg/dl, 4 + protein on urinalysis, worsening urine protein to creatinine (PC) ratio of 1.9 (N: 0.0–0.1), and 24-hour urine protein of 1170 mg/24 hours (N: 50–150 mg/24 hours). Lupus nephritis grade IV was confirmed. Therefore, the child received intermittent hemodialysis; in addition, the doses of the prescribed immunosuppressant was increased: prednisone (40 mg/day), hydroxychloroquine (6 mg/kg/day), and mycophenolate mofetil (2 g/day). The patient was kept under this protocol; she gradually improved and was discharged. A simplified chart representing the sequence of the disease in the presented case is illustrated in Figure 1.
After two months, the child manifested skin ulcers in her lower extremities which were progressive in course. Drug allergies, insect bites, and family history were excluded. First, these lesions were nonwell-demarcated, erythematous, painful on palpation, nonpruritic with increasing local edema, and bullae formation. A few days later, lesions spread to involve entire her legs up to the groin area, the bullae began to coalescence together, ruptured, and a huge amount of serous discharge was drained from the lesions; no corresponding lesions appeared on the face, trunk, or upper extremities, and fever was not present at first, but with worsening of the lesions, the patient became feverish, hematuric, anemic, and hypotensive with deteriorated general condition; hence, she was admitted for the 2nd time.
At the time of admission, laboratory profile revealed hemoglobin 8.2 g/dL, white blood cell (WBC) count 10,800/mm³, platelet count 129,000 cells/mm³, serum aspartate transaminase (AST) 10 U/L, serum alanine transaminase (ALT) 17 U/L, CRP 12 mg/L, and ESR 60 mm. Upon worsening the skin lesions, bacterial skin infection was suspected; so empirical treatment with amikacin and cefepime was started and the dose of prednisone decreased to 30 mg/day; microbiological cultures revealed no microorganism growth after 48 hours of incubation. Upon suspicion of bacterial cellulitis and due to the lack of improvements of the skin lesions, vancomycin was added to the treatment regimen.
After three days, the patient medical condition deteriorated rapidly. She complained of severe headache, altered memory, continuous agitation, neck rigidity, stiffness, photophobia, and total loss of appetite; so, meningitis was suspected; hence, lumbar puncture was performed, and a CSF sample was sent for cytological examination in addition to culture procedures. The sample was clear colorless on physical inspection (Figure 2)(a), and cell count was 25 cells/HPF.
Direct Gram examination of CSF showed spherical budding encapsulated yeast cells surrounded by translucent hallow around the cells (Figures 2(b) and 2)(c). CSF chemical examination revealed protein level 74 mg/dL (normal range 15–60 mg/dL) and glucose levels 41 mg/dL (normal range 50–80 mg/dL). The sample was cultured on aerobic blood agar, anaerobic blood agar, chocolate, and MacConkey agar; the plates showed delayed growth at the end of the third day (72 hours incubation according to CSF standard operating procedures (SOPs) of our microbiology lab). It was a minute whitish milky colony, which was highly suggestive of fungal infection, confirmed by further subculture, the sample on Sabouraud's dextrose agar (SDA) plates (Figures 2(d)–2(f)). Indian ink stain and positive biochemical reactions were confirmatory for the diagnosis of Cryptococcus infection (Figures 3 and 4). Additionally, antifungal susceptibility testing was performed which was positive for both amphotericin B and flucytosine.
Despite that, the child manifested obvious clinical signs and symptoms of meningitis. Magnetic resonance imaging (MRI) brain with contrast showed findings within normal limits, and blood culture was negative for microbiological growth after 7 days incubation.
Based on the available laboratory results, treatment for disseminated cryptococcosis was initiated immediately upon laboratory notification, prednisone was further decreased to 20 mg/day, and fluconazole was discontinued. Amphotericin B was started at a dose of 0.7 mg/kg/day with an infusion time of 6 hours, since the patient had repeated reactions (fever, chills, and nausea) with a shorter infusion time. Concerning flucytosine, which is indicated as the drug of choice in cryptococcal meningitis treatment, it was not used for treatment of our presented case due to financial aspects and nonavailability in our country, Egypt. Repeated lumber tapping was performed to relieve persistent increased intracranial tension as a consequence of severe meningitis; in addition, plasmapheresis was performed to remove lupus autoantibodies.
The child was subjected for further workup to rule out pneumonia and other organs affection, and for follow up purpose, chest X-ray was ordered, which revealed normal findings, ESR, CRP, complete blood count (CBC), and sepsis marker, neutrophil CD64. These laboratory tests were performed every 3 days on a routine base for monitoring the medical progress which showed dramatic gradual improvement (Table 1 and Figure 5); in conjugation with clinical signs and symptoms improvement evident by regaining her mental and motor skills, besides healing of the leg ulcers, pus draining stopped and swelling disappeared (Figure 6). In this setting, a lumbar puncture was intended to be performed upon this obvious clinical and laboratory improvement preparing the patient to be discharged, but the child refused at her own request and was discharged on her demand after almost 30 days since amphotericin B infusion was first prescribed.
At the time of discharge, the patient had no pulmonary sequelae, but she had residual weakness in her lower limbs. The laboratory results at the time of discharge were hemoglobin 9.2 g/dL, WBC 16.700 cells per mm³, platelet 303.000 cells per mm³, AST 10 U/L, ALT 4 U/L, CRP 6 mg/L, and ESR 53 mm/h. The child was instructed to continue fluconazole (400 mg/day) at home for 8 weeks and then reduced its dose to 200 mg/day for 1 year. And she was weaned gradually from corticosteroid therapy.
One month later, the child was brought to the emergency department complaining of severe headache, projectile vomiting, and blurred vision. She was admitted for the 3rd time. An MRI brain was ordered, and a lumbar puncture was performed urgently to relieve intracranial tension, and for chemical, cytological, and microbiological analyses, all were negative for infection except for CRP slightly positive (12 mg/L). So, lupus flare-up was suspected, and pulse steroid therapy was started, in addition to antifungal (fluconazole) and antibiotic (amikacin and cefepime) coverage. The patient was subjected for plasmapheresis; upon it, she manifested dramatical improvement and discharge. She started to attend the immunotherapy clinic every two weeks for follow up purpose; she did well for 5 months and regained her functions except for difficulty in talking and walking abilities as she could not walk without support; so, the mother was advised to bring her for regular physiotherapy sessions every week.
Five months later, the patient complained of shivering in her legs and hands followed by seizures attacks which were gradually increasing in frequency and duration till her mother brought her to the E/R. She was admitted for the 4th time. Phenytoin was prescribed, initial dose 2.5 mg/kg/dose twice a day and increased gradually to maximum 5 mg/kg/dose twice daily, and intensive work up profile was conducted searching for the cause of the seizures which included electroencephalogram (EEG), MRI brain, full lab evaluation, and CSF chemical analysis and microbiological examination. EEG revealed normal electric impulses without focal activities (Figure 7). MRI brain showed mildly dilated 3rd ventricles, CSF chemistry analysis revealed protein level 82 mg/dL (normal range 15–60 mg/dL), and glucose levels of 35 mg/dL (normal range 50–80 mg/dL). Upon receiving the sample in our microbiology lab, the sample physical criteria were very similar to the previous one, clear colorless, and cell count was 15 cell/cm3. A direct wet film examination was positive for budding yeast cells which were suspected and notified immediately to the pediatric team, and protocol of treatment was decided rapidly. CSF culture results were again confirmatory for C. neoformans.
An intensive course of antifungal therapy was initiated which included amphotericin B (0.7 mg/kg/day) with an infusion time of 6 hours, and fluconazole. Resolution of patient signs and symptoms of infection was clinically evident in addition to negative culture results and improved laboratory sepsis parameters. The child general condition improved, but at this setting, she complained of poor visual acuity. The pediatric team immediately consulted the specialist neurosurgeon, ophthalmologist, and an MRI brain urgently performed which showed evidence of brain cell atrophy with subsequent increased intracranial ventricular sizes and evidence of optic nerve atrophy; the ophthalmologist confirmed bilateral optic nerve degeneration which was more evident on the left side (Figure 8).
After almost one month and, however, signs and symptoms of infection were resolved, cryptococcosis longstanding course with brain cell atrophy as a sequel of cryptococcal meningitis resulted in the child's death after almost one year from her first attack.
3. Discussion and Conclusion
Cryptococcus is an opportunistic fungal pathogen that leads to rare life-threatening infection. Meningoencephalitis and disseminated cryptococcosis are usually common complications reported in immunocompromised hosts [7, 8]. In the presented case, we reported a pediatric systemic lupus erythematosus patient complicated by rapidly disseminating cryptococcal infection which exhibited a latency in the child CNS followed by an attack of infection flare-up which was successfully treated, but slowly progressive brain cell atrophy due to longstanding disease resulted in her death.
Infections and sepsis are major causes of hospitalization, mortality, and morbidity in immunosuppressed patients [9]. Cryptococcosis is one of the fatal fungal infections reported mainly in immunocompromised hosts; however, several reported cases point to its incidence also in immunocompetent patients [10–12]. Cryptococcosis has a low incidence in non-HIV patients, approximately 1 : 100.000 [5, 13]. Patients with SLE are highly susceptible to infections due to the combined effects of their immunosuppressive therapy and the abnormalities of the immune system that the disease itself causes [14]. Concerning our presented case, prolonged corticosteroid therapy and immunosuppressants due to her underlying disease (SLE) were the major risk factors for disseminated cryptococcosis with poor outcomes.
The patient had a progressive renal course complicated by lupus nephritis class IV for which immunosuppressants was given. Lupus nephritis is clinically evident in 50–60% of patients with SLE [15]. Both mycophenolate mofetil and cyclophosphamide were prescribed to our case. Mycophenolate mofetil depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation [16]. While, cyclophosphamide inhibits protein synthesis through DNA and RNA crosslinking [17].
By discussing Cryptococcus as the causative pathogen, C. neoformans is the most common strain causing infections in humans, and it is an encapsulated yeast that has been isolated from chickens' droppings and grows readily in soil contaminated with avian excreta particularly that of pigeons. In humans, it can colonize the upper airway system. Nevertheless, no animal-to-human nor person-to-person respiratory transmission has been documented [9]. Our presented case lived in low socioeconomic and hygienic status, and she denied contact with pigeon or birds. However, the fungus might have been indirectly transmitted via other sources such as vegetables, fruits, and dairy products [8].
C. neoformans generally cause three types of infections: cryptococcal meningitis, pulmonary, and cutaneous cryptococcosis [18]. The dissemination of this disease occurs when at least two noncontiguous sites are affected, which is unusual and mostly observed in HIV patients [4, 19]. In our case, only pulmonary involvement was not present while cutaneous manifestations were the first presenting symptoms followed by cryptococcal meningitis. Some studies support the importance of lumbar puncture in patients with cryptococcosis, even when CNS symptoms are not observed because asymptomatic meningitis is reported to be an early stage of the disease [20].
Systemic lupus erythematosus disease activity index (SLEDAI) was calculated for our presented case in order to be used as a predictor for SLE mortality and as a measure of global disease activity, and it was achieving high values (79) which reflect why the patient underwent into cryptococcal meningitis with poor clinical course. Eventhough, for patients with low SLE activity, the possibility of cryptococcal meningitis should not be underestimated [21].
Skin involvement is a rare presenting symptom of Cryptococcus infection, but it is usually a sign of disseminated disease; it may precede the systemic symptoms even eight months earlier [5, 18]. It is important to stress the rarity and polymorphism of the skin conditions, with the possible development of vesicles or blisters and the potential progression to ulceration [1, 4].
Cryptococcal cellulitis is a rare specific cutaneous manifestation, which was developed in our case. It was initially suspected to be a bacterial infection for which antibiotics were prescribed until its failure and microbiological results confirmed the fungal diagnosis. Although rare, the present case, cryptococcal cellulitis was restricted mainly to the lower body, particularly to the lower extremities, and this was reported in other rare reported cases [1, 2]. Despite that, cryptococcal cellulitis is uncommon and undistinguishable from acute bacterial cellulitis for appearance and presentation [6], but high suspicion especially in a risky patient should be considered.
More than 80% of patients manifested cryptococcal cellulitis and are expected to survive in immunocompetent status when they receive the appropriate antifungal therapy [6]. According to the current guidelines of the American Society of Infectious Diseases for disseminated cryptococcosis management, amphotericin B combined with flucytosine is recommended as the primary therapy, followed by fluconazole as a consolidation therapy [4, 18]. Flucytosine is expensive and was not available in our country; so, it was not considered for the treatment. Instead, it was replaced by the addition of fluconazole to amphotericin B regimen.
Cryptococcal laboratory diagnosis relies on three main methods: latex agglutination test, fungal culture, and direct microscopic examination [22]. In the present case, both the microscopic examination and microbiological cultures were the cornerstone for the diagnosis. C. neoformans was differentiated from other fungal species especially Candida spp. by the characterized morphology in the Gram-stained smear, microbiological culture characters, Indian ink stain positivity, and biochemical reactions.
Indian ink stain was positive in our case. In HIV-positive patients, its sensitivity increases up to 80% due to higher fungal loads in the CSF, while in HIV negative patients, the sensitivity is only 30–50% [8, 23]. CSF culture is considered the gold standard for cryptococcal diagnosis, but it has several diagnostic obstacles as long time is needed for fungus to grow, while time is very critical for management of meningitis cases with evolving lifetime neurological complications [24]. Besides, fungal cultures are not available in all medical facilities and therefore may not be performed. It is also associated with false-negative results, especially in cases with low fungal load, and this may be the attributed cause of negative blood culture result in our case.
Regarding management of cryptococcosis, the prolonged course (6–10 weeks) of IV amphotericin B monotherapy, together with the reduction of chemotherapy to improve immune status, was the main target. Caution was taken while reducing immunosuppressive therapy, since a rapid reduction is reported to be associated with immune reconstitution inflammatory syndrome (IRIS) in some patients [9]. There is evidence that supports the requirement for maintenance therapy with fluconazole administered as indefinite secondary prophylaxis, since the rate of recurrence exceeds 50% after apparently successful treatment [25].
Differential diagnosis of the present case must be addressed which includes besides to what was mentioned, infection versus flare-up attacks in lupus patients; several sepsis markers including CRP increase significantly in SLE patients with concomitant infection but increase only slightly or not at all in patients with a lupus flare without infection [14, 26] which is exactly encountered in our presented case. Additionally, decreased visual acuity due to increased intracranial tension (papilledema) was differentiated from decreased visual acuity due to optic nerve atrophy. For the presented case, papilledema was evident on fundus examination at the time of cryptococcal meningitis first diagnosed, while optic nerve atrophy was evident on fundus examination at the end.
Finally, we highlight the importance of clinicians' awareness about such infection among non-HIV immunocompromised patients including those who are diagnosed with autoimmune diseases. The latency of Cryptococcus should be considered and suspected during the management of such cases which necessitate early recognition and proper management.
For preparing Indian ink-stained film, take two drops from the examined CSF sample directly or a small part of the growing colony from the plate, mix it well with the ink, put a cover slide, and leave the slide for an hour to give a chance for the cells to be settled, and for better contrast view, lower the condenser and reduce the microscopic light and examine the film by using the lens with magnification power (40x). Cryptococcus will be evident as shiny spherical budding in a dark background.
4. Conclusion
Cryptococcal meningitis should be considered as one of the possible diagnoses in a patient with altered sensorium and neck stiffness, especially those who are immunocompromised. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening complications.
Early management of cryptococcal meningitis is associated with better prognosis and lower neurological complications. Despite that, flucytosine is being described as the best antifungal medication for cryptococcal infections. Amphotericin B still gives good results in such cases.
Negative bacterial growth from a skin lesion does not necessitate that it is a sterile lesion; it may be an atypical microorganism or microorganism that needs special media to grow or longer duration to be cultivated. Clinical pathologists should be aware of Cryptococcus laboratory diagnosis and how to differentiate it from Candida spp. Microbiological culture is a confirmatory step for Cryptococcus diagnosis; however, Gram-stained and Indian ink-stained films are rapid and informative diagnostic methods especially in limited resources facilities. The communication between laboratory staff members and treating medical team is very crucial for better clinical judgment specifically in a circumstance where an unusual diagnostic result is released or diagnosing a rare disease.
CSF examination may show low cell count; however, infection presents; this is commonly seen in immunocompromised patients as no adequate inflammation. Cryptococcal infection associated with CNS latency which should to be suspected; hence, meticulous follow-up is an essential step in cryptococcal management. The second activation of cryptococcal latency is usually life-threatening and mostly fatal.
Acknowledgments
The authors would like to thank all members of Immunology Unit-Pediatric Department and Microbiology Unit-Clinical Pathology Department of Ain Shams University Hospital. The authors gratefully acknowledge Professor Dalia Helmy El-Ghoneimy and Professor Malaka Zakaria Amer for their efforts to diagnose and follow up severe medical cases including this presented case and special gratitude to the mother of the child for supporting with detailed medical information and for her medical awareness and patience throughout her daughter's longstanding disease.
Abbreviations
ALT:Alanine transaminase
ANA:Antinuclear antibody
AST:Aspartate transaminase
C. neoformans:
Cryptococcus neoformans
CBC:Complete blood count
CNS:Central nervous system
CRP:C-reactive protein
CSF:Cerebrospinal fluid
DNA:Deoxyribonucleic acid
dsDNA:Double-strand DNA
E.R:Emergency room
EEG:Electroencephalogram
eGFR:Estimated glomerular filtration rate
ESR:Erythrocyte sedimentation rate
HIV:Human immunodeficiency virus
IgG:Immunoglobulin G
IRIS:Immune reconstitution inflammatory syndrome
IV:Intravenous
MPA:Mycophenolic acid
MRI:Magnetic resonance imaging
PC ratio:Protein creatinine ratio
RF:Rheumatoid factor
RNA:Ribonucleic acid
RNP:Ribonucleoprotein antibodies
SDA:Sabouraud's dextrose agar
SLE:Systemic lupus erythematosus
SOPs:Standard operating procedures
WBC:White blood cell.
Data Availability
The data underlying the findings of this research are publicly available.
Ethical Approval
Compliance with ethics guidelines, all procedures followed the ethical standards of the responsible committee on human experimentation (institutional and national).
Consent
Written informed consent for publication of clinical details was obtained from the mother of the patient.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
Authors' Contributions
Heba Ezzat Hashem contributed to acquisition, analysis, and interpretation of data, drafting of paper, conception and design, revision for critical intellectual content, final approval, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Zakaria Hamza Ibrahim involved in revision for critical intellectual content, final approval, and financial support.
Figure 1 A simplified chart representing the sequence of the disease in our case.
Figure 2 (a) Clear colorless CSF sample; other etiological causes of meningitis especially viral meningitis versus fungal meningitis must be differentiated, specifically in the presence of clear colorless CSF samples with low cell count and minimal changes of CSF parameters. (b) Spherical budding yeast in the CSF; it should be differentiated from the elliptical budding yeast cells of Candida spp. which is more commonly encountered during CSF examination as a fungal cause of meningitis. (c) Gram-stained film; direct film from CSF shows spherical budding yeast cells with surrounding translucent haloes due to capsular structure. (d) Blood agar shows small white colonies, after 72 hours of incubation. (e) Sabouraud dextrose agar (SDA) shows pasty colonies that were confirmed to be Cryptococcus neoformans. (f) Gram from culture shows spherical yeast cells with surrounding translucent haloes.
Figure 3 Biochemical reaction; the urease test was positive.
Figure 4
Cryptococcus as shiny spherical budding in a dark background.
Figure 5 Laboratory course of the present case and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation; the patient improved clinically and discharged after almost one month with minimal residual weakness in her lower limbs. The nCD64 test was available in our hospital as a sepsis biomarker, and it was performed for our case for follow-up purposes.
Figure 6 Patient developed extensive skin ulceration with serous oozing from both lower limbs; this image was taken upon her clinical improvement on amphotericin B. The local edema resolved leaving the skin redundant, cracked, and the oozing discharge was first serous-like followed by purulent discharge then pus draining stopped.
Figure 7 EEG at the 4th admission, seizures, and other CNS manifestations in patients who had previous cryptococcal meningitis is very essential to be distinguished; it is due to reactivation of latent infection or due to seizures attributed to other medical causes. For the present case, EEG showed normal electric activates without focal localization.
Figure 8 MRI brain performed at the time of 3rd admission; dilated third ventricles were evident due to brain cell atrophy; at this occasion, signs of increase intracranial tension were negative which excluded it as a cause for cerebral ventricles dilatations.
Table 1 Laboratory course of the present case, and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation.
Hb TLC ANC ALC AMC PLT CRP CD64% CD64 MFI
08/05/2016 10.6 12.2 11.2 0.6 0.4 44 6 98.5 2.87
11/05/2016 9 10.9 9.2 1.1 0.51 81 6 91.5 1.91
15/05/2016 7.7 14.8 12.72 1.57 0.48 209 4 80.1 1.56
22/05/2016 7.2 10 7.6 1.1 0.5 238 4 68.9 1.45
Hb, hemoglobin (g/dl); TLC, total leukocytic count (X109/L); ANC, absolute neutrophil count (X109/L); ALC, absolute lymphocyte count (X109/L); AMC, absolute monocyte count (X109/L); PLT, platelet (X109/L); CRP, C-reactive protein (mg/L); nCD64%, neutrophil CD64%; nCD64MFI, nCD64 mean fluorescence intensity. | AMIKACIN, AMPHOTERICIN B, CEFEPIME HYDROCHLORIDE, CYCLOPHOSPHAMIDE, FLUCONAZOLE, HYDROXYCHLOROQUINE, MYCOPHENOLATE MOFETIL, PREDNISONE, VANCOMYCIN | DrugsGivenReaction | CC BY | 33628263 | 19,577,937 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Atypical Presentation of Pediatric Systemic Lupus Erythematosus Complicated by Cryptococcal Meningitis.
Cryptococcus is an opportunistic fungal pathogen that leads to life-threatening infections. Cryptococcal infections are mainly reported in HIV patients and less commonly encountered in non-HIV immunocompromised host. Cryptococcus neoformans (C. neoformans) is the most common Cryptococcus species causing diseases in humans which can be presented as pulmonary, meningitis, cutaneous, and/or disseminated cryptococcosis. Case Presentation. A 12-year-old female girl from Cairo, Egypt, presented to the pediatric hospital with signs of systemic lupus erythematosus (SLE). She had an aggressive lupus nephritis course for which corticosteroids, mycophenolate mofetil, and cyclophosphamide were prescribed, and the child gradually improved and was discharged. Two months later, the patient exhibited skin lesions involved both in her legs, massive ulcers were developed and extended rapidly through the entire legs followed by deterioration in her conscious level, and signs of meningitis were documented. Cerebrospinal fluid (CSF) examination and microbiological workup were confirmatory for C. neoformans infection, and mental and motor functions were rapidly deteriorated. Treatment with amphotericin B in addition to supportive treatment and close follow-up of the patient's medical condition result in obvious clinical improvement and patient discharge with minimal residual weakness in her legs after almost a one-month duration. After six months, the patient was brought to the emergency department complaining of repeated attacks of seizures, a lumbar puncture was performed, and culture results were again confirmatory for C. neoformans. An intensive course of antifungal therapy was prescribed which was successful, evident by resolution of the signs and symptoms of infection in addition to negative culture results and negative sepsis biomarkers. The child clinically improved, but unfortunately, gradual optic nerve degeneration and brain cell atrophy as a sequel of severe and longstanding cryptococcal infection resulted in her death after almost one year from her first attack.
Cryptococcal infection among non-HIV patients is a rare disease but can result in advanced medical complications which may be fatal. The disease should be suspected to be reliably diagnosed. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening consequences. Amphotericin B can be used effectively in cryptococcosis management in the settings where flucytosine is not available. Signs of cryptococcal meningitis can be manifested again after a period of remission and clinical cure which signifies the latency of Cryptococcus in the central nervous system. The second activation of Cryptococcus after its latency is usually life-threatening and mostly fatal.
1. Background
Immunocompromised individuals including HIV, SLE, and patients on prolonged corticosteroid and immunosuppressant therapy are more prone to various bacterial, viral, and fungal opportunistic infections. One of the most important fatal fungal infections is cryptococcal infection [1–4]. C. neoformans is the most frequent cryptococcal species infect humans, and it is an encapsulated yeast microorganism, which is commonly transmitted through bird feces, plants, dust, soil, and contaminated food [2, 3]. Cryptococcosis can cause disseminated infection reaching to the lungs, central nervous system (CNS), and skin [2, 3, 5]. Dermal manifestations can present in different clinical morphologies including ulcers, acneiform papules, subcutaneous nodules, and rarely, cellulitis [4, 6].
2. Case Presentation
A 12-years-old Egyptian female student presented to Ain Shams University Pediatric Hospital complaining of generalized body edema, frothy urine, and proteinuria (3.7 g/day). The child was diagnosed as nephrotic syndrome, with repeated albumin infusions, and steroid therapy was initiated, but the child was nonresponding; instead, her medical condition deteriorated. Laboratory profile was in concordance with serologically quiescent SLE which included antinuclear antibody titer 1: 1280 finely speckled, elevated rheumatoid factor (RF) of 456 IU/ml (N: 0–20 IU/ml), positive SS-A/Ro > 8.0 and SS-B/La > 8.0 antibodies, anti-beta-2 glycoprotein IgM Ab > 100 U/ml, C-reactive protein (CRP) level 3.9 mg/l (N: 0–5 mg/l), and erythrocyte sedimentation rate (ESR) 51 mm/hour (N: 0–10 mm/hour). The serologic tests that were negative included anti-dsDNA Abs, complement C3 level 154 mg/dl (N: 106–194 mg/dl), complement C4 level 38 mg/dl (N: 19–50 mg/dl), cyclic citrullinated peptide IgG, cryoglobulin, serum immunofixation, Scl-70 scleroderma, Smith, RNP, cardiolipin antibodies, and lupus anticoagulant. Urine studies at the time revealed 3 + proteinuria, no hematuria or pyuria, a creatinine level of 0.93 mg/dl, and eGFR > 60 ml/min/1.73 m2. The diagnosis of SLE with nephrotic presentation was established, upon which the child received a medical regimen for lupus management including corticosteroids, mycophenolate mofetil, and cyclophosphamide which resulted in patient clinical improvement.
Two months later, the child was admitted complaining of poor appetite, nausea and vomiting, tiredness, swollen ankles, and shortness of breath, and deteriorated renal functions were evident in her laboratory profile: creatinine increased to 1.92 mg/dl, 4 + protein on urinalysis, worsening urine protein to creatinine (PC) ratio of 1.9 (N: 0.0–0.1), and 24-hour urine protein of 1170 mg/24 hours (N: 50–150 mg/24 hours). Lupus nephritis grade IV was confirmed. Therefore, the child received intermittent hemodialysis; in addition, the doses of the prescribed immunosuppressant was increased: prednisone (40 mg/day), hydroxychloroquine (6 mg/kg/day), and mycophenolate mofetil (2 g/day). The patient was kept under this protocol; she gradually improved and was discharged. A simplified chart representing the sequence of the disease in the presented case is illustrated in Figure 1.
After two months, the child manifested skin ulcers in her lower extremities which were progressive in course. Drug allergies, insect bites, and family history were excluded. First, these lesions were nonwell-demarcated, erythematous, painful on palpation, nonpruritic with increasing local edema, and bullae formation. A few days later, lesions spread to involve entire her legs up to the groin area, the bullae began to coalescence together, ruptured, and a huge amount of serous discharge was drained from the lesions; no corresponding lesions appeared on the face, trunk, or upper extremities, and fever was not present at first, but with worsening of the lesions, the patient became feverish, hematuric, anemic, and hypotensive with deteriorated general condition; hence, she was admitted for the 2nd time.
At the time of admission, laboratory profile revealed hemoglobin 8.2 g/dL, white blood cell (WBC) count 10,800/mm³, platelet count 129,000 cells/mm³, serum aspartate transaminase (AST) 10 U/L, serum alanine transaminase (ALT) 17 U/L, CRP 12 mg/L, and ESR 60 mm. Upon worsening the skin lesions, bacterial skin infection was suspected; so empirical treatment with amikacin and cefepime was started and the dose of prednisone decreased to 30 mg/day; microbiological cultures revealed no microorganism growth after 48 hours of incubation. Upon suspicion of bacterial cellulitis and due to the lack of improvements of the skin lesions, vancomycin was added to the treatment regimen.
After three days, the patient medical condition deteriorated rapidly. She complained of severe headache, altered memory, continuous agitation, neck rigidity, stiffness, photophobia, and total loss of appetite; so, meningitis was suspected; hence, lumbar puncture was performed, and a CSF sample was sent for cytological examination in addition to culture procedures. The sample was clear colorless on physical inspection (Figure 2)(a), and cell count was 25 cells/HPF.
Direct Gram examination of CSF showed spherical budding encapsulated yeast cells surrounded by translucent hallow around the cells (Figures 2(b) and 2)(c). CSF chemical examination revealed protein level 74 mg/dL (normal range 15–60 mg/dL) and glucose levels 41 mg/dL (normal range 50–80 mg/dL). The sample was cultured on aerobic blood agar, anaerobic blood agar, chocolate, and MacConkey agar; the plates showed delayed growth at the end of the third day (72 hours incubation according to CSF standard operating procedures (SOPs) of our microbiology lab). It was a minute whitish milky colony, which was highly suggestive of fungal infection, confirmed by further subculture, the sample on Sabouraud's dextrose agar (SDA) plates (Figures 2(d)–2(f)). Indian ink stain and positive biochemical reactions were confirmatory for the diagnosis of Cryptococcus infection (Figures 3 and 4). Additionally, antifungal susceptibility testing was performed which was positive for both amphotericin B and flucytosine.
Despite that, the child manifested obvious clinical signs and symptoms of meningitis. Magnetic resonance imaging (MRI) brain with contrast showed findings within normal limits, and blood culture was negative for microbiological growth after 7 days incubation.
Based on the available laboratory results, treatment for disseminated cryptococcosis was initiated immediately upon laboratory notification, prednisone was further decreased to 20 mg/day, and fluconazole was discontinued. Amphotericin B was started at a dose of 0.7 mg/kg/day with an infusion time of 6 hours, since the patient had repeated reactions (fever, chills, and nausea) with a shorter infusion time. Concerning flucytosine, which is indicated as the drug of choice in cryptococcal meningitis treatment, it was not used for treatment of our presented case due to financial aspects and nonavailability in our country, Egypt. Repeated lumber tapping was performed to relieve persistent increased intracranial tension as a consequence of severe meningitis; in addition, plasmapheresis was performed to remove lupus autoantibodies.
The child was subjected for further workup to rule out pneumonia and other organs affection, and for follow up purpose, chest X-ray was ordered, which revealed normal findings, ESR, CRP, complete blood count (CBC), and sepsis marker, neutrophil CD64. These laboratory tests were performed every 3 days on a routine base for monitoring the medical progress which showed dramatic gradual improvement (Table 1 and Figure 5); in conjugation with clinical signs and symptoms improvement evident by regaining her mental and motor skills, besides healing of the leg ulcers, pus draining stopped and swelling disappeared (Figure 6). In this setting, a lumbar puncture was intended to be performed upon this obvious clinical and laboratory improvement preparing the patient to be discharged, but the child refused at her own request and was discharged on her demand after almost 30 days since amphotericin B infusion was first prescribed.
At the time of discharge, the patient had no pulmonary sequelae, but she had residual weakness in her lower limbs. The laboratory results at the time of discharge were hemoglobin 9.2 g/dL, WBC 16.700 cells per mm³, platelet 303.000 cells per mm³, AST 10 U/L, ALT 4 U/L, CRP 6 mg/L, and ESR 53 mm/h. The child was instructed to continue fluconazole (400 mg/day) at home for 8 weeks and then reduced its dose to 200 mg/day for 1 year. And she was weaned gradually from corticosteroid therapy.
One month later, the child was brought to the emergency department complaining of severe headache, projectile vomiting, and blurred vision. She was admitted for the 3rd time. An MRI brain was ordered, and a lumbar puncture was performed urgently to relieve intracranial tension, and for chemical, cytological, and microbiological analyses, all were negative for infection except for CRP slightly positive (12 mg/L). So, lupus flare-up was suspected, and pulse steroid therapy was started, in addition to antifungal (fluconazole) and antibiotic (amikacin and cefepime) coverage. The patient was subjected for plasmapheresis; upon it, she manifested dramatical improvement and discharge. She started to attend the immunotherapy clinic every two weeks for follow up purpose; she did well for 5 months and regained her functions except for difficulty in talking and walking abilities as she could not walk without support; so, the mother was advised to bring her for regular physiotherapy sessions every week.
Five months later, the patient complained of shivering in her legs and hands followed by seizures attacks which were gradually increasing in frequency and duration till her mother brought her to the E/R. She was admitted for the 4th time. Phenytoin was prescribed, initial dose 2.5 mg/kg/dose twice a day and increased gradually to maximum 5 mg/kg/dose twice daily, and intensive work up profile was conducted searching for the cause of the seizures which included electroencephalogram (EEG), MRI brain, full lab evaluation, and CSF chemical analysis and microbiological examination. EEG revealed normal electric impulses without focal activities (Figure 7). MRI brain showed mildly dilated 3rd ventricles, CSF chemistry analysis revealed protein level 82 mg/dL (normal range 15–60 mg/dL), and glucose levels of 35 mg/dL (normal range 50–80 mg/dL). Upon receiving the sample in our microbiology lab, the sample physical criteria were very similar to the previous one, clear colorless, and cell count was 15 cell/cm3. A direct wet film examination was positive for budding yeast cells which were suspected and notified immediately to the pediatric team, and protocol of treatment was decided rapidly. CSF culture results were again confirmatory for C. neoformans.
An intensive course of antifungal therapy was initiated which included amphotericin B (0.7 mg/kg/day) with an infusion time of 6 hours, and fluconazole. Resolution of patient signs and symptoms of infection was clinically evident in addition to negative culture results and improved laboratory sepsis parameters. The child general condition improved, but at this setting, she complained of poor visual acuity. The pediatric team immediately consulted the specialist neurosurgeon, ophthalmologist, and an MRI brain urgently performed which showed evidence of brain cell atrophy with subsequent increased intracranial ventricular sizes and evidence of optic nerve atrophy; the ophthalmologist confirmed bilateral optic nerve degeneration which was more evident on the left side (Figure 8).
After almost one month and, however, signs and symptoms of infection were resolved, cryptococcosis longstanding course with brain cell atrophy as a sequel of cryptococcal meningitis resulted in the child's death after almost one year from her first attack.
3. Discussion and Conclusion
Cryptococcus is an opportunistic fungal pathogen that leads to rare life-threatening infection. Meningoencephalitis and disseminated cryptococcosis are usually common complications reported in immunocompromised hosts [7, 8]. In the presented case, we reported a pediatric systemic lupus erythematosus patient complicated by rapidly disseminating cryptococcal infection which exhibited a latency in the child CNS followed by an attack of infection flare-up which was successfully treated, but slowly progressive brain cell atrophy due to longstanding disease resulted in her death.
Infections and sepsis are major causes of hospitalization, mortality, and morbidity in immunosuppressed patients [9]. Cryptococcosis is one of the fatal fungal infections reported mainly in immunocompromised hosts; however, several reported cases point to its incidence also in immunocompetent patients [10–12]. Cryptococcosis has a low incidence in non-HIV patients, approximately 1 : 100.000 [5, 13]. Patients with SLE are highly susceptible to infections due to the combined effects of their immunosuppressive therapy and the abnormalities of the immune system that the disease itself causes [14]. Concerning our presented case, prolonged corticosteroid therapy and immunosuppressants due to her underlying disease (SLE) were the major risk factors for disseminated cryptococcosis with poor outcomes.
The patient had a progressive renal course complicated by lupus nephritis class IV for which immunosuppressants was given. Lupus nephritis is clinically evident in 50–60% of patients with SLE [15]. Both mycophenolate mofetil and cyclophosphamide were prescribed to our case. Mycophenolate mofetil depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation [16]. While, cyclophosphamide inhibits protein synthesis through DNA and RNA crosslinking [17].
By discussing Cryptococcus as the causative pathogen, C. neoformans is the most common strain causing infections in humans, and it is an encapsulated yeast that has been isolated from chickens' droppings and grows readily in soil contaminated with avian excreta particularly that of pigeons. In humans, it can colonize the upper airway system. Nevertheless, no animal-to-human nor person-to-person respiratory transmission has been documented [9]. Our presented case lived in low socioeconomic and hygienic status, and she denied contact with pigeon or birds. However, the fungus might have been indirectly transmitted via other sources such as vegetables, fruits, and dairy products [8].
C. neoformans generally cause three types of infections: cryptococcal meningitis, pulmonary, and cutaneous cryptococcosis [18]. The dissemination of this disease occurs when at least two noncontiguous sites are affected, which is unusual and mostly observed in HIV patients [4, 19]. In our case, only pulmonary involvement was not present while cutaneous manifestations were the first presenting symptoms followed by cryptococcal meningitis. Some studies support the importance of lumbar puncture in patients with cryptococcosis, even when CNS symptoms are not observed because asymptomatic meningitis is reported to be an early stage of the disease [20].
Systemic lupus erythematosus disease activity index (SLEDAI) was calculated for our presented case in order to be used as a predictor for SLE mortality and as a measure of global disease activity, and it was achieving high values (79) which reflect why the patient underwent into cryptococcal meningitis with poor clinical course. Eventhough, for patients with low SLE activity, the possibility of cryptococcal meningitis should not be underestimated [21].
Skin involvement is a rare presenting symptom of Cryptococcus infection, but it is usually a sign of disseminated disease; it may precede the systemic symptoms even eight months earlier [5, 18]. It is important to stress the rarity and polymorphism of the skin conditions, with the possible development of vesicles or blisters and the potential progression to ulceration [1, 4].
Cryptococcal cellulitis is a rare specific cutaneous manifestation, which was developed in our case. It was initially suspected to be a bacterial infection for which antibiotics were prescribed until its failure and microbiological results confirmed the fungal diagnosis. Although rare, the present case, cryptococcal cellulitis was restricted mainly to the lower body, particularly to the lower extremities, and this was reported in other rare reported cases [1, 2]. Despite that, cryptococcal cellulitis is uncommon and undistinguishable from acute bacterial cellulitis for appearance and presentation [6], but high suspicion especially in a risky patient should be considered.
More than 80% of patients manifested cryptococcal cellulitis and are expected to survive in immunocompetent status when they receive the appropriate antifungal therapy [6]. According to the current guidelines of the American Society of Infectious Diseases for disseminated cryptococcosis management, amphotericin B combined with flucytosine is recommended as the primary therapy, followed by fluconazole as a consolidation therapy [4, 18]. Flucytosine is expensive and was not available in our country; so, it was not considered for the treatment. Instead, it was replaced by the addition of fluconazole to amphotericin B regimen.
Cryptococcal laboratory diagnosis relies on three main methods: latex agglutination test, fungal culture, and direct microscopic examination [22]. In the present case, both the microscopic examination and microbiological cultures were the cornerstone for the diagnosis. C. neoformans was differentiated from other fungal species especially Candida spp. by the characterized morphology in the Gram-stained smear, microbiological culture characters, Indian ink stain positivity, and biochemical reactions.
Indian ink stain was positive in our case. In HIV-positive patients, its sensitivity increases up to 80% due to higher fungal loads in the CSF, while in HIV negative patients, the sensitivity is only 30–50% [8, 23]. CSF culture is considered the gold standard for cryptococcal diagnosis, but it has several diagnostic obstacles as long time is needed for fungus to grow, while time is very critical for management of meningitis cases with evolving lifetime neurological complications [24]. Besides, fungal cultures are not available in all medical facilities and therefore may not be performed. It is also associated with false-negative results, especially in cases with low fungal load, and this may be the attributed cause of negative blood culture result in our case.
Regarding management of cryptococcosis, the prolonged course (6–10 weeks) of IV amphotericin B monotherapy, together with the reduction of chemotherapy to improve immune status, was the main target. Caution was taken while reducing immunosuppressive therapy, since a rapid reduction is reported to be associated with immune reconstitution inflammatory syndrome (IRIS) in some patients [9]. There is evidence that supports the requirement for maintenance therapy with fluconazole administered as indefinite secondary prophylaxis, since the rate of recurrence exceeds 50% after apparently successful treatment [25].
Differential diagnosis of the present case must be addressed which includes besides to what was mentioned, infection versus flare-up attacks in lupus patients; several sepsis markers including CRP increase significantly in SLE patients with concomitant infection but increase only slightly or not at all in patients with a lupus flare without infection [14, 26] which is exactly encountered in our presented case. Additionally, decreased visual acuity due to increased intracranial tension (papilledema) was differentiated from decreased visual acuity due to optic nerve atrophy. For the presented case, papilledema was evident on fundus examination at the time of cryptococcal meningitis first diagnosed, while optic nerve atrophy was evident on fundus examination at the end.
Finally, we highlight the importance of clinicians' awareness about such infection among non-HIV immunocompromised patients including those who are diagnosed with autoimmune diseases. The latency of Cryptococcus should be considered and suspected during the management of such cases which necessitate early recognition and proper management.
For preparing Indian ink-stained film, take two drops from the examined CSF sample directly or a small part of the growing colony from the plate, mix it well with the ink, put a cover slide, and leave the slide for an hour to give a chance for the cells to be settled, and for better contrast view, lower the condenser and reduce the microscopic light and examine the film by using the lens with magnification power (40x). Cryptococcus will be evident as shiny spherical budding in a dark background.
4. Conclusion
Cryptococcal meningitis should be considered as one of the possible diagnoses in a patient with altered sensorium and neck stiffness, especially those who are immunocompromised. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening complications.
Early management of cryptococcal meningitis is associated with better prognosis and lower neurological complications. Despite that, flucytosine is being described as the best antifungal medication for cryptococcal infections. Amphotericin B still gives good results in such cases.
Negative bacterial growth from a skin lesion does not necessitate that it is a sterile lesion; it may be an atypical microorganism or microorganism that needs special media to grow or longer duration to be cultivated. Clinical pathologists should be aware of Cryptococcus laboratory diagnosis and how to differentiate it from Candida spp. Microbiological culture is a confirmatory step for Cryptococcus diagnosis; however, Gram-stained and Indian ink-stained films are rapid and informative diagnostic methods especially in limited resources facilities. The communication between laboratory staff members and treating medical team is very crucial for better clinical judgment specifically in a circumstance where an unusual diagnostic result is released or diagnosing a rare disease.
CSF examination may show low cell count; however, infection presents; this is commonly seen in immunocompromised patients as no adequate inflammation. Cryptococcal infection associated with CNS latency which should to be suspected; hence, meticulous follow-up is an essential step in cryptococcal management. The second activation of cryptococcal latency is usually life-threatening and mostly fatal.
Acknowledgments
The authors would like to thank all members of Immunology Unit-Pediatric Department and Microbiology Unit-Clinical Pathology Department of Ain Shams University Hospital. The authors gratefully acknowledge Professor Dalia Helmy El-Ghoneimy and Professor Malaka Zakaria Amer for their efforts to diagnose and follow up severe medical cases including this presented case and special gratitude to the mother of the child for supporting with detailed medical information and for her medical awareness and patience throughout her daughter's longstanding disease.
Abbreviations
ALT:Alanine transaminase
ANA:Antinuclear antibody
AST:Aspartate transaminase
C. neoformans:
Cryptococcus neoformans
CBC:Complete blood count
CNS:Central nervous system
CRP:C-reactive protein
CSF:Cerebrospinal fluid
DNA:Deoxyribonucleic acid
dsDNA:Double-strand DNA
E.R:Emergency room
EEG:Electroencephalogram
eGFR:Estimated glomerular filtration rate
ESR:Erythrocyte sedimentation rate
HIV:Human immunodeficiency virus
IgG:Immunoglobulin G
IRIS:Immune reconstitution inflammatory syndrome
IV:Intravenous
MPA:Mycophenolic acid
MRI:Magnetic resonance imaging
PC ratio:Protein creatinine ratio
RF:Rheumatoid factor
RNA:Ribonucleic acid
RNP:Ribonucleoprotein antibodies
SDA:Sabouraud's dextrose agar
SLE:Systemic lupus erythematosus
SOPs:Standard operating procedures
WBC:White blood cell.
Data Availability
The data underlying the findings of this research are publicly available.
Ethical Approval
Compliance with ethics guidelines, all procedures followed the ethical standards of the responsible committee on human experimentation (institutional and national).
Consent
Written informed consent for publication of clinical details was obtained from the mother of the patient.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
Authors' Contributions
Heba Ezzat Hashem contributed to acquisition, analysis, and interpretation of data, drafting of paper, conception and design, revision for critical intellectual content, final approval, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Zakaria Hamza Ibrahim involved in revision for critical intellectual content, final approval, and financial support.
Figure 1 A simplified chart representing the sequence of the disease in our case.
Figure 2 (a) Clear colorless CSF sample; other etiological causes of meningitis especially viral meningitis versus fungal meningitis must be differentiated, specifically in the presence of clear colorless CSF samples with low cell count and minimal changes of CSF parameters. (b) Spherical budding yeast in the CSF; it should be differentiated from the elliptical budding yeast cells of Candida spp. which is more commonly encountered during CSF examination as a fungal cause of meningitis. (c) Gram-stained film; direct film from CSF shows spherical budding yeast cells with surrounding translucent haloes due to capsular structure. (d) Blood agar shows small white colonies, after 72 hours of incubation. (e) Sabouraud dextrose agar (SDA) shows pasty colonies that were confirmed to be Cryptococcus neoformans. (f) Gram from culture shows spherical yeast cells with surrounding translucent haloes.
Figure 3 Biochemical reaction; the urease test was positive.
Figure 4
Cryptococcus as shiny spherical budding in a dark background.
Figure 5 Laboratory course of the present case and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation; the patient improved clinically and discharged after almost one month with minimal residual weakness in her lower limbs. The nCD64 test was available in our hospital as a sepsis biomarker, and it was performed for our case for follow-up purposes.
Figure 6 Patient developed extensive skin ulceration with serous oozing from both lower limbs; this image was taken upon her clinical improvement on amphotericin B. The local edema resolved leaving the skin redundant, cracked, and the oozing discharge was first serous-like followed by purulent discharge then pus draining stopped.
Figure 7 EEG at the 4th admission, seizures, and other CNS manifestations in patients who had previous cryptococcal meningitis is very essential to be distinguished; it is due to reactivation of latent infection or due to seizures attributed to other medical causes. For the present case, EEG showed normal electric activates without focal localization.
Figure 8 MRI brain performed at the time of 3rd admission; dilated third ventricles were evident due to brain cell atrophy; at this occasion, signs of increase intracranial tension were negative which excluded it as a cause for cerebral ventricles dilatations.
Table 1 Laboratory course of the present case, and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation.
Hb TLC ANC ALC AMC PLT CRP CD64% CD64 MFI
08/05/2016 10.6 12.2 11.2 0.6 0.4 44 6 98.5 2.87
11/05/2016 9 10.9 9.2 1.1 0.51 81 6 91.5 1.91
15/05/2016 7.7 14.8 12.72 1.57 0.48 209 4 80.1 1.56
22/05/2016 7.2 10 7.6 1.1 0.5 238 4 68.9 1.45
Hb, hemoglobin (g/dl); TLC, total leukocytic count (X109/L); ANC, absolute neutrophil count (X109/L); ALC, absolute lymphocyte count (X109/L); AMC, absolute monocyte count (X109/L); PLT, platelet (X109/L); CRP, C-reactive protein (mg/L); nCD64%, neutrophil CD64%; nCD64MFI, nCD64 mean fluorescence intensity. | AMIKACIN, CEFEPIME HYDROCHLORIDE, CYCLOPHOSPHAMIDE, FLUCONAZOLE, HYDROXYCHLOROQUINE, MYCOPHENOLATE MOFETIL, PREDNISONE, VANCOMYCIN | DrugsGivenReaction | CC BY | 33628263 | 19,565,138 | 2021 |
What was the administration route of drug 'AMPHOTERICIN B'? | Atypical Presentation of Pediatric Systemic Lupus Erythematosus Complicated by Cryptococcal Meningitis.
Cryptococcus is an opportunistic fungal pathogen that leads to life-threatening infections. Cryptococcal infections are mainly reported in HIV patients and less commonly encountered in non-HIV immunocompromised host. Cryptococcus neoformans (C. neoformans) is the most common Cryptococcus species causing diseases in humans which can be presented as pulmonary, meningitis, cutaneous, and/or disseminated cryptococcosis. Case Presentation. A 12-year-old female girl from Cairo, Egypt, presented to the pediatric hospital with signs of systemic lupus erythematosus (SLE). She had an aggressive lupus nephritis course for which corticosteroids, mycophenolate mofetil, and cyclophosphamide were prescribed, and the child gradually improved and was discharged. Two months later, the patient exhibited skin lesions involved both in her legs, massive ulcers were developed and extended rapidly through the entire legs followed by deterioration in her conscious level, and signs of meningitis were documented. Cerebrospinal fluid (CSF) examination and microbiological workup were confirmatory for C. neoformans infection, and mental and motor functions were rapidly deteriorated. Treatment with amphotericin B in addition to supportive treatment and close follow-up of the patient's medical condition result in obvious clinical improvement and patient discharge with minimal residual weakness in her legs after almost a one-month duration. After six months, the patient was brought to the emergency department complaining of repeated attacks of seizures, a lumbar puncture was performed, and culture results were again confirmatory for C. neoformans. An intensive course of antifungal therapy was prescribed which was successful, evident by resolution of the signs and symptoms of infection in addition to negative culture results and negative sepsis biomarkers. The child clinically improved, but unfortunately, gradual optic nerve degeneration and brain cell atrophy as a sequel of severe and longstanding cryptococcal infection resulted in her death after almost one year from her first attack.
Cryptococcal infection among non-HIV patients is a rare disease but can result in advanced medical complications which may be fatal. The disease should be suspected to be reliably diagnosed. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening consequences. Amphotericin B can be used effectively in cryptococcosis management in the settings where flucytosine is not available. Signs of cryptococcal meningitis can be manifested again after a period of remission and clinical cure which signifies the latency of Cryptococcus in the central nervous system. The second activation of Cryptococcus after its latency is usually life-threatening and mostly fatal.
1. Background
Immunocompromised individuals including HIV, SLE, and patients on prolonged corticosteroid and immunosuppressant therapy are more prone to various bacterial, viral, and fungal opportunistic infections. One of the most important fatal fungal infections is cryptococcal infection [1–4]. C. neoformans is the most frequent cryptococcal species infect humans, and it is an encapsulated yeast microorganism, which is commonly transmitted through bird feces, plants, dust, soil, and contaminated food [2, 3]. Cryptococcosis can cause disseminated infection reaching to the lungs, central nervous system (CNS), and skin [2, 3, 5]. Dermal manifestations can present in different clinical morphologies including ulcers, acneiform papules, subcutaneous nodules, and rarely, cellulitis [4, 6].
2. Case Presentation
A 12-years-old Egyptian female student presented to Ain Shams University Pediatric Hospital complaining of generalized body edema, frothy urine, and proteinuria (3.7 g/day). The child was diagnosed as nephrotic syndrome, with repeated albumin infusions, and steroid therapy was initiated, but the child was nonresponding; instead, her medical condition deteriorated. Laboratory profile was in concordance with serologically quiescent SLE which included antinuclear antibody titer 1: 1280 finely speckled, elevated rheumatoid factor (RF) of 456 IU/ml (N: 0–20 IU/ml), positive SS-A/Ro > 8.0 and SS-B/La > 8.0 antibodies, anti-beta-2 glycoprotein IgM Ab > 100 U/ml, C-reactive protein (CRP) level 3.9 mg/l (N: 0–5 mg/l), and erythrocyte sedimentation rate (ESR) 51 mm/hour (N: 0–10 mm/hour). The serologic tests that were negative included anti-dsDNA Abs, complement C3 level 154 mg/dl (N: 106–194 mg/dl), complement C4 level 38 mg/dl (N: 19–50 mg/dl), cyclic citrullinated peptide IgG, cryoglobulin, serum immunofixation, Scl-70 scleroderma, Smith, RNP, cardiolipin antibodies, and lupus anticoagulant. Urine studies at the time revealed 3 + proteinuria, no hematuria or pyuria, a creatinine level of 0.93 mg/dl, and eGFR > 60 ml/min/1.73 m2. The diagnosis of SLE with nephrotic presentation was established, upon which the child received a medical regimen for lupus management including corticosteroids, mycophenolate mofetil, and cyclophosphamide which resulted in patient clinical improvement.
Two months later, the child was admitted complaining of poor appetite, nausea and vomiting, tiredness, swollen ankles, and shortness of breath, and deteriorated renal functions were evident in her laboratory profile: creatinine increased to 1.92 mg/dl, 4 + protein on urinalysis, worsening urine protein to creatinine (PC) ratio of 1.9 (N: 0.0–0.1), and 24-hour urine protein of 1170 mg/24 hours (N: 50–150 mg/24 hours). Lupus nephritis grade IV was confirmed. Therefore, the child received intermittent hemodialysis; in addition, the doses of the prescribed immunosuppressant was increased: prednisone (40 mg/day), hydroxychloroquine (6 mg/kg/day), and mycophenolate mofetil (2 g/day). The patient was kept under this protocol; she gradually improved and was discharged. A simplified chart representing the sequence of the disease in the presented case is illustrated in Figure 1.
After two months, the child manifested skin ulcers in her lower extremities which were progressive in course. Drug allergies, insect bites, and family history were excluded. First, these lesions were nonwell-demarcated, erythematous, painful on palpation, nonpruritic with increasing local edema, and bullae formation. A few days later, lesions spread to involve entire her legs up to the groin area, the bullae began to coalescence together, ruptured, and a huge amount of serous discharge was drained from the lesions; no corresponding lesions appeared on the face, trunk, or upper extremities, and fever was not present at first, but with worsening of the lesions, the patient became feverish, hematuric, anemic, and hypotensive with deteriorated general condition; hence, she was admitted for the 2nd time.
At the time of admission, laboratory profile revealed hemoglobin 8.2 g/dL, white blood cell (WBC) count 10,800/mm³, platelet count 129,000 cells/mm³, serum aspartate transaminase (AST) 10 U/L, serum alanine transaminase (ALT) 17 U/L, CRP 12 mg/L, and ESR 60 mm. Upon worsening the skin lesions, bacterial skin infection was suspected; so empirical treatment with amikacin and cefepime was started and the dose of prednisone decreased to 30 mg/day; microbiological cultures revealed no microorganism growth after 48 hours of incubation. Upon suspicion of bacterial cellulitis and due to the lack of improvements of the skin lesions, vancomycin was added to the treatment regimen.
After three days, the patient medical condition deteriorated rapidly. She complained of severe headache, altered memory, continuous agitation, neck rigidity, stiffness, photophobia, and total loss of appetite; so, meningitis was suspected; hence, lumbar puncture was performed, and a CSF sample was sent for cytological examination in addition to culture procedures. The sample was clear colorless on physical inspection (Figure 2)(a), and cell count was 25 cells/HPF.
Direct Gram examination of CSF showed spherical budding encapsulated yeast cells surrounded by translucent hallow around the cells (Figures 2(b) and 2)(c). CSF chemical examination revealed protein level 74 mg/dL (normal range 15–60 mg/dL) and glucose levels 41 mg/dL (normal range 50–80 mg/dL). The sample was cultured on aerobic blood agar, anaerobic blood agar, chocolate, and MacConkey agar; the plates showed delayed growth at the end of the third day (72 hours incubation according to CSF standard operating procedures (SOPs) of our microbiology lab). It was a minute whitish milky colony, which was highly suggestive of fungal infection, confirmed by further subculture, the sample on Sabouraud's dextrose agar (SDA) plates (Figures 2(d)–2(f)). Indian ink stain and positive biochemical reactions were confirmatory for the diagnosis of Cryptococcus infection (Figures 3 and 4). Additionally, antifungal susceptibility testing was performed which was positive for both amphotericin B and flucytosine.
Despite that, the child manifested obvious clinical signs and symptoms of meningitis. Magnetic resonance imaging (MRI) brain with contrast showed findings within normal limits, and blood culture was negative for microbiological growth after 7 days incubation.
Based on the available laboratory results, treatment for disseminated cryptococcosis was initiated immediately upon laboratory notification, prednisone was further decreased to 20 mg/day, and fluconazole was discontinued. Amphotericin B was started at a dose of 0.7 mg/kg/day with an infusion time of 6 hours, since the patient had repeated reactions (fever, chills, and nausea) with a shorter infusion time. Concerning flucytosine, which is indicated as the drug of choice in cryptococcal meningitis treatment, it was not used for treatment of our presented case due to financial aspects and nonavailability in our country, Egypt. Repeated lumber tapping was performed to relieve persistent increased intracranial tension as a consequence of severe meningitis; in addition, plasmapheresis was performed to remove lupus autoantibodies.
The child was subjected for further workup to rule out pneumonia and other organs affection, and for follow up purpose, chest X-ray was ordered, which revealed normal findings, ESR, CRP, complete blood count (CBC), and sepsis marker, neutrophil CD64. These laboratory tests were performed every 3 days on a routine base for monitoring the medical progress which showed dramatic gradual improvement (Table 1 and Figure 5); in conjugation with clinical signs and symptoms improvement evident by regaining her mental and motor skills, besides healing of the leg ulcers, pus draining stopped and swelling disappeared (Figure 6). In this setting, a lumbar puncture was intended to be performed upon this obvious clinical and laboratory improvement preparing the patient to be discharged, but the child refused at her own request and was discharged on her demand after almost 30 days since amphotericin B infusion was first prescribed.
At the time of discharge, the patient had no pulmonary sequelae, but she had residual weakness in her lower limbs. The laboratory results at the time of discharge were hemoglobin 9.2 g/dL, WBC 16.700 cells per mm³, platelet 303.000 cells per mm³, AST 10 U/L, ALT 4 U/L, CRP 6 mg/L, and ESR 53 mm/h. The child was instructed to continue fluconazole (400 mg/day) at home for 8 weeks and then reduced its dose to 200 mg/day for 1 year. And she was weaned gradually from corticosteroid therapy.
One month later, the child was brought to the emergency department complaining of severe headache, projectile vomiting, and blurred vision. She was admitted for the 3rd time. An MRI brain was ordered, and a lumbar puncture was performed urgently to relieve intracranial tension, and for chemical, cytological, and microbiological analyses, all were negative for infection except for CRP slightly positive (12 mg/L). So, lupus flare-up was suspected, and pulse steroid therapy was started, in addition to antifungal (fluconazole) and antibiotic (amikacin and cefepime) coverage. The patient was subjected for plasmapheresis; upon it, she manifested dramatical improvement and discharge. She started to attend the immunotherapy clinic every two weeks for follow up purpose; she did well for 5 months and regained her functions except for difficulty in talking and walking abilities as she could not walk without support; so, the mother was advised to bring her for regular physiotherapy sessions every week.
Five months later, the patient complained of shivering in her legs and hands followed by seizures attacks which were gradually increasing in frequency and duration till her mother brought her to the E/R. She was admitted for the 4th time. Phenytoin was prescribed, initial dose 2.5 mg/kg/dose twice a day and increased gradually to maximum 5 mg/kg/dose twice daily, and intensive work up profile was conducted searching for the cause of the seizures which included electroencephalogram (EEG), MRI brain, full lab evaluation, and CSF chemical analysis and microbiological examination. EEG revealed normal electric impulses without focal activities (Figure 7). MRI brain showed mildly dilated 3rd ventricles, CSF chemistry analysis revealed protein level 82 mg/dL (normal range 15–60 mg/dL), and glucose levels of 35 mg/dL (normal range 50–80 mg/dL). Upon receiving the sample in our microbiology lab, the sample physical criteria were very similar to the previous one, clear colorless, and cell count was 15 cell/cm3. A direct wet film examination was positive for budding yeast cells which were suspected and notified immediately to the pediatric team, and protocol of treatment was decided rapidly. CSF culture results were again confirmatory for C. neoformans.
An intensive course of antifungal therapy was initiated which included amphotericin B (0.7 mg/kg/day) with an infusion time of 6 hours, and fluconazole. Resolution of patient signs and symptoms of infection was clinically evident in addition to negative culture results and improved laboratory sepsis parameters. The child general condition improved, but at this setting, she complained of poor visual acuity. The pediatric team immediately consulted the specialist neurosurgeon, ophthalmologist, and an MRI brain urgently performed which showed evidence of brain cell atrophy with subsequent increased intracranial ventricular sizes and evidence of optic nerve atrophy; the ophthalmologist confirmed bilateral optic nerve degeneration which was more evident on the left side (Figure 8).
After almost one month and, however, signs and symptoms of infection were resolved, cryptococcosis longstanding course with brain cell atrophy as a sequel of cryptococcal meningitis resulted in the child's death after almost one year from her first attack.
3. Discussion and Conclusion
Cryptococcus is an opportunistic fungal pathogen that leads to rare life-threatening infection. Meningoencephalitis and disseminated cryptococcosis are usually common complications reported in immunocompromised hosts [7, 8]. In the presented case, we reported a pediatric systemic lupus erythematosus patient complicated by rapidly disseminating cryptococcal infection which exhibited a latency in the child CNS followed by an attack of infection flare-up which was successfully treated, but slowly progressive brain cell atrophy due to longstanding disease resulted in her death.
Infections and sepsis are major causes of hospitalization, mortality, and morbidity in immunosuppressed patients [9]. Cryptococcosis is one of the fatal fungal infections reported mainly in immunocompromised hosts; however, several reported cases point to its incidence also in immunocompetent patients [10–12]. Cryptococcosis has a low incidence in non-HIV patients, approximately 1 : 100.000 [5, 13]. Patients with SLE are highly susceptible to infections due to the combined effects of their immunosuppressive therapy and the abnormalities of the immune system that the disease itself causes [14]. Concerning our presented case, prolonged corticosteroid therapy and immunosuppressants due to her underlying disease (SLE) were the major risk factors for disseminated cryptococcosis with poor outcomes.
The patient had a progressive renal course complicated by lupus nephritis class IV for which immunosuppressants was given. Lupus nephritis is clinically evident in 50–60% of patients with SLE [15]. Both mycophenolate mofetil and cyclophosphamide were prescribed to our case. Mycophenolate mofetil depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation [16]. While, cyclophosphamide inhibits protein synthesis through DNA and RNA crosslinking [17].
By discussing Cryptococcus as the causative pathogen, C. neoformans is the most common strain causing infections in humans, and it is an encapsulated yeast that has been isolated from chickens' droppings and grows readily in soil contaminated with avian excreta particularly that of pigeons. In humans, it can colonize the upper airway system. Nevertheless, no animal-to-human nor person-to-person respiratory transmission has been documented [9]. Our presented case lived in low socioeconomic and hygienic status, and she denied contact with pigeon or birds. However, the fungus might have been indirectly transmitted via other sources such as vegetables, fruits, and dairy products [8].
C. neoformans generally cause three types of infections: cryptococcal meningitis, pulmonary, and cutaneous cryptococcosis [18]. The dissemination of this disease occurs when at least two noncontiguous sites are affected, which is unusual and mostly observed in HIV patients [4, 19]. In our case, only pulmonary involvement was not present while cutaneous manifestations were the first presenting symptoms followed by cryptococcal meningitis. Some studies support the importance of lumbar puncture in patients with cryptococcosis, even when CNS symptoms are not observed because asymptomatic meningitis is reported to be an early stage of the disease [20].
Systemic lupus erythematosus disease activity index (SLEDAI) was calculated for our presented case in order to be used as a predictor for SLE mortality and as a measure of global disease activity, and it was achieving high values (79) which reflect why the patient underwent into cryptococcal meningitis with poor clinical course. Eventhough, for patients with low SLE activity, the possibility of cryptococcal meningitis should not be underestimated [21].
Skin involvement is a rare presenting symptom of Cryptococcus infection, but it is usually a sign of disseminated disease; it may precede the systemic symptoms even eight months earlier [5, 18]. It is important to stress the rarity and polymorphism of the skin conditions, with the possible development of vesicles or blisters and the potential progression to ulceration [1, 4].
Cryptococcal cellulitis is a rare specific cutaneous manifestation, which was developed in our case. It was initially suspected to be a bacterial infection for which antibiotics were prescribed until its failure and microbiological results confirmed the fungal diagnosis. Although rare, the present case, cryptococcal cellulitis was restricted mainly to the lower body, particularly to the lower extremities, and this was reported in other rare reported cases [1, 2]. Despite that, cryptococcal cellulitis is uncommon and undistinguishable from acute bacterial cellulitis for appearance and presentation [6], but high suspicion especially in a risky patient should be considered.
More than 80% of patients manifested cryptococcal cellulitis and are expected to survive in immunocompetent status when they receive the appropriate antifungal therapy [6]. According to the current guidelines of the American Society of Infectious Diseases for disseminated cryptococcosis management, amphotericin B combined with flucytosine is recommended as the primary therapy, followed by fluconazole as a consolidation therapy [4, 18]. Flucytosine is expensive and was not available in our country; so, it was not considered for the treatment. Instead, it was replaced by the addition of fluconazole to amphotericin B regimen.
Cryptococcal laboratory diagnosis relies on three main methods: latex agglutination test, fungal culture, and direct microscopic examination [22]. In the present case, both the microscopic examination and microbiological cultures were the cornerstone for the diagnosis. C. neoformans was differentiated from other fungal species especially Candida spp. by the characterized morphology in the Gram-stained smear, microbiological culture characters, Indian ink stain positivity, and biochemical reactions.
Indian ink stain was positive in our case. In HIV-positive patients, its sensitivity increases up to 80% due to higher fungal loads in the CSF, while in HIV negative patients, the sensitivity is only 30–50% [8, 23]. CSF culture is considered the gold standard for cryptococcal diagnosis, but it has several diagnostic obstacles as long time is needed for fungus to grow, while time is very critical for management of meningitis cases with evolving lifetime neurological complications [24]. Besides, fungal cultures are not available in all medical facilities and therefore may not be performed. It is also associated with false-negative results, especially in cases with low fungal load, and this may be the attributed cause of negative blood culture result in our case.
Regarding management of cryptococcosis, the prolonged course (6–10 weeks) of IV amphotericin B monotherapy, together with the reduction of chemotherapy to improve immune status, was the main target. Caution was taken while reducing immunosuppressive therapy, since a rapid reduction is reported to be associated with immune reconstitution inflammatory syndrome (IRIS) in some patients [9]. There is evidence that supports the requirement for maintenance therapy with fluconazole administered as indefinite secondary prophylaxis, since the rate of recurrence exceeds 50% after apparently successful treatment [25].
Differential diagnosis of the present case must be addressed which includes besides to what was mentioned, infection versus flare-up attacks in lupus patients; several sepsis markers including CRP increase significantly in SLE patients with concomitant infection but increase only slightly or not at all in patients with a lupus flare without infection [14, 26] which is exactly encountered in our presented case. Additionally, decreased visual acuity due to increased intracranial tension (papilledema) was differentiated from decreased visual acuity due to optic nerve atrophy. For the presented case, papilledema was evident on fundus examination at the time of cryptococcal meningitis first diagnosed, while optic nerve atrophy was evident on fundus examination at the end.
Finally, we highlight the importance of clinicians' awareness about such infection among non-HIV immunocompromised patients including those who are diagnosed with autoimmune diseases. The latency of Cryptococcus should be considered and suspected during the management of such cases which necessitate early recognition and proper management.
For preparing Indian ink-stained film, take two drops from the examined CSF sample directly or a small part of the growing colony from the plate, mix it well with the ink, put a cover slide, and leave the slide for an hour to give a chance for the cells to be settled, and for better contrast view, lower the condenser and reduce the microscopic light and examine the film by using the lens with magnification power (40x). Cryptococcus will be evident as shiny spherical budding in a dark background.
4. Conclusion
Cryptococcal meningitis should be considered as one of the possible diagnoses in a patient with altered sensorium and neck stiffness, especially those who are immunocompromised. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening complications.
Early management of cryptococcal meningitis is associated with better prognosis and lower neurological complications. Despite that, flucytosine is being described as the best antifungal medication for cryptococcal infections. Amphotericin B still gives good results in such cases.
Negative bacterial growth from a skin lesion does not necessitate that it is a sterile lesion; it may be an atypical microorganism or microorganism that needs special media to grow or longer duration to be cultivated. Clinical pathologists should be aware of Cryptococcus laboratory diagnosis and how to differentiate it from Candida spp. Microbiological culture is a confirmatory step for Cryptococcus diagnosis; however, Gram-stained and Indian ink-stained films are rapid and informative diagnostic methods especially in limited resources facilities. The communication between laboratory staff members and treating medical team is very crucial for better clinical judgment specifically in a circumstance where an unusual diagnostic result is released or diagnosing a rare disease.
CSF examination may show low cell count; however, infection presents; this is commonly seen in immunocompromised patients as no adequate inflammation. Cryptococcal infection associated with CNS latency which should to be suspected; hence, meticulous follow-up is an essential step in cryptococcal management. The second activation of cryptococcal latency is usually life-threatening and mostly fatal.
Acknowledgments
The authors would like to thank all members of Immunology Unit-Pediatric Department and Microbiology Unit-Clinical Pathology Department of Ain Shams University Hospital. The authors gratefully acknowledge Professor Dalia Helmy El-Ghoneimy and Professor Malaka Zakaria Amer for their efforts to diagnose and follow up severe medical cases including this presented case and special gratitude to the mother of the child for supporting with detailed medical information and for her medical awareness and patience throughout her daughter's longstanding disease.
Abbreviations
ALT:Alanine transaminase
ANA:Antinuclear antibody
AST:Aspartate transaminase
C. neoformans:
Cryptococcus neoformans
CBC:Complete blood count
CNS:Central nervous system
CRP:C-reactive protein
CSF:Cerebrospinal fluid
DNA:Deoxyribonucleic acid
dsDNA:Double-strand DNA
E.R:Emergency room
EEG:Electroencephalogram
eGFR:Estimated glomerular filtration rate
ESR:Erythrocyte sedimentation rate
HIV:Human immunodeficiency virus
IgG:Immunoglobulin G
IRIS:Immune reconstitution inflammatory syndrome
IV:Intravenous
MPA:Mycophenolic acid
MRI:Magnetic resonance imaging
PC ratio:Protein creatinine ratio
RF:Rheumatoid factor
RNA:Ribonucleic acid
RNP:Ribonucleoprotein antibodies
SDA:Sabouraud's dextrose agar
SLE:Systemic lupus erythematosus
SOPs:Standard operating procedures
WBC:White blood cell.
Data Availability
The data underlying the findings of this research are publicly available.
Ethical Approval
Compliance with ethics guidelines, all procedures followed the ethical standards of the responsible committee on human experimentation (institutional and national).
Consent
Written informed consent for publication of clinical details was obtained from the mother of the patient.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
Authors' Contributions
Heba Ezzat Hashem contributed to acquisition, analysis, and interpretation of data, drafting of paper, conception and design, revision for critical intellectual content, final approval, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Zakaria Hamza Ibrahim involved in revision for critical intellectual content, final approval, and financial support.
Figure 1 A simplified chart representing the sequence of the disease in our case.
Figure 2 (a) Clear colorless CSF sample; other etiological causes of meningitis especially viral meningitis versus fungal meningitis must be differentiated, specifically in the presence of clear colorless CSF samples with low cell count and minimal changes of CSF parameters. (b) Spherical budding yeast in the CSF; it should be differentiated from the elliptical budding yeast cells of Candida spp. which is more commonly encountered during CSF examination as a fungal cause of meningitis. (c) Gram-stained film; direct film from CSF shows spherical budding yeast cells with surrounding translucent haloes due to capsular structure. (d) Blood agar shows small white colonies, after 72 hours of incubation. (e) Sabouraud dextrose agar (SDA) shows pasty colonies that were confirmed to be Cryptococcus neoformans. (f) Gram from culture shows spherical yeast cells with surrounding translucent haloes.
Figure 3 Biochemical reaction; the urease test was positive.
Figure 4
Cryptococcus as shiny spherical budding in a dark background.
Figure 5 Laboratory course of the present case and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation; the patient improved clinically and discharged after almost one month with minimal residual weakness in her lower limbs. The nCD64 test was available in our hospital as a sepsis biomarker, and it was performed for our case for follow-up purposes.
Figure 6 Patient developed extensive skin ulceration with serous oozing from both lower limbs; this image was taken upon her clinical improvement on amphotericin B. The local edema resolved leaving the skin redundant, cracked, and the oozing discharge was first serous-like followed by purulent discharge then pus draining stopped.
Figure 7 EEG at the 4th admission, seizures, and other CNS manifestations in patients who had previous cryptococcal meningitis is very essential to be distinguished; it is due to reactivation of latent infection or due to seizures attributed to other medical causes. For the present case, EEG showed normal electric activates without focal localization.
Figure 8 MRI brain performed at the time of 3rd admission; dilated third ventricles were evident due to brain cell atrophy; at this occasion, signs of increase intracranial tension were negative which excluded it as a cause for cerebral ventricles dilatations.
Table 1 Laboratory course of the present case, and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation.
Hb TLC ANC ALC AMC PLT CRP CD64% CD64 MFI
08/05/2016 10.6 12.2 11.2 0.6 0.4 44 6 98.5 2.87
11/05/2016 9 10.9 9.2 1.1 0.51 81 6 91.5 1.91
15/05/2016 7.7 14.8 12.72 1.57 0.48 209 4 80.1 1.56
22/05/2016 7.2 10 7.6 1.1 0.5 238 4 68.9 1.45
Hb, hemoglobin (g/dl); TLC, total leukocytic count (X109/L); ANC, absolute neutrophil count (X109/L); ALC, absolute lymphocyte count (X109/L); AMC, absolute monocyte count (X109/L); PLT, platelet (X109/L); CRP, C-reactive protein (mg/L); nCD64%, neutrophil CD64%; nCD64MFI, nCD64 mean fluorescence intensity. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33628263 | 19,577,937 | 2021 |
What was the dosage of drug 'AMPHOTERICIN B'? | Atypical Presentation of Pediatric Systemic Lupus Erythematosus Complicated by Cryptococcal Meningitis.
Cryptococcus is an opportunistic fungal pathogen that leads to life-threatening infections. Cryptococcal infections are mainly reported in HIV patients and less commonly encountered in non-HIV immunocompromised host. Cryptococcus neoformans (C. neoformans) is the most common Cryptococcus species causing diseases in humans which can be presented as pulmonary, meningitis, cutaneous, and/or disseminated cryptococcosis. Case Presentation. A 12-year-old female girl from Cairo, Egypt, presented to the pediatric hospital with signs of systemic lupus erythematosus (SLE). She had an aggressive lupus nephritis course for which corticosteroids, mycophenolate mofetil, and cyclophosphamide were prescribed, and the child gradually improved and was discharged. Two months later, the patient exhibited skin lesions involved both in her legs, massive ulcers were developed and extended rapidly through the entire legs followed by deterioration in her conscious level, and signs of meningitis were documented. Cerebrospinal fluid (CSF) examination and microbiological workup were confirmatory for C. neoformans infection, and mental and motor functions were rapidly deteriorated. Treatment with amphotericin B in addition to supportive treatment and close follow-up of the patient's medical condition result in obvious clinical improvement and patient discharge with minimal residual weakness in her legs after almost a one-month duration. After six months, the patient was brought to the emergency department complaining of repeated attacks of seizures, a lumbar puncture was performed, and culture results were again confirmatory for C. neoformans. An intensive course of antifungal therapy was prescribed which was successful, evident by resolution of the signs and symptoms of infection in addition to negative culture results and negative sepsis biomarkers. The child clinically improved, but unfortunately, gradual optic nerve degeneration and brain cell atrophy as a sequel of severe and longstanding cryptococcal infection resulted in her death after almost one year from her first attack.
Cryptococcal infection among non-HIV patients is a rare disease but can result in advanced medical complications which may be fatal. The disease should be suspected to be reliably diagnosed. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening consequences. Amphotericin B can be used effectively in cryptococcosis management in the settings where flucytosine is not available. Signs of cryptococcal meningitis can be manifested again after a period of remission and clinical cure which signifies the latency of Cryptococcus in the central nervous system. The second activation of Cryptococcus after its latency is usually life-threatening and mostly fatal.
1. Background
Immunocompromised individuals including HIV, SLE, and patients on prolonged corticosteroid and immunosuppressant therapy are more prone to various bacterial, viral, and fungal opportunistic infections. One of the most important fatal fungal infections is cryptococcal infection [1–4]. C. neoformans is the most frequent cryptococcal species infect humans, and it is an encapsulated yeast microorganism, which is commonly transmitted through bird feces, plants, dust, soil, and contaminated food [2, 3]. Cryptococcosis can cause disseminated infection reaching to the lungs, central nervous system (CNS), and skin [2, 3, 5]. Dermal manifestations can present in different clinical morphologies including ulcers, acneiform papules, subcutaneous nodules, and rarely, cellulitis [4, 6].
2. Case Presentation
A 12-years-old Egyptian female student presented to Ain Shams University Pediatric Hospital complaining of generalized body edema, frothy urine, and proteinuria (3.7 g/day). The child was diagnosed as nephrotic syndrome, with repeated albumin infusions, and steroid therapy was initiated, but the child was nonresponding; instead, her medical condition deteriorated. Laboratory profile was in concordance with serologically quiescent SLE which included antinuclear antibody titer 1: 1280 finely speckled, elevated rheumatoid factor (RF) of 456 IU/ml (N: 0–20 IU/ml), positive SS-A/Ro > 8.0 and SS-B/La > 8.0 antibodies, anti-beta-2 glycoprotein IgM Ab > 100 U/ml, C-reactive protein (CRP) level 3.9 mg/l (N: 0–5 mg/l), and erythrocyte sedimentation rate (ESR) 51 mm/hour (N: 0–10 mm/hour). The serologic tests that were negative included anti-dsDNA Abs, complement C3 level 154 mg/dl (N: 106–194 mg/dl), complement C4 level 38 mg/dl (N: 19–50 mg/dl), cyclic citrullinated peptide IgG, cryoglobulin, serum immunofixation, Scl-70 scleroderma, Smith, RNP, cardiolipin antibodies, and lupus anticoagulant. Urine studies at the time revealed 3 + proteinuria, no hematuria or pyuria, a creatinine level of 0.93 mg/dl, and eGFR > 60 ml/min/1.73 m2. The diagnosis of SLE with nephrotic presentation was established, upon which the child received a medical regimen for lupus management including corticosteroids, mycophenolate mofetil, and cyclophosphamide which resulted in patient clinical improvement.
Two months later, the child was admitted complaining of poor appetite, nausea and vomiting, tiredness, swollen ankles, and shortness of breath, and deteriorated renal functions were evident in her laboratory profile: creatinine increased to 1.92 mg/dl, 4 + protein on urinalysis, worsening urine protein to creatinine (PC) ratio of 1.9 (N: 0.0–0.1), and 24-hour urine protein of 1170 mg/24 hours (N: 50–150 mg/24 hours). Lupus nephritis grade IV was confirmed. Therefore, the child received intermittent hemodialysis; in addition, the doses of the prescribed immunosuppressant was increased: prednisone (40 mg/day), hydroxychloroquine (6 mg/kg/day), and mycophenolate mofetil (2 g/day). The patient was kept under this protocol; she gradually improved and was discharged. A simplified chart representing the sequence of the disease in the presented case is illustrated in Figure 1.
After two months, the child manifested skin ulcers in her lower extremities which were progressive in course. Drug allergies, insect bites, and family history were excluded. First, these lesions were nonwell-demarcated, erythematous, painful on palpation, nonpruritic with increasing local edema, and bullae formation. A few days later, lesions spread to involve entire her legs up to the groin area, the bullae began to coalescence together, ruptured, and a huge amount of serous discharge was drained from the lesions; no corresponding lesions appeared on the face, trunk, or upper extremities, and fever was not present at first, but with worsening of the lesions, the patient became feverish, hematuric, anemic, and hypotensive with deteriorated general condition; hence, she was admitted for the 2nd time.
At the time of admission, laboratory profile revealed hemoglobin 8.2 g/dL, white blood cell (WBC) count 10,800/mm³, platelet count 129,000 cells/mm³, serum aspartate transaminase (AST) 10 U/L, serum alanine transaminase (ALT) 17 U/L, CRP 12 mg/L, and ESR 60 mm. Upon worsening the skin lesions, bacterial skin infection was suspected; so empirical treatment with amikacin and cefepime was started and the dose of prednisone decreased to 30 mg/day; microbiological cultures revealed no microorganism growth after 48 hours of incubation. Upon suspicion of bacterial cellulitis and due to the lack of improvements of the skin lesions, vancomycin was added to the treatment regimen.
After three days, the patient medical condition deteriorated rapidly. She complained of severe headache, altered memory, continuous agitation, neck rigidity, stiffness, photophobia, and total loss of appetite; so, meningitis was suspected; hence, lumbar puncture was performed, and a CSF sample was sent for cytological examination in addition to culture procedures. The sample was clear colorless on physical inspection (Figure 2)(a), and cell count was 25 cells/HPF.
Direct Gram examination of CSF showed spherical budding encapsulated yeast cells surrounded by translucent hallow around the cells (Figures 2(b) and 2)(c). CSF chemical examination revealed protein level 74 mg/dL (normal range 15–60 mg/dL) and glucose levels 41 mg/dL (normal range 50–80 mg/dL). The sample was cultured on aerobic blood agar, anaerobic blood agar, chocolate, and MacConkey agar; the plates showed delayed growth at the end of the third day (72 hours incubation according to CSF standard operating procedures (SOPs) of our microbiology lab). It was a minute whitish milky colony, which was highly suggestive of fungal infection, confirmed by further subculture, the sample on Sabouraud's dextrose agar (SDA) plates (Figures 2(d)–2(f)). Indian ink stain and positive biochemical reactions were confirmatory for the diagnosis of Cryptococcus infection (Figures 3 and 4). Additionally, antifungal susceptibility testing was performed which was positive for both amphotericin B and flucytosine.
Despite that, the child manifested obvious clinical signs and symptoms of meningitis. Magnetic resonance imaging (MRI) brain with contrast showed findings within normal limits, and blood culture was negative for microbiological growth after 7 days incubation.
Based on the available laboratory results, treatment for disseminated cryptococcosis was initiated immediately upon laboratory notification, prednisone was further decreased to 20 mg/day, and fluconazole was discontinued. Amphotericin B was started at a dose of 0.7 mg/kg/day with an infusion time of 6 hours, since the patient had repeated reactions (fever, chills, and nausea) with a shorter infusion time. Concerning flucytosine, which is indicated as the drug of choice in cryptococcal meningitis treatment, it was not used for treatment of our presented case due to financial aspects and nonavailability in our country, Egypt. Repeated lumber tapping was performed to relieve persistent increased intracranial tension as a consequence of severe meningitis; in addition, plasmapheresis was performed to remove lupus autoantibodies.
The child was subjected for further workup to rule out pneumonia and other organs affection, and for follow up purpose, chest X-ray was ordered, which revealed normal findings, ESR, CRP, complete blood count (CBC), and sepsis marker, neutrophil CD64. These laboratory tests were performed every 3 days on a routine base for monitoring the medical progress which showed dramatic gradual improvement (Table 1 and Figure 5); in conjugation with clinical signs and symptoms improvement evident by regaining her mental and motor skills, besides healing of the leg ulcers, pus draining stopped and swelling disappeared (Figure 6). In this setting, a lumbar puncture was intended to be performed upon this obvious clinical and laboratory improvement preparing the patient to be discharged, but the child refused at her own request and was discharged on her demand after almost 30 days since amphotericin B infusion was first prescribed.
At the time of discharge, the patient had no pulmonary sequelae, but she had residual weakness in her lower limbs. The laboratory results at the time of discharge were hemoglobin 9.2 g/dL, WBC 16.700 cells per mm³, platelet 303.000 cells per mm³, AST 10 U/L, ALT 4 U/L, CRP 6 mg/L, and ESR 53 mm/h. The child was instructed to continue fluconazole (400 mg/day) at home for 8 weeks and then reduced its dose to 200 mg/day for 1 year. And she was weaned gradually from corticosteroid therapy.
One month later, the child was brought to the emergency department complaining of severe headache, projectile vomiting, and blurred vision. She was admitted for the 3rd time. An MRI brain was ordered, and a lumbar puncture was performed urgently to relieve intracranial tension, and for chemical, cytological, and microbiological analyses, all were negative for infection except for CRP slightly positive (12 mg/L). So, lupus flare-up was suspected, and pulse steroid therapy was started, in addition to antifungal (fluconazole) and antibiotic (amikacin and cefepime) coverage. The patient was subjected for plasmapheresis; upon it, she manifested dramatical improvement and discharge. She started to attend the immunotherapy clinic every two weeks for follow up purpose; she did well for 5 months and regained her functions except for difficulty in talking and walking abilities as she could not walk without support; so, the mother was advised to bring her for regular physiotherapy sessions every week.
Five months later, the patient complained of shivering in her legs and hands followed by seizures attacks which were gradually increasing in frequency and duration till her mother brought her to the E/R. She was admitted for the 4th time. Phenytoin was prescribed, initial dose 2.5 mg/kg/dose twice a day and increased gradually to maximum 5 mg/kg/dose twice daily, and intensive work up profile was conducted searching for the cause of the seizures which included electroencephalogram (EEG), MRI brain, full lab evaluation, and CSF chemical analysis and microbiological examination. EEG revealed normal electric impulses without focal activities (Figure 7). MRI brain showed mildly dilated 3rd ventricles, CSF chemistry analysis revealed protein level 82 mg/dL (normal range 15–60 mg/dL), and glucose levels of 35 mg/dL (normal range 50–80 mg/dL). Upon receiving the sample in our microbiology lab, the sample physical criteria were very similar to the previous one, clear colorless, and cell count was 15 cell/cm3. A direct wet film examination was positive for budding yeast cells which were suspected and notified immediately to the pediatric team, and protocol of treatment was decided rapidly. CSF culture results were again confirmatory for C. neoformans.
An intensive course of antifungal therapy was initiated which included amphotericin B (0.7 mg/kg/day) with an infusion time of 6 hours, and fluconazole. Resolution of patient signs and symptoms of infection was clinically evident in addition to negative culture results and improved laboratory sepsis parameters. The child general condition improved, but at this setting, she complained of poor visual acuity. The pediatric team immediately consulted the specialist neurosurgeon, ophthalmologist, and an MRI brain urgently performed which showed evidence of brain cell atrophy with subsequent increased intracranial ventricular sizes and evidence of optic nerve atrophy; the ophthalmologist confirmed bilateral optic nerve degeneration which was more evident on the left side (Figure 8).
After almost one month and, however, signs and symptoms of infection were resolved, cryptococcosis longstanding course with brain cell atrophy as a sequel of cryptococcal meningitis resulted in the child's death after almost one year from her first attack.
3. Discussion and Conclusion
Cryptococcus is an opportunistic fungal pathogen that leads to rare life-threatening infection. Meningoencephalitis and disseminated cryptococcosis are usually common complications reported in immunocompromised hosts [7, 8]. In the presented case, we reported a pediatric systemic lupus erythematosus patient complicated by rapidly disseminating cryptococcal infection which exhibited a latency in the child CNS followed by an attack of infection flare-up which was successfully treated, but slowly progressive brain cell atrophy due to longstanding disease resulted in her death.
Infections and sepsis are major causes of hospitalization, mortality, and morbidity in immunosuppressed patients [9]. Cryptococcosis is one of the fatal fungal infections reported mainly in immunocompromised hosts; however, several reported cases point to its incidence also in immunocompetent patients [10–12]. Cryptococcosis has a low incidence in non-HIV patients, approximately 1 : 100.000 [5, 13]. Patients with SLE are highly susceptible to infections due to the combined effects of their immunosuppressive therapy and the abnormalities of the immune system that the disease itself causes [14]. Concerning our presented case, prolonged corticosteroid therapy and immunosuppressants due to her underlying disease (SLE) were the major risk factors for disseminated cryptococcosis with poor outcomes.
The patient had a progressive renal course complicated by lupus nephritis class IV for which immunosuppressants was given. Lupus nephritis is clinically evident in 50–60% of patients with SLE [15]. Both mycophenolate mofetil and cyclophosphamide were prescribed to our case. Mycophenolate mofetil depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation [16]. While, cyclophosphamide inhibits protein synthesis through DNA and RNA crosslinking [17].
By discussing Cryptococcus as the causative pathogen, C. neoformans is the most common strain causing infections in humans, and it is an encapsulated yeast that has been isolated from chickens' droppings and grows readily in soil contaminated with avian excreta particularly that of pigeons. In humans, it can colonize the upper airway system. Nevertheless, no animal-to-human nor person-to-person respiratory transmission has been documented [9]. Our presented case lived in low socioeconomic and hygienic status, and she denied contact with pigeon or birds. However, the fungus might have been indirectly transmitted via other sources such as vegetables, fruits, and dairy products [8].
C. neoformans generally cause three types of infections: cryptococcal meningitis, pulmonary, and cutaneous cryptococcosis [18]. The dissemination of this disease occurs when at least two noncontiguous sites are affected, which is unusual and mostly observed in HIV patients [4, 19]. In our case, only pulmonary involvement was not present while cutaneous manifestations were the first presenting symptoms followed by cryptococcal meningitis. Some studies support the importance of lumbar puncture in patients with cryptococcosis, even when CNS symptoms are not observed because asymptomatic meningitis is reported to be an early stage of the disease [20].
Systemic lupus erythematosus disease activity index (SLEDAI) was calculated for our presented case in order to be used as a predictor for SLE mortality and as a measure of global disease activity, and it was achieving high values (79) which reflect why the patient underwent into cryptococcal meningitis with poor clinical course. Eventhough, for patients with low SLE activity, the possibility of cryptococcal meningitis should not be underestimated [21].
Skin involvement is a rare presenting symptom of Cryptococcus infection, but it is usually a sign of disseminated disease; it may precede the systemic symptoms even eight months earlier [5, 18]. It is important to stress the rarity and polymorphism of the skin conditions, with the possible development of vesicles or blisters and the potential progression to ulceration [1, 4].
Cryptococcal cellulitis is a rare specific cutaneous manifestation, which was developed in our case. It was initially suspected to be a bacterial infection for which antibiotics were prescribed until its failure and microbiological results confirmed the fungal diagnosis. Although rare, the present case, cryptococcal cellulitis was restricted mainly to the lower body, particularly to the lower extremities, and this was reported in other rare reported cases [1, 2]. Despite that, cryptococcal cellulitis is uncommon and undistinguishable from acute bacterial cellulitis for appearance and presentation [6], but high suspicion especially in a risky patient should be considered.
More than 80% of patients manifested cryptococcal cellulitis and are expected to survive in immunocompetent status when they receive the appropriate antifungal therapy [6]. According to the current guidelines of the American Society of Infectious Diseases for disseminated cryptococcosis management, amphotericin B combined with flucytosine is recommended as the primary therapy, followed by fluconazole as a consolidation therapy [4, 18]. Flucytosine is expensive and was not available in our country; so, it was not considered for the treatment. Instead, it was replaced by the addition of fluconazole to amphotericin B regimen.
Cryptococcal laboratory diagnosis relies on three main methods: latex agglutination test, fungal culture, and direct microscopic examination [22]. In the present case, both the microscopic examination and microbiological cultures were the cornerstone for the diagnosis. C. neoformans was differentiated from other fungal species especially Candida spp. by the characterized morphology in the Gram-stained smear, microbiological culture characters, Indian ink stain positivity, and biochemical reactions.
Indian ink stain was positive in our case. In HIV-positive patients, its sensitivity increases up to 80% due to higher fungal loads in the CSF, while in HIV negative patients, the sensitivity is only 30–50% [8, 23]. CSF culture is considered the gold standard for cryptococcal diagnosis, but it has several diagnostic obstacles as long time is needed for fungus to grow, while time is very critical for management of meningitis cases with evolving lifetime neurological complications [24]. Besides, fungal cultures are not available in all medical facilities and therefore may not be performed. It is also associated with false-negative results, especially in cases with low fungal load, and this may be the attributed cause of negative blood culture result in our case.
Regarding management of cryptococcosis, the prolonged course (6–10 weeks) of IV amphotericin B monotherapy, together with the reduction of chemotherapy to improve immune status, was the main target. Caution was taken while reducing immunosuppressive therapy, since a rapid reduction is reported to be associated with immune reconstitution inflammatory syndrome (IRIS) in some patients [9]. There is evidence that supports the requirement for maintenance therapy with fluconazole administered as indefinite secondary prophylaxis, since the rate of recurrence exceeds 50% after apparently successful treatment [25].
Differential diagnosis of the present case must be addressed which includes besides to what was mentioned, infection versus flare-up attacks in lupus patients; several sepsis markers including CRP increase significantly in SLE patients with concomitant infection but increase only slightly or not at all in patients with a lupus flare without infection [14, 26] which is exactly encountered in our presented case. Additionally, decreased visual acuity due to increased intracranial tension (papilledema) was differentiated from decreased visual acuity due to optic nerve atrophy. For the presented case, papilledema was evident on fundus examination at the time of cryptococcal meningitis first diagnosed, while optic nerve atrophy was evident on fundus examination at the end.
Finally, we highlight the importance of clinicians' awareness about such infection among non-HIV immunocompromised patients including those who are diagnosed with autoimmune diseases. The latency of Cryptococcus should be considered and suspected during the management of such cases which necessitate early recognition and proper management.
For preparing Indian ink-stained film, take two drops from the examined CSF sample directly or a small part of the growing colony from the plate, mix it well with the ink, put a cover slide, and leave the slide for an hour to give a chance for the cells to be settled, and for better contrast view, lower the condenser and reduce the microscopic light and examine the film by using the lens with magnification power (40x). Cryptococcus will be evident as shiny spherical budding in a dark background.
4. Conclusion
Cryptococcal meningitis should be considered as one of the possible diagnoses in a patient with altered sensorium and neck stiffness, especially those who are immunocompromised. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening complications.
Early management of cryptococcal meningitis is associated with better prognosis and lower neurological complications. Despite that, flucytosine is being described as the best antifungal medication for cryptococcal infections. Amphotericin B still gives good results in such cases.
Negative bacterial growth from a skin lesion does not necessitate that it is a sterile lesion; it may be an atypical microorganism or microorganism that needs special media to grow or longer duration to be cultivated. Clinical pathologists should be aware of Cryptococcus laboratory diagnosis and how to differentiate it from Candida spp. Microbiological culture is a confirmatory step for Cryptococcus diagnosis; however, Gram-stained and Indian ink-stained films are rapid and informative diagnostic methods especially in limited resources facilities. The communication between laboratory staff members and treating medical team is very crucial for better clinical judgment specifically in a circumstance where an unusual diagnostic result is released or diagnosing a rare disease.
CSF examination may show low cell count; however, infection presents; this is commonly seen in immunocompromised patients as no adequate inflammation. Cryptococcal infection associated with CNS latency which should to be suspected; hence, meticulous follow-up is an essential step in cryptococcal management. The second activation of cryptococcal latency is usually life-threatening and mostly fatal.
Acknowledgments
The authors would like to thank all members of Immunology Unit-Pediatric Department and Microbiology Unit-Clinical Pathology Department of Ain Shams University Hospital. The authors gratefully acknowledge Professor Dalia Helmy El-Ghoneimy and Professor Malaka Zakaria Amer for their efforts to diagnose and follow up severe medical cases including this presented case and special gratitude to the mother of the child for supporting with detailed medical information and for her medical awareness and patience throughout her daughter's longstanding disease.
Abbreviations
ALT:Alanine transaminase
ANA:Antinuclear antibody
AST:Aspartate transaminase
C. neoformans:
Cryptococcus neoformans
CBC:Complete blood count
CNS:Central nervous system
CRP:C-reactive protein
CSF:Cerebrospinal fluid
DNA:Deoxyribonucleic acid
dsDNA:Double-strand DNA
E.R:Emergency room
EEG:Electroencephalogram
eGFR:Estimated glomerular filtration rate
ESR:Erythrocyte sedimentation rate
HIV:Human immunodeficiency virus
IgG:Immunoglobulin G
IRIS:Immune reconstitution inflammatory syndrome
IV:Intravenous
MPA:Mycophenolic acid
MRI:Magnetic resonance imaging
PC ratio:Protein creatinine ratio
RF:Rheumatoid factor
RNA:Ribonucleic acid
RNP:Ribonucleoprotein antibodies
SDA:Sabouraud's dextrose agar
SLE:Systemic lupus erythematosus
SOPs:Standard operating procedures
WBC:White blood cell.
Data Availability
The data underlying the findings of this research are publicly available.
Ethical Approval
Compliance with ethics guidelines, all procedures followed the ethical standards of the responsible committee on human experimentation (institutional and national).
Consent
Written informed consent for publication of clinical details was obtained from the mother of the patient.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
Authors' Contributions
Heba Ezzat Hashem contributed to acquisition, analysis, and interpretation of data, drafting of paper, conception and design, revision for critical intellectual content, final approval, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Zakaria Hamza Ibrahim involved in revision for critical intellectual content, final approval, and financial support.
Figure 1 A simplified chart representing the sequence of the disease in our case.
Figure 2 (a) Clear colorless CSF sample; other etiological causes of meningitis especially viral meningitis versus fungal meningitis must be differentiated, specifically in the presence of clear colorless CSF samples with low cell count and minimal changes of CSF parameters. (b) Spherical budding yeast in the CSF; it should be differentiated from the elliptical budding yeast cells of Candida spp. which is more commonly encountered during CSF examination as a fungal cause of meningitis. (c) Gram-stained film; direct film from CSF shows spherical budding yeast cells with surrounding translucent haloes due to capsular structure. (d) Blood agar shows small white colonies, after 72 hours of incubation. (e) Sabouraud dextrose agar (SDA) shows pasty colonies that were confirmed to be Cryptococcus neoformans. (f) Gram from culture shows spherical yeast cells with surrounding translucent haloes.
Figure 3 Biochemical reaction; the urease test was positive.
Figure 4
Cryptococcus as shiny spherical budding in a dark background.
Figure 5 Laboratory course of the present case and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation; the patient improved clinically and discharged after almost one month with minimal residual weakness in her lower limbs. The nCD64 test was available in our hospital as a sepsis biomarker, and it was performed for our case for follow-up purposes.
Figure 6 Patient developed extensive skin ulceration with serous oozing from both lower limbs; this image was taken upon her clinical improvement on amphotericin B. The local edema resolved leaving the skin redundant, cracked, and the oozing discharge was first serous-like followed by purulent discharge then pus draining stopped.
Figure 7 EEG at the 4th admission, seizures, and other CNS manifestations in patients who had previous cryptococcal meningitis is very essential to be distinguished; it is due to reactivation of latent infection or due to seizures attributed to other medical causes. For the present case, EEG showed normal electric activates without focal localization.
Figure 8 MRI brain performed at the time of 3rd admission; dilated third ventricles were evident due to brain cell atrophy; at this occasion, signs of increase intracranial tension were negative which excluded it as a cause for cerebral ventricles dilatations.
Table 1 Laboratory course of the present case, and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation.
Hb TLC ANC ALC AMC PLT CRP CD64% CD64 MFI
08/05/2016 10.6 12.2 11.2 0.6 0.4 44 6 98.5 2.87
11/05/2016 9 10.9 9.2 1.1 0.51 81 6 91.5 1.91
15/05/2016 7.7 14.8 12.72 1.57 0.48 209 4 80.1 1.56
22/05/2016 7.2 10 7.6 1.1 0.5 238 4 68.9 1.45
Hb, hemoglobin (g/dl); TLC, total leukocytic count (X109/L); ANC, absolute neutrophil count (X109/L); ALC, absolute lymphocyte count (X109/L); AMC, absolute monocyte count (X109/L); PLT, platelet (X109/L); CRP, C-reactive protein (mg/L); nCD64%, neutrophil CD64%; nCD64MFI, nCD64 mean fluorescence intensity. | 0.7 MILLIGRAM/KILOGRAM, QD, INFUSION TIME OF 6 HOURS | DrugDosageText | CC BY | 33628263 | 19,577,937 | 2021 |
What was the outcome of reaction 'Atrophy'? | Atypical Presentation of Pediatric Systemic Lupus Erythematosus Complicated by Cryptococcal Meningitis.
Cryptococcus is an opportunistic fungal pathogen that leads to life-threatening infections. Cryptococcal infections are mainly reported in HIV patients and less commonly encountered in non-HIV immunocompromised host. Cryptococcus neoformans (C. neoformans) is the most common Cryptococcus species causing diseases in humans which can be presented as pulmonary, meningitis, cutaneous, and/or disseminated cryptococcosis. Case Presentation. A 12-year-old female girl from Cairo, Egypt, presented to the pediatric hospital with signs of systemic lupus erythematosus (SLE). She had an aggressive lupus nephritis course for which corticosteroids, mycophenolate mofetil, and cyclophosphamide were prescribed, and the child gradually improved and was discharged. Two months later, the patient exhibited skin lesions involved both in her legs, massive ulcers were developed and extended rapidly through the entire legs followed by deterioration in her conscious level, and signs of meningitis were documented. Cerebrospinal fluid (CSF) examination and microbiological workup were confirmatory for C. neoformans infection, and mental and motor functions were rapidly deteriorated. Treatment with amphotericin B in addition to supportive treatment and close follow-up of the patient's medical condition result in obvious clinical improvement and patient discharge with minimal residual weakness in her legs after almost a one-month duration. After six months, the patient was brought to the emergency department complaining of repeated attacks of seizures, a lumbar puncture was performed, and culture results were again confirmatory for C. neoformans. An intensive course of antifungal therapy was prescribed which was successful, evident by resolution of the signs and symptoms of infection in addition to negative culture results and negative sepsis biomarkers. The child clinically improved, but unfortunately, gradual optic nerve degeneration and brain cell atrophy as a sequel of severe and longstanding cryptococcal infection resulted in her death after almost one year from her first attack.
Cryptococcal infection among non-HIV patients is a rare disease but can result in advanced medical complications which may be fatal. The disease should be suspected to be reliably diagnosed. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening consequences. Amphotericin B can be used effectively in cryptococcosis management in the settings where flucytosine is not available. Signs of cryptococcal meningitis can be manifested again after a period of remission and clinical cure which signifies the latency of Cryptococcus in the central nervous system. The second activation of Cryptococcus after its latency is usually life-threatening and mostly fatal.
1. Background
Immunocompromised individuals including HIV, SLE, and patients on prolonged corticosteroid and immunosuppressant therapy are more prone to various bacterial, viral, and fungal opportunistic infections. One of the most important fatal fungal infections is cryptococcal infection [1–4]. C. neoformans is the most frequent cryptococcal species infect humans, and it is an encapsulated yeast microorganism, which is commonly transmitted through bird feces, plants, dust, soil, and contaminated food [2, 3]. Cryptococcosis can cause disseminated infection reaching to the lungs, central nervous system (CNS), and skin [2, 3, 5]. Dermal manifestations can present in different clinical morphologies including ulcers, acneiform papules, subcutaneous nodules, and rarely, cellulitis [4, 6].
2. Case Presentation
A 12-years-old Egyptian female student presented to Ain Shams University Pediatric Hospital complaining of generalized body edema, frothy urine, and proteinuria (3.7 g/day). The child was diagnosed as nephrotic syndrome, with repeated albumin infusions, and steroid therapy was initiated, but the child was nonresponding; instead, her medical condition deteriorated. Laboratory profile was in concordance with serologically quiescent SLE which included antinuclear antibody titer 1: 1280 finely speckled, elevated rheumatoid factor (RF) of 456 IU/ml (N: 0–20 IU/ml), positive SS-A/Ro > 8.0 and SS-B/La > 8.0 antibodies, anti-beta-2 glycoprotein IgM Ab > 100 U/ml, C-reactive protein (CRP) level 3.9 mg/l (N: 0–5 mg/l), and erythrocyte sedimentation rate (ESR) 51 mm/hour (N: 0–10 mm/hour). The serologic tests that were negative included anti-dsDNA Abs, complement C3 level 154 mg/dl (N: 106–194 mg/dl), complement C4 level 38 mg/dl (N: 19–50 mg/dl), cyclic citrullinated peptide IgG, cryoglobulin, serum immunofixation, Scl-70 scleroderma, Smith, RNP, cardiolipin antibodies, and lupus anticoagulant. Urine studies at the time revealed 3 + proteinuria, no hematuria or pyuria, a creatinine level of 0.93 mg/dl, and eGFR > 60 ml/min/1.73 m2. The diagnosis of SLE with nephrotic presentation was established, upon which the child received a medical regimen for lupus management including corticosteroids, mycophenolate mofetil, and cyclophosphamide which resulted in patient clinical improvement.
Two months later, the child was admitted complaining of poor appetite, nausea and vomiting, tiredness, swollen ankles, and shortness of breath, and deteriorated renal functions were evident in her laboratory profile: creatinine increased to 1.92 mg/dl, 4 + protein on urinalysis, worsening urine protein to creatinine (PC) ratio of 1.9 (N: 0.0–0.1), and 24-hour urine protein of 1170 mg/24 hours (N: 50–150 mg/24 hours). Lupus nephritis grade IV was confirmed. Therefore, the child received intermittent hemodialysis; in addition, the doses of the prescribed immunosuppressant was increased: prednisone (40 mg/day), hydroxychloroquine (6 mg/kg/day), and mycophenolate mofetil (2 g/day). The patient was kept under this protocol; she gradually improved and was discharged. A simplified chart representing the sequence of the disease in the presented case is illustrated in Figure 1.
After two months, the child manifested skin ulcers in her lower extremities which were progressive in course. Drug allergies, insect bites, and family history were excluded. First, these lesions were nonwell-demarcated, erythematous, painful on palpation, nonpruritic with increasing local edema, and bullae formation. A few days later, lesions spread to involve entire her legs up to the groin area, the bullae began to coalescence together, ruptured, and a huge amount of serous discharge was drained from the lesions; no corresponding lesions appeared on the face, trunk, or upper extremities, and fever was not present at first, but with worsening of the lesions, the patient became feverish, hematuric, anemic, and hypotensive with deteriorated general condition; hence, she was admitted for the 2nd time.
At the time of admission, laboratory profile revealed hemoglobin 8.2 g/dL, white blood cell (WBC) count 10,800/mm³, platelet count 129,000 cells/mm³, serum aspartate transaminase (AST) 10 U/L, serum alanine transaminase (ALT) 17 U/L, CRP 12 mg/L, and ESR 60 mm. Upon worsening the skin lesions, bacterial skin infection was suspected; so empirical treatment with amikacin and cefepime was started and the dose of prednisone decreased to 30 mg/day; microbiological cultures revealed no microorganism growth after 48 hours of incubation. Upon suspicion of bacterial cellulitis and due to the lack of improvements of the skin lesions, vancomycin was added to the treatment regimen.
After three days, the patient medical condition deteriorated rapidly. She complained of severe headache, altered memory, continuous agitation, neck rigidity, stiffness, photophobia, and total loss of appetite; so, meningitis was suspected; hence, lumbar puncture was performed, and a CSF sample was sent for cytological examination in addition to culture procedures. The sample was clear colorless on physical inspection (Figure 2)(a), and cell count was 25 cells/HPF.
Direct Gram examination of CSF showed spherical budding encapsulated yeast cells surrounded by translucent hallow around the cells (Figures 2(b) and 2)(c). CSF chemical examination revealed protein level 74 mg/dL (normal range 15–60 mg/dL) and glucose levels 41 mg/dL (normal range 50–80 mg/dL). The sample was cultured on aerobic blood agar, anaerobic blood agar, chocolate, and MacConkey agar; the plates showed delayed growth at the end of the third day (72 hours incubation according to CSF standard operating procedures (SOPs) of our microbiology lab). It was a minute whitish milky colony, which was highly suggestive of fungal infection, confirmed by further subculture, the sample on Sabouraud's dextrose agar (SDA) plates (Figures 2(d)–2(f)). Indian ink stain and positive biochemical reactions were confirmatory for the diagnosis of Cryptococcus infection (Figures 3 and 4). Additionally, antifungal susceptibility testing was performed which was positive for both amphotericin B and flucytosine.
Despite that, the child manifested obvious clinical signs and symptoms of meningitis. Magnetic resonance imaging (MRI) brain with contrast showed findings within normal limits, and blood culture was negative for microbiological growth after 7 days incubation.
Based on the available laboratory results, treatment for disseminated cryptococcosis was initiated immediately upon laboratory notification, prednisone was further decreased to 20 mg/day, and fluconazole was discontinued. Amphotericin B was started at a dose of 0.7 mg/kg/day with an infusion time of 6 hours, since the patient had repeated reactions (fever, chills, and nausea) with a shorter infusion time. Concerning flucytosine, which is indicated as the drug of choice in cryptococcal meningitis treatment, it was not used for treatment of our presented case due to financial aspects and nonavailability in our country, Egypt. Repeated lumber tapping was performed to relieve persistent increased intracranial tension as a consequence of severe meningitis; in addition, plasmapheresis was performed to remove lupus autoantibodies.
The child was subjected for further workup to rule out pneumonia and other organs affection, and for follow up purpose, chest X-ray was ordered, which revealed normal findings, ESR, CRP, complete blood count (CBC), and sepsis marker, neutrophil CD64. These laboratory tests were performed every 3 days on a routine base for monitoring the medical progress which showed dramatic gradual improvement (Table 1 and Figure 5); in conjugation with clinical signs and symptoms improvement evident by regaining her mental and motor skills, besides healing of the leg ulcers, pus draining stopped and swelling disappeared (Figure 6). In this setting, a lumbar puncture was intended to be performed upon this obvious clinical and laboratory improvement preparing the patient to be discharged, but the child refused at her own request and was discharged on her demand after almost 30 days since amphotericin B infusion was first prescribed.
At the time of discharge, the patient had no pulmonary sequelae, but she had residual weakness in her lower limbs. The laboratory results at the time of discharge were hemoglobin 9.2 g/dL, WBC 16.700 cells per mm³, platelet 303.000 cells per mm³, AST 10 U/L, ALT 4 U/L, CRP 6 mg/L, and ESR 53 mm/h. The child was instructed to continue fluconazole (400 mg/day) at home for 8 weeks and then reduced its dose to 200 mg/day for 1 year. And she was weaned gradually from corticosteroid therapy.
One month later, the child was brought to the emergency department complaining of severe headache, projectile vomiting, and blurred vision. She was admitted for the 3rd time. An MRI brain was ordered, and a lumbar puncture was performed urgently to relieve intracranial tension, and for chemical, cytological, and microbiological analyses, all were negative for infection except for CRP slightly positive (12 mg/L). So, lupus flare-up was suspected, and pulse steroid therapy was started, in addition to antifungal (fluconazole) and antibiotic (amikacin and cefepime) coverage. The patient was subjected for plasmapheresis; upon it, she manifested dramatical improvement and discharge. She started to attend the immunotherapy clinic every two weeks for follow up purpose; she did well for 5 months and regained her functions except for difficulty in talking and walking abilities as she could not walk without support; so, the mother was advised to bring her for regular physiotherapy sessions every week.
Five months later, the patient complained of shivering in her legs and hands followed by seizures attacks which were gradually increasing in frequency and duration till her mother brought her to the E/R. She was admitted for the 4th time. Phenytoin was prescribed, initial dose 2.5 mg/kg/dose twice a day and increased gradually to maximum 5 mg/kg/dose twice daily, and intensive work up profile was conducted searching for the cause of the seizures which included electroencephalogram (EEG), MRI brain, full lab evaluation, and CSF chemical analysis and microbiological examination. EEG revealed normal electric impulses without focal activities (Figure 7). MRI brain showed mildly dilated 3rd ventricles, CSF chemistry analysis revealed protein level 82 mg/dL (normal range 15–60 mg/dL), and glucose levels of 35 mg/dL (normal range 50–80 mg/dL). Upon receiving the sample in our microbiology lab, the sample physical criteria were very similar to the previous one, clear colorless, and cell count was 15 cell/cm3. A direct wet film examination was positive for budding yeast cells which were suspected and notified immediately to the pediatric team, and protocol of treatment was decided rapidly. CSF culture results were again confirmatory for C. neoformans.
An intensive course of antifungal therapy was initiated which included amphotericin B (0.7 mg/kg/day) with an infusion time of 6 hours, and fluconazole. Resolution of patient signs and symptoms of infection was clinically evident in addition to negative culture results and improved laboratory sepsis parameters. The child general condition improved, but at this setting, she complained of poor visual acuity. The pediatric team immediately consulted the specialist neurosurgeon, ophthalmologist, and an MRI brain urgently performed which showed evidence of brain cell atrophy with subsequent increased intracranial ventricular sizes and evidence of optic nerve atrophy; the ophthalmologist confirmed bilateral optic nerve degeneration which was more evident on the left side (Figure 8).
After almost one month and, however, signs and symptoms of infection were resolved, cryptococcosis longstanding course with brain cell atrophy as a sequel of cryptococcal meningitis resulted in the child's death after almost one year from her first attack.
3. Discussion and Conclusion
Cryptococcus is an opportunistic fungal pathogen that leads to rare life-threatening infection. Meningoencephalitis and disseminated cryptococcosis are usually common complications reported in immunocompromised hosts [7, 8]. In the presented case, we reported a pediatric systemic lupus erythematosus patient complicated by rapidly disseminating cryptococcal infection which exhibited a latency in the child CNS followed by an attack of infection flare-up which was successfully treated, but slowly progressive brain cell atrophy due to longstanding disease resulted in her death.
Infections and sepsis are major causes of hospitalization, mortality, and morbidity in immunosuppressed patients [9]. Cryptococcosis is one of the fatal fungal infections reported mainly in immunocompromised hosts; however, several reported cases point to its incidence also in immunocompetent patients [10–12]. Cryptococcosis has a low incidence in non-HIV patients, approximately 1 : 100.000 [5, 13]. Patients with SLE are highly susceptible to infections due to the combined effects of their immunosuppressive therapy and the abnormalities of the immune system that the disease itself causes [14]. Concerning our presented case, prolonged corticosteroid therapy and immunosuppressants due to her underlying disease (SLE) were the major risk factors for disseminated cryptococcosis with poor outcomes.
The patient had a progressive renal course complicated by lupus nephritis class IV for which immunosuppressants was given. Lupus nephritis is clinically evident in 50–60% of patients with SLE [15]. Both mycophenolate mofetil and cyclophosphamide were prescribed to our case. Mycophenolate mofetil depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation [16]. While, cyclophosphamide inhibits protein synthesis through DNA and RNA crosslinking [17].
By discussing Cryptococcus as the causative pathogen, C. neoformans is the most common strain causing infections in humans, and it is an encapsulated yeast that has been isolated from chickens' droppings and grows readily in soil contaminated with avian excreta particularly that of pigeons. In humans, it can colonize the upper airway system. Nevertheless, no animal-to-human nor person-to-person respiratory transmission has been documented [9]. Our presented case lived in low socioeconomic and hygienic status, and she denied contact with pigeon or birds. However, the fungus might have been indirectly transmitted via other sources such as vegetables, fruits, and dairy products [8].
C. neoformans generally cause three types of infections: cryptococcal meningitis, pulmonary, and cutaneous cryptococcosis [18]. The dissemination of this disease occurs when at least two noncontiguous sites are affected, which is unusual and mostly observed in HIV patients [4, 19]. In our case, only pulmonary involvement was not present while cutaneous manifestations were the first presenting symptoms followed by cryptococcal meningitis. Some studies support the importance of lumbar puncture in patients with cryptococcosis, even when CNS symptoms are not observed because asymptomatic meningitis is reported to be an early stage of the disease [20].
Systemic lupus erythematosus disease activity index (SLEDAI) was calculated for our presented case in order to be used as a predictor for SLE mortality and as a measure of global disease activity, and it was achieving high values (79) which reflect why the patient underwent into cryptococcal meningitis with poor clinical course. Eventhough, for patients with low SLE activity, the possibility of cryptococcal meningitis should not be underestimated [21].
Skin involvement is a rare presenting symptom of Cryptococcus infection, but it is usually a sign of disseminated disease; it may precede the systemic symptoms even eight months earlier [5, 18]. It is important to stress the rarity and polymorphism of the skin conditions, with the possible development of vesicles or blisters and the potential progression to ulceration [1, 4].
Cryptococcal cellulitis is a rare specific cutaneous manifestation, which was developed in our case. It was initially suspected to be a bacterial infection for which antibiotics were prescribed until its failure and microbiological results confirmed the fungal diagnosis. Although rare, the present case, cryptococcal cellulitis was restricted mainly to the lower body, particularly to the lower extremities, and this was reported in other rare reported cases [1, 2]. Despite that, cryptococcal cellulitis is uncommon and undistinguishable from acute bacterial cellulitis for appearance and presentation [6], but high suspicion especially in a risky patient should be considered.
More than 80% of patients manifested cryptococcal cellulitis and are expected to survive in immunocompetent status when they receive the appropriate antifungal therapy [6]. According to the current guidelines of the American Society of Infectious Diseases for disseminated cryptococcosis management, amphotericin B combined with flucytosine is recommended as the primary therapy, followed by fluconazole as a consolidation therapy [4, 18]. Flucytosine is expensive and was not available in our country; so, it was not considered for the treatment. Instead, it was replaced by the addition of fluconazole to amphotericin B regimen.
Cryptococcal laboratory diagnosis relies on three main methods: latex agglutination test, fungal culture, and direct microscopic examination [22]. In the present case, both the microscopic examination and microbiological cultures were the cornerstone for the diagnosis. C. neoformans was differentiated from other fungal species especially Candida spp. by the characterized morphology in the Gram-stained smear, microbiological culture characters, Indian ink stain positivity, and biochemical reactions.
Indian ink stain was positive in our case. In HIV-positive patients, its sensitivity increases up to 80% due to higher fungal loads in the CSF, while in HIV negative patients, the sensitivity is only 30–50% [8, 23]. CSF culture is considered the gold standard for cryptococcal diagnosis, but it has several diagnostic obstacles as long time is needed for fungus to grow, while time is very critical for management of meningitis cases with evolving lifetime neurological complications [24]. Besides, fungal cultures are not available in all medical facilities and therefore may not be performed. It is also associated with false-negative results, especially in cases with low fungal load, and this may be the attributed cause of negative blood culture result in our case.
Regarding management of cryptococcosis, the prolonged course (6–10 weeks) of IV amphotericin B monotherapy, together with the reduction of chemotherapy to improve immune status, was the main target. Caution was taken while reducing immunosuppressive therapy, since a rapid reduction is reported to be associated with immune reconstitution inflammatory syndrome (IRIS) in some patients [9]. There is evidence that supports the requirement for maintenance therapy with fluconazole administered as indefinite secondary prophylaxis, since the rate of recurrence exceeds 50% after apparently successful treatment [25].
Differential diagnosis of the present case must be addressed which includes besides to what was mentioned, infection versus flare-up attacks in lupus patients; several sepsis markers including CRP increase significantly in SLE patients with concomitant infection but increase only slightly or not at all in patients with a lupus flare without infection [14, 26] which is exactly encountered in our presented case. Additionally, decreased visual acuity due to increased intracranial tension (papilledema) was differentiated from decreased visual acuity due to optic nerve atrophy. For the presented case, papilledema was evident on fundus examination at the time of cryptococcal meningitis first diagnosed, while optic nerve atrophy was evident on fundus examination at the end.
Finally, we highlight the importance of clinicians' awareness about such infection among non-HIV immunocompromised patients including those who are diagnosed with autoimmune diseases. The latency of Cryptococcus should be considered and suspected during the management of such cases which necessitate early recognition and proper management.
For preparing Indian ink-stained film, take two drops from the examined CSF sample directly or a small part of the growing colony from the plate, mix it well with the ink, put a cover slide, and leave the slide for an hour to give a chance for the cells to be settled, and for better contrast view, lower the condenser and reduce the microscopic light and examine the film by using the lens with magnification power (40x). Cryptococcus will be evident as shiny spherical budding in a dark background.
4. Conclusion
Cryptococcal meningitis should be considered as one of the possible diagnoses in a patient with altered sensorium and neck stiffness, especially those who are immunocompromised. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening complications.
Early management of cryptococcal meningitis is associated with better prognosis and lower neurological complications. Despite that, flucytosine is being described as the best antifungal medication for cryptococcal infections. Amphotericin B still gives good results in such cases.
Negative bacterial growth from a skin lesion does not necessitate that it is a sterile lesion; it may be an atypical microorganism or microorganism that needs special media to grow or longer duration to be cultivated. Clinical pathologists should be aware of Cryptococcus laboratory diagnosis and how to differentiate it from Candida spp. Microbiological culture is a confirmatory step for Cryptococcus diagnosis; however, Gram-stained and Indian ink-stained films are rapid and informative diagnostic methods especially in limited resources facilities. The communication between laboratory staff members and treating medical team is very crucial for better clinical judgment specifically in a circumstance where an unusual diagnostic result is released or diagnosing a rare disease.
CSF examination may show low cell count; however, infection presents; this is commonly seen in immunocompromised patients as no adequate inflammation. Cryptococcal infection associated with CNS latency which should to be suspected; hence, meticulous follow-up is an essential step in cryptococcal management. The second activation of cryptococcal latency is usually life-threatening and mostly fatal.
Acknowledgments
The authors would like to thank all members of Immunology Unit-Pediatric Department and Microbiology Unit-Clinical Pathology Department of Ain Shams University Hospital. The authors gratefully acknowledge Professor Dalia Helmy El-Ghoneimy and Professor Malaka Zakaria Amer for their efforts to diagnose and follow up severe medical cases including this presented case and special gratitude to the mother of the child for supporting with detailed medical information and for her medical awareness and patience throughout her daughter's longstanding disease.
Abbreviations
ALT:Alanine transaminase
ANA:Antinuclear antibody
AST:Aspartate transaminase
C. neoformans:
Cryptococcus neoformans
CBC:Complete blood count
CNS:Central nervous system
CRP:C-reactive protein
CSF:Cerebrospinal fluid
DNA:Deoxyribonucleic acid
dsDNA:Double-strand DNA
E.R:Emergency room
EEG:Electroencephalogram
eGFR:Estimated glomerular filtration rate
ESR:Erythrocyte sedimentation rate
HIV:Human immunodeficiency virus
IgG:Immunoglobulin G
IRIS:Immune reconstitution inflammatory syndrome
IV:Intravenous
MPA:Mycophenolic acid
MRI:Magnetic resonance imaging
PC ratio:Protein creatinine ratio
RF:Rheumatoid factor
RNA:Ribonucleic acid
RNP:Ribonucleoprotein antibodies
SDA:Sabouraud's dextrose agar
SLE:Systemic lupus erythematosus
SOPs:Standard operating procedures
WBC:White blood cell.
Data Availability
The data underlying the findings of this research are publicly available.
Ethical Approval
Compliance with ethics guidelines, all procedures followed the ethical standards of the responsible committee on human experimentation (institutional and national).
Consent
Written informed consent for publication of clinical details was obtained from the mother of the patient.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
Authors' Contributions
Heba Ezzat Hashem contributed to acquisition, analysis, and interpretation of data, drafting of paper, conception and design, revision for critical intellectual content, final approval, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Zakaria Hamza Ibrahim involved in revision for critical intellectual content, final approval, and financial support.
Figure 1 A simplified chart representing the sequence of the disease in our case.
Figure 2 (a) Clear colorless CSF sample; other etiological causes of meningitis especially viral meningitis versus fungal meningitis must be differentiated, specifically in the presence of clear colorless CSF samples with low cell count and minimal changes of CSF parameters. (b) Spherical budding yeast in the CSF; it should be differentiated from the elliptical budding yeast cells of Candida spp. which is more commonly encountered during CSF examination as a fungal cause of meningitis. (c) Gram-stained film; direct film from CSF shows spherical budding yeast cells with surrounding translucent haloes due to capsular structure. (d) Blood agar shows small white colonies, after 72 hours of incubation. (e) Sabouraud dextrose agar (SDA) shows pasty colonies that were confirmed to be Cryptococcus neoformans. (f) Gram from culture shows spherical yeast cells with surrounding translucent haloes.
Figure 3 Biochemical reaction; the urease test was positive.
Figure 4
Cryptococcus as shiny spherical budding in a dark background.
Figure 5 Laboratory course of the present case and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation; the patient improved clinically and discharged after almost one month with minimal residual weakness in her lower limbs. The nCD64 test was available in our hospital as a sepsis biomarker, and it was performed for our case for follow-up purposes.
Figure 6 Patient developed extensive skin ulceration with serous oozing from both lower limbs; this image was taken upon her clinical improvement on amphotericin B. The local edema resolved leaving the skin redundant, cracked, and the oozing discharge was first serous-like followed by purulent discharge then pus draining stopped.
Figure 7 EEG at the 4th admission, seizures, and other CNS manifestations in patients who had previous cryptococcal meningitis is very essential to be distinguished; it is due to reactivation of latent infection or due to seizures attributed to other medical causes. For the present case, EEG showed normal electric activates without focal localization.
Figure 8 MRI brain performed at the time of 3rd admission; dilated third ventricles were evident due to brain cell atrophy; at this occasion, signs of increase intracranial tension were negative which excluded it as a cause for cerebral ventricles dilatations.
Table 1 Laboratory course of the present case, and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation.
Hb TLC ANC ALC AMC PLT CRP CD64% CD64 MFI
08/05/2016 10.6 12.2 11.2 0.6 0.4 44 6 98.5 2.87
11/05/2016 9 10.9 9.2 1.1 0.51 81 6 91.5 1.91
15/05/2016 7.7 14.8 12.72 1.57 0.48 209 4 80.1 1.56
22/05/2016 7.2 10 7.6 1.1 0.5 238 4 68.9 1.45
Hb, hemoglobin (g/dl); TLC, total leukocytic count (X109/L); ANC, absolute neutrophil count (X109/L); ALC, absolute lymphocyte count (X109/L); AMC, absolute monocyte count (X109/L); PLT, platelet (X109/L); CRP, C-reactive protein (mg/L); nCD64%, neutrophil CD64%; nCD64MFI, nCD64 mean fluorescence intensity. | Fatal | ReactionOutcome | CC BY | 33628263 | 19,577,937 | 2021 |
What was the outcome of reaction 'Cerebral atrophy'? | Atypical Presentation of Pediatric Systemic Lupus Erythematosus Complicated by Cryptococcal Meningitis.
Cryptococcus is an opportunistic fungal pathogen that leads to life-threatening infections. Cryptococcal infections are mainly reported in HIV patients and less commonly encountered in non-HIV immunocompromised host. Cryptococcus neoformans (C. neoformans) is the most common Cryptococcus species causing diseases in humans which can be presented as pulmonary, meningitis, cutaneous, and/or disseminated cryptococcosis. Case Presentation. A 12-year-old female girl from Cairo, Egypt, presented to the pediatric hospital with signs of systemic lupus erythematosus (SLE). She had an aggressive lupus nephritis course for which corticosteroids, mycophenolate mofetil, and cyclophosphamide were prescribed, and the child gradually improved and was discharged. Two months later, the patient exhibited skin lesions involved both in her legs, massive ulcers were developed and extended rapidly through the entire legs followed by deterioration in her conscious level, and signs of meningitis were documented. Cerebrospinal fluid (CSF) examination and microbiological workup were confirmatory for C. neoformans infection, and mental and motor functions were rapidly deteriorated. Treatment with amphotericin B in addition to supportive treatment and close follow-up of the patient's medical condition result in obvious clinical improvement and patient discharge with minimal residual weakness in her legs after almost a one-month duration. After six months, the patient was brought to the emergency department complaining of repeated attacks of seizures, a lumbar puncture was performed, and culture results were again confirmatory for C. neoformans. An intensive course of antifungal therapy was prescribed which was successful, evident by resolution of the signs and symptoms of infection in addition to negative culture results and negative sepsis biomarkers. The child clinically improved, but unfortunately, gradual optic nerve degeneration and brain cell atrophy as a sequel of severe and longstanding cryptococcal infection resulted in her death after almost one year from her first attack.
Cryptococcal infection among non-HIV patients is a rare disease but can result in advanced medical complications which may be fatal. The disease should be suspected to be reliably diagnosed. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening consequences. Amphotericin B can be used effectively in cryptococcosis management in the settings where flucytosine is not available. Signs of cryptococcal meningitis can be manifested again after a period of remission and clinical cure which signifies the latency of Cryptococcus in the central nervous system. The second activation of Cryptococcus after its latency is usually life-threatening and mostly fatal.
1. Background
Immunocompromised individuals including HIV, SLE, and patients on prolonged corticosteroid and immunosuppressant therapy are more prone to various bacterial, viral, and fungal opportunistic infections. One of the most important fatal fungal infections is cryptococcal infection [1–4]. C. neoformans is the most frequent cryptococcal species infect humans, and it is an encapsulated yeast microorganism, which is commonly transmitted through bird feces, plants, dust, soil, and contaminated food [2, 3]. Cryptococcosis can cause disseminated infection reaching to the lungs, central nervous system (CNS), and skin [2, 3, 5]. Dermal manifestations can present in different clinical morphologies including ulcers, acneiform papules, subcutaneous nodules, and rarely, cellulitis [4, 6].
2. Case Presentation
A 12-years-old Egyptian female student presented to Ain Shams University Pediatric Hospital complaining of generalized body edema, frothy urine, and proteinuria (3.7 g/day). The child was diagnosed as nephrotic syndrome, with repeated albumin infusions, and steroid therapy was initiated, but the child was nonresponding; instead, her medical condition deteriorated. Laboratory profile was in concordance with serologically quiescent SLE which included antinuclear antibody titer 1: 1280 finely speckled, elevated rheumatoid factor (RF) of 456 IU/ml (N: 0–20 IU/ml), positive SS-A/Ro > 8.0 and SS-B/La > 8.0 antibodies, anti-beta-2 glycoprotein IgM Ab > 100 U/ml, C-reactive protein (CRP) level 3.9 mg/l (N: 0–5 mg/l), and erythrocyte sedimentation rate (ESR) 51 mm/hour (N: 0–10 mm/hour). The serologic tests that were negative included anti-dsDNA Abs, complement C3 level 154 mg/dl (N: 106–194 mg/dl), complement C4 level 38 mg/dl (N: 19–50 mg/dl), cyclic citrullinated peptide IgG, cryoglobulin, serum immunofixation, Scl-70 scleroderma, Smith, RNP, cardiolipin antibodies, and lupus anticoagulant. Urine studies at the time revealed 3 + proteinuria, no hematuria or pyuria, a creatinine level of 0.93 mg/dl, and eGFR > 60 ml/min/1.73 m2. The diagnosis of SLE with nephrotic presentation was established, upon which the child received a medical regimen for lupus management including corticosteroids, mycophenolate mofetil, and cyclophosphamide which resulted in patient clinical improvement.
Two months later, the child was admitted complaining of poor appetite, nausea and vomiting, tiredness, swollen ankles, and shortness of breath, and deteriorated renal functions were evident in her laboratory profile: creatinine increased to 1.92 mg/dl, 4 + protein on urinalysis, worsening urine protein to creatinine (PC) ratio of 1.9 (N: 0.0–0.1), and 24-hour urine protein of 1170 mg/24 hours (N: 50–150 mg/24 hours). Lupus nephritis grade IV was confirmed. Therefore, the child received intermittent hemodialysis; in addition, the doses of the prescribed immunosuppressant was increased: prednisone (40 mg/day), hydroxychloroquine (6 mg/kg/day), and mycophenolate mofetil (2 g/day). The patient was kept under this protocol; she gradually improved and was discharged. A simplified chart representing the sequence of the disease in the presented case is illustrated in Figure 1.
After two months, the child manifested skin ulcers in her lower extremities which were progressive in course. Drug allergies, insect bites, and family history were excluded. First, these lesions were nonwell-demarcated, erythematous, painful on palpation, nonpruritic with increasing local edema, and bullae formation. A few days later, lesions spread to involve entire her legs up to the groin area, the bullae began to coalescence together, ruptured, and a huge amount of serous discharge was drained from the lesions; no corresponding lesions appeared on the face, trunk, or upper extremities, and fever was not present at first, but with worsening of the lesions, the patient became feverish, hematuric, anemic, and hypotensive with deteriorated general condition; hence, she was admitted for the 2nd time.
At the time of admission, laboratory profile revealed hemoglobin 8.2 g/dL, white blood cell (WBC) count 10,800/mm³, platelet count 129,000 cells/mm³, serum aspartate transaminase (AST) 10 U/L, serum alanine transaminase (ALT) 17 U/L, CRP 12 mg/L, and ESR 60 mm. Upon worsening the skin lesions, bacterial skin infection was suspected; so empirical treatment with amikacin and cefepime was started and the dose of prednisone decreased to 30 mg/day; microbiological cultures revealed no microorganism growth after 48 hours of incubation. Upon suspicion of bacterial cellulitis and due to the lack of improvements of the skin lesions, vancomycin was added to the treatment regimen.
After three days, the patient medical condition deteriorated rapidly. She complained of severe headache, altered memory, continuous agitation, neck rigidity, stiffness, photophobia, and total loss of appetite; so, meningitis was suspected; hence, lumbar puncture was performed, and a CSF sample was sent for cytological examination in addition to culture procedures. The sample was clear colorless on physical inspection (Figure 2)(a), and cell count was 25 cells/HPF.
Direct Gram examination of CSF showed spherical budding encapsulated yeast cells surrounded by translucent hallow around the cells (Figures 2(b) and 2)(c). CSF chemical examination revealed protein level 74 mg/dL (normal range 15–60 mg/dL) and glucose levels 41 mg/dL (normal range 50–80 mg/dL). The sample was cultured on aerobic blood agar, anaerobic blood agar, chocolate, and MacConkey agar; the plates showed delayed growth at the end of the third day (72 hours incubation according to CSF standard operating procedures (SOPs) of our microbiology lab). It was a minute whitish milky colony, which was highly suggestive of fungal infection, confirmed by further subculture, the sample on Sabouraud's dextrose agar (SDA) plates (Figures 2(d)–2(f)). Indian ink stain and positive biochemical reactions were confirmatory for the diagnosis of Cryptococcus infection (Figures 3 and 4). Additionally, antifungal susceptibility testing was performed which was positive for both amphotericin B and flucytosine.
Despite that, the child manifested obvious clinical signs and symptoms of meningitis. Magnetic resonance imaging (MRI) brain with contrast showed findings within normal limits, and blood culture was negative for microbiological growth after 7 days incubation.
Based on the available laboratory results, treatment for disseminated cryptococcosis was initiated immediately upon laboratory notification, prednisone was further decreased to 20 mg/day, and fluconazole was discontinued. Amphotericin B was started at a dose of 0.7 mg/kg/day with an infusion time of 6 hours, since the patient had repeated reactions (fever, chills, and nausea) with a shorter infusion time. Concerning flucytosine, which is indicated as the drug of choice in cryptococcal meningitis treatment, it was not used for treatment of our presented case due to financial aspects and nonavailability in our country, Egypt. Repeated lumber tapping was performed to relieve persistent increased intracranial tension as a consequence of severe meningitis; in addition, plasmapheresis was performed to remove lupus autoantibodies.
The child was subjected for further workup to rule out pneumonia and other organs affection, and for follow up purpose, chest X-ray was ordered, which revealed normal findings, ESR, CRP, complete blood count (CBC), and sepsis marker, neutrophil CD64. These laboratory tests were performed every 3 days on a routine base for monitoring the medical progress which showed dramatic gradual improvement (Table 1 and Figure 5); in conjugation with clinical signs and symptoms improvement evident by regaining her mental and motor skills, besides healing of the leg ulcers, pus draining stopped and swelling disappeared (Figure 6). In this setting, a lumbar puncture was intended to be performed upon this obvious clinical and laboratory improvement preparing the patient to be discharged, but the child refused at her own request and was discharged on her demand after almost 30 days since amphotericin B infusion was first prescribed.
At the time of discharge, the patient had no pulmonary sequelae, but she had residual weakness in her lower limbs. The laboratory results at the time of discharge were hemoglobin 9.2 g/dL, WBC 16.700 cells per mm³, platelet 303.000 cells per mm³, AST 10 U/L, ALT 4 U/L, CRP 6 mg/L, and ESR 53 mm/h. The child was instructed to continue fluconazole (400 mg/day) at home for 8 weeks and then reduced its dose to 200 mg/day for 1 year. And she was weaned gradually from corticosteroid therapy.
One month later, the child was brought to the emergency department complaining of severe headache, projectile vomiting, and blurred vision. She was admitted for the 3rd time. An MRI brain was ordered, and a lumbar puncture was performed urgently to relieve intracranial tension, and for chemical, cytological, and microbiological analyses, all were negative for infection except for CRP slightly positive (12 mg/L). So, lupus flare-up was suspected, and pulse steroid therapy was started, in addition to antifungal (fluconazole) and antibiotic (amikacin and cefepime) coverage. The patient was subjected for plasmapheresis; upon it, she manifested dramatical improvement and discharge. She started to attend the immunotherapy clinic every two weeks for follow up purpose; she did well for 5 months and regained her functions except for difficulty in talking and walking abilities as she could not walk without support; so, the mother was advised to bring her for regular physiotherapy sessions every week.
Five months later, the patient complained of shivering in her legs and hands followed by seizures attacks which were gradually increasing in frequency and duration till her mother brought her to the E/R. She was admitted for the 4th time. Phenytoin was prescribed, initial dose 2.5 mg/kg/dose twice a day and increased gradually to maximum 5 mg/kg/dose twice daily, and intensive work up profile was conducted searching for the cause of the seizures which included electroencephalogram (EEG), MRI brain, full lab evaluation, and CSF chemical analysis and microbiological examination. EEG revealed normal electric impulses without focal activities (Figure 7). MRI brain showed mildly dilated 3rd ventricles, CSF chemistry analysis revealed protein level 82 mg/dL (normal range 15–60 mg/dL), and glucose levels of 35 mg/dL (normal range 50–80 mg/dL). Upon receiving the sample in our microbiology lab, the sample physical criteria were very similar to the previous one, clear colorless, and cell count was 15 cell/cm3. A direct wet film examination was positive for budding yeast cells which were suspected and notified immediately to the pediatric team, and protocol of treatment was decided rapidly. CSF culture results were again confirmatory for C. neoformans.
An intensive course of antifungal therapy was initiated which included amphotericin B (0.7 mg/kg/day) with an infusion time of 6 hours, and fluconazole. Resolution of patient signs and symptoms of infection was clinically evident in addition to negative culture results and improved laboratory sepsis parameters. The child general condition improved, but at this setting, she complained of poor visual acuity. The pediatric team immediately consulted the specialist neurosurgeon, ophthalmologist, and an MRI brain urgently performed which showed evidence of brain cell atrophy with subsequent increased intracranial ventricular sizes and evidence of optic nerve atrophy; the ophthalmologist confirmed bilateral optic nerve degeneration which was more evident on the left side (Figure 8).
After almost one month and, however, signs and symptoms of infection were resolved, cryptococcosis longstanding course with brain cell atrophy as a sequel of cryptococcal meningitis resulted in the child's death after almost one year from her first attack.
3. Discussion and Conclusion
Cryptococcus is an opportunistic fungal pathogen that leads to rare life-threatening infection. Meningoencephalitis and disseminated cryptococcosis are usually common complications reported in immunocompromised hosts [7, 8]. In the presented case, we reported a pediatric systemic lupus erythematosus patient complicated by rapidly disseminating cryptococcal infection which exhibited a latency in the child CNS followed by an attack of infection flare-up which was successfully treated, but slowly progressive brain cell atrophy due to longstanding disease resulted in her death.
Infections and sepsis are major causes of hospitalization, mortality, and morbidity in immunosuppressed patients [9]. Cryptococcosis is one of the fatal fungal infections reported mainly in immunocompromised hosts; however, several reported cases point to its incidence also in immunocompetent patients [10–12]. Cryptococcosis has a low incidence in non-HIV patients, approximately 1 : 100.000 [5, 13]. Patients with SLE are highly susceptible to infections due to the combined effects of their immunosuppressive therapy and the abnormalities of the immune system that the disease itself causes [14]. Concerning our presented case, prolonged corticosteroid therapy and immunosuppressants due to her underlying disease (SLE) were the major risk factors for disseminated cryptococcosis with poor outcomes.
The patient had a progressive renal course complicated by lupus nephritis class IV for which immunosuppressants was given. Lupus nephritis is clinically evident in 50–60% of patients with SLE [15]. Both mycophenolate mofetil and cyclophosphamide were prescribed to our case. Mycophenolate mofetil depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation [16]. While, cyclophosphamide inhibits protein synthesis through DNA and RNA crosslinking [17].
By discussing Cryptococcus as the causative pathogen, C. neoformans is the most common strain causing infections in humans, and it is an encapsulated yeast that has been isolated from chickens' droppings and grows readily in soil contaminated with avian excreta particularly that of pigeons. In humans, it can colonize the upper airway system. Nevertheless, no animal-to-human nor person-to-person respiratory transmission has been documented [9]. Our presented case lived in low socioeconomic and hygienic status, and she denied contact with pigeon or birds. However, the fungus might have been indirectly transmitted via other sources such as vegetables, fruits, and dairy products [8].
C. neoformans generally cause three types of infections: cryptococcal meningitis, pulmonary, and cutaneous cryptococcosis [18]. The dissemination of this disease occurs when at least two noncontiguous sites are affected, which is unusual and mostly observed in HIV patients [4, 19]. In our case, only pulmonary involvement was not present while cutaneous manifestations were the first presenting symptoms followed by cryptococcal meningitis. Some studies support the importance of lumbar puncture in patients with cryptococcosis, even when CNS symptoms are not observed because asymptomatic meningitis is reported to be an early stage of the disease [20].
Systemic lupus erythematosus disease activity index (SLEDAI) was calculated for our presented case in order to be used as a predictor for SLE mortality and as a measure of global disease activity, and it was achieving high values (79) which reflect why the patient underwent into cryptococcal meningitis with poor clinical course. Eventhough, for patients with low SLE activity, the possibility of cryptococcal meningitis should not be underestimated [21].
Skin involvement is a rare presenting symptom of Cryptococcus infection, but it is usually a sign of disseminated disease; it may precede the systemic symptoms even eight months earlier [5, 18]. It is important to stress the rarity and polymorphism of the skin conditions, with the possible development of vesicles or blisters and the potential progression to ulceration [1, 4].
Cryptococcal cellulitis is a rare specific cutaneous manifestation, which was developed in our case. It was initially suspected to be a bacterial infection for which antibiotics were prescribed until its failure and microbiological results confirmed the fungal diagnosis. Although rare, the present case, cryptococcal cellulitis was restricted mainly to the lower body, particularly to the lower extremities, and this was reported in other rare reported cases [1, 2]. Despite that, cryptococcal cellulitis is uncommon and undistinguishable from acute bacterial cellulitis for appearance and presentation [6], but high suspicion especially in a risky patient should be considered.
More than 80% of patients manifested cryptococcal cellulitis and are expected to survive in immunocompetent status when they receive the appropriate antifungal therapy [6]. According to the current guidelines of the American Society of Infectious Diseases for disseminated cryptococcosis management, amphotericin B combined with flucytosine is recommended as the primary therapy, followed by fluconazole as a consolidation therapy [4, 18]. Flucytosine is expensive and was not available in our country; so, it was not considered for the treatment. Instead, it was replaced by the addition of fluconazole to amphotericin B regimen.
Cryptococcal laboratory diagnosis relies on three main methods: latex agglutination test, fungal culture, and direct microscopic examination [22]. In the present case, both the microscopic examination and microbiological cultures were the cornerstone for the diagnosis. C. neoformans was differentiated from other fungal species especially Candida spp. by the characterized morphology in the Gram-stained smear, microbiological culture characters, Indian ink stain positivity, and biochemical reactions.
Indian ink stain was positive in our case. In HIV-positive patients, its sensitivity increases up to 80% due to higher fungal loads in the CSF, while in HIV negative patients, the sensitivity is only 30–50% [8, 23]. CSF culture is considered the gold standard for cryptococcal diagnosis, but it has several diagnostic obstacles as long time is needed for fungus to grow, while time is very critical for management of meningitis cases with evolving lifetime neurological complications [24]. Besides, fungal cultures are not available in all medical facilities and therefore may not be performed. It is also associated with false-negative results, especially in cases with low fungal load, and this may be the attributed cause of negative blood culture result in our case.
Regarding management of cryptococcosis, the prolonged course (6–10 weeks) of IV amphotericin B monotherapy, together with the reduction of chemotherapy to improve immune status, was the main target. Caution was taken while reducing immunosuppressive therapy, since a rapid reduction is reported to be associated with immune reconstitution inflammatory syndrome (IRIS) in some patients [9]. There is evidence that supports the requirement for maintenance therapy with fluconazole administered as indefinite secondary prophylaxis, since the rate of recurrence exceeds 50% after apparently successful treatment [25].
Differential diagnosis of the present case must be addressed which includes besides to what was mentioned, infection versus flare-up attacks in lupus patients; several sepsis markers including CRP increase significantly in SLE patients with concomitant infection but increase only slightly or not at all in patients with a lupus flare without infection [14, 26] which is exactly encountered in our presented case. Additionally, decreased visual acuity due to increased intracranial tension (papilledema) was differentiated from decreased visual acuity due to optic nerve atrophy. For the presented case, papilledema was evident on fundus examination at the time of cryptococcal meningitis first diagnosed, while optic nerve atrophy was evident on fundus examination at the end.
Finally, we highlight the importance of clinicians' awareness about such infection among non-HIV immunocompromised patients including those who are diagnosed with autoimmune diseases. The latency of Cryptococcus should be considered and suspected during the management of such cases which necessitate early recognition and proper management.
For preparing Indian ink-stained film, take two drops from the examined CSF sample directly or a small part of the growing colony from the plate, mix it well with the ink, put a cover slide, and leave the slide for an hour to give a chance for the cells to be settled, and for better contrast view, lower the condenser and reduce the microscopic light and examine the film by using the lens with magnification power (40x). Cryptococcus will be evident as shiny spherical budding in a dark background.
4. Conclusion
Cryptococcal meningitis should be considered as one of the possible diagnoses in a patient with altered sensorium and neck stiffness, especially those who are immunocompromised. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening complications.
Early management of cryptococcal meningitis is associated with better prognosis and lower neurological complications. Despite that, flucytosine is being described as the best antifungal medication for cryptococcal infections. Amphotericin B still gives good results in such cases.
Negative bacterial growth from a skin lesion does not necessitate that it is a sterile lesion; it may be an atypical microorganism or microorganism that needs special media to grow or longer duration to be cultivated. Clinical pathologists should be aware of Cryptococcus laboratory diagnosis and how to differentiate it from Candida spp. Microbiological culture is a confirmatory step for Cryptococcus diagnosis; however, Gram-stained and Indian ink-stained films are rapid and informative diagnostic methods especially in limited resources facilities. The communication between laboratory staff members and treating medical team is very crucial for better clinical judgment specifically in a circumstance where an unusual diagnostic result is released or diagnosing a rare disease.
CSF examination may show low cell count; however, infection presents; this is commonly seen in immunocompromised patients as no adequate inflammation. Cryptococcal infection associated with CNS latency which should to be suspected; hence, meticulous follow-up is an essential step in cryptococcal management. The second activation of cryptococcal latency is usually life-threatening and mostly fatal.
Acknowledgments
The authors would like to thank all members of Immunology Unit-Pediatric Department and Microbiology Unit-Clinical Pathology Department of Ain Shams University Hospital. The authors gratefully acknowledge Professor Dalia Helmy El-Ghoneimy and Professor Malaka Zakaria Amer for their efforts to diagnose and follow up severe medical cases including this presented case and special gratitude to the mother of the child for supporting with detailed medical information and for her medical awareness and patience throughout her daughter's longstanding disease.
Abbreviations
ALT:Alanine transaminase
ANA:Antinuclear antibody
AST:Aspartate transaminase
C. neoformans:
Cryptococcus neoformans
CBC:Complete blood count
CNS:Central nervous system
CRP:C-reactive protein
CSF:Cerebrospinal fluid
DNA:Deoxyribonucleic acid
dsDNA:Double-strand DNA
E.R:Emergency room
EEG:Electroencephalogram
eGFR:Estimated glomerular filtration rate
ESR:Erythrocyte sedimentation rate
HIV:Human immunodeficiency virus
IgG:Immunoglobulin G
IRIS:Immune reconstitution inflammatory syndrome
IV:Intravenous
MPA:Mycophenolic acid
MRI:Magnetic resonance imaging
PC ratio:Protein creatinine ratio
RF:Rheumatoid factor
RNA:Ribonucleic acid
RNP:Ribonucleoprotein antibodies
SDA:Sabouraud's dextrose agar
SLE:Systemic lupus erythematosus
SOPs:Standard operating procedures
WBC:White blood cell.
Data Availability
The data underlying the findings of this research are publicly available.
Ethical Approval
Compliance with ethics guidelines, all procedures followed the ethical standards of the responsible committee on human experimentation (institutional and national).
Consent
Written informed consent for publication of clinical details was obtained from the mother of the patient.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
Authors' Contributions
Heba Ezzat Hashem contributed to acquisition, analysis, and interpretation of data, drafting of paper, conception and design, revision for critical intellectual content, final approval, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Zakaria Hamza Ibrahim involved in revision for critical intellectual content, final approval, and financial support.
Figure 1 A simplified chart representing the sequence of the disease in our case.
Figure 2 (a) Clear colorless CSF sample; other etiological causes of meningitis especially viral meningitis versus fungal meningitis must be differentiated, specifically in the presence of clear colorless CSF samples with low cell count and minimal changes of CSF parameters. (b) Spherical budding yeast in the CSF; it should be differentiated from the elliptical budding yeast cells of Candida spp. which is more commonly encountered during CSF examination as a fungal cause of meningitis. (c) Gram-stained film; direct film from CSF shows spherical budding yeast cells with surrounding translucent haloes due to capsular structure. (d) Blood agar shows small white colonies, after 72 hours of incubation. (e) Sabouraud dextrose agar (SDA) shows pasty colonies that were confirmed to be Cryptococcus neoformans. (f) Gram from culture shows spherical yeast cells with surrounding translucent haloes.
Figure 3 Biochemical reaction; the urease test was positive.
Figure 4
Cryptococcus as shiny spherical budding in a dark background.
Figure 5 Laboratory course of the present case and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation; the patient improved clinically and discharged after almost one month with minimal residual weakness in her lower limbs. The nCD64 test was available in our hospital as a sepsis biomarker, and it was performed for our case for follow-up purposes.
Figure 6 Patient developed extensive skin ulceration with serous oozing from both lower limbs; this image was taken upon her clinical improvement on amphotericin B. The local edema resolved leaving the skin redundant, cracked, and the oozing discharge was first serous-like followed by purulent discharge then pus draining stopped.
Figure 7 EEG at the 4th admission, seizures, and other CNS manifestations in patients who had previous cryptococcal meningitis is very essential to be distinguished; it is due to reactivation of latent infection or due to seizures attributed to other medical causes. For the present case, EEG showed normal electric activates without focal localization.
Figure 8 MRI brain performed at the time of 3rd admission; dilated third ventricles were evident due to brain cell atrophy; at this occasion, signs of increase intracranial tension were negative which excluded it as a cause for cerebral ventricles dilatations.
Table 1 Laboratory course of the present case, and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation.
Hb TLC ANC ALC AMC PLT CRP CD64% CD64 MFI
08/05/2016 10.6 12.2 11.2 0.6 0.4 44 6 98.5 2.87
11/05/2016 9 10.9 9.2 1.1 0.51 81 6 91.5 1.91
15/05/2016 7.7 14.8 12.72 1.57 0.48 209 4 80.1 1.56
22/05/2016 7.2 10 7.6 1.1 0.5 238 4 68.9 1.45
Hb, hemoglobin (g/dl); TLC, total leukocytic count (X109/L); ANC, absolute neutrophil count (X109/L); ALC, absolute lymphocyte count (X109/L); AMC, absolute monocyte count (X109/L); PLT, platelet (X109/L); CRP, C-reactive protein (mg/L); nCD64%, neutrophil CD64%; nCD64MFI, nCD64 mean fluorescence intensity. | Fatal | ReactionOutcome | CC BY | 33628263 | 19,588,393 | 2021 |
What was the outcome of reaction 'Cerebral ventricle dilatation'? | Atypical Presentation of Pediatric Systemic Lupus Erythematosus Complicated by Cryptococcal Meningitis.
Cryptococcus is an opportunistic fungal pathogen that leads to life-threatening infections. Cryptococcal infections are mainly reported in HIV patients and less commonly encountered in non-HIV immunocompromised host. Cryptococcus neoformans (C. neoformans) is the most common Cryptococcus species causing diseases in humans which can be presented as pulmonary, meningitis, cutaneous, and/or disseminated cryptococcosis. Case Presentation. A 12-year-old female girl from Cairo, Egypt, presented to the pediatric hospital with signs of systemic lupus erythematosus (SLE). She had an aggressive lupus nephritis course for which corticosteroids, mycophenolate mofetil, and cyclophosphamide were prescribed, and the child gradually improved and was discharged. Two months later, the patient exhibited skin lesions involved both in her legs, massive ulcers were developed and extended rapidly through the entire legs followed by deterioration in her conscious level, and signs of meningitis were documented. Cerebrospinal fluid (CSF) examination and microbiological workup were confirmatory for C. neoformans infection, and mental and motor functions were rapidly deteriorated. Treatment with amphotericin B in addition to supportive treatment and close follow-up of the patient's medical condition result in obvious clinical improvement and patient discharge with minimal residual weakness in her legs after almost a one-month duration. After six months, the patient was brought to the emergency department complaining of repeated attacks of seizures, a lumbar puncture was performed, and culture results were again confirmatory for C. neoformans. An intensive course of antifungal therapy was prescribed which was successful, evident by resolution of the signs and symptoms of infection in addition to negative culture results and negative sepsis biomarkers. The child clinically improved, but unfortunately, gradual optic nerve degeneration and brain cell atrophy as a sequel of severe and longstanding cryptococcal infection resulted in her death after almost one year from her first attack.
Cryptococcal infection among non-HIV patients is a rare disease but can result in advanced medical complications which may be fatal. The disease should be suspected to be reliably diagnosed. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening consequences. Amphotericin B can be used effectively in cryptococcosis management in the settings where flucytosine is not available. Signs of cryptococcal meningitis can be manifested again after a period of remission and clinical cure which signifies the latency of Cryptococcus in the central nervous system. The second activation of Cryptococcus after its latency is usually life-threatening and mostly fatal.
1. Background
Immunocompromised individuals including HIV, SLE, and patients on prolonged corticosteroid and immunosuppressant therapy are more prone to various bacterial, viral, and fungal opportunistic infections. One of the most important fatal fungal infections is cryptococcal infection [1–4]. C. neoformans is the most frequent cryptococcal species infect humans, and it is an encapsulated yeast microorganism, which is commonly transmitted through bird feces, plants, dust, soil, and contaminated food [2, 3]. Cryptococcosis can cause disseminated infection reaching to the lungs, central nervous system (CNS), and skin [2, 3, 5]. Dermal manifestations can present in different clinical morphologies including ulcers, acneiform papules, subcutaneous nodules, and rarely, cellulitis [4, 6].
2. Case Presentation
A 12-years-old Egyptian female student presented to Ain Shams University Pediatric Hospital complaining of generalized body edema, frothy urine, and proteinuria (3.7 g/day). The child was diagnosed as nephrotic syndrome, with repeated albumin infusions, and steroid therapy was initiated, but the child was nonresponding; instead, her medical condition deteriorated. Laboratory profile was in concordance with serologically quiescent SLE which included antinuclear antibody titer 1: 1280 finely speckled, elevated rheumatoid factor (RF) of 456 IU/ml (N: 0–20 IU/ml), positive SS-A/Ro > 8.0 and SS-B/La > 8.0 antibodies, anti-beta-2 glycoprotein IgM Ab > 100 U/ml, C-reactive protein (CRP) level 3.9 mg/l (N: 0–5 mg/l), and erythrocyte sedimentation rate (ESR) 51 mm/hour (N: 0–10 mm/hour). The serologic tests that were negative included anti-dsDNA Abs, complement C3 level 154 mg/dl (N: 106–194 mg/dl), complement C4 level 38 mg/dl (N: 19–50 mg/dl), cyclic citrullinated peptide IgG, cryoglobulin, serum immunofixation, Scl-70 scleroderma, Smith, RNP, cardiolipin antibodies, and lupus anticoagulant. Urine studies at the time revealed 3 + proteinuria, no hematuria or pyuria, a creatinine level of 0.93 mg/dl, and eGFR > 60 ml/min/1.73 m2. The diagnosis of SLE with nephrotic presentation was established, upon which the child received a medical regimen for lupus management including corticosteroids, mycophenolate mofetil, and cyclophosphamide which resulted in patient clinical improvement.
Two months later, the child was admitted complaining of poor appetite, nausea and vomiting, tiredness, swollen ankles, and shortness of breath, and deteriorated renal functions were evident in her laboratory profile: creatinine increased to 1.92 mg/dl, 4 + protein on urinalysis, worsening urine protein to creatinine (PC) ratio of 1.9 (N: 0.0–0.1), and 24-hour urine protein of 1170 mg/24 hours (N: 50–150 mg/24 hours). Lupus nephritis grade IV was confirmed. Therefore, the child received intermittent hemodialysis; in addition, the doses of the prescribed immunosuppressant was increased: prednisone (40 mg/day), hydroxychloroquine (6 mg/kg/day), and mycophenolate mofetil (2 g/day). The patient was kept under this protocol; she gradually improved and was discharged. A simplified chart representing the sequence of the disease in the presented case is illustrated in Figure 1.
After two months, the child manifested skin ulcers in her lower extremities which were progressive in course. Drug allergies, insect bites, and family history were excluded. First, these lesions were nonwell-demarcated, erythematous, painful on palpation, nonpruritic with increasing local edema, and bullae formation. A few days later, lesions spread to involve entire her legs up to the groin area, the bullae began to coalescence together, ruptured, and a huge amount of serous discharge was drained from the lesions; no corresponding lesions appeared on the face, trunk, or upper extremities, and fever was not present at first, but with worsening of the lesions, the patient became feverish, hematuric, anemic, and hypotensive with deteriorated general condition; hence, she was admitted for the 2nd time.
At the time of admission, laboratory profile revealed hemoglobin 8.2 g/dL, white blood cell (WBC) count 10,800/mm³, platelet count 129,000 cells/mm³, serum aspartate transaminase (AST) 10 U/L, serum alanine transaminase (ALT) 17 U/L, CRP 12 mg/L, and ESR 60 mm. Upon worsening the skin lesions, bacterial skin infection was suspected; so empirical treatment with amikacin and cefepime was started and the dose of prednisone decreased to 30 mg/day; microbiological cultures revealed no microorganism growth after 48 hours of incubation. Upon suspicion of bacterial cellulitis and due to the lack of improvements of the skin lesions, vancomycin was added to the treatment regimen.
After three days, the patient medical condition deteriorated rapidly. She complained of severe headache, altered memory, continuous agitation, neck rigidity, stiffness, photophobia, and total loss of appetite; so, meningitis was suspected; hence, lumbar puncture was performed, and a CSF sample was sent for cytological examination in addition to culture procedures. The sample was clear colorless on physical inspection (Figure 2)(a), and cell count was 25 cells/HPF.
Direct Gram examination of CSF showed spherical budding encapsulated yeast cells surrounded by translucent hallow around the cells (Figures 2(b) and 2)(c). CSF chemical examination revealed protein level 74 mg/dL (normal range 15–60 mg/dL) and glucose levels 41 mg/dL (normal range 50–80 mg/dL). The sample was cultured on aerobic blood agar, anaerobic blood agar, chocolate, and MacConkey agar; the plates showed delayed growth at the end of the third day (72 hours incubation according to CSF standard operating procedures (SOPs) of our microbiology lab). It was a minute whitish milky colony, which was highly suggestive of fungal infection, confirmed by further subculture, the sample on Sabouraud's dextrose agar (SDA) plates (Figures 2(d)–2(f)). Indian ink stain and positive biochemical reactions were confirmatory for the diagnosis of Cryptococcus infection (Figures 3 and 4). Additionally, antifungal susceptibility testing was performed which was positive for both amphotericin B and flucytosine.
Despite that, the child manifested obvious clinical signs and symptoms of meningitis. Magnetic resonance imaging (MRI) brain with contrast showed findings within normal limits, and blood culture was negative for microbiological growth after 7 days incubation.
Based on the available laboratory results, treatment for disseminated cryptococcosis was initiated immediately upon laboratory notification, prednisone was further decreased to 20 mg/day, and fluconazole was discontinued. Amphotericin B was started at a dose of 0.7 mg/kg/day with an infusion time of 6 hours, since the patient had repeated reactions (fever, chills, and nausea) with a shorter infusion time. Concerning flucytosine, which is indicated as the drug of choice in cryptococcal meningitis treatment, it was not used for treatment of our presented case due to financial aspects and nonavailability in our country, Egypt. Repeated lumber tapping was performed to relieve persistent increased intracranial tension as a consequence of severe meningitis; in addition, plasmapheresis was performed to remove lupus autoantibodies.
The child was subjected for further workup to rule out pneumonia and other organs affection, and for follow up purpose, chest X-ray was ordered, which revealed normal findings, ESR, CRP, complete blood count (CBC), and sepsis marker, neutrophil CD64. These laboratory tests were performed every 3 days on a routine base for monitoring the medical progress which showed dramatic gradual improvement (Table 1 and Figure 5); in conjugation with clinical signs and symptoms improvement evident by regaining her mental and motor skills, besides healing of the leg ulcers, pus draining stopped and swelling disappeared (Figure 6). In this setting, a lumbar puncture was intended to be performed upon this obvious clinical and laboratory improvement preparing the patient to be discharged, but the child refused at her own request and was discharged on her demand after almost 30 days since amphotericin B infusion was first prescribed.
At the time of discharge, the patient had no pulmonary sequelae, but she had residual weakness in her lower limbs. The laboratory results at the time of discharge were hemoglobin 9.2 g/dL, WBC 16.700 cells per mm³, platelet 303.000 cells per mm³, AST 10 U/L, ALT 4 U/L, CRP 6 mg/L, and ESR 53 mm/h. The child was instructed to continue fluconazole (400 mg/day) at home for 8 weeks and then reduced its dose to 200 mg/day for 1 year. And she was weaned gradually from corticosteroid therapy.
One month later, the child was brought to the emergency department complaining of severe headache, projectile vomiting, and blurred vision. She was admitted for the 3rd time. An MRI brain was ordered, and a lumbar puncture was performed urgently to relieve intracranial tension, and for chemical, cytological, and microbiological analyses, all were negative for infection except for CRP slightly positive (12 mg/L). So, lupus flare-up was suspected, and pulse steroid therapy was started, in addition to antifungal (fluconazole) and antibiotic (amikacin and cefepime) coverage. The patient was subjected for plasmapheresis; upon it, she manifested dramatical improvement and discharge. She started to attend the immunotherapy clinic every two weeks for follow up purpose; she did well for 5 months and regained her functions except for difficulty in talking and walking abilities as she could not walk without support; so, the mother was advised to bring her for regular physiotherapy sessions every week.
Five months later, the patient complained of shivering in her legs and hands followed by seizures attacks which were gradually increasing in frequency and duration till her mother brought her to the E/R. She was admitted for the 4th time. Phenytoin was prescribed, initial dose 2.5 mg/kg/dose twice a day and increased gradually to maximum 5 mg/kg/dose twice daily, and intensive work up profile was conducted searching for the cause of the seizures which included electroencephalogram (EEG), MRI brain, full lab evaluation, and CSF chemical analysis and microbiological examination. EEG revealed normal electric impulses without focal activities (Figure 7). MRI brain showed mildly dilated 3rd ventricles, CSF chemistry analysis revealed protein level 82 mg/dL (normal range 15–60 mg/dL), and glucose levels of 35 mg/dL (normal range 50–80 mg/dL). Upon receiving the sample in our microbiology lab, the sample physical criteria were very similar to the previous one, clear colorless, and cell count was 15 cell/cm3. A direct wet film examination was positive for budding yeast cells which were suspected and notified immediately to the pediatric team, and protocol of treatment was decided rapidly. CSF culture results were again confirmatory for C. neoformans.
An intensive course of antifungal therapy was initiated which included amphotericin B (0.7 mg/kg/day) with an infusion time of 6 hours, and fluconazole. Resolution of patient signs and symptoms of infection was clinically evident in addition to negative culture results and improved laboratory sepsis parameters. The child general condition improved, but at this setting, she complained of poor visual acuity. The pediatric team immediately consulted the specialist neurosurgeon, ophthalmologist, and an MRI brain urgently performed which showed evidence of brain cell atrophy with subsequent increased intracranial ventricular sizes and evidence of optic nerve atrophy; the ophthalmologist confirmed bilateral optic nerve degeneration which was more evident on the left side (Figure 8).
After almost one month and, however, signs and symptoms of infection were resolved, cryptococcosis longstanding course with brain cell atrophy as a sequel of cryptococcal meningitis resulted in the child's death after almost one year from her first attack.
3. Discussion and Conclusion
Cryptococcus is an opportunistic fungal pathogen that leads to rare life-threatening infection. Meningoencephalitis and disseminated cryptococcosis are usually common complications reported in immunocompromised hosts [7, 8]. In the presented case, we reported a pediatric systemic lupus erythematosus patient complicated by rapidly disseminating cryptococcal infection which exhibited a latency in the child CNS followed by an attack of infection flare-up which was successfully treated, but slowly progressive brain cell atrophy due to longstanding disease resulted in her death.
Infections and sepsis are major causes of hospitalization, mortality, and morbidity in immunosuppressed patients [9]. Cryptococcosis is one of the fatal fungal infections reported mainly in immunocompromised hosts; however, several reported cases point to its incidence also in immunocompetent patients [10–12]. Cryptococcosis has a low incidence in non-HIV patients, approximately 1 : 100.000 [5, 13]. Patients with SLE are highly susceptible to infections due to the combined effects of their immunosuppressive therapy and the abnormalities of the immune system that the disease itself causes [14]. Concerning our presented case, prolonged corticosteroid therapy and immunosuppressants due to her underlying disease (SLE) were the major risk factors for disseminated cryptococcosis with poor outcomes.
The patient had a progressive renal course complicated by lupus nephritis class IV for which immunosuppressants was given. Lupus nephritis is clinically evident in 50–60% of patients with SLE [15]. Both mycophenolate mofetil and cyclophosphamide were prescribed to our case. Mycophenolate mofetil depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation [16]. While, cyclophosphamide inhibits protein synthesis through DNA and RNA crosslinking [17].
By discussing Cryptococcus as the causative pathogen, C. neoformans is the most common strain causing infections in humans, and it is an encapsulated yeast that has been isolated from chickens' droppings and grows readily in soil contaminated with avian excreta particularly that of pigeons. In humans, it can colonize the upper airway system. Nevertheless, no animal-to-human nor person-to-person respiratory transmission has been documented [9]. Our presented case lived in low socioeconomic and hygienic status, and she denied contact with pigeon or birds. However, the fungus might have been indirectly transmitted via other sources such as vegetables, fruits, and dairy products [8].
C. neoformans generally cause three types of infections: cryptococcal meningitis, pulmonary, and cutaneous cryptococcosis [18]. The dissemination of this disease occurs when at least two noncontiguous sites are affected, which is unusual and mostly observed in HIV patients [4, 19]. In our case, only pulmonary involvement was not present while cutaneous manifestations were the first presenting symptoms followed by cryptococcal meningitis. Some studies support the importance of lumbar puncture in patients with cryptococcosis, even when CNS symptoms are not observed because asymptomatic meningitis is reported to be an early stage of the disease [20].
Systemic lupus erythematosus disease activity index (SLEDAI) was calculated for our presented case in order to be used as a predictor for SLE mortality and as a measure of global disease activity, and it was achieving high values (79) which reflect why the patient underwent into cryptococcal meningitis with poor clinical course. Eventhough, for patients with low SLE activity, the possibility of cryptococcal meningitis should not be underestimated [21].
Skin involvement is a rare presenting symptom of Cryptococcus infection, but it is usually a sign of disseminated disease; it may precede the systemic symptoms even eight months earlier [5, 18]. It is important to stress the rarity and polymorphism of the skin conditions, with the possible development of vesicles or blisters and the potential progression to ulceration [1, 4].
Cryptococcal cellulitis is a rare specific cutaneous manifestation, which was developed in our case. It was initially suspected to be a bacterial infection for which antibiotics were prescribed until its failure and microbiological results confirmed the fungal diagnosis. Although rare, the present case, cryptococcal cellulitis was restricted mainly to the lower body, particularly to the lower extremities, and this was reported in other rare reported cases [1, 2]. Despite that, cryptococcal cellulitis is uncommon and undistinguishable from acute bacterial cellulitis for appearance and presentation [6], but high suspicion especially in a risky patient should be considered.
More than 80% of patients manifested cryptococcal cellulitis and are expected to survive in immunocompetent status when they receive the appropriate antifungal therapy [6]. According to the current guidelines of the American Society of Infectious Diseases for disseminated cryptococcosis management, amphotericin B combined with flucytosine is recommended as the primary therapy, followed by fluconazole as a consolidation therapy [4, 18]. Flucytosine is expensive and was not available in our country; so, it was not considered for the treatment. Instead, it was replaced by the addition of fluconazole to amphotericin B regimen.
Cryptococcal laboratory diagnosis relies on three main methods: latex agglutination test, fungal culture, and direct microscopic examination [22]. In the present case, both the microscopic examination and microbiological cultures were the cornerstone for the diagnosis. C. neoformans was differentiated from other fungal species especially Candida spp. by the characterized morphology in the Gram-stained smear, microbiological culture characters, Indian ink stain positivity, and biochemical reactions.
Indian ink stain was positive in our case. In HIV-positive patients, its sensitivity increases up to 80% due to higher fungal loads in the CSF, while in HIV negative patients, the sensitivity is only 30–50% [8, 23]. CSF culture is considered the gold standard for cryptococcal diagnosis, but it has several diagnostic obstacles as long time is needed for fungus to grow, while time is very critical for management of meningitis cases with evolving lifetime neurological complications [24]. Besides, fungal cultures are not available in all medical facilities and therefore may not be performed. It is also associated with false-negative results, especially in cases with low fungal load, and this may be the attributed cause of negative blood culture result in our case.
Regarding management of cryptococcosis, the prolonged course (6–10 weeks) of IV amphotericin B monotherapy, together with the reduction of chemotherapy to improve immune status, was the main target. Caution was taken while reducing immunosuppressive therapy, since a rapid reduction is reported to be associated with immune reconstitution inflammatory syndrome (IRIS) in some patients [9]. There is evidence that supports the requirement for maintenance therapy with fluconazole administered as indefinite secondary prophylaxis, since the rate of recurrence exceeds 50% after apparently successful treatment [25].
Differential diagnosis of the present case must be addressed which includes besides to what was mentioned, infection versus flare-up attacks in lupus patients; several sepsis markers including CRP increase significantly in SLE patients with concomitant infection but increase only slightly or not at all in patients with a lupus flare without infection [14, 26] which is exactly encountered in our presented case. Additionally, decreased visual acuity due to increased intracranial tension (papilledema) was differentiated from decreased visual acuity due to optic nerve atrophy. For the presented case, papilledema was evident on fundus examination at the time of cryptococcal meningitis first diagnosed, while optic nerve atrophy was evident on fundus examination at the end.
Finally, we highlight the importance of clinicians' awareness about such infection among non-HIV immunocompromised patients including those who are diagnosed with autoimmune diseases. The latency of Cryptococcus should be considered and suspected during the management of such cases which necessitate early recognition and proper management.
For preparing Indian ink-stained film, take two drops from the examined CSF sample directly or a small part of the growing colony from the plate, mix it well with the ink, put a cover slide, and leave the slide for an hour to give a chance for the cells to be settled, and for better contrast view, lower the condenser and reduce the microscopic light and examine the film by using the lens with magnification power (40x). Cryptococcus will be evident as shiny spherical budding in a dark background.
4. Conclusion
Cryptococcal meningitis should be considered as one of the possible diagnoses in a patient with altered sensorium and neck stiffness, especially those who are immunocompromised. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening complications.
Early management of cryptococcal meningitis is associated with better prognosis and lower neurological complications. Despite that, flucytosine is being described as the best antifungal medication for cryptococcal infections. Amphotericin B still gives good results in such cases.
Negative bacterial growth from a skin lesion does not necessitate that it is a sterile lesion; it may be an atypical microorganism or microorganism that needs special media to grow or longer duration to be cultivated. Clinical pathologists should be aware of Cryptococcus laboratory diagnosis and how to differentiate it from Candida spp. Microbiological culture is a confirmatory step for Cryptococcus diagnosis; however, Gram-stained and Indian ink-stained films are rapid and informative diagnostic methods especially in limited resources facilities. The communication between laboratory staff members and treating medical team is very crucial for better clinical judgment specifically in a circumstance where an unusual diagnostic result is released or diagnosing a rare disease.
CSF examination may show low cell count; however, infection presents; this is commonly seen in immunocompromised patients as no adequate inflammation. Cryptococcal infection associated with CNS latency which should to be suspected; hence, meticulous follow-up is an essential step in cryptococcal management. The second activation of cryptococcal latency is usually life-threatening and mostly fatal.
Acknowledgments
The authors would like to thank all members of Immunology Unit-Pediatric Department and Microbiology Unit-Clinical Pathology Department of Ain Shams University Hospital. The authors gratefully acknowledge Professor Dalia Helmy El-Ghoneimy and Professor Malaka Zakaria Amer for their efforts to diagnose and follow up severe medical cases including this presented case and special gratitude to the mother of the child for supporting with detailed medical information and for her medical awareness and patience throughout her daughter's longstanding disease.
Abbreviations
ALT:Alanine transaminase
ANA:Antinuclear antibody
AST:Aspartate transaminase
C. neoformans:
Cryptococcus neoformans
CBC:Complete blood count
CNS:Central nervous system
CRP:C-reactive protein
CSF:Cerebrospinal fluid
DNA:Deoxyribonucleic acid
dsDNA:Double-strand DNA
E.R:Emergency room
EEG:Electroencephalogram
eGFR:Estimated glomerular filtration rate
ESR:Erythrocyte sedimentation rate
HIV:Human immunodeficiency virus
IgG:Immunoglobulin G
IRIS:Immune reconstitution inflammatory syndrome
IV:Intravenous
MPA:Mycophenolic acid
MRI:Magnetic resonance imaging
PC ratio:Protein creatinine ratio
RF:Rheumatoid factor
RNA:Ribonucleic acid
RNP:Ribonucleoprotein antibodies
SDA:Sabouraud's dextrose agar
SLE:Systemic lupus erythematosus
SOPs:Standard operating procedures
WBC:White blood cell.
Data Availability
The data underlying the findings of this research are publicly available.
Ethical Approval
Compliance with ethics guidelines, all procedures followed the ethical standards of the responsible committee on human experimentation (institutional and national).
Consent
Written informed consent for publication of clinical details was obtained from the mother of the patient.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
Authors' Contributions
Heba Ezzat Hashem contributed to acquisition, analysis, and interpretation of data, drafting of paper, conception and design, revision for critical intellectual content, final approval, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Zakaria Hamza Ibrahim involved in revision for critical intellectual content, final approval, and financial support.
Figure 1 A simplified chart representing the sequence of the disease in our case.
Figure 2 (a) Clear colorless CSF sample; other etiological causes of meningitis especially viral meningitis versus fungal meningitis must be differentiated, specifically in the presence of clear colorless CSF samples with low cell count and minimal changes of CSF parameters. (b) Spherical budding yeast in the CSF; it should be differentiated from the elliptical budding yeast cells of Candida spp. which is more commonly encountered during CSF examination as a fungal cause of meningitis. (c) Gram-stained film; direct film from CSF shows spherical budding yeast cells with surrounding translucent haloes due to capsular structure. (d) Blood agar shows small white colonies, after 72 hours of incubation. (e) Sabouraud dextrose agar (SDA) shows pasty colonies that were confirmed to be Cryptococcus neoformans. (f) Gram from culture shows spherical yeast cells with surrounding translucent haloes.
Figure 3 Biochemical reaction; the urease test was positive.
Figure 4
Cryptococcus as shiny spherical budding in a dark background.
Figure 5 Laboratory course of the present case and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation; the patient improved clinically and discharged after almost one month with minimal residual weakness in her lower limbs. The nCD64 test was available in our hospital as a sepsis biomarker, and it was performed for our case for follow-up purposes.
Figure 6 Patient developed extensive skin ulceration with serous oozing from both lower limbs; this image was taken upon her clinical improvement on amphotericin B. The local edema resolved leaving the skin redundant, cracked, and the oozing discharge was first serous-like followed by purulent discharge then pus draining stopped.
Figure 7 EEG at the 4th admission, seizures, and other CNS manifestations in patients who had previous cryptococcal meningitis is very essential to be distinguished; it is due to reactivation of latent infection or due to seizures attributed to other medical causes. For the present case, EEG showed normal electric activates without focal localization.
Figure 8 MRI brain performed at the time of 3rd admission; dilated third ventricles were evident due to brain cell atrophy; at this occasion, signs of increase intracranial tension were negative which excluded it as a cause for cerebral ventricles dilatations.
Table 1 Laboratory course of the present case, and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation.
Hb TLC ANC ALC AMC PLT CRP CD64% CD64 MFI
08/05/2016 10.6 12.2 11.2 0.6 0.4 44 6 98.5 2.87
11/05/2016 9 10.9 9.2 1.1 0.51 81 6 91.5 1.91
15/05/2016 7.7 14.8 12.72 1.57 0.48 209 4 80.1 1.56
22/05/2016 7.2 10 7.6 1.1 0.5 238 4 68.9 1.45
Hb, hemoglobin (g/dl); TLC, total leukocytic count (X109/L); ANC, absolute neutrophil count (X109/L); ALC, absolute lymphocyte count (X109/L); AMC, absolute monocyte count (X109/L); PLT, platelet (X109/L); CRP, C-reactive protein (mg/L); nCD64%, neutrophil CD64%; nCD64MFI, nCD64 mean fluorescence intensity. | Fatal | ReactionOutcome | CC BY | 33628263 | 19,588,393 | 2021 |
What was the outcome of reaction 'Cryptococcosis'? | Atypical Presentation of Pediatric Systemic Lupus Erythematosus Complicated by Cryptococcal Meningitis.
Cryptococcus is an opportunistic fungal pathogen that leads to life-threatening infections. Cryptococcal infections are mainly reported in HIV patients and less commonly encountered in non-HIV immunocompromised host. Cryptococcus neoformans (C. neoformans) is the most common Cryptococcus species causing diseases in humans which can be presented as pulmonary, meningitis, cutaneous, and/or disseminated cryptococcosis. Case Presentation. A 12-year-old female girl from Cairo, Egypt, presented to the pediatric hospital with signs of systemic lupus erythematosus (SLE). She had an aggressive lupus nephritis course for which corticosteroids, mycophenolate mofetil, and cyclophosphamide were prescribed, and the child gradually improved and was discharged. Two months later, the patient exhibited skin lesions involved both in her legs, massive ulcers were developed and extended rapidly through the entire legs followed by deterioration in her conscious level, and signs of meningitis were documented. Cerebrospinal fluid (CSF) examination and microbiological workup were confirmatory for C. neoformans infection, and mental and motor functions were rapidly deteriorated. Treatment with amphotericin B in addition to supportive treatment and close follow-up of the patient's medical condition result in obvious clinical improvement and patient discharge with minimal residual weakness in her legs after almost a one-month duration. After six months, the patient was brought to the emergency department complaining of repeated attacks of seizures, a lumbar puncture was performed, and culture results were again confirmatory for C. neoformans. An intensive course of antifungal therapy was prescribed which was successful, evident by resolution of the signs and symptoms of infection in addition to negative culture results and negative sepsis biomarkers. The child clinically improved, but unfortunately, gradual optic nerve degeneration and brain cell atrophy as a sequel of severe and longstanding cryptococcal infection resulted in her death after almost one year from her first attack.
Cryptococcal infection among non-HIV patients is a rare disease but can result in advanced medical complications which may be fatal. The disease should be suspected to be reliably diagnosed. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening consequences. Amphotericin B can be used effectively in cryptococcosis management in the settings where flucytosine is not available. Signs of cryptococcal meningitis can be manifested again after a period of remission and clinical cure which signifies the latency of Cryptococcus in the central nervous system. The second activation of Cryptococcus after its latency is usually life-threatening and mostly fatal.
1. Background
Immunocompromised individuals including HIV, SLE, and patients on prolonged corticosteroid and immunosuppressant therapy are more prone to various bacterial, viral, and fungal opportunistic infections. One of the most important fatal fungal infections is cryptococcal infection [1–4]. C. neoformans is the most frequent cryptococcal species infect humans, and it is an encapsulated yeast microorganism, which is commonly transmitted through bird feces, plants, dust, soil, and contaminated food [2, 3]. Cryptococcosis can cause disseminated infection reaching to the lungs, central nervous system (CNS), and skin [2, 3, 5]. Dermal manifestations can present in different clinical morphologies including ulcers, acneiform papules, subcutaneous nodules, and rarely, cellulitis [4, 6].
2. Case Presentation
A 12-years-old Egyptian female student presented to Ain Shams University Pediatric Hospital complaining of generalized body edema, frothy urine, and proteinuria (3.7 g/day). The child was diagnosed as nephrotic syndrome, with repeated albumin infusions, and steroid therapy was initiated, but the child was nonresponding; instead, her medical condition deteriorated. Laboratory profile was in concordance with serologically quiescent SLE which included antinuclear antibody titer 1: 1280 finely speckled, elevated rheumatoid factor (RF) of 456 IU/ml (N: 0–20 IU/ml), positive SS-A/Ro > 8.0 and SS-B/La > 8.0 antibodies, anti-beta-2 glycoprotein IgM Ab > 100 U/ml, C-reactive protein (CRP) level 3.9 mg/l (N: 0–5 mg/l), and erythrocyte sedimentation rate (ESR) 51 mm/hour (N: 0–10 mm/hour). The serologic tests that were negative included anti-dsDNA Abs, complement C3 level 154 mg/dl (N: 106–194 mg/dl), complement C4 level 38 mg/dl (N: 19–50 mg/dl), cyclic citrullinated peptide IgG, cryoglobulin, serum immunofixation, Scl-70 scleroderma, Smith, RNP, cardiolipin antibodies, and lupus anticoagulant. Urine studies at the time revealed 3 + proteinuria, no hematuria or pyuria, a creatinine level of 0.93 mg/dl, and eGFR > 60 ml/min/1.73 m2. The diagnosis of SLE with nephrotic presentation was established, upon which the child received a medical regimen for lupus management including corticosteroids, mycophenolate mofetil, and cyclophosphamide which resulted in patient clinical improvement.
Two months later, the child was admitted complaining of poor appetite, nausea and vomiting, tiredness, swollen ankles, and shortness of breath, and deteriorated renal functions were evident in her laboratory profile: creatinine increased to 1.92 mg/dl, 4 + protein on urinalysis, worsening urine protein to creatinine (PC) ratio of 1.9 (N: 0.0–0.1), and 24-hour urine protein of 1170 mg/24 hours (N: 50–150 mg/24 hours). Lupus nephritis grade IV was confirmed. Therefore, the child received intermittent hemodialysis; in addition, the doses of the prescribed immunosuppressant was increased: prednisone (40 mg/day), hydroxychloroquine (6 mg/kg/day), and mycophenolate mofetil (2 g/day). The patient was kept under this protocol; she gradually improved and was discharged. A simplified chart representing the sequence of the disease in the presented case is illustrated in Figure 1.
After two months, the child manifested skin ulcers in her lower extremities which were progressive in course. Drug allergies, insect bites, and family history were excluded. First, these lesions were nonwell-demarcated, erythematous, painful on palpation, nonpruritic with increasing local edema, and bullae formation. A few days later, lesions spread to involve entire her legs up to the groin area, the bullae began to coalescence together, ruptured, and a huge amount of serous discharge was drained from the lesions; no corresponding lesions appeared on the face, trunk, or upper extremities, and fever was not present at first, but with worsening of the lesions, the patient became feverish, hematuric, anemic, and hypotensive with deteriorated general condition; hence, she was admitted for the 2nd time.
At the time of admission, laboratory profile revealed hemoglobin 8.2 g/dL, white blood cell (WBC) count 10,800/mm³, platelet count 129,000 cells/mm³, serum aspartate transaminase (AST) 10 U/L, serum alanine transaminase (ALT) 17 U/L, CRP 12 mg/L, and ESR 60 mm. Upon worsening the skin lesions, bacterial skin infection was suspected; so empirical treatment with amikacin and cefepime was started and the dose of prednisone decreased to 30 mg/day; microbiological cultures revealed no microorganism growth after 48 hours of incubation. Upon suspicion of bacterial cellulitis and due to the lack of improvements of the skin lesions, vancomycin was added to the treatment regimen.
After three days, the patient medical condition deteriorated rapidly. She complained of severe headache, altered memory, continuous agitation, neck rigidity, stiffness, photophobia, and total loss of appetite; so, meningitis was suspected; hence, lumbar puncture was performed, and a CSF sample was sent for cytological examination in addition to culture procedures. The sample was clear colorless on physical inspection (Figure 2)(a), and cell count was 25 cells/HPF.
Direct Gram examination of CSF showed spherical budding encapsulated yeast cells surrounded by translucent hallow around the cells (Figures 2(b) and 2)(c). CSF chemical examination revealed protein level 74 mg/dL (normal range 15–60 mg/dL) and glucose levels 41 mg/dL (normal range 50–80 mg/dL). The sample was cultured on aerobic blood agar, anaerobic blood agar, chocolate, and MacConkey agar; the plates showed delayed growth at the end of the third day (72 hours incubation according to CSF standard operating procedures (SOPs) of our microbiology lab). It was a minute whitish milky colony, which was highly suggestive of fungal infection, confirmed by further subculture, the sample on Sabouraud's dextrose agar (SDA) plates (Figures 2(d)–2(f)). Indian ink stain and positive biochemical reactions were confirmatory for the diagnosis of Cryptococcus infection (Figures 3 and 4). Additionally, antifungal susceptibility testing was performed which was positive for both amphotericin B and flucytosine.
Despite that, the child manifested obvious clinical signs and symptoms of meningitis. Magnetic resonance imaging (MRI) brain with contrast showed findings within normal limits, and blood culture was negative for microbiological growth after 7 days incubation.
Based on the available laboratory results, treatment for disseminated cryptococcosis was initiated immediately upon laboratory notification, prednisone was further decreased to 20 mg/day, and fluconazole was discontinued. Amphotericin B was started at a dose of 0.7 mg/kg/day with an infusion time of 6 hours, since the patient had repeated reactions (fever, chills, and nausea) with a shorter infusion time. Concerning flucytosine, which is indicated as the drug of choice in cryptococcal meningitis treatment, it was not used for treatment of our presented case due to financial aspects and nonavailability in our country, Egypt. Repeated lumber tapping was performed to relieve persistent increased intracranial tension as a consequence of severe meningitis; in addition, plasmapheresis was performed to remove lupus autoantibodies.
The child was subjected for further workup to rule out pneumonia and other organs affection, and for follow up purpose, chest X-ray was ordered, which revealed normal findings, ESR, CRP, complete blood count (CBC), and sepsis marker, neutrophil CD64. These laboratory tests were performed every 3 days on a routine base for monitoring the medical progress which showed dramatic gradual improvement (Table 1 and Figure 5); in conjugation with clinical signs and symptoms improvement evident by regaining her mental and motor skills, besides healing of the leg ulcers, pus draining stopped and swelling disappeared (Figure 6). In this setting, a lumbar puncture was intended to be performed upon this obvious clinical and laboratory improvement preparing the patient to be discharged, but the child refused at her own request and was discharged on her demand after almost 30 days since amphotericin B infusion was first prescribed.
At the time of discharge, the patient had no pulmonary sequelae, but she had residual weakness in her lower limbs. The laboratory results at the time of discharge were hemoglobin 9.2 g/dL, WBC 16.700 cells per mm³, platelet 303.000 cells per mm³, AST 10 U/L, ALT 4 U/L, CRP 6 mg/L, and ESR 53 mm/h. The child was instructed to continue fluconazole (400 mg/day) at home for 8 weeks and then reduced its dose to 200 mg/day for 1 year. And she was weaned gradually from corticosteroid therapy.
One month later, the child was brought to the emergency department complaining of severe headache, projectile vomiting, and blurred vision. She was admitted for the 3rd time. An MRI brain was ordered, and a lumbar puncture was performed urgently to relieve intracranial tension, and for chemical, cytological, and microbiological analyses, all were negative for infection except for CRP slightly positive (12 mg/L). So, lupus flare-up was suspected, and pulse steroid therapy was started, in addition to antifungal (fluconazole) and antibiotic (amikacin and cefepime) coverage. The patient was subjected for plasmapheresis; upon it, she manifested dramatical improvement and discharge. She started to attend the immunotherapy clinic every two weeks for follow up purpose; she did well for 5 months and regained her functions except for difficulty in talking and walking abilities as she could not walk without support; so, the mother was advised to bring her for regular physiotherapy sessions every week.
Five months later, the patient complained of shivering in her legs and hands followed by seizures attacks which were gradually increasing in frequency and duration till her mother brought her to the E/R. She was admitted for the 4th time. Phenytoin was prescribed, initial dose 2.5 mg/kg/dose twice a day and increased gradually to maximum 5 mg/kg/dose twice daily, and intensive work up profile was conducted searching for the cause of the seizures which included electroencephalogram (EEG), MRI brain, full lab evaluation, and CSF chemical analysis and microbiological examination. EEG revealed normal electric impulses without focal activities (Figure 7). MRI brain showed mildly dilated 3rd ventricles, CSF chemistry analysis revealed protein level 82 mg/dL (normal range 15–60 mg/dL), and glucose levels of 35 mg/dL (normal range 50–80 mg/dL). Upon receiving the sample in our microbiology lab, the sample physical criteria were very similar to the previous one, clear colorless, and cell count was 15 cell/cm3. A direct wet film examination was positive for budding yeast cells which were suspected and notified immediately to the pediatric team, and protocol of treatment was decided rapidly. CSF culture results were again confirmatory for C. neoformans.
An intensive course of antifungal therapy was initiated which included amphotericin B (0.7 mg/kg/day) with an infusion time of 6 hours, and fluconazole. Resolution of patient signs and symptoms of infection was clinically evident in addition to negative culture results and improved laboratory sepsis parameters. The child general condition improved, but at this setting, she complained of poor visual acuity. The pediatric team immediately consulted the specialist neurosurgeon, ophthalmologist, and an MRI brain urgently performed which showed evidence of brain cell atrophy with subsequent increased intracranial ventricular sizes and evidence of optic nerve atrophy; the ophthalmologist confirmed bilateral optic nerve degeneration which was more evident on the left side (Figure 8).
After almost one month and, however, signs and symptoms of infection were resolved, cryptococcosis longstanding course with brain cell atrophy as a sequel of cryptococcal meningitis resulted in the child's death after almost one year from her first attack.
3. Discussion and Conclusion
Cryptococcus is an opportunistic fungal pathogen that leads to rare life-threatening infection. Meningoencephalitis and disseminated cryptococcosis are usually common complications reported in immunocompromised hosts [7, 8]. In the presented case, we reported a pediatric systemic lupus erythematosus patient complicated by rapidly disseminating cryptococcal infection which exhibited a latency in the child CNS followed by an attack of infection flare-up which was successfully treated, but slowly progressive brain cell atrophy due to longstanding disease resulted in her death.
Infections and sepsis are major causes of hospitalization, mortality, and morbidity in immunosuppressed patients [9]. Cryptococcosis is one of the fatal fungal infections reported mainly in immunocompromised hosts; however, several reported cases point to its incidence also in immunocompetent patients [10–12]. Cryptococcosis has a low incidence in non-HIV patients, approximately 1 : 100.000 [5, 13]. Patients with SLE are highly susceptible to infections due to the combined effects of their immunosuppressive therapy and the abnormalities of the immune system that the disease itself causes [14]. Concerning our presented case, prolonged corticosteroid therapy and immunosuppressants due to her underlying disease (SLE) were the major risk factors for disseminated cryptococcosis with poor outcomes.
The patient had a progressive renal course complicated by lupus nephritis class IV for which immunosuppressants was given. Lupus nephritis is clinically evident in 50–60% of patients with SLE [15]. Both mycophenolate mofetil and cyclophosphamide were prescribed to our case. Mycophenolate mofetil depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation [16]. While, cyclophosphamide inhibits protein synthesis through DNA and RNA crosslinking [17].
By discussing Cryptococcus as the causative pathogen, C. neoformans is the most common strain causing infections in humans, and it is an encapsulated yeast that has been isolated from chickens' droppings and grows readily in soil contaminated with avian excreta particularly that of pigeons. In humans, it can colonize the upper airway system. Nevertheless, no animal-to-human nor person-to-person respiratory transmission has been documented [9]. Our presented case lived in low socioeconomic and hygienic status, and she denied contact with pigeon or birds. However, the fungus might have been indirectly transmitted via other sources such as vegetables, fruits, and dairy products [8].
C. neoformans generally cause three types of infections: cryptococcal meningitis, pulmonary, and cutaneous cryptococcosis [18]. The dissemination of this disease occurs when at least two noncontiguous sites are affected, which is unusual and mostly observed in HIV patients [4, 19]. In our case, only pulmonary involvement was not present while cutaneous manifestations were the first presenting symptoms followed by cryptococcal meningitis. Some studies support the importance of lumbar puncture in patients with cryptococcosis, even when CNS symptoms are not observed because asymptomatic meningitis is reported to be an early stage of the disease [20].
Systemic lupus erythematosus disease activity index (SLEDAI) was calculated for our presented case in order to be used as a predictor for SLE mortality and as a measure of global disease activity, and it was achieving high values (79) which reflect why the patient underwent into cryptococcal meningitis with poor clinical course. Eventhough, for patients with low SLE activity, the possibility of cryptococcal meningitis should not be underestimated [21].
Skin involvement is a rare presenting symptom of Cryptococcus infection, but it is usually a sign of disseminated disease; it may precede the systemic symptoms even eight months earlier [5, 18]. It is important to stress the rarity and polymorphism of the skin conditions, with the possible development of vesicles or blisters and the potential progression to ulceration [1, 4].
Cryptococcal cellulitis is a rare specific cutaneous manifestation, which was developed in our case. It was initially suspected to be a bacterial infection for which antibiotics were prescribed until its failure and microbiological results confirmed the fungal diagnosis. Although rare, the present case, cryptococcal cellulitis was restricted mainly to the lower body, particularly to the lower extremities, and this was reported in other rare reported cases [1, 2]. Despite that, cryptococcal cellulitis is uncommon and undistinguishable from acute bacterial cellulitis for appearance and presentation [6], but high suspicion especially in a risky patient should be considered.
More than 80% of patients manifested cryptococcal cellulitis and are expected to survive in immunocompetent status when they receive the appropriate antifungal therapy [6]. According to the current guidelines of the American Society of Infectious Diseases for disseminated cryptococcosis management, amphotericin B combined with flucytosine is recommended as the primary therapy, followed by fluconazole as a consolidation therapy [4, 18]. Flucytosine is expensive and was not available in our country; so, it was not considered for the treatment. Instead, it was replaced by the addition of fluconazole to amphotericin B regimen.
Cryptococcal laboratory diagnosis relies on three main methods: latex agglutination test, fungal culture, and direct microscopic examination [22]. In the present case, both the microscopic examination and microbiological cultures were the cornerstone for the diagnosis. C. neoformans was differentiated from other fungal species especially Candida spp. by the characterized morphology in the Gram-stained smear, microbiological culture characters, Indian ink stain positivity, and biochemical reactions.
Indian ink stain was positive in our case. In HIV-positive patients, its sensitivity increases up to 80% due to higher fungal loads in the CSF, while in HIV negative patients, the sensitivity is only 30–50% [8, 23]. CSF culture is considered the gold standard for cryptococcal diagnosis, but it has several diagnostic obstacles as long time is needed for fungus to grow, while time is very critical for management of meningitis cases with evolving lifetime neurological complications [24]. Besides, fungal cultures are not available in all medical facilities and therefore may not be performed. It is also associated with false-negative results, especially in cases with low fungal load, and this may be the attributed cause of negative blood culture result in our case.
Regarding management of cryptococcosis, the prolonged course (6–10 weeks) of IV amphotericin B monotherapy, together with the reduction of chemotherapy to improve immune status, was the main target. Caution was taken while reducing immunosuppressive therapy, since a rapid reduction is reported to be associated with immune reconstitution inflammatory syndrome (IRIS) in some patients [9]. There is evidence that supports the requirement for maintenance therapy with fluconazole administered as indefinite secondary prophylaxis, since the rate of recurrence exceeds 50% after apparently successful treatment [25].
Differential diagnosis of the present case must be addressed which includes besides to what was mentioned, infection versus flare-up attacks in lupus patients; several sepsis markers including CRP increase significantly in SLE patients with concomitant infection but increase only slightly or not at all in patients with a lupus flare without infection [14, 26] which is exactly encountered in our presented case. Additionally, decreased visual acuity due to increased intracranial tension (papilledema) was differentiated from decreased visual acuity due to optic nerve atrophy. For the presented case, papilledema was evident on fundus examination at the time of cryptococcal meningitis first diagnosed, while optic nerve atrophy was evident on fundus examination at the end.
Finally, we highlight the importance of clinicians' awareness about such infection among non-HIV immunocompromised patients including those who are diagnosed with autoimmune diseases. The latency of Cryptococcus should be considered and suspected during the management of such cases which necessitate early recognition and proper management.
For preparing Indian ink-stained film, take two drops from the examined CSF sample directly or a small part of the growing colony from the plate, mix it well with the ink, put a cover slide, and leave the slide for an hour to give a chance for the cells to be settled, and for better contrast view, lower the condenser and reduce the microscopic light and examine the film by using the lens with magnification power (40x). Cryptococcus will be evident as shiny spherical budding in a dark background.
4. Conclusion
Cryptococcal meningitis should be considered as one of the possible diagnoses in a patient with altered sensorium and neck stiffness, especially those who are immunocompromised. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening complications.
Early management of cryptococcal meningitis is associated with better prognosis and lower neurological complications. Despite that, flucytosine is being described as the best antifungal medication for cryptococcal infections. Amphotericin B still gives good results in such cases.
Negative bacterial growth from a skin lesion does not necessitate that it is a sterile lesion; it may be an atypical microorganism or microorganism that needs special media to grow or longer duration to be cultivated. Clinical pathologists should be aware of Cryptococcus laboratory diagnosis and how to differentiate it from Candida spp. Microbiological culture is a confirmatory step for Cryptococcus diagnosis; however, Gram-stained and Indian ink-stained films are rapid and informative diagnostic methods especially in limited resources facilities. The communication between laboratory staff members and treating medical team is very crucial for better clinical judgment specifically in a circumstance where an unusual diagnostic result is released or diagnosing a rare disease.
CSF examination may show low cell count; however, infection presents; this is commonly seen in immunocompromised patients as no adequate inflammation. Cryptococcal infection associated with CNS latency which should to be suspected; hence, meticulous follow-up is an essential step in cryptococcal management. The second activation of cryptococcal latency is usually life-threatening and mostly fatal.
Acknowledgments
The authors would like to thank all members of Immunology Unit-Pediatric Department and Microbiology Unit-Clinical Pathology Department of Ain Shams University Hospital. The authors gratefully acknowledge Professor Dalia Helmy El-Ghoneimy and Professor Malaka Zakaria Amer for their efforts to diagnose and follow up severe medical cases including this presented case and special gratitude to the mother of the child for supporting with detailed medical information and for her medical awareness and patience throughout her daughter's longstanding disease.
Abbreviations
ALT:Alanine transaminase
ANA:Antinuclear antibody
AST:Aspartate transaminase
C. neoformans:
Cryptococcus neoformans
CBC:Complete blood count
CNS:Central nervous system
CRP:C-reactive protein
CSF:Cerebrospinal fluid
DNA:Deoxyribonucleic acid
dsDNA:Double-strand DNA
E.R:Emergency room
EEG:Electroencephalogram
eGFR:Estimated glomerular filtration rate
ESR:Erythrocyte sedimentation rate
HIV:Human immunodeficiency virus
IgG:Immunoglobulin G
IRIS:Immune reconstitution inflammatory syndrome
IV:Intravenous
MPA:Mycophenolic acid
MRI:Magnetic resonance imaging
PC ratio:Protein creatinine ratio
RF:Rheumatoid factor
RNA:Ribonucleic acid
RNP:Ribonucleoprotein antibodies
SDA:Sabouraud's dextrose agar
SLE:Systemic lupus erythematosus
SOPs:Standard operating procedures
WBC:White blood cell.
Data Availability
The data underlying the findings of this research are publicly available.
Ethical Approval
Compliance with ethics guidelines, all procedures followed the ethical standards of the responsible committee on human experimentation (institutional and national).
Consent
Written informed consent for publication of clinical details was obtained from the mother of the patient.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
Authors' Contributions
Heba Ezzat Hashem contributed to acquisition, analysis, and interpretation of data, drafting of paper, conception and design, revision for critical intellectual content, final approval, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Zakaria Hamza Ibrahim involved in revision for critical intellectual content, final approval, and financial support.
Figure 1 A simplified chart representing the sequence of the disease in our case.
Figure 2 (a) Clear colorless CSF sample; other etiological causes of meningitis especially viral meningitis versus fungal meningitis must be differentiated, specifically in the presence of clear colorless CSF samples with low cell count and minimal changes of CSF parameters. (b) Spherical budding yeast in the CSF; it should be differentiated from the elliptical budding yeast cells of Candida spp. which is more commonly encountered during CSF examination as a fungal cause of meningitis. (c) Gram-stained film; direct film from CSF shows spherical budding yeast cells with surrounding translucent haloes due to capsular structure. (d) Blood agar shows small white colonies, after 72 hours of incubation. (e) Sabouraud dextrose agar (SDA) shows pasty colonies that were confirmed to be Cryptococcus neoformans. (f) Gram from culture shows spherical yeast cells with surrounding translucent haloes.
Figure 3 Biochemical reaction; the urease test was positive.
Figure 4
Cryptococcus as shiny spherical budding in a dark background.
Figure 5 Laboratory course of the present case and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation; the patient improved clinically and discharged after almost one month with minimal residual weakness in her lower limbs. The nCD64 test was available in our hospital as a sepsis biomarker, and it was performed for our case for follow-up purposes.
Figure 6 Patient developed extensive skin ulceration with serous oozing from both lower limbs; this image was taken upon her clinical improvement on amphotericin B. The local edema resolved leaving the skin redundant, cracked, and the oozing discharge was first serous-like followed by purulent discharge then pus draining stopped.
Figure 7 EEG at the 4th admission, seizures, and other CNS manifestations in patients who had previous cryptococcal meningitis is very essential to be distinguished; it is due to reactivation of latent infection or due to seizures attributed to other medical causes. For the present case, EEG showed normal electric activates without focal localization.
Figure 8 MRI brain performed at the time of 3rd admission; dilated third ventricles were evident due to brain cell atrophy; at this occasion, signs of increase intracranial tension were negative which excluded it as a cause for cerebral ventricles dilatations.
Table 1 Laboratory course of the present case, and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation.
Hb TLC ANC ALC AMC PLT CRP CD64% CD64 MFI
08/05/2016 10.6 12.2 11.2 0.6 0.4 44 6 98.5 2.87
11/05/2016 9 10.9 9.2 1.1 0.51 81 6 91.5 1.91
15/05/2016 7.7 14.8 12.72 1.57 0.48 209 4 80.1 1.56
22/05/2016 7.2 10 7.6 1.1 0.5 238 4 68.9 1.45
Hb, hemoglobin (g/dl); TLC, total leukocytic count (X109/L); ANC, absolute neutrophil count (X109/L); ALC, absolute lymphocyte count (X109/L); AMC, absolute monocyte count (X109/L); PLT, platelet (X109/L); CRP, C-reactive protein (mg/L); nCD64%, neutrophil CD64%; nCD64MFI, nCD64 mean fluorescence intensity. | Fatal | ReactionOutcome | CC BY | 33628263 | 19,588,393 | 2021 |
What was the outcome of reaction 'Disseminated cryptococcosis'? | Atypical Presentation of Pediatric Systemic Lupus Erythematosus Complicated by Cryptococcal Meningitis.
Cryptococcus is an opportunistic fungal pathogen that leads to life-threatening infections. Cryptococcal infections are mainly reported in HIV patients and less commonly encountered in non-HIV immunocompromised host. Cryptococcus neoformans (C. neoformans) is the most common Cryptococcus species causing diseases in humans which can be presented as pulmonary, meningitis, cutaneous, and/or disseminated cryptococcosis. Case Presentation. A 12-year-old female girl from Cairo, Egypt, presented to the pediatric hospital with signs of systemic lupus erythematosus (SLE). She had an aggressive lupus nephritis course for which corticosteroids, mycophenolate mofetil, and cyclophosphamide were prescribed, and the child gradually improved and was discharged. Two months later, the patient exhibited skin lesions involved both in her legs, massive ulcers were developed and extended rapidly through the entire legs followed by deterioration in her conscious level, and signs of meningitis were documented. Cerebrospinal fluid (CSF) examination and microbiological workup were confirmatory for C. neoformans infection, and mental and motor functions were rapidly deteriorated. Treatment with amphotericin B in addition to supportive treatment and close follow-up of the patient's medical condition result in obvious clinical improvement and patient discharge with minimal residual weakness in her legs after almost a one-month duration. After six months, the patient was brought to the emergency department complaining of repeated attacks of seizures, a lumbar puncture was performed, and culture results were again confirmatory for C. neoformans. An intensive course of antifungal therapy was prescribed which was successful, evident by resolution of the signs and symptoms of infection in addition to negative culture results and negative sepsis biomarkers. The child clinically improved, but unfortunately, gradual optic nerve degeneration and brain cell atrophy as a sequel of severe and longstanding cryptococcal infection resulted in her death after almost one year from her first attack.
Cryptococcal infection among non-HIV patients is a rare disease but can result in advanced medical complications which may be fatal. The disease should be suspected to be reliably diagnosed. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening consequences. Amphotericin B can be used effectively in cryptococcosis management in the settings where flucytosine is not available. Signs of cryptococcal meningitis can be manifested again after a period of remission and clinical cure which signifies the latency of Cryptococcus in the central nervous system. The second activation of Cryptococcus after its latency is usually life-threatening and mostly fatal.
1. Background
Immunocompromised individuals including HIV, SLE, and patients on prolonged corticosteroid and immunosuppressant therapy are more prone to various bacterial, viral, and fungal opportunistic infections. One of the most important fatal fungal infections is cryptococcal infection [1–4]. C. neoformans is the most frequent cryptococcal species infect humans, and it is an encapsulated yeast microorganism, which is commonly transmitted through bird feces, plants, dust, soil, and contaminated food [2, 3]. Cryptococcosis can cause disseminated infection reaching to the lungs, central nervous system (CNS), and skin [2, 3, 5]. Dermal manifestations can present in different clinical morphologies including ulcers, acneiform papules, subcutaneous nodules, and rarely, cellulitis [4, 6].
2. Case Presentation
A 12-years-old Egyptian female student presented to Ain Shams University Pediatric Hospital complaining of generalized body edema, frothy urine, and proteinuria (3.7 g/day). The child was diagnosed as nephrotic syndrome, with repeated albumin infusions, and steroid therapy was initiated, but the child was nonresponding; instead, her medical condition deteriorated. Laboratory profile was in concordance with serologically quiescent SLE which included antinuclear antibody titer 1: 1280 finely speckled, elevated rheumatoid factor (RF) of 456 IU/ml (N: 0–20 IU/ml), positive SS-A/Ro > 8.0 and SS-B/La > 8.0 antibodies, anti-beta-2 glycoprotein IgM Ab > 100 U/ml, C-reactive protein (CRP) level 3.9 mg/l (N: 0–5 mg/l), and erythrocyte sedimentation rate (ESR) 51 mm/hour (N: 0–10 mm/hour). The serologic tests that were negative included anti-dsDNA Abs, complement C3 level 154 mg/dl (N: 106–194 mg/dl), complement C4 level 38 mg/dl (N: 19–50 mg/dl), cyclic citrullinated peptide IgG, cryoglobulin, serum immunofixation, Scl-70 scleroderma, Smith, RNP, cardiolipin antibodies, and lupus anticoagulant. Urine studies at the time revealed 3 + proteinuria, no hematuria or pyuria, a creatinine level of 0.93 mg/dl, and eGFR > 60 ml/min/1.73 m2. The diagnosis of SLE with nephrotic presentation was established, upon which the child received a medical regimen for lupus management including corticosteroids, mycophenolate mofetil, and cyclophosphamide which resulted in patient clinical improvement.
Two months later, the child was admitted complaining of poor appetite, nausea and vomiting, tiredness, swollen ankles, and shortness of breath, and deteriorated renal functions were evident in her laboratory profile: creatinine increased to 1.92 mg/dl, 4 + protein on urinalysis, worsening urine protein to creatinine (PC) ratio of 1.9 (N: 0.0–0.1), and 24-hour urine protein of 1170 mg/24 hours (N: 50–150 mg/24 hours). Lupus nephritis grade IV was confirmed. Therefore, the child received intermittent hemodialysis; in addition, the doses of the prescribed immunosuppressant was increased: prednisone (40 mg/day), hydroxychloroquine (6 mg/kg/day), and mycophenolate mofetil (2 g/day). The patient was kept under this protocol; she gradually improved and was discharged. A simplified chart representing the sequence of the disease in the presented case is illustrated in Figure 1.
After two months, the child manifested skin ulcers in her lower extremities which were progressive in course. Drug allergies, insect bites, and family history were excluded. First, these lesions were nonwell-demarcated, erythematous, painful on palpation, nonpruritic with increasing local edema, and bullae formation. A few days later, lesions spread to involve entire her legs up to the groin area, the bullae began to coalescence together, ruptured, and a huge amount of serous discharge was drained from the lesions; no corresponding lesions appeared on the face, trunk, or upper extremities, and fever was not present at first, but with worsening of the lesions, the patient became feverish, hematuric, anemic, and hypotensive with deteriorated general condition; hence, she was admitted for the 2nd time.
At the time of admission, laboratory profile revealed hemoglobin 8.2 g/dL, white blood cell (WBC) count 10,800/mm³, platelet count 129,000 cells/mm³, serum aspartate transaminase (AST) 10 U/L, serum alanine transaminase (ALT) 17 U/L, CRP 12 mg/L, and ESR 60 mm. Upon worsening the skin lesions, bacterial skin infection was suspected; so empirical treatment with amikacin and cefepime was started and the dose of prednisone decreased to 30 mg/day; microbiological cultures revealed no microorganism growth after 48 hours of incubation. Upon suspicion of bacterial cellulitis and due to the lack of improvements of the skin lesions, vancomycin was added to the treatment regimen.
After three days, the patient medical condition deteriorated rapidly. She complained of severe headache, altered memory, continuous agitation, neck rigidity, stiffness, photophobia, and total loss of appetite; so, meningitis was suspected; hence, lumbar puncture was performed, and a CSF sample was sent for cytological examination in addition to culture procedures. The sample was clear colorless on physical inspection (Figure 2)(a), and cell count was 25 cells/HPF.
Direct Gram examination of CSF showed spherical budding encapsulated yeast cells surrounded by translucent hallow around the cells (Figures 2(b) and 2)(c). CSF chemical examination revealed protein level 74 mg/dL (normal range 15–60 mg/dL) and glucose levels 41 mg/dL (normal range 50–80 mg/dL). The sample was cultured on aerobic blood agar, anaerobic blood agar, chocolate, and MacConkey agar; the plates showed delayed growth at the end of the third day (72 hours incubation according to CSF standard operating procedures (SOPs) of our microbiology lab). It was a minute whitish milky colony, which was highly suggestive of fungal infection, confirmed by further subculture, the sample on Sabouraud's dextrose agar (SDA) plates (Figures 2(d)–2(f)). Indian ink stain and positive biochemical reactions were confirmatory for the diagnosis of Cryptococcus infection (Figures 3 and 4). Additionally, antifungal susceptibility testing was performed which was positive for both amphotericin B and flucytosine.
Despite that, the child manifested obvious clinical signs and symptoms of meningitis. Magnetic resonance imaging (MRI) brain with contrast showed findings within normal limits, and blood culture was negative for microbiological growth after 7 days incubation.
Based on the available laboratory results, treatment for disseminated cryptococcosis was initiated immediately upon laboratory notification, prednisone was further decreased to 20 mg/day, and fluconazole was discontinued. Amphotericin B was started at a dose of 0.7 mg/kg/day with an infusion time of 6 hours, since the patient had repeated reactions (fever, chills, and nausea) with a shorter infusion time. Concerning flucytosine, which is indicated as the drug of choice in cryptococcal meningitis treatment, it was not used for treatment of our presented case due to financial aspects and nonavailability in our country, Egypt. Repeated lumber tapping was performed to relieve persistent increased intracranial tension as a consequence of severe meningitis; in addition, plasmapheresis was performed to remove lupus autoantibodies.
The child was subjected for further workup to rule out pneumonia and other organs affection, and for follow up purpose, chest X-ray was ordered, which revealed normal findings, ESR, CRP, complete blood count (CBC), and sepsis marker, neutrophil CD64. These laboratory tests were performed every 3 days on a routine base for monitoring the medical progress which showed dramatic gradual improvement (Table 1 and Figure 5); in conjugation with clinical signs and symptoms improvement evident by regaining her mental and motor skills, besides healing of the leg ulcers, pus draining stopped and swelling disappeared (Figure 6). In this setting, a lumbar puncture was intended to be performed upon this obvious clinical and laboratory improvement preparing the patient to be discharged, but the child refused at her own request and was discharged on her demand after almost 30 days since amphotericin B infusion was first prescribed.
At the time of discharge, the patient had no pulmonary sequelae, but she had residual weakness in her lower limbs. The laboratory results at the time of discharge were hemoglobin 9.2 g/dL, WBC 16.700 cells per mm³, platelet 303.000 cells per mm³, AST 10 U/L, ALT 4 U/L, CRP 6 mg/L, and ESR 53 mm/h. The child was instructed to continue fluconazole (400 mg/day) at home for 8 weeks and then reduced its dose to 200 mg/day for 1 year. And she was weaned gradually from corticosteroid therapy.
One month later, the child was brought to the emergency department complaining of severe headache, projectile vomiting, and blurred vision. She was admitted for the 3rd time. An MRI brain was ordered, and a lumbar puncture was performed urgently to relieve intracranial tension, and for chemical, cytological, and microbiological analyses, all were negative for infection except for CRP slightly positive (12 mg/L). So, lupus flare-up was suspected, and pulse steroid therapy was started, in addition to antifungal (fluconazole) and antibiotic (amikacin and cefepime) coverage. The patient was subjected for plasmapheresis; upon it, she manifested dramatical improvement and discharge. She started to attend the immunotherapy clinic every two weeks for follow up purpose; she did well for 5 months and regained her functions except for difficulty in talking and walking abilities as she could not walk without support; so, the mother was advised to bring her for regular physiotherapy sessions every week.
Five months later, the patient complained of shivering in her legs and hands followed by seizures attacks which were gradually increasing in frequency and duration till her mother brought her to the E/R. She was admitted for the 4th time. Phenytoin was prescribed, initial dose 2.5 mg/kg/dose twice a day and increased gradually to maximum 5 mg/kg/dose twice daily, and intensive work up profile was conducted searching for the cause of the seizures which included electroencephalogram (EEG), MRI brain, full lab evaluation, and CSF chemical analysis and microbiological examination. EEG revealed normal electric impulses without focal activities (Figure 7). MRI brain showed mildly dilated 3rd ventricles, CSF chemistry analysis revealed protein level 82 mg/dL (normal range 15–60 mg/dL), and glucose levels of 35 mg/dL (normal range 50–80 mg/dL). Upon receiving the sample in our microbiology lab, the sample physical criteria were very similar to the previous one, clear colorless, and cell count was 15 cell/cm3. A direct wet film examination was positive for budding yeast cells which were suspected and notified immediately to the pediatric team, and protocol of treatment was decided rapidly. CSF culture results were again confirmatory for C. neoformans.
An intensive course of antifungal therapy was initiated which included amphotericin B (0.7 mg/kg/day) with an infusion time of 6 hours, and fluconazole. Resolution of patient signs and symptoms of infection was clinically evident in addition to negative culture results and improved laboratory sepsis parameters. The child general condition improved, but at this setting, she complained of poor visual acuity. The pediatric team immediately consulted the specialist neurosurgeon, ophthalmologist, and an MRI brain urgently performed which showed evidence of brain cell atrophy with subsequent increased intracranial ventricular sizes and evidence of optic nerve atrophy; the ophthalmologist confirmed bilateral optic nerve degeneration which was more evident on the left side (Figure 8).
After almost one month and, however, signs and symptoms of infection were resolved, cryptococcosis longstanding course with brain cell atrophy as a sequel of cryptococcal meningitis resulted in the child's death after almost one year from her first attack.
3. Discussion and Conclusion
Cryptococcus is an opportunistic fungal pathogen that leads to rare life-threatening infection. Meningoencephalitis and disseminated cryptococcosis are usually common complications reported in immunocompromised hosts [7, 8]. In the presented case, we reported a pediatric systemic lupus erythematosus patient complicated by rapidly disseminating cryptococcal infection which exhibited a latency in the child CNS followed by an attack of infection flare-up which was successfully treated, but slowly progressive brain cell atrophy due to longstanding disease resulted in her death.
Infections and sepsis are major causes of hospitalization, mortality, and morbidity in immunosuppressed patients [9]. Cryptococcosis is one of the fatal fungal infections reported mainly in immunocompromised hosts; however, several reported cases point to its incidence also in immunocompetent patients [10–12]. Cryptococcosis has a low incidence in non-HIV patients, approximately 1 : 100.000 [5, 13]. Patients with SLE are highly susceptible to infections due to the combined effects of their immunosuppressive therapy and the abnormalities of the immune system that the disease itself causes [14]. Concerning our presented case, prolonged corticosteroid therapy and immunosuppressants due to her underlying disease (SLE) were the major risk factors for disseminated cryptococcosis with poor outcomes.
The patient had a progressive renal course complicated by lupus nephritis class IV for which immunosuppressants was given. Lupus nephritis is clinically evident in 50–60% of patients with SLE [15]. Both mycophenolate mofetil and cyclophosphamide were prescribed to our case. Mycophenolate mofetil depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation [16]. While, cyclophosphamide inhibits protein synthesis through DNA and RNA crosslinking [17].
By discussing Cryptococcus as the causative pathogen, C. neoformans is the most common strain causing infections in humans, and it is an encapsulated yeast that has been isolated from chickens' droppings and grows readily in soil contaminated with avian excreta particularly that of pigeons. In humans, it can colonize the upper airway system. Nevertheless, no animal-to-human nor person-to-person respiratory transmission has been documented [9]. Our presented case lived in low socioeconomic and hygienic status, and she denied contact with pigeon or birds. However, the fungus might have been indirectly transmitted via other sources such as vegetables, fruits, and dairy products [8].
C. neoformans generally cause three types of infections: cryptococcal meningitis, pulmonary, and cutaneous cryptococcosis [18]. The dissemination of this disease occurs when at least two noncontiguous sites are affected, which is unusual and mostly observed in HIV patients [4, 19]. In our case, only pulmonary involvement was not present while cutaneous manifestations were the first presenting symptoms followed by cryptococcal meningitis. Some studies support the importance of lumbar puncture in patients with cryptococcosis, even when CNS symptoms are not observed because asymptomatic meningitis is reported to be an early stage of the disease [20].
Systemic lupus erythematosus disease activity index (SLEDAI) was calculated for our presented case in order to be used as a predictor for SLE mortality and as a measure of global disease activity, and it was achieving high values (79) which reflect why the patient underwent into cryptococcal meningitis with poor clinical course. Eventhough, for patients with low SLE activity, the possibility of cryptococcal meningitis should not be underestimated [21].
Skin involvement is a rare presenting symptom of Cryptococcus infection, but it is usually a sign of disseminated disease; it may precede the systemic symptoms even eight months earlier [5, 18]. It is important to stress the rarity and polymorphism of the skin conditions, with the possible development of vesicles or blisters and the potential progression to ulceration [1, 4].
Cryptococcal cellulitis is a rare specific cutaneous manifestation, which was developed in our case. It was initially suspected to be a bacterial infection for which antibiotics were prescribed until its failure and microbiological results confirmed the fungal diagnosis. Although rare, the present case, cryptococcal cellulitis was restricted mainly to the lower body, particularly to the lower extremities, and this was reported in other rare reported cases [1, 2]. Despite that, cryptococcal cellulitis is uncommon and undistinguishable from acute bacterial cellulitis for appearance and presentation [6], but high suspicion especially in a risky patient should be considered.
More than 80% of patients manifested cryptococcal cellulitis and are expected to survive in immunocompetent status when they receive the appropriate antifungal therapy [6]. According to the current guidelines of the American Society of Infectious Diseases for disseminated cryptococcosis management, amphotericin B combined with flucytosine is recommended as the primary therapy, followed by fluconazole as a consolidation therapy [4, 18]. Flucytosine is expensive and was not available in our country; so, it was not considered for the treatment. Instead, it was replaced by the addition of fluconazole to amphotericin B regimen.
Cryptococcal laboratory diagnosis relies on three main methods: latex agglutination test, fungal culture, and direct microscopic examination [22]. In the present case, both the microscopic examination and microbiological cultures were the cornerstone for the diagnosis. C. neoformans was differentiated from other fungal species especially Candida spp. by the characterized morphology in the Gram-stained smear, microbiological culture characters, Indian ink stain positivity, and biochemical reactions.
Indian ink stain was positive in our case. In HIV-positive patients, its sensitivity increases up to 80% due to higher fungal loads in the CSF, while in HIV negative patients, the sensitivity is only 30–50% [8, 23]. CSF culture is considered the gold standard for cryptococcal diagnosis, but it has several diagnostic obstacles as long time is needed for fungus to grow, while time is very critical for management of meningitis cases with evolving lifetime neurological complications [24]. Besides, fungal cultures are not available in all medical facilities and therefore may not be performed. It is also associated with false-negative results, especially in cases with low fungal load, and this may be the attributed cause of negative blood culture result in our case.
Regarding management of cryptococcosis, the prolonged course (6–10 weeks) of IV amphotericin B monotherapy, together with the reduction of chemotherapy to improve immune status, was the main target. Caution was taken while reducing immunosuppressive therapy, since a rapid reduction is reported to be associated with immune reconstitution inflammatory syndrome (IRIS) in some patients [9]. There is evidence that supports the requirement for maintenance therapy with fluconazole administered as indefinite secondary prophylaxis, since the rate of recurrence exceeds 50% after apparently successful treatment [25].
Differential diagnosis of the present case must be addressed which includes besides to what was mentioned, infection versus flare-up attacks in lupus patients; several sepsis markers including CRP increase significantly in SLE patients with concomitant infection but increase only slightly or not at all in patients with a lupus flare without infection [14, 26] which is exactly encountered in our presented case. Additionally, decreased visual acuity due to increased intracranial tension (papilledema) was differentiated from decreased visual acuity due to optic nerve atrophy. For the presented case, papilledema was evident on fundus examination at the time of cryptococcal meningitis first diagnosed, while optic nerve atrophy was evident on fundus examination at the end.
Finally, we highlight the importance of clinicians' awareness about such infection among non-HIV immunocompromised patients including those who are diagnosed with autoimmune diseases. The latency of Cryptococcus should be considered and suspected during the management of such cases which necessitate early recognition and proper management.
For preparing Indian ink-stained film, take two drops from the examined CSF sample directly or a small part of the growing colony from the plate, mix it well with the ink, put a cover slide, and leave the slide for an hour to give a chance for the cells to be settled, and for better contrast view, lower the condenser and reduce the microscopic light and examine the film by using the lens with magnification power (40x). Cryptococcus will be evident as shiny spherical budding in a dark background.
4. Conclusion
Cryptococcal meningitis should be considered as one of the possible diagnoses in a patient with altered sensorium and neck stiffness, especially those who are immunocompromised. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening complications.
Early management of cryptococcal meningitis is associated with better prognosis and lower neurological complications. Despite that, flucytosine is being described as the best antifungal medication for cryptococcal infections. Amphotericin B still gives good results in such cases.
Negative bacterial growth from a skin lesion does not necessitate that it is a sterile lesion; it may be an atypical microorganism or microorganism that needs special media to grow or longer duration to be cultivated. Clinical pathologists should be aware of Cryptococcus laboratory diagnosis and how to differentiate it from Candida spp. Microbiological culture is a confirmatory step for Cryptococcus diagnosis; however, Gram-stained and Indian ink-stained films are rapid and informative diagnostic methods especially in limited resources facilities. The communication between laboratory staff members and treating medical team is very crucial for better clinical judgment specifically in a circumstance where an unusual diagnostic result is released or diagnosing a rare disease.
CSF examination may show low cell count; however, infection presents; this is commonly seen in immunocompromised patients as no adequate inflammation. Cryptococcal infection associated with CNS latency which should to be suspected; hence, meticulous follow-up is an essential step in cryptococcal management. The second activation of cryptococcal latency is usually life-threatening and mostly fatal.
Acknowledgments
The authors would like to thank all members of Immunology Unit-Pediatric Department and Microbiology Unit-Clinical Pathology Department of Ain Shams University Hospital. The authors gratefully acknowledge Professor Dalia Helmy El-Ghoneimy and Professor Malaka Zakaria Amer for their efforts to diagnose and follow up severe medical cases including this presented case and special gratitude to the mother of the child for supporting with detailed medical information and for her medical awareness and patience throughout her daughter's longstanding disease.
Abbreviations
ALT:Alanine transaminase
ANA:Antinuclear antibody
AST:Aspartate transaminase
C. neoformans:
Cryptococcus neoformans
CBC:Complete blood count
CNS:Central nervous system
CRP:C-reactive protein
CSF:Cerebrospinal fluid
DNA:Deoxyribonucleic acid
dsDNA:Double-strand DNA
E.R:Emergency room
EEG:Electroencephalogram
eGFR:Estimated glomerular filtration rate
ESR:Erythrocyte sedimentation rate
HIV:Human immunodeficiency virus
IgG:Immunoglobulin G
IRIS:Immune reconstitution inflammatory syndrome
IV:Intravenous
MPA:Mycophenolic acid
MRI:Magnetic resonance imaging
PC ratio:Protein creatinine ratio
RF:Rheumatoid factor
RNA:Ribonucleic acid
RNP:Ribonucleoprotein antibodies
SDA:Sabouraud's dextrose agar
SLE:Systemic lupus erythematosus
SOPs:Standard operating procedures
WBC:White blood cell.
Data Availability
The data underlying the findings of this research are publicly available.
Ethical Approval
Compliance with ethics guidelines, all procedures followed the ethical standards of the responsible committee on human experimentation (institutional and national).
Consent
Written informed consent for publication of clinical details was obtained from the mother of the patient.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
Authors' Contributions
Heba Ezzat Hashem contributed to acquisition, analysis, and interpretation of data, drafting of paper, conception and design, revision for critical intellectual content, final approval, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Zakaria Hamza Ibrahim involved in revision for critical intellectual content, final approval, and financial support.
Figure 1 A simplified chart representing the sequence of the disease in our case.
Figure 2 (a) Clear colorless CSF sample; other etiological causes of meningitis especially viral meningitis versus fungal meningitis must be differentiated, specifically in the presence of clear colorless CSF samples with low cell count and minimal changes of CSF parameters. (b) Spherical budding yeast in the CSF; it should be differentiated from the elliptical budding yeast cells of Candida spp. which is more commonly encountered during CSF examination as a fungal cause of meningitis. (c) Gram-stained film; direct film from CSF shows spherical budding yeast cells with surrounding translucent haloes due to capsular structure. (d) Blood agar shows small white colonies, after 72 hours of incubation. (e) Sabouraud dextrose agar (SDA) shows pasty colonies that were confirmed to be Cryptococcus neoformans. (f) Gram from culture shows spherical yeast cells with surrounding translucent haloes.
Figure 3 Biochemical reaction; the urease test was positive.
Figure 4
Cryptococcus as shiny spherical budding in a dark background.
Figure 5 Laboratory course of the present case and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation; the patient improved clinically and discharged after almost one month with minimal residual weakness in her lower limbs. The nCD64 test was available in our hospital as a sepsis biomarker, and it was performed for our case for follow-up purposes.
Figure 6 Patient developed extensive skin ulceration with serous oozing from both lower limbs; this image was taken upon her clinical improvement on amphotericin B. The local edema resolved leaving the skin redundant, cracked, and the oozing discharge was first serous-like followed by purulent discharge then pus draining stopped.
Figure 7 EEG at the 4th admission, seizures, and other CNS manifestations in patients who had previous cryptococcal meningitis is very essential to be distinguished; it is due to reactivation of latent infection or due to seizures attributed to other medical causes. For the present case, EEG showed normal electric activates without focal localization.
Figure 8 MRI brain performed at the time of 3rd admission; dilated third ventricles were evident due to brain cell atrophy; at this occasion, signs of increase intracranial tension were negative which excluded it as a cause for cerebral ventricles dilatations.
Table 1 Laboratory course of the present case, and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation.
Hb TLC ANC ALC AMC PLT CRP CD64% CD64 MFI
08/05/2016 10.6 12.2 11.2 0.6 0.4 44 6 98.5 2.87
11/05/2016 9 10.9 9.2 1.1 0.51 81 6 91.5 1.91
15/05/2016 7.7 14.8 12.72 1.57 0.48 209 4 80.1 1.56
22/05/2016 7.2 10 7.6 1.1 0.5 238 4 68.9 1.45
Hb, hemoglobin (g/dl); TLC, total leukocytic count (X109/L); ANC, absolute neutrophil count (X109/L); ALC, absolute lymphocyte count (X109/L); AMC, absolute monocyte count (X109/L); PLT, platelet (X109/L); CRP, C-reactive protein (mg/L); nCD64%, neutrophil CD64%; nCD64MFI, nCD64 mean fluorescence intensity. | Fatal | ReactionOutcome | CC BY | 33628263 | 19,577,937 | 2021 |
What was the outcome of reaction 'Infection'? | Atypical Presentation of Pediatric Systemic Lupus Erythematosus Complicated by Cryptococcal Meningitis.
Cryptococcus is an opportunistic fungal pathogen that leads to life-threatening infections. Cryptococcal infections are mainly reported in HIV patients and less commonly encountered in non-HIV immunocompromised host. Cryptococcus neoformans (C. neoformans) is the most common Cryptococcus species causing diseases in humans which can be presented as pulmonary, meningitis, cutaneous, and/or disseminated cryptococcosis. Case Presentation. A 12-year-old female girl from Cairo, Egypt, presented to the pediatric hospital with signs of systemic lupus erythematosus (SLE). She had an aggressive lupus nephritis course for which corticosteroids, mycophenolate mofetil, and cyclophosphamide were prescribed, and the child gradually improved and was discharged. Two months later, the patient exhibited skin lesions involved both in her legs, massive ulcers were developed and extended rapidly through the entire legs followed by deterioration in her conscious level, and signs of meningitis were documented. Cerebrospinal fluid (CSF) examination and microbiological workup were confirmatory for C. neoformans infection, and mental and motor functions were rapidly deteriorated. Treatment with amphotericin B in addition to supportive treatment and close follow-up of the patient's medical condition result in obvious clinical improvement and patient discharge with minimal residual weakness in her legs after almost a one-month duration. After six months, the patient was brought to the emergency department complaining of repeated attacks of seizures, a lumbar puncture was performed, and culture results were again confirmatory for C. neoformans. An intensive course of antifungal therapy was prescribed which was successful, evident by resolution of the signs and symptoms of infection in addition to negative culture results and negative sepsis biomarkers. The child clinically improved, but unfortunately, gradual optic nerve degeneration and brain cell atrophy as a sequel of severe and longstanding cryptococcal infection resulted in her death after almost one year from her first attack.
Cryptococcal infection among non-HIV patients is a rare disease but can result in advanced medical complications which may be fatal. The disease should be suspected to be reliably diagnosed. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening consequences. Amphotericin B can be used effectively in cryptococcosis management in the settings where flucytosine is not available. Signs of cryptococcal meningitis can be manifested again after a period of remission and clinical cure which signifies the latency of Cryptococcus in the central nervous system. The second activation of Cryptococcus after its latency is usually life-threatening and mostly fatal.
1. Background
Immunocompromised individuals including HIV, SLE, and patients on prolonged corticosteroid and immunosuppressant therapy are more prone to various bacterial, viral, and fungal opportunistic infections. One of the most important fatal fungal infections is cryptococcal infection [1–4]. C. neoformans is the most frequent cryptococcal species infect humans, and it is an encapsulated yeast microorganism, which is commonly transmitted through bird feces, plants, dust, soil, and contaminated food [2, 3]. Cryptococcosis can cause disseminated infection reaching to the lungs, central nervous system (CNS), and skin [2, 3, 5]. Dermal manifestations can present in different clinical morphologies including ulcers, acneiform papules, subcutaneous nodules, and rarely, cellulitis [4, 6].
2. Case Presentation
A 12-years-old Egyptian female student presented to Ain Shams University Pediatric Hospital complaining of generalized body edema, frothy urine, and proteinuria (3.7 g/day). The child was diagnosed as nephrotic syndrome, with repeated albumin infusions, and steroid therapy was initiated, but the child was nonresponding; instead, her medical condition deteriorated. Laboratory profile was in concordance with serologically quiescent SLE which included antinuclear antibody titer 1: 1280 finely speckled, elevated rheumatoid factor (RF) of 456 IU/ml (N: 0–20 IU/ml), positive SS-A/Ro > 8.0 and SS-B/La > 8.0 antibodies, anti-beta-2 glycoprotein IgM Ab > 100 U/ml, C-reactive protein (CRP) level 3.9 mg/l (N: 0–5 mg/l), and erythrocyte sedimentation rate (ESR) 51 mm/hour (N: 0–10 mm/hour). The serologic tests that were negative included anti-dsDNA Abs, complement C3 level 154 mg/dl (N: 106–194 mg/dl), complement C4 level 38 mg/dl (N: 19–50 mg/dl), cyclic citrullinated peptide IgG, cryoglobulin, serum immunofixation, Scl-70 scleroderma, Smith, RNP, cardiolipin antibodies, and lupus anticoagulant. Urine studies at the time revealed 3 + proteinuria, no hematuria or pyuria, a creatinine level of 0.93 mg/dl, and eGFR > 60 ml/min/1.73 m2. The diagnosis of SLE with nephrotic presentation was established, upon which the child received a medical regimen for lupus management including corticosteroids, mycophenolate mofetil, and cyclophosphamide which resulted in patient clinical improvement.
Two months later, the child was admitted complaining of poor appetite, nausea and vomiting, tiredness, swollen ankles, and shortness of breath, and deteriorated renal functions were evident in her laboratory profile: creatinine increased to 1.92 mg/dl, 4 + protein on urinalysis, worsening urine protein to creatinine (PC) ratio of 1.9 (N: 0.0–0.1), and 24-hour urine protein of 1170 mg/24 hours (N: 50–150 mg/24 hours). Lupus nephritis grade IV was confirmed. Therefore, the child received intermittent hemodialysis; in addition, the doses of the prescribed immunosuppressant was increased: prednisone (40 mg/day), hydroxychloroquine (6 mg/kg/day), and mycophenolate mofetil (2 g/day). The patient was kept under this protocol; she gradually improved and was discharged. A simplified chart representing the sequence of the disease in the presented case is illustrated in Figure 1.
After two months, the child manifested skin ulcers in her lower extremities which were progressive in course. Drug allergies, insect bites, and family history were excluded. First, these lesions were nonwell-demarcated, erythematous, painful on palpation, nonpruritic with increasing local edema, and bullae formation. A few days later, lesions spread to involve entire her legs up to the groin area, the bullae began to coalescence together, ruptured, and a huge amount of serous discharge was drained from the lesions; no corresponding lesions appeared on the face, trunk, or upper extremities, and fever was not present at first, but with worsening of the lesions, the patient became feverish, hematuric, anemic, and hypotensive with deteriorated general condition; hence, she was admitted for the 2nd time.
At the time of admission, laboratory profile revealed hemoglobin 8.2 g/dL, white blood cell (WBC) count 10,800/mm³, platelet count 129,000 cells/mm³, serum aspartate transaminase (AST) 10 U/L, serum alanine transaminase (ALT) 17 U/L, CRP 12 mg/L, and ESR 60 mm. Upon worsening the skin lesions, bacterial skin infection was suspected; so empirical treatment with amikacin and cefepime was started and the dose of prednisone decreased to 30 mg/day; microbiological cultures revealed no microorganism growth after 48 hours of incubation. Upon suspicion of bacterial cellulitis and due to the lack of improvements of the skin lesions, vancomycin was added to the treatment regimen.
After three days, the patient medical condition deteriorated rapidly. She complained of severe headache, altered memory, continuous agitation, neck rigidity, stiffness, photophobia, and total loss of appetite; so, meningitis was suspected; hence, lumbar puncture was performed, and a CSF sample was sent for cytological examination in addition to culture procedures. The sample was clear colorless on physical inspection (Figure 2)(a), and cell count was 25 cells/HPF.
Direct Gram examination of CSF showed spherical budding encapsulated yeast cells surrounded by translucent hallow around the cells (Figures 2(b) and 2)(c). CSF chemical examination revealed protein level 74 mg/dL (normal range 15–60 mg/dL) and glucose levels 41 mg/dL (normal range 50–80 mg/dL). The sample was cultured on aerobic blood agar, anaerobic blood agar, chocolate, and MacConkey agar; the plates showed delayed growth at the end of the third day (72 hours incubation according to CSF standard operating procedures (SOPs) of our microbiology lab). It was a minute whitish milky colony, which was highly suggestive of fungal infection, confirmed by further subculture, the sample on Sabouraud's dextrose agar (SDA) plates (Figures 2(d)–2(f)). Indian ink stain and positive biochemical reactions were confirmatory for the diagnosis of Cryptococcus infection (Figures 3 and 4). Additionally, antifungal susceptibility testing was performed which was positive for both amphotericin B and flucytosine.
Despite that, the child manifested obvious clinical signs and symptoms of meningitis. Magnetic resonance imaging (MRI) brain with contrast showed findings within normal limits, and blood culture was negative for microbiological growth after 7 days incubation.
Based on the available laboratory results, treatment for disseminated cryptococcosis was initiated immediately upon laboratory notification, prednisone was further decreased to 20 mg/day, and fluconazole was discontinued. Amphotericin B was started at a dose of 0.7 mg/kg/day with an infusion time of 6 hours, since the patient had repeated reactions (fever, chills, and nausea) with a shorter infusion time. Concerning flucytosine, which is indicated as the drug of choice in cryptococcal meningitis treatment, it was not used for treatment of our presented case due to financial aspects and nonavailability in our country, Egypt. Repeated lumber tapping was performed to relieve persistent increased intracranial tension as a consequence of severe meningitis; in addition, plasmapheresis was performed to remove lupus autoantibodies.
The child was subjected for further workup to rule out pneumonia and other organs affection, and for follow up purpose, chest X-ray was ordered, which revealed normal findings, ESR, CRP, complete blood count (CBC), and sepsis marker, neutrophil CD64. These laboratory tests were performed every 3 days on a routine base for monitoring the medical progress which showed dramatic gradual improvement (Table 1 and Figure 5); in conjugation with clinical signs and symptoms improvement evident by regaining her mental and motor skills, besides healing of the leg ulcers, pus draining stopped and swelling disappeared (Figure 6). In this setting, a lumbar puncture was intended to be performed upon this obvious clinical and laboratory improvement preparing the patient to be discharged, but the child refused at her own request and was discharged on her demand after almost 30 days since amphotericin B infusion was first prescribed.
At the time of discharge, the patient had no pulmonary sequelae, but she had residual weakness in her lower limbs. The laboratory results at the time of discharge were hemoglobin 9.2 g/dL, WBC 16.700 cells per mm³, platelet 303.000 cells per mm³, AST 10 U/L, ALT 4 U/L, CRP 6 mg/L, and ESR 53 mm/h. The child was instructed to continue fluconazole (400 mg/day) at home for 8 weeks and then reduced its dose to 200 mg/day for 1 year. And she was weaned gradually from corticosteroid therapy.
One month later, the child was brought to the emergency department complaining of severe headache, projectile vomiting, and blurred vision. She was admitted for the 3rd time. An MRI brain was ordered, and a lumbar puncture was performed urgently to relieve intracranial tension, and for chemical, cytological, and microbiological analyses, all were negative for infection except for CRP slightly positive (12 mg/L). So, lupus flare-up was suspected, and pulse steroid therapy was started, in addition to antifungal (fluconazole) and antibiotic (amikacin and cefepime) coverage. The patient was subjected for plasmapheresis; upon it, she manifested dramatical improvement and discharge. She started to attend the immunotherapy clinic every two weeks for follow up purpose; she did well for 5 months and regained her functions except for difficulty in talking and walking abilities as she could not walk without support; so, the mother was advised to bring her for regular physiotherapy sessions every week.
Five months later, the patient complained of shivering in her legs and hands followed by seizures attacks which were gradually increasing in frequency and duration till her mother brought her to the E/R. She was admitted for the 4th time. Phenytoin was prescribed, initial dose 2.5 mg/kg/dose twice a day and increased gradually to maximum 5 mg/kg/dose twice daily, and intensive work up profile was conducted searching for the cause of the seizures which included electroencephalogram (EEG), MRI brain, full lab evaluation, and CSF chemical analysis and microbiological examination. EEG revealed normal electric impulses without focal activities (Figure 7). MRI brain showed mildly dilated 3rd ventricles, CSF chemistry analysis revealed protein level 82 mg/dL (normal range 15–60 mg/dL), and glucose levels of 35 mg/dL (normal range 50–80 mg/dL). Upon receiving the sample in our microbiology lab, the sample physical criteria were very similar to the previous one, clear colorless, and cell count was 15 cell/cm3. A direct wet film examination was positive for budding yeast cells which were suspected and notified immediately to the pediatric team, and protocol of treatment was decided rapidly. CSF culture results were again confirmatory for C. neoformans.
An intensive course of antifungal therapy was initiated which included amphotericin B (0.7 mg/kg/day) with an infusion time of 6 hours, and fluconazole. Resolution of patient signs and symptoms of infection was clinically evident in addition to negative culture results and improved laboratory sepsis parameters. The child general condition improved, but at this setting, she complained of poor visual acuity. The pediatric team immediately consulted the specialist neurosurgeon, ophthalmologist, and an MRI brain urgently performed which showed evidence of brain cell atrophy with subsequent increased intracranial ventricular sizes and evidence of optic nerve atrophy; the ophthalmologist confirmed bilateral optic nerve degeneration which was more evident on the left side (Figure 8).
After almost one month and, however, signs and symptoms of infection were resolved, cryptococcosis longstanding course with brain cell atrophy as a sequel of cryptococcal meningitis resulted in the child's death after almost one year from her first attack.
3. Discussion and Conclusion
Cryptococcus is an opportunistic fungal pathogen that leads to rare life-threatening infection. Meningoencephalitis and disseminated cryptococcosis are usually common complications reported in immunocompromised hosts [7, 8]. In the presented case, we reported a pediatric systemic lupus erythematosus patient complicated by rapidly disseminating cryptococcal infection which exhibited a latency in the child CNS followed by an attack of infection flare-up which was successfully treated, but slowly progressive brain cell atrophy due to longstanding disease resulted in her death.
Infections and sepsis are major causes of hospitalization, mortality, and morbidity in immunosuppressed patients [9]. Cryptococcosis is one of the fatal fungal infections reported mainly in immunocompromised hosts; however, several reported cases point to its incidence also in immunocompetent patients [10–12]. Cryptococcosis has a low incidence in non-HIV patients, approximately 1 : 100.000 [5, 13]. Patients with SLE are highly susceptible to infections due to the combined effects of their immunosuppressive therapy and the abnormalities of the immune system that the disease itself causes [14]. Concerning our presented case, prolonged corticosteroid therapy and immunosuppressants due to her underlying disease (SLE) were the major risk factors for disseminated cryptococcosis with poor outcomes.
The patient had a progressive renal course complicated by lupus nephritis class IV for which immunosuppressants was given. Lupus nephritis is clinically evident in 50–60% of patients with SLE [15]. Both mycophenolate mofetil and cyclophosphamide were prescribed to our case. Mycophenolate mofetil depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation [16]. While, cyclophosphamide inhibits protein synthesis through DNA and RNA crosslinking [17].
By discussing Cryptococcus as the causative pathogen, C. neoformans is the most common strain causing infections in humans, and it is an encapsulated yeast that has been isolated from chickens' droppings and grows readily in soil contaminated with avian excreta particularly that of pigeons. In humans, it can colonize the upper airway system. Nevertheless, no animal-to-human nor person-to-person respiratory transmission has been documented [9]. Our presented case lived in low socioeconomic and hygienic status, and she denied contact with pigeon or birds. However, the fungus might have been indirectly transmitted via other sources such as vegetables, fruits, and dairy products [8].
C. neoformans generally cause three types of infections: cryptococcal meningitis, pulmonary, and cutaneous cryptococcosis [18]. The dissemination of this disease occurs when at least two noncontiguous sites are affected, which is unusual and mostly observed in HIV patients [4, 19]. In our case, only pulmonary involvement was not present while cutaneous manifestations were the first presenting symptoms followed by cryptococcal meningitis. Some studies support the importance of lumbar puncture in patients with cryptococcosis, even when CNS symptoms are not observed because asymptomatic meningitis is reported to be an early stage of the disease [20].
Systemic lupus erythematosus disease activity index (SLEDAI) was calculated for our presented case in order to be used as a predictor for SLE mortality and as a measure of global disease activity, and it was achieving high values (79) which reflect why the patient underwent into cryptococcal meningitis with poor clinical course. Eventhough, for patients with low SLE activity, the possibility of cryptococcal meningitis should not be underestimated [21].
Skin involvement is a rare presenting symptom of Cryptococcus infection, but it is usually a sign of disseminated disease; it may precede the systemic symptoms even eight months earlier [5, 18]. It is important to stress the rarity and polymorphism of the skin conditions, with the possible development of vesicles or blisters and the potential progression to ulceration [1, 4].
Cryptococcal cellulitis is a rare specific cutaneous manifestation, which was developed in our case. It was initially suspected to be a bacterial infection for which antibiotics were prescribed until its failure and microbiological results confirmed the fungal diagnosis. Although rare, the present case, cryptococcal cellulitis was restricted mainly to the lower body, particularly to the lower extremities, and this was reported in other rare reported cases [1, 2]. Despite that, cryptococcal cellulitis is uncommon and undistinguishable from acute bacterial cellulitis for appearance and presentation [6], but high suspicion especially in a risky patient should be considered.
More than 80% of patients manifested cryptococcal cellulitis and are expected to survive in immunocompetent status when they receive the appropriate antifungal therapy [6]. According to the current guidelines of the American Society of Infectious Diseases for disseminated cryptococcosis management, amphotericin B combined with flucytosine is recommended as the primary therapy, followed by fluconazole as a consolidation therapy [4, 18]. Flucytosine is expensive and was not available in our country; so, it was not considered for the treatment. Instead, it was replaced by the addition of fluconazole to amphotericin B regimen.
Cryptococcal laboratory diagnosis relies on three main methods: latex agglutination test, fungal culture, and direct microscopic examination [22]. In the present case, both the microscopic examination and microbiological cultures were the cornerstone for the diagnosis. C. neoformans was differentiated from other fungal species especially Candida spp. by the characterized morphology in the Gram-stained smear, microbiological culture characters, Indian ink stain positivity, and biochemical reactions.
Indian ink stain was positive in our case. In HIV-positive patients, its sensitivity increases up to 80% due to higher fungal loads in the CSF, while in HIV negative patients, the sensitivity is only 30–50% [8, 23]. CSF culture is considered the gold standard for cryptococcal diagnosis, but it has several diagnostic obstacles as long time is needed for fungus to grow, while time is very critical for management of meningitis cases with evolving lifetime neurological complications [24]. Besides, fungal cultures are not available in all medical facilities and therefore may not be performed. It is also associated with false-negative results, especially in cases with low fungal load, and this may be the attributed cause of negative blood culture result in our case.
Regarding management of cryptococcosis, the prolonged course (6–10 weeks) of IV amphotericin B monotherapy, together with the reduction of chemotherapy to improve immune status, was the main target. Caution was taken while reducing immunosuppressive therapy, since a rapid reduction is reported to be associated with immune reconstitution inflammatory syndrome (IRIS) in some patients [9]. There is evidence that supports the requirement for maintenance therapy with fluconazole administered as indefinite secondary prophylaxis, since the rate of recurrence exceeds 50% after apparently successful treatment [25].
Differential diagnosis of the present case must be addressed which includes besides to what was mentioned, infection versus flare-up attacks in lupus patients; several sepsis markers including CRP increase significantly in SLE patients with concomitant infection but increase only slightly or not at all in patients with a lupus flare without infection [14, 26] which is exactly encountered in our presented case. Additionally, decreased visual acuity due to increased intracranial tension (papilledema) was differentiated from decreased visual acuity due to optic nerve atrophy. For the presented case, papilledema was evident on fundus examination at the time of cryptococcal meningitis first diagnosed, while optic nerve atrophy was evident on fundus examination at the end.
Finally, we highlight the importance of clinicians' awareness about such infection among non-HIV immunocompromised patients including those who are diagnosed with autoimmune diseases. The latency of Cryptococcus should be considered and suspected during the management of such cases which necessitate early recognition and proper management.
For preparing Indian ink-stained film, take two drops from the examined CSF sample directly or a small part of the growing colony from the plate, mix it well with the ink, put a cover slide, and leave the slide for an hour to give a chance for the cells to be settled, and for better contrast view, lower the condenser and reduce the microscopic light and examine the film by using the lens with magnification power (40x). Cryptococcus will be evident as shiny spherical budding in a dark background.
4. Conclusion
Cryptococcal meningitis should be considered as one of the possible diagnoses in a patient with altered sensorium and neck stiffness, especially those who are immunocompromised. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening complications.
Early management of cryptococcal meningitis is associated with better prognosis and lower neurological complications. Despite that, flucytosine is being described as the best antifungal medication for cryptococcal infections. Amphotericin B still gives good results in such cases.
Negative bacterial growth from a skin lesion does not necessitate that it is a sterile lesion; it may be an atypical microorganism or microorganism that needs special media to grow or longer duration to be cultivated. Clinical pathologists should be aware of Cryptococcus laboratory diagnosis and how to differentiate it from Candida spp. Microbiological culture is a confirmatory step for Cryptococcus diagnosis; however, Gram-stained and Indian ink-stained films are rapid and informative diagnostic methods especially in limited resources facilities. The communication between laboratory staff members and treating medical team is very crucial for better clinical judgment specifically in a circumstance where an unusual diagnostic result is released or diagnosing a rare disease.
CSF examination may show low cell count; however, infection presents; this is commonly seen in immunocompromised patients as no adequate inflammation. Cryptococcal infection associated with CNS latency which should to be suspected; hence, meticulous follow-up is an essential step in cryptococcal management. The second activation of cryptococcal latency is usually life-threatening and mostly fatal.
Acknowledgments
The authors would like to thank all members of Immunology Unit-Pediatric Department and Microbiology Unit-Clinical Pathology Department of Ain Shams University Hospital. The authors gratefully acknowledge Professor Dalia Helmy El-Ghoneimy and Professor Malaka Zakaria Amer for their efforts to diagnose and follow up severe medical cases including this presented case and special gratitude to the mother of the child for supporting with detailed medical information and for her medical awareness and patience throughout her daughter's longstanding disease.
Abbreviations
ALT:Alanine transaminase
ANA:Antinuclear antibody
AST:Aspartate transaminase
C. neoformans:
Cryptococcus neoformans
CBC:Complete blood count
CNS:Central nervous system
CRP:C-reactive protein
CSF:Cerebrospinal fluid
DNA:Deoxyribonucleic acid
dsDNA:Double-strand DNA
E.R:Emergency room
EEG:Electroencephalogram
eGFR:Estimated glomerular filtration rate
ESR:Erythrocyte sedimentation rate
HIV:Human immunodeficiency virus
IgG:Immunoglobulin G
IRIS:Immune reconstitution inflammatory syndrome
IV:Intravenous
MPA:Mycophenolic acid
MRI:Magnetic resonance imaging
PC ratio:Protein creatinine ratio
RF:Rheumatoid factor
RNA:Ribonucleic acid
RNP:Ribonucleoprotein antibodies
SDA:Sabouraud's dextrose agar
SLE:Systemic lupus erythematosus
SOPs:Standard operating procedures
WBC:White blood cell.
Data Availability
The data underlying the findings of this research are publicly available.
Ethical Approval
Compliance with ethics guidelines, all procedures followed the ethical standards of the responsible committee on human experimentation (institutional and national).
Consent
Written informed consent for publication of clinical details was obtained from the mother of the patient.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
Authors' Contributions
Heba Ezzat Hashem contributed to acquisition, analysis, and interpretation of data, drafting of paper, conception and design, revision for critical intellectual content, final approval, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Zakaria Hamza Ibrahim involved in revision for critical intellectual content, final approval, and financial support.
Figure 1 A simplified chart representing the sequence of the disease in our case.
Figure 2 (a) Clear colorless CSF sample; other etiological causes of meningitis especially viral meningitis versus fungal meningitis must be differentiated, specifically in the presence of clear colorless CSF samples with low cell count and minimal changes of CSF parameters. (b) Spherical budding yeast in the CSF; it should be differentiated from the elliptical budding yeast cells of Candida spp. which is more commonly encountered during CSF examination as a fungal cause of meningitis. (c) Gram-stained film; direct film from CSF shows spherical budding yeast cells with surrounding translucent haloes due to capsular structure. (d) Blood agar shows small white colonies, after 72 hours of incubation. (e) Sabouraud dextrose agar (SDA) shows pasty colonies that were confirmed to be Cryptococcus neoformans. (f) Gram from culture shows spherical yeast cells with surrounding translucent haloes.
Figure 3 Biochemical reaction; the urease test was positive.
Figure 4
Cryptococcus as shiny spherical budding in a dark background.
Figure 5 Laboratory course of the present case and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation; the patient improved clinically and discharged after almost one month with minimal residual weakness in her lower limbs. The nCD64 test was available in our hospital as a sepsis biomarker, and it was performed for our case for follow-up purposes.
Figure 6 Patient developed extensive skin ulceration with serous oozing from both lower limbs; this image was taken upon her clinical improvement on amphotericin B. The local edema resolved leaving the skin redundant, cracked, and the oozing discharge was first serous-like followed by purulent discharge then pus draining stopped.
Figure 7 EEG at the 4th admission, seizures, and other CNS manifestations in patients who had previous cryptococcal meningitis is very essential to be distinguished; it is due to reactivation of latent infection or due to seizures attributed to other medical causes. For the present case, EEG showed normal electric activates without focal localization.
Figure 8 MRI brain performed at the time of 3rd admission; dilated third ventricles were evident due to brain cell atrophy; at this occasion, signs of increase intracranial tension were negative which excluded it as a cause for cerebral ventricles dilatations.
Table 1 Laboratory course of the present case, and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation.
Hb TLC ANC ALC AMC PLT CRP CD64% CD64 MFI
08/05/2016 10.6 12.2 11.2 0.6 0.4 44 6 98.5 2.87
11/05/2016 9 10.9 9.2 1.1 0.51 81 6 91.5 1.91
15/05/2016 7.7 14.8 12.72 1.57 0.48 209 4 80.1 1.56
22/05/2016 7.2 10 7.6 1.1 0.5 238 4 68.9 1.45
Hb, hemoglobin (g/dl); TLC, total leukocytic count (X109/L); ANC, absolute neutrophil count (X109/L); ALC, absolute lymphocyte count (X109/L); AMC, absolute monocyte count (X109/L); PLT, platelet (X109/L); CRP, C-reactive protein (mg/L); nCD64%, neutrophil CD64%; nCD64MFI, nCD64 mean fluorescence intensity. | Fatal | ReactionOutcome | CC BY | 33628263 | 19,588,393 | 2021 |
What was the outcome of reaction 'Intracranial pressure increased'? | Atypical Presentation of Pediatric Systemic Lupus Erythematosus Complicated by Cryptococcal Meningitis.
Cryptococcus is an opportunistic fungal pathogen that leads to life-threatening infections. Cryptococcal infections are mainly reported in HIV patients and less commonly encountered in non-HIV immunocompromised host. Cryptococcus neoformans (C. neoformans) is the most common Cryptococcus species causing diseases in humans which can be presented as pulmonary, meningitis, cutaneous, and/or disseminated cryptococcosis. Case Presentation. A 12-year-old female girl from Cairo, Egypt, presented to the pediatric hospital with signs of systemic lupus erythematosus (SLE). She had an aggressive lupus nephritis course for which corticosteroids, mycophenolate mofetil, and cyclophosphamide were prescribed, and the child gradually improved and was discharged. Two months later, the patient exhibited skin lesions involved both in her legs, massive ulcers were developed and extended rapidly through the entire legs followed by deterioration in her conscious level, and signs of meningitis were documented. Cerebrospinal fluid (CSF) examination and microbiological workup were confirmatory for C. neoformans infection, and mental and motor functions were rapidly deteriorated. Treatment with amphotericin B in addition to supportive treatment and close follow-up of the patient's medical condition result in obvious clinical improvement and patient discharge with minimal residual weakness in her legs after almost a one-month duration. After six months, the patient was brought to the emergency department complaining of repeated attacks of seizures, a lumbar puncture was performed, and culture results were again confirmatory for C. neoformans. An intensive course of antifungal therapy was prescribed which was successful, evident by resolution of the signs and symptoms of infection in addition to negative culture results and negative sepsis biomarkers. The child clinically improved, but unfortunately, gradual optic nerve degeneration and brain cell atrophy as a sequel of severe and longstanding cryptococcal infection resulted in her death after almost one year from her first attack.
Cryptococcal infection among non-HIV patients is a rare disease but can result in advanced medical complications which may be fatal. The disease should be suspected to be reliably diagnosed. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening consequences. Amphotericin B can be used effectively in cryptococcosis management in the settings where flucytosine is not available. Signs of cryptococcal meningitis can be manifested again after a period of remission and clinical cure which signifies the latency of Cryptococcus in the central nervous system. The second activation of Cryptococcus after its latency is usually life-threatening and mostly fatal.
1. Background
Immunocompromised individuals including HIV, SLE, and patients on prolonged corticosteroid and immunosuppressant therapy are more prone to various bacterial, viral, and fungal opportunistic infections. One of the most important fatal fungal infections is cryptococcal infection [1–4]. C. neoformans is the most frequent cryptococcal species infect humans, and it is an encapsulated yeast microorganism, which is commonly transmitted through bird feces, plants, dust, soil, and contaminated food [2, 3]. Cryptococcosis can cause disseminated infection reaching to the lungs, central nervous system (CNS), and skin [2, 3, 5]. Dermal manifestations can present in different clinical morphologies including ulcers, acneiform papules, subcutaneous nodules, and rarely, cellulitis [4, 6].
2. Case Presentation
A 12-years-old Egyptian female student presented to Ain Shams University Pediatric Hospital complaining of generalized body edema, frothy urine, and proteinuria (3.7 g/day). The child was diagnosed as nephrotic syndrome, with repeated albumin infusions, and steroid therapy was initiated, but the child was nonresponding; instead, her medical condition deteriorated. Laboratory profile was in concordance with serologically quiescent SLE which included antinuclear antibody titer 1: 1280 finely speckled, elevated rheumatoid factor (RF) of 456 IU/ml (N: 0–20 IU/ml), positive SS-A/Ro > 8.0 and SS-B/La > 8.0 antibodies, anti-beta-2 glycoprotein IgM Ab > 100 U/ml, C-reactive protein (CRP) level 3.9 mg/l (N: 0–5 mg/l), and erythrocyte sedimentation rate (ESR) 51 mm/hour (N: 0–10 mm/hour). The serologic tests that were negative included anti-dsDNA Abs, complement C3 level 154 mg/dl (N: 106–194 mg/dl), complement C4 level 38 mg/dl (N: 19–50 mg/dl), cyclic citrullinated peptide IgG, cryoglobulin, serum immunofixation, Scl-70 scleroderma, Smith, RNP, cardiolipin antibodies, and lupus anticoagulant. Urine studies at the time revealed 3 + proteinuria, no hematuria or pyuria, a creatinine level of 0.93 mg/dl, and eGFR > 60 ml/min/1.73 m2. The diagnosis of SLE with nephrotic presentation was established, upon which the child received a medical regimen for lupus management including corticosteroids, mycophenolate mofetil, and cyclophosphamide which resulted in patient clinical improvement.
Two months later, the child was admitted complaining of poor appetite, nausea and vomiting, tiredness, swollen ankles, and shortness of breath, and deteriorated renal functions were evident in her laboratory profile: creatinine increased to 1.92 mg/dl, 4 + protein on urinalysis, worsening urine protein to creatinine (PC) ratio of 1.9 (N: 0.0–0.1), and 24-hour urine protein of 1170 mg/24 hours (N: 50–150 mg/24 hours). Lupus nephritis grade IV was confirmed. Therefore, the child received intermittent hemodialysis; in addition, the doses of the prescribed immunosuppressant was increased: prednisone (40 mg/day), hydroxychloroquine (6 mg/kg/day), and mycophenolate mofetil (2 g/day). The patient was kept under this protocol; she gradually improved and was discharged. A simplified chart representing the sequence of the disease in the presented case is illustrated in Figure 1.
After two months, the child manifested skin ulcers in her lower extremities which were progressive in course. Drug allergies, insect bites, and family history were excluded. First, these lesions were nonwell-demarcated, erythematous, painful on palpation, nonpruritic with increasing local edema, and bullae formation. A few days later, lesions spread to involve entire her legs up to the groin area, the bullae began to coalescence together, ruptured, and a huge amount of serous discharge was drained from the lesions; no corresponding lesions appeared on the face, trunk, or upper extremities, and fever was not present at first, but with worsening of the lesions, the patient became feverish, hematuric, anemic, and hypotensive with deteriorated general condition; hence, she was admitted for the 2nd time.
At the time of admission, laboratory profile revealed hemoglobin 8.2 g/dL, white blood cell (WBC) count 10,800/mm³, platelet count 129,000 cells/mm³, serum aspartate transaminase (AST) 10 U/L, serum alanine transaminase (ALT) 17 U/L, CRP 12 mg/L, and ESR 60 mm. Upon worsening the skin lesions, bacterial skin infection was suspected; so empirical treatment with amikacin and cefepime was started and the dose of prednisone decreased to 30 mg/day; microbiological cultures revealed no microorganism growth after 48 hours of incubation. Upon suspicion of bacterial cellulitis and due to the lack of improvements of the skin lesions, vancomycin was added to the treatment regimen.
After three days, the patient medical condition deteriorated rapidly. She complained of severe headache, altered memory, continuous agitation, neck rigidity, stiffness, photophobia, and total loss of appetite; so, meningitis was suspected; hence, lumbar puncture was performed, and a CSF sample was sent for cytological examination in addition to culture procedures. The sample was clear colorless on physical inspection (Figure 2)(a), and cell count was 25 cells/HPF.
Direct Gram examination of CSF showed spherical budding encapsulated yeast cells surrounded by translucent hallow around the cells (Figures 2(b) and 2)(c). CSF chemical examination revealed protein level 74 mg/dL (normal range 15–60 mg/dL) and glucose levels 41 mg/dL (normal range 50–80 mg/dL). The sample was cultured on aerobic blood agar, anaerobic blood agar, chocolate, and MacConkey agar; the plates showed delayed growth at the end of the third day (72 hours incubation according to CSF standard operating procedures (SOPs) of our microbiology lab). It was a minute whitish milky colony, which was highly suggestive of fungal infection, confirmed by further subculture, the sample on Sabouraud's dextrose agar (SDA) plates (Figures 2(d)–2(f)). Indian ink stain and positive biochemical reactions were confirmatory for the diagnosis of Cryptococcus infection (Figures 3 and 4). Additionally, antifungal susceptibility testing was performed which was positive for both amphotericin B and flucytosine.
Despite that, the child manifested obvious clinical signs and symptoms of meningitis. Magnetic resonance imaging (MRI) brain with contrast showed findings within normal limits, and blood culture was negative for microbiological growth after 7 days incubation.
Based on the available laboratory results, treatment for disseminated cryptococcosis was initiated immediately upon laboratory notification, prednisone was further decreased to 20 mg/day, and fluconazole was discontinued. Amphotericin B was started at a dose of 0.7 mg/kg/day with an infusion time of 6 hours, since the patient had repeated reactions (fever, chills, and nausea) with a shorter infusion time. Concerning flucytosine, which is indicated as the drug of choice in cryptococcal meningitis treatment, it was not used for treatment of our presented case due to financial aspects and nonavailability in our country, Egypt. Repeated lumber tapping was performed to relieve persistent increased intracranial tension as a consequence of severe meningitis; in addition, plasmapheresis was performed to remove lupus autoantibodies.
The child was subjected for further workup to rule out pneumonia and other organs affection, and for follow up purpose, chest X-ray was ordered, which revealed normal findings, ESR, CRP, complete blood count (CBC), and sepsis marker, neutrophil CD64. These laboratory tests were performed every 3 days on a routine base for monitoring the medical progress which showed dramatic gradual improvement (Table 1 and Figure 5); in conjugation with clinical signs and symptoms improvement evident by regaining her mental and motor skills, besides healing of the leg ulcers, pus draining stopped and swelling disappeared (Figure 6). In this setting, a lumbar puncture was intended to be performed upon this obvious clinical and laboratory improvement preparing the patient to be discharged, but the child refused at her own request and was discharged on her demand after almost 30 days since amphotericin B infusion was first prescribed.
At the time of discharge, the patient had no pulmonary sequelae, but she had residual weakness in her lower limbs. The laboratory results at the time of discharge were hemoglobin 9.2 g/dL, WBC 16.700 cells per mm³, platelet 303.000 cells per mm³, AST 10 U/L, ALT 4 U/L, CRP 6 mg/L, and ESR 53 mm/h. The child was instructed to continue fluconazole (400 mg/day) at home for 8 weeks and then reduced its dose to 200 mg/day for 1 year. And she was weaned gradually from corticosteroid therapy.
One month later, the child was brought to the emergency department complaining of severe headache, projectile vomiting, and blurred vision. She was admitted for the 3rd time. An MRI brain was ordered, and a lumbar puncture was performed urgently to relieve intracranial tension, and for chemical, cytological, and microbiological analyses, all were negative for infection except for CRP slightly positive (12 mg/L). So, lupus flare-up was suspected, and pulse steroid therapy was started, in addition to antifungal (fluconazole) and antibiotic (amikacin and cefepime) coverage. The patient was subjected for plasmapheresis; upon it, she manifested dramatical improvement and discharge. She started to attend the immunotherapy clinic every two weeks for follow up purpose; she did well for 5 months and regained her functions except for difficulty in talking and walking abilities as she could not walk without support; so, the mother was advised to bring her for regular physiotherapy sessions every week.
Five months later, the patient complained of shivering in her legs and hands followed by seizures attacks which were gradually increasing in frequency and duration till her mother brought her to the E/R. She was admitted for the 4th time. Phenytoin was prescribed, initial dose 2.5 mg/kg/dose twice a day and increased gradually to maximum 5 mg/kg/dose twice daily, and intensive work up profile was conducted searching for the cause of the seizures which included electroencephalogram (EEG), MRI brain, full lab evaluation, and CSF chemical analysis and microbiological examination. EEG revealed normal electric impulses without focal activities (Figure 7). MRI brain showed mildly dilated 3rd ventricles, CSF chemistry analysis revealed protein level 82 mg/dL (normal range 15–60 mg/dL), and glucose levels of 35 mg/dL (normal range 50–80 mg/dL). Upon receiving the sample in our microbiology lab, the sample physical criteria were very similar to the previous one, clear colorless, and cell count was 15 cell/cm3. A direct wet film examination was positive for budding yeast cells which were suspected and notified immediately to the pediatric team, and protocol of treatment was decided rapidly. CSF culture results were again confirmatory for C. neoformans.
An intensive course of antifungal therapy was initiated which included amphotericin B (0.7 mg/kg/day) with an infusion time of 6 hours, and fluconazole. Resolution of patient signs and symptoms of infection was clinically evident in addition to negative culture results and improved laboratory sepsis parameters. The child general condition improved, but at this setting, she complained of poor visual acuity. The pediatric team immediately consulted the specialist neurosurgeon, ophthalmologist, and an MRI brain urgently performed which showed evidence of brain cell atrophy with subsequent increased intracranial ventricular sizes and evidence of optic nerve atrophy; the ophthalmologist confirmed bilateral optic nerve degeneration which was more evident on the left side (Figure 8).
After almost one month and, however, signs and symptoms of infection were resolved, cryptococcosis longstanding course with brain cell atrophy as a sequel of cryptococcal meningitis resulted in the child's death after almost one year from her first attack.
3. Discussion and Conclusion
Cryptococcus is an opportunistic fungal pathogen that leads to rare life-threatening infection. Meningoencephalitis and disseminated cryptococcosis are usually common complications reported in immunocompromised hosts [7, 8]. In the presented case, we reported a pediatric systemic lupus erythematosus patient complicated by rapidly disseminating cryptococcal infection which exhibited a latency in the child CNS followed by an attack of infection flare-up which was successfully treated, but slowly progressive brain cell atrophy due to longstanding disease resulted in her death.
Infections and sepsis are major causes of hospitalization, mortality, and morbidity in immunosuppressed patients [9]. Cryptococcosis is one of the fatal fungal infections reported mainly in immunocompromised hosts; however, several reported cases point to its incidence also in immunocompetent patients [10–12]. Cryptococcosis has a low incidence in non-HIV patients, approximately 1 : 100.000 [5, 13]. Patients with SLE are highly susceptible to infections due to the combined effects of their immunosuppressive therapy and the abnormalities of the immune system that the disease itself causes [14]. Concerning our presented case, prolonged corticosteroid therapy and immunosuppressants due to her underlying disease (SLE) were the major risk factors for disseminated cryptococcosis with poor outcomes.
The patient had a progressive renal course complicated by lupus nephritis class IV for which immunosuppressants was given. Lupus nephritis is clinically evident in 50–60% of patients with SLE [15]. Both mycophenolate mofetil and cyclophosphamide were prescribed to our case. Mycophenolate mofetil depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation [16]. While, cyclophosphamide inhibits protein synthesis through DNA and RNA crosslinking [17].
By discussing Cryptococcus as the causative pathogen, C. neoformans is the most common strain causing infections in humans, and it is an encapsulated yeast that has been isolated from chickens' droppings and grows readily in soil contaminated with avian excreta particularly that of pigeons. In humans, it can colonize the upper airway system. Nevertheless, no animal-to-human nor person-to-person respiratory transmission has been documented [9]. Our presented case lived in low socioeconomic and hygienic status, and she denied contact with pigeon or birds. However, the fungus might have been indirectly transmitted via other sources such as vegetables, fruits, and dairy products [8].
C. neoformans generally cause three types of infections: cryptococcal meningitis, pulmonary, and cutaneous cryptococcosis [18]. The dissemination of this disease occurs when at least two noncontiguous sites are affected, which is unusual and mostly observed in HIV patients [4, 19]. In our case, only pulmonary involvement was not present while cutaneous manifestations were the first presenting symptoms followed by cryptococcal meningitis. Some studies support the importance of lumbar puncture in patients with cryptococcosis, even when CNS symptoms are not observed because asymptomatic meningitis is reported to be an early stage of the disease [20].
Systemic lupus erythematosus disease activity index (SLEDAI) was calculated for our presented case in order to be used as a predictor for SLE mortality and as a measure of global disease activity, and it was achieving high values (79) which reflect why the patient underwent into cryptococcal meningitis with poor clinical course. Eventhough, for patients with low SLE activity, the possibility of cryptococcal meningitis should not be underestimated [21].
Skin involvement is a rare presenting symptom of Cryptococcus infection, but it is usually a sign of disseminated disease; it may precede the systemic symptoms even eight months earlier [5, 18]. It is important to stress the rarity and polymorphism of the skin conditions, with the possible development of vesicles or blisters and the potential progression to ulceration [1, 4].
Cryptococcal cellulitis is a rare specific cutaneous manifestation, which was developed in our case. It was initially suspected to be a bacterial infection for which antibiotics were prescribed until its failure and microbiological results confirmed the fungal diagnosis. Although rare, the present case, cryptococcal cellulitis was restricted mainly to the lower body, particularly to the lower extremities, and this was reported in other rare reported cases [1, 2]. Despite that, cryptococcal cellulitis is uncommon and undistinguishable from acute bacterial cellulitis for appearance and presentation [6], but high suspicion especially in a risky patient should be considered.
More than 80% of patients manifested cryptococcal cellulitis and are expected to survive in immunocompetent status when they receive the appropriate antifungal therapy [6]. According to the current guidelines of the American Society of Infectious Diseases for disseminated cryptococcosis management, amphotericin B combined with flucytosine is recommended as the primary therapy, followed by fluconazole as a consolidation therapy [4, 18]. Flucytosine is expensive and was not available in our country; so, it was not considered for the treatment. Instead, it was replaced by the addition of fluconazole to amphotericin B regimen.
Cryptococcal laboratory diagnosis relies on three main methods: latex agglutination test, fungal culture, and direct microscopic examination [22]. In the present case, both the microscopic examination and microbiological cultures were the cornerstone for the diagnosis. C. neoformans was differentiated from other fungal species especially Candida spp. by the characterized morphology in the Gram-stained smear, microbiological culture characters, Indian ink stain positivity, and biochemical reactions.
Indian ink stain was positive in our case. In HIV-positive patients, its sensitivity increases up to 80% due to higher fungal loads in the CSF, while in HIV negative patients, the sensitivity is only 30–50% [8, 23]. CSF culture is considered the gold standard for cryptococcal diagnosis, but it has several diagnostic obstacles as long time is needed for fungus to grow, while time is very critical for management of meningitis cases with evolving lifetime neurological complications [24]. Besides, fungal cultures are not available in all medical facilities and therefore may not be performed. It is also associated with false-negative results, especially in cases with low fungal load, and this may be the attributed cause of negative blood culture result in our case.
Regarding management of cryptococcosis, the prolonged course (6–10 weeks) of IV amphotericin B monotherapy, together with the reduction of chemotherapy to improve immune status, was the main target. Caution was taken while reducing immunosuppressive therapy, since a rapid reduction is reported to be associated with immune reconstitution inflammatory syndrome (IRIS) in some patients [9]. There is evidence that supports the requirement for maintenance therapy with fluconazole administered as indefinite secondary prophylaxis, since the rate of recurrence exceeds 50% after apparently successful treatment [25].
Differential diagnosis of the present case must be addressed which includes besides to what was mentioned, infection versus flare-up attacks in lupus patients; several sepsis markers including CRP increase significantly in SLE patients with concomitant infection but increase only slightly or not at all in patients with a lupus flare without infection [14, 26] which is exactly encountered in our presented case. Additionally, decreased visual acuity due to increased intracranial tension (papilledema) was differentiated from decreased visual acuity due to optic nerve atrophy. For the presented case, papilledema was evident on fundus examination at the time of cryptococcal meningitis first diagnosed, while optic nerve atrophy was evident on fundus examination at the end.
Finally, we highlight the importance of clinicians' awareness about such infection among non-HIV immunocompromised patients including those who are diagnosed with autoimmune diseases. The latency of Cryptococcus should be considered and suspected during the management of such cases which necessitate early recognition and proper management.
For preparing Indian ink-stained film, take two drops from the examined CSF sample directly or a small part of the growing colony from the plate, mix it well with the ink, put a cover slide, and leave the slide for an hour to give a chance for the cells to be settled, and for better contrast view, lower the condenser and reduce the microscopic light and examine the film by using the lens with magnification power (40x). Cryptococcus will be evident as shiny spherical budding in a dark background.
4. Conclusion
Cryptococcal meningitis should be considered as one of the possible diagnoses in a patient with altered sensorium and neck stiffness, especially those who are immunocompromised. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening complications.
Early management of cryptococcal meningitis is associated with better prognosis and lower neurological complications. Despite that, flucytosine is being described as the best antifungal medication for cryptococcal infections. Amphotericin B still gives good results in such cases.
Negative bacterial growth from a skin lesion does not necessitate that it is a sterile lesion; it may be an atypical microorganism or microorganism that needs special media to grow or longer duration to be cultivated. Clinical pathologists should be aware of Cryptococcus laboratory diagnosis and how to differentiate it from Candida spp. Microbiological culture is a confirmatory step for Cryptococcus diagnosis; however, Gram-stained and Indian ink-stained films are rapid and informative diagnostic methods especially in limited resources facilities. The communication between laboratory staff members and treating medical team is very crucial for better clinical judgment specifically in a circumstance where an unusual diagnostic result is released or diagnosing a rare disease.
CSF examination may show low cell count; however, infection presents; this is commonly seen in immunocompromised patients as no adequate inflammation. Cryptococcal infection associated with CNS latency which should to be suspected; hence, meticulous follow-up is an essential step in cryptococcal management. The second activation of cryptococcal latency is usually life-threatening and mostly fatal.
Acknowledgments
The authors would like to thank all members of Immunology Unit-Pediatric Department and Microbiology Unit-Clinical Pathology Department of Ain Shams University Hospital. The authors gratefully acknowledge Professor Dalia Helmy El-Ghoneimy and Professor Malaka Zakaria Amer for their efforts to diagnose and follow up severe medical cases including this presented case and special gratitude to the mother of the child for supporting with detailed medical information and for her medical awareness and patience throughout her daughter's longstanding disease.
Abbreviations
ALT:Alanine transaminase
ANA:Antinuclear antibody
AST:Aspartate transaminase
C. neoformans:
Cryptococcus neoformans
CBC:Complete blood count
CNS:Central nervous system
CRP:C-reactive protein
CSF:Cerebrospinal fluid
DNA:Deoxyribonucleic acid
dsDNA:Double-strand DNA
E.R:Emergency room
EEG:Electroencephalogram
eGFR:Estimated glomerular filtration rate
ESR:Erythrocyte sedimentation rate
HIV:Human immunodeficiency virus
IgG:Immunoglobulin G
IRIS:Immune reconstitution inflammatory syndrome
IV:Intravenous
MPA:Mycophenolic acid
MRI:Magnetic resonance imaging
PC ratio:Protein creatinine ratio
RF:Rheumatoid factor
RNA:Ribonucleic acid
RNP:Ribonucleoprotein antibodies
SDA:Sabouraud's dextrose agar
SLE:Systemic lupus erythematosus
SOPs:Standard operating procedures
WBC:White blood cell.
Data Availability
The data underlying the findings of this research are publicly available.
Ethical Approval
Compliance with ethics guidelines, all procedures followed the ethical standards of the responsible committee on human experimentation (institutional and national).
Consent
Written informed consent for publication of clinical details was obtained from the mother of the patient.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
Authors' Contributions
Heba Ezzat Hashem contributed to acquisition, analysis, and interpretation of data, drafting of paper, conception and design, revision for critical intellectual content, final approval, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Zakaria Hamza Ibrahim involved in revision for critical intellectual content, final approval, and financial support.
Figure 1 A simplified chart representing the sequence of the disease in our case.
Figure 2 (a) Clear colorless CSF sample; other etiological causes of meningitis especially viral meningitis versus fungal meningitis must be differentiated, specifically in the presence of clear colorless CSF samples with low cell count and minimal changes of CSF parameters. (b) Spherical budding yeast in the CSF; it should be differentiated from the elliptical budding yeast cells of Candida spp. which is more commonly encountered during CSF examination as a fungal cause of meningitis. (c) Gram-stained film; direct film from CSF shows spherical budding yeast cells with surrounding translucent haloes due to capsular structure. (d) Blood agar shows small white colonies, after 72 hours of incubation. (e) Sabouraud dextrose agar (SDA) shows pasty colonies that were confirmed to be Cryptococcus neoformans. (f) Gram from culture shows spherical yeast cells with surrounding translucent haloes.
Figure 3 Biochemical reaction; the urease test was positive.
Figure 4
Cryptococcus as shiny spherical budding in a dark background.
Figure 5 Laboratory course of the present case and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation; the patient improved clinically and discharged after almost one month with minimal residual weakness in her lower limbs. The nCD64 test was available in our hospital as a sepsis biomarker, and it was performed for our case for follow-up purposes.
Figure 6 Patient developed extensive skin ulceration with serous oozing from both lower limbs; this image was taken upon her clinical improvement on amphotericin B. The local edema resolved leaving the skin redundant, cracked, and the oozing discharge was first serous-like followed by purulent discharge then pus draining stopped.
Figure 7 EEG at the 4th admission, seizures, and other CNS manifestations in patients who had previous cryptococcal meningitis is very essential to be distinguished; it is due to reactivation of latent infection or due to seizures attributed to other medical causes. For the present case, EEG showed normal electric activates without focal localization.
Figure 8 MRI brain performed at the time of 3rd admission; dilated third ventricles were evident due to brain cell atrophy; at this occasion, signs of increase intracranial tension were negative which excluded it as a cause for cerebral ventricles dilatations.
Table 1 Laboratory course of the present case, and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation.
Hb TLC ANC ALC AMC PLT CRP CD64% CD64 MFI
08/05/2016 10.6 12.2 11.2 0.6 0.4 44 6 98.5 2.87
11/05/2016 9 10.9 9.2 1.1 0.51 81 6 91.5 1.91
15/05/2016 7.7 14.8 12.72 1.57 0.48 209 4 80.1 1.56
22/05/2016 7.2 10 7.6 1.1 0.5 238 4 68.9 1.45
Hb, hemoglobin (g/dl); TLC, total leukocytic count (X109/L); ANC, absolute neutrophil count (X109/L); ALC, absolute lymphocyte count (X109/L); AMC, absolute monocyte count (X109/L); PLT, platelet (X109/L); CRP, C-reactive protein (mg/L); nCD64%, neutrophil CD64%; nCD64MFI, nCD64 mean fluorescence intensity. | Fatal | ReactionOutcome | CC BY | 33628263 | 19,588,393 | 2021 |
What was the outcome of reaction 'Meningitis cryptococcal'? | Atypical Presentation of Pediatric Systemic Lupus Erythematosus Complicated by Cryptococcal Meningitis.
Cryptococcus is an opportunistic fungal pathogen that leads to life-threatening infections. Cryptococcal infections are mainly reported in HIV patients and less commonly encountered in non-HIV immunocompromised host. Cryptococcus neoformans (C. neoformans) is the most common Cryptococcus species causing diseases in humans which can be presented as pulmonary, meningitis, cutaneous, and/or disseminated cryptococcosis. Case Presentation. A 12-year-old female girl from Cairo, Egypt, presented to the pediatric hospital with signs of systemic lupus erythematosus (SLE). She had an aggressive lupus nephritis course for which corticosteroids, mycophenolate mofetil, and cyclophosphamide were prescribed, and the child gradually improved and was discharged. Two months later, the patient exhibited skin lesions involved both in her legs, massive ulcers were developed and extended rapidly through the entire legs followed by deterioration in her conscious level, and signs of meningitis were documented. Cerebrospinal fluid (CSF) examination and microbiological workup were confirmatory for C. neoformans infection, and mental and motor functions were rapidly deteriorated. Treatment with amphotericin B in addition to supportive treatment and close follow-up of the patient's medical condition result in obvious clinical improvement and patient discharge with minimal residual weakness in her legs after almost a one-month duration. After six months, the patient was brought to the emergency department complaining of repeated attacks of seizures, a lumbar puncture was performed, and culture results were again confirmatory for C. neoformans. An intensive course of antifungal therapy was prescribed which was successful, evident by resolution of the signs and symptoms of infection in addition to negative culture results and negative sepsis biomarkers. The child clinically improved, but unfortunately, gradual optic nerve degeneration and brain cell atrophy as a sequel of severe and longstanding cryptococcal infection resulted in her death after almost one year from her first attack.
Cryptococcal infection among non-HIV patients is a rare disease but can result in advanced medical complications which may be fatal. The disease should be suspected to be reliably diagnosed. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening consequences. Amphotericin B can be used effectively in cryptococcosis management in the settings where flucytosine is not available. Signs of cryptococcal meningitis can be manifested again after a period of remission and clinical cure which signifies the latency of Cryptococcus in the central nervous system. The second activation of Cryptococcus after its latency is usually life-threatening and mostly fatal.
1. Background
Immunocompromised individuals including HIV, SLE, and patients on prolonged corticosteroid and immunosuppressant therapy are more prone to various bacterial, viral, and fungal opportunistic infections. One of the most important fatal fungal infections is cryptococcal infection [1–4]. C. neoformans is the most frequent cryptococcal species infect humans, and it is an encapsulated yeast microorganism, which is commonly transmitted through bird feces, plants, dust, soil, and contaminated food [2, 3]. Cryptococcosis can cause disseminated infection reaching to the lungs, central nervous system (CNS), and skin [2, 3, 5]. Dermal manifestations can present in different clinical morphologies including ulcers, acneiform papules, subcutaneous nodules, and rarely, cellulitis [4, 6].
2. Case Presentation
A 12-years-old Egyptian female student presented to Ain Shams University Pediatric Hospital complaining of generalized body edema, frothy urine, and proteinuria (3.7 g/day). The child was diagnosed as nephrotic syndrome, with repeated albumin infusions, and steroid therapy was initiated, but the child was nonresponding; instead, her medical condition deteriorated. Laboratory profile was in concordance with serologically quiescent SLE which included antinuclear antibody titer 1: 1280 finely speckled, elevated rheumatoid factor (RF) of 456 IU/ml (N: 0–20 IU/ml), positive SS-A/Ro > 8.0 and SS-B/La > 8.0 antibodies, anti-beta-2 glycoprotein IgM Ab > 100 U/ml, C-reactive protein (CRP) level 3.9 mg/l (N: 0–5 mg/l), and erythrocyte sedimentation rate (ESR) 51 mm/hour (N: 0–10 mm/hour). The serologic tests that were negative included anti-dsDNA Abs, complement C3 level 154 mg/dl (N: 106–194 mg/dl), complement C4 level 38 mg/dl (N: 19–50 mg/dl), cyclic citrullinated peptide IgG, cryoglobulin, serum immunofixation, Scl-70 scleroderma, Smith, RNP, cardiolipin antibodies, and lupus anticoagulant. Urine studies at the time revealed 3 + proteinuria, no hematuria or pyuria, a creatinine level of 0.93 mg/dl, and eGFR > 60 ml/min/1.73 m2. The diagnosis of SLE with nephrotic presentation was established, upon which the child received a medical regimen for lupus management including corticosteroids, mycophenolate mofetil, and cyclophosphamide which resulted in patient clinical improvement.
Two months later, the child was admitted complaining of poor appetite, nausea and vomiting, tiredness, swollen ankles, and shortness of breath, and deteriorated renal functions were evident in her laboratory profile: creatinine increased to 1.92 mg/dl, 4 + protein on urinalysis, worsening urine protein to creatinine (PC) ratio of 1.9 (N: 0.0–0.1), and 24-hour urine protein of 1170 mg/24 hours (N: 50–150 mg/24 hours). Lupus nephritis grade IV was confirmed. Therefore, the child received intermittent hemodialysis; in addition, the doses of the prescribed immunosuppressant was increased: prednisone (40 mg/day), hydroxychloroquine (6 mg/kg/day), and mycophenolate mofetil (2 g/day). The patient was kept under this protocol; she gradually improved and was discharged. A simplified chart representing the sequence of the disease in the presented case is illustrated in Figure 1.
After two months, the child manifested skin ulcers in her lower extremities which were progressive in course. Drug allergies, insect bites, and family history were excluded. First, these lesions were nonwell-demarcated, erythematous, painful on palpation, nonpruritic with increasing local edema, and bullae formation. A few days later, lesions spread to involve entire her legs up to the groin area, the bullae began to coalescence together, ruptured, and a huge amount of serous discharge was drained from the lesions; no corresponding lesions appeared on the face, trunk, or upper extremities, and fever was not present at first, but with worsening of the lesions, the patient became feverish, hematuric, anemic, and hypotensive with deteriorated general condition; hence, she was admitted for the 2nd time.
At the time of admission, laboratory profile revealed hemoglobin 8.2 g/dL, white blood cell (WBC) count 10,800/mm³, platelet count 129,000 cells/mm³, serum aspartate transaminase (AST) 10 U/L, serum alanine transaminase (ALT) 17 U/L, CRP 12 mg/L, and ESR 60 mm. Upon worsening the skin lesions, bacterial skin infection was suspected; so empirical treatment with amikacin and cefepime was started and the dose of prednisone decreased to 30 mg/day; microbiological cultures revealed no microorganism growth after 48 hours of incubation. Upon suspicion of bacterial cellulitis and due to the lack of improvements of the skin lesions, vancomycin was added to the treatment regimen.
After three days, the patient medical condition deteriorated rapidly. She complained of severe headache, altered memory, continuous agitation, neck rigidity, stiffness, photophobia, and total loss of appetite; so, meningitis was suspected; hence, lumbar puncture was performed, and a CSF sample was sent for cytological examination in addition to culture procedures. The sample was clear colorless on physical inspection (Figure 2)(a), and cell count was 25 cells/HPF.
Direct Gram examination of CSF showed spherical budding encapsulated yeast cells surrounded by translucent hallow around the cells (Figures 2(b) and 2)(c). CSF chemical examination revealed protein level 74 mg/dL (normal range 15–60 mg/dL) and glucose levels 41 mg/dL (normal range 50–80 mg/dL). The sample was cultured on aerobic blood agar, anaerobic blood agar, chocolate, and MacConkey agar; the plates showed delayed growth at the end of the third day (72 hours incubation according to CSF standard operating procedures (SOPs) of our microbiology lab). It was a minute whitish milky colony, which was highly suggestive of fungal infection, confirmed by further subculture, the sample on Sabouraud's dextrose agar (SDA) plates (Figures 2(d)–2(f)). Indian ink stain and positive biochemical reactions were confirmatory for the diagnosis of Cryptococcus infection (Figures 3 and 4). Additionally, antifungal susceptibility testing was performed which was positive for both amphotericin B and flucytosine.
Despite that, the child manifested obvious clinical signs and symptoms of meningitis. Magnetic resonance imaging (MRI) brain with contrast showed findings within normal limits, and blood culture was negative for microbiological growth after 7 days incubation.
Based on the available laboratory results, treatment for disseminated cryptococcosis was initiated immediately upon laboratory notification, prednisone was further decreased to 20 mg/day, and fluconazole was discontinued. Amphotericin B was started at a dose of 0.7 mg/kg/day with an infusion time of 6 hours, since the patient had repeated reactions (fever, chills, and nausea) with a shorter infusion time. Concerning flucytosine, which is indicated as the drug of choice in cryptococcal meningitis treatment, it was not used for treatment of our presented case due to financial aspects and nonavailability in our country, Egypt. Repeated lumber tapping was performed to relieve persistent increased intracranial tension as a consequence of severe meningitis; in addition, plasmapheresis was performed to remove lupus autoantibodies.
The child was subjected for further workup to rule out pneumonia and other organs affection, and for follow up purpose, chest X-ray was ordered, which revealed normal findings, ESR, CRP, complete blood count (CBC), and sepsis marker, neutrophil CD64. These laboratory tests were performed every 3 days on a routine base for monitoring the medical progress which showed dramatic gradual improvement (Table 1 and Figure 5); in conjugation with clinical signs and symptoms improvement evident by regaining her mental and motor skills, besides healing of the leg ulcers, pus draining stopped and swelling disappeared (Figure 6). In this setting, a lumbar puncture was intended to be performed upon this obvious clinical and laboratory improvement preparing the patient to be discharged, but the child refused at her own request and was discharged on her demand after almost 30 days since amphotericin B infusion was first prescribed.
At the time of discharge, the patient had no pulmonary sequelae, but she had residual weakness in her lower limbs. The laboratory results at the time of discharge were hemoglobin 9.2 g/dL, WBC 16.700 cells per mm³, platelet 303.000 cells per mm³, AST 10 U/L, ALT 4 U/L, CRP 6 mg/L, and ESR 53 mm/h. The child was instructed to continue fluconazole (400 mg/day) at home for 8 weeks and then reduced its dose to 200 mg/day for 1 year. And she was weaned gradually from corticosteroid therapy.
One month later, the child was brought to the emergency department complaining of severe headache, projectile vomiting, and blurred vision. She was admitted for the 3rd time. An MRI brain was ordered, and a lumbar puncture was performed urgently to relieve intracranial tension, and for chemical, cytological, and microbiological analyses, all were negative for infection except for CRP slightly positive (12 mg/L). So, lupus flare-up was suspected, and pulse steroid therapy was started, in addition to antifungal (fluconazole) and antibiotic (amikacin and cefepime) coverage. The patient was subjected for plasmapheresis; upon it, she manifested dramatical improvement and discharge. She started to attend the immunotherapy clinic every two weeks for follow up purpose; she did well for 5 months and regained her functions except for difficulty in talking and walking abilities as she could not walk without support; so, the mother was advised to bring her for regular physiotherapy sessions every week.
Five months later, the patient complained of shivering in her legs and hands followed by seizures attacks which were gradually increasing in frequency and duration till her mother brought her to the E/R. She was admitted for the 4th time. Phenytoin was prescribed, initial dose 2.5 mg/kg/dose twice a day and increased gradually to maximum 5 mg/kg/dose twice daily, and intensive work up profile was conducted searching for the cause of the seizures which included electroencephalogram (EEG), MRI brain, full lab evaluation, and CSF chemical analysis and microbiological examination. EEG revealed normal electric impulses without focal activities (Figure 7). MRI brain showed mildly dilated 3rd ventricles, CSF chemistry analysis revealed protein level 82 mg/dL (normal range 15–60 mg/dL), and glucose levels of 35 mg/dL (normal range 50–80 mg/dL). Upon receiving the sample in our microbiology lab, the sample physical criteria were very similar to the previous one, clear colorless, and cell count was 15 cell/cm3. A direct wet film examination was positive for budding yeast cells which were suspected and notified immediately to the pediatric team, and protocol of treatment was decided rapidly. CSF culture results were again confirmatory for C. neoformans.
An intensive course of antifungal therapy was initiated which included amphotericin B (0.7 mg/kg/day) with an infusion time of 6 hours, and fluconazole. Resolution of patient signs and symptoms of infection was clinically evident in addition to negative culture results and improved laboratory sepsis parameters. The child general condition improved, but at this setting, she complained of poor visual acuity. The pediatric team immediately consulted the specialist neurosurgeon, ophthalmologist, and an MRI brain urgently performed which showed evidence of brain cell atrophy with subsequent increased intracranial ventricular sizes and evidence of optic nerve atrophy; the ophthalmologist confirmed bilateral optic nerve degeneration which was more evident on the left side (Figure 8).
After almost one month and, however, signs and symptoms of infection were resolved, cryptococcosis longstanding course with brain cell atrophy as a sequel of cryptococcal meningitis resulted in the child's death after almost one year from her first attack.
3. Discussion and Conclusion
Cryptococcus is an opportunistic fungal pathogen that leads to rare life-threatening infection. Meningoencephalitis and disseminated cryptococcosis are usually common complications reported in immunocompromised hosts [7, 8]. In the presented case, we reported a pediatric systemic lupus erythematosus patient complicated by rapidly disseminating cryptococcal infection which exhibited a latency in the child CNS followed by an attack of infection flare-up which was successfully treated, but slowly progressive brain cell atrophy due to longstanding disease resulted in her death.
Infections and sepsis are major causes of hospitalization, mortality, and morbidity in immunosuppressed patients [9]. Cryptococcosis is one of the fatal fungal infections reported mainly in immunocompromised hosts; however, several reported cases point to its incidence also in immunocompetent patients [10–12]. Cryptococcosis has a low incidence in non-HIV patients, approximately 1 : 100.000 [5, 13]. Patients with SLE are highly susceptible to infections due to the combined effects of their immunosuppressive therapy and the abnormalities of the immune system that the disease itself causes [14]. Concerning our presented case, prolonged corticosteroid therapy and immunosuppressants due to her underlying disease (SLE) were the major risk factors for disseminated cryptococcosis with poor outcomes.
The patient had a progressive renal course complicated by lupus nephritis class IV for which immunosuppressants was given. Lupus nephritis is clinically evident in 50–60% of patients with SLE [15]. Both mycophenolate mofetil and cyclophosphamide were prescribed to our case. Mycophenolate mofetil depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation [16]. While, cyclophosphamide inhibits protein synthesis through DNA and RNA crosslinking [17].
By discussing Cryptococcus as the causative pathogen, C. neoformans is the most common strain causing infections in humans, and it is an encapsulated yeast that has been isolated from chickens' droppings and grows readily in soil contaminated with avian excreta particularly that of pigeons. In humans, it can colonize the upper airway system. Nevertheless, no animal-to-human nor person-to-person respiratory transmission has been documented [9]. Our presented case lived in low socioeconomic and hygienic status, and she denied contact with pigeon or birds. However, the fungus might have been indirectly transmitted via other sources such as vegetables, fruits, and dairy products [8].
C. neoformans generally cause three types of infections: cryptococcal meningitis, pulmonary, and cutaneous cryptococcosis [18]. The dissemination of this disease occurs when at least two noncontiguous sites are affected, which is unusual and mostly observed in HIV patients [4, 19]. In our case, only pulmonary involvement was not present while cutaneous manifestations were the first presenting symptoms followed by cryptococcal meningitis. Some studies support the importance of lumbar puncture in patients with cryptococcosis, even when CNS symptoms are not observed because asymptomatic meningitis is reported to be an early stage of the disease [20].
Systemic lupus erythematosus disease activity index (SLEDAI) was calculated for our presented case in order to be used as a predictor for SLE mortality and as a measure of global disease activity, and it was achieving high values (79) which reflect why the patient underwent into cryptococcal meningitis with poor clinical course. Eventhough, for patients with low SLE activity, the possibility of cryptococcal meningitis should not be underestimated [21].
Skin involvement is a rare presenting symptom of Cryptococcus infection, but it is usually a sign of disseminated disease; it may precede the systemic symptoms even eight months earlier [5, 18]. It is important to stress the rarity and polymorphism of the skin conditions, with the possible development of vesicles or blisters and the potential progression to ulceration [1, 4].
Cryptococcal cellulitis is a rare specific cutaneous manifestation, which was developed in our case. It was initially suspected to be a bacterial infection for which antibiotics were prescribed until its failure and microbiological results confirmed the fungal diagnosis. Although rare, the present case, cryptococcal cellulitis was restricted mainly to the lower body, particularly to the lower extremities, and this was reported in other rare reported cases [1, 2]. Despite that, cryptococcal cellulitis is uncommon and undistinguishable from acute bacterial cellulitis for appearance and presentation [6], but high suspicion especially in a risky patient should be considered.
More than 80% of patients manifested cryptococcal cellulitis and are expected to survive in immunocompetent status when they receive the appropriate antifungal therapy [6]. According to the current guidelines of the American Society of Infectious Diseases for disseminated cryptococcosis management, amphotericin B combined with flucytosine is recommended as the primary therapy, followed by fluconazole as a consolidation therapy [4, 18]. Flucytosine is expensive and was not available in our country; so, it was not considered for the treatment. Instead, it was replaced by the addition of fluconazole to amphotericin B regimen.
Cryptococcal laboratory diagnosis relies on three main methods: latex agglutination test, fungal culture, and direct microscopic examination [22]. In the present case, both the microscopic examination and microbiological cultures were the cornerstone for the diagnosis. C. neoformans was differentiated from other fungal species especially Candida spp. by the characterized morphology in the Gram-stained smear, microbiological culture characters, Indian ink stain positivity, and biochemical reactions.
Indian ink stain was positive in our case. In HIV-positive patients, its sensitivity increases up to 80% due to higher fungal loads in the CSF, while in HIV negative patients, the sensitivity is only 30–50% [8, 23]. CSF culture is considered the gold standard for cryptococcal diagnosis, but it has several diagnostic obstacles as long time is needed for fungus to grow, while time is very critical for management of meningitis cases with evolving lifetime neurological complications [24]. Besides, fungal cultures are not available in all medical facilities and therefore may not be performed. It is also associated with false-negative results, especially in cases with low fungal load, and this may be the attributed cause of negative blood culture result in our case.
Regarding management of cryptococcosis, the prolonged course (6–10 weeks) of IV amphotericin B monotherapy, together with the reduction of chemotherapy to improve immune status, was the main target. Caution was taken while reducing immunosuppressive therapy, since a rapid reduction is reported to be associated with immune reconstitution inflammatory syndrome (IRIS) in some patients [9]. There is evidence that supports the requirement for maintenance therapy with fluconazole administered as indefinite secondary prophylaxis, since the rate of recurrence exceeds 50% after apparently successful treatment [25].
Differential diagnosis of the present case must be addressed which includes besides to what was mentioned, infection versus flare-up attacks in lupus patients; several sepsis markers including CRP increase significantly in SLE patients with concomitant infection but increase only slightly or not at all in patients with a lupus flare without infection [14, 26] which is exactly encountered in our presented case. Additionally, decreased visual acuity due to increased intracranial tension (papilledema) was differentiated from decreased visual acuity due to optic nerve atrophy. For the presented case, papilledema was evident on fundus examination at the time of cryptococcal meningitis first diagnosed, while optic nerve atrophy was evident on fundus examination at the end.
Finally, we highlight the importance of clinicians' awareness about such infection among non-HIV immunocompromised patients including those who are diagnosed with autoimmune diseases. The latency of Cryptococcus should be considered and suspected during the management of such cases which necessitate early recognition and proper management.
For preparing Indian ink-stained film, take two drops from the examined CSF sample directly or a small part of the growing colony from the plate, mix it well with the ink, put a cover slide, and leave the slide for an hour to give a chance for the cells to be settled, and for better contrast view, lower the condenser and reduce the microscopic light and examine the film by using the lens with magnification power (40x). Cryptococcus will be evident as shiny spherical budding in a dark background.
4. Conclusion
Cryptococcal meningitis should be considered as one of the possible diagnoses in a patient with altered sensorium and neck stiffness, especially those who are immunocompromised. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening complications.
Early management of cryptococcal meningitis is associated with better prognosis and lower neurological complications. Despite that, flucytosine is being described as the best antifungal medication for cryptococcal infections. Amphotericin B still gives good results in such cases.
Negative bacterial growth from a skin lesion does not necessitate that it is a sterile lesion; it may be an atypical microorganism or microorganism that needs special media to grow or longer duration to be cultivated. Clinical pathologists should be aware of Cryptococcus laboratory diagnosis and how to differentiate it from Candida spp. Microbiological culture is a confirmatory step for Cryptococcus diagnosis; however, Gram-stained and Indian ink-stained films are rapid and informative diagnostic methods especially in limited resources facilities. The communication between laboratory staff members and treating medical team is very crucial for better clinical judgment specifically in a circumstance where an unusual diagnostic result is released or diagnosing a rare disease.
CSF examination may show low cell count; however, infection presents; this is commonly seen in immunocompromised patients as no adequate inflammation. Cryptococcal infection associated with CNS latency which should to be suspected; hence, meticulous follow-up is an essential step in cryptococcal management. The second activation of cryptococcal latency is usually life-threatening and mostly fatal.
Acknowledgments
The authors would like to thank all members of Immunology Unit-Pediatric Department and Microbiology Unit-Clinical Pathology Department of Ain Shams University Hospital. The authors gratefully acknowledge Professor Dalia Helmy El-Ghoneimy and Professor Malaka Zakaria Amer for their efforts to diagnose and follow up severe medical cases including this presented case and special gratitude to the mother of the child for supporting with detailed medical information and for her medical awareness and patience throughout her daughter's longstanding disease.
Abbreviations
ALT:Alanine transaminase
ANA:Antinuclear antibody
AST:Aspartate transaminase
C. neoformans:
Cryptococcus neoformans
CBC:Complete blood count
CNS:Central nervous system
CRP:C-reactive protein
CSF:Cerebrospinal fluid
DNA:Deoxyribonucleic acid
dsDNA:Double-strand DNA
E.R:Emergency room
EEG:Electroencephalogram
eGFR:Estimated glomerular filtration rate
ESR:Erythrocyte sedimentation rate
HIV:Human immunodeficiency virus
IgG:Immunoglobulin G
IRIS:Immune reconstitution inflammatory syndrome
IV:Intravenous
MPA:Mycophenolic acid
MRI:Magnetic resonance imaging
PC ratio:Protein creatinine ratio
RF:Rheumatoid factor
RNA:Ribonucleic acid
RNP:Ribonucleoprotein antibodies
SDA:Sabouraud's dextrose agar
SLE:Systemic lupus erythematosus
SOPs:Standard operating procedures
WBC:White blood cell.
Data Availability
The data underlying the findings of this research are publicly available.
Ethical Approval
Compliance with ethics guidelines, all procedures followed the ethical standards of the responsible committee on human experimentation (institutional and national).
Consent
Written informed consent for publication of clinical details was obtained from the mother of the patient.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
Authors' Contributions
Heba Ezzat Hashem contributed to acquisition, analysis, and interpretation of data, drafting of paper, conception and design, revision for critical intellectual content, final approval, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Zakaria Hamza Ibrahim involved in revision for critical intellectual content, final approval, and financial support.
Figure 1 A simplified chart representing the sequence of the disease in our case.
Figure 2 (a) Clear colorless CSF sample; other etiological causes of meningitis especially viral meningitis versus fungal meningitis must be differentiated, specifically in the presence of clear colorless CSF samples with low cell count and minimal changes of CSF parameters. (b) Spherical budding yeast in the CSF; it should be differentiated from the elliptical budding yeast cells of Candida spp. which is more commonly encountered during CSF examination as a fungal cause of meningitis. (c) Gram-stained film; direct film from CSF shows spherical budding yeast cells with surrounding translucent haloes due to capsular structure. (d) Blood agar shows small white colonies, after 72 hours of incubation. (e) Sabouraud dextrose agar (SDA) shows pasty colonies that were confirmed to be Cryptococcus neoformans. (f) Gram from culture shows spherical yeast cells with surrounding translucent haloes.
Figure 3 Biochemical reaction; the urease test was positive.
Figure 4
Cryptococcus as shiny spherical budding in a dark background.
Figure 5 Laboratory course of the present case and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation; the patient improved clinically and discharged after almost one month with minimal residual weakness in her lower limbs. The nCD64 test was available in our hospital as a sepsis biomarker, and it was performed for our case for follow-up purposes.
Figure 6 Patient developed extensive skin ulceration with serous oozing from both lower limbs; this image was taken upon her clinical improvement on amphotericin B. The local edema resolved leaving the skin redundant, cracked, and the oozing discharge was first serous-like followed by purulent discharge then pus draining stopped.
Figure 7 EEG at the 4th admission, seizures, and other CNS manifestations in patients who had previous cryptococcal meningitis is very essential to be distinguished; it is due to reactivation of latent infection or due to seizures attributed to other medical causes. For the present case, EEG showed normal electric activates without focal localization.
Figure 8 MRI brain performed at the time of 3rd admission; dilated third ventricles were evident due to brain cell atrophy; at this occasion, signs of increase intracranial tension were negative which excluded it as a cause for cerebral ventricles dilatations.
Table 1 Laboratory course of the present case, and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation.
Hb TLC ANC ALC AMC PLT CRP CD64% CD64 MFI
08/05/2016 10.6 12.2 11.2 0.6 0.4 44 6 98.5 2.87
11/05/2016 9 10.9 9.2 1.1 0.51 81 6 91.5 1.91
15/05/2016 7.7 14.8 12.72 1.57 0.48 209 4 80.1 1.56
22/05/2016 7.2 10 7.6 1.1 0.5 238 4 68.9 1.45
Hb, hemoglobin (g/dl); TLC, total leukocytic count (X109/L); ANC, absolute neutrophil count (X109/L); ALC, absolute lymphocyte count (X109/L); AMC, absolute monocyte count (X109/L); PLT, platelet (X109/L); CRP, C-reactive protein (mg/L); nCD64%, neutrophil CD64%; nCD64MFI, nCD64 mean fluorescence intensity. | Fatal | ReactionOutcome | CC BY | 33628263 | 19,577,937 | 2021 |
What was the outcome of reaction 'Nerve degeneration'? | Atypical Presentation of Pediatric Systemic Lupus Erythematosus Complicated by Cryptococcal Meningitis.
Cryptococcus is an opportunistic fungal pathogen that leads to life-threatening infections. Cryptococcal infections are mainly reported in HIV patients and less commonly encountered in non-HIV immunocompromised host. Cryptococcus neoformans (C. neoformans) is the most common Cryptococcus species causing diseases in humans which can be presented as pulmonary, meningitis, cutaneous, and/or disseminated cryptococcosis. Case Presentation. A 12-year-old female girl from Cairo, Egypt, presented to the pediatric hospital with signs of systemic lupus erythematosus (SLE). She had an aggressive lupus nephritis course for which corticosteroids, mycophenolate mofetil, and cyclophosphamide were prescribed, and the child gradually improved and was discharged. Two months later, the patient exhibited skin lesions involved both in her legs, massive ulcers were developed and extended rapidly through the entire legs followed by deterioration in her conscious level, and signs of meningitis were documented. Cerebrospinal fluid (CSF) examination and microbiological workup were confirmatory for C. neoformans infection, and mental and motor functions were rapidly deteriorated. Treatment with amphotericin B in addition to supportive treatment and close follow-up of the patient's medical condition result in obvious clinical improvement and patient discharge with minimal residual weakness in her legs after almost a one-month duration. After six months, the patient was brought to the emergency department complaining of repeated attacks of seizures, a lumbar puncture was performed, and culture results were again confirmatory for C. neoformans. An intensive course of antifungal therapy was prescribed which was successful, evident by resolution of the signs and symptoms of infection in addition to negative culture results and negative sepsis biomarkers. The child clinically improved, but unfortunately, gradual optic nerve degeneration and brain cell atrophy as a sequel of severe and longstanding cryptococcal infection resulted in her death after almost one year from her first attack.
Cryptococcal infection among non-HIV patients is a rare disease but can result in advanced medical complications which may be fatal. The disease should be suspected to be reliably diagnosed. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening consequences. Amphotericin B can be used effectively in cryptococcosis management in the settings where flucytosine is not available. Signs of cryptococcal meningitis can be manifested again after a period of remission and clinical cure which signifies the latency of Cryptococcus in the central nervous system. The second activation of Cryptococcus after its latency is usually life-threatening and mostly fatal.
1. Background
Immunocompromised individuals including HIV, SLE, and patients on prolonged corticosteroid and immunosuppressant therapy are more prone to various bacterial, viral, and fungal opportunistic infections. One of the most important fatal fungal infections is cryptococcal infection [1–4]. C. neoformans is the most frequent cryptococcal species infect humans, and it is an encapsulated yeast microorganism, which is commonly transmitted through bird feces, plants, dust, soil, and contaminated food [2, 3]. Cryptococcosis can cause disseminated infection reaching to the lungs, central nervous system (CNS), and skin [2, 3, 5]. Dermal manifestations can present in different clinical morphologies including ulcers, acneiform papules, subcutaneous nodules, and rarely, cellulitis [4, 6].
2. Case Presentation
A 12-years-old Egyptian female student presented to Ain Shams University Pediatric Hospital complaining of generalized body edema, frothy urine, and proteinuria (3.7 g/day). The child was diagnosed as nephrotic syndrome, with repeated albumin infusions, and steroid therapy was initiated, but the child was nonresponding; instead, her medical condition deteriorated. Laboratory profile was in concordance with serologically quiescent SLE which included antinuclear antibody titer 1: 1280 finely speckled, elevated rheumatoid factor (RF) of 456 IU/ml (N: 0–20 IU/ml), positive SS-A/Ro > 8.0 and SS-B/La > 8.0 antibodies, anti-beta-2 glycoprotein IgM Ab > 100 U/ml, C-reactive protein (CRP) level 3.9 mg/l (N: 0–5 mg/l), and erythrocyte sedimentation rate (ESR) 51 mm/hour (N: 0–10 mm/hour). The serologic tests that were negative included anti-dsDNA Abs, complement C3 level 154 mg/dl (N: 106–194 mg/dl), complement C4 level 38 mg/dl (N: 19–50 mg/dl), cyclic citrullinated peptide IgG, cryoglobulin, serum immunofixation, Scl-70 scleroderma, Smith, RNP, cardiolipin antibodies, and lupus anticoagulant. Urine studies at the time revealed 3 + proteinuria, no hematuria or pyuria, a creatinine level of 0.93 mg/dl, and eGFR > 60 ml/min/1.73 m2. The diagnosis of SLE with nephrotic presentation was established, upon which the child received a medical regimen for lupus management including corticosteroids, mycophenolate mofetil, and cyclophosphamide which resulted in patient clinical improvement.
Two months later, the child was admitted complaining of poor appetite, nausea and vomiting, tiredness, swollen ankles, and shortness of breath, and deteriorated renal functions were evident in her laboratory profile: creatinine increased to 1.92 mg/dl, 4 + protein on urinalysis, worsening urine protein to creatinine (PC) ratio of 1.9 (N: 0.0–0.1), and 24-hour urine protein of 1170 mg/24 hours (N: 50–150 mg/24 hours). Lupus nephritis grade IV was confirmed. Therefore, the child received intermittent hemodialysis; in addition, the doses of the prescribed immunosuppressant was increased: prednisone (40 mg/day), hydroxychloroquine (6 mg/kg/day), and mycophenolate mofetil (2 g/day). The patient was kept under this protocol; she gradually improved and was discharged. A simplified chart representing the sequence of the disease in the presented case is illustrated in Figure 1.
After two months, the child manifested skin ulcers in her lower extremities which were progressive in course. Drug allergies, insect bites, and family history were excluded. First, these lesions were nonwell-demarcated, erythematous, painful on palpation, nonpruritic with increasing local edema, and bullae formation. A few days later, lesions spread to involve entire her legs up to the groin area, the bullae began to coalescence together, ruptured, and a huge amount of serous discharge was drained from the lesions; no corresponding lesions appeared on the face, trunk, or upper extremities, and fever was not present at first, but with worsening of the lesions, the patient became feverish, hematuric, anemic, and hypotensive with deteriorated general condition; hence, she was admitted for the 2nd time.
At the time of admission, laboratory profile revealed hemoglobin 8.2 g/dL, white blood cell (WBC) count 10,800/mm³, platelet count 129,000 cells/mm³, serum aspartate transaminase (AST) 10 U/L, serum alanine transaminase (ALT) 17 U/L, CRP 12 mg/L, and ESR 60 mm. Upon worsening the skin lesions, bacterial skin infection was suspected; so empirical treatment with amikacin and cefepime was started and the dose of prednisone decreased to 30 mg/day; microbiological cultures revealed no microorganism growth after 48 hours of incubation. Upon suspicion of bacterial cellulitis and due to the lack of improvements of the skin lesions, vancomycin was added to the treatment regimen.
After three days, the patient medical condition deteriorated rapidly. She complained of severe headache, altered memory, continuous agitation, neck rigidity, stiffness, photophobia, and total loss of appetite; so, meningitis was suspected; hence, lumbar puncture was performed, and a CSF sample was sent for cytological examination in addition to culture procedures. The sample was clear colorless on physical inspection (Figure 2)(a), and cell count was 25 cells/HPF.
Direct Gram examination of CSF showed spherical budding encapsulated yeast cells surrounded by translucent hallow around the cells (Figures 2(b) and 2)(c). CSF chemical examination revealed protein level 74 mg/dL (normal range 15–60 mg/dL) and glucose levels 41 mg/dL (normal range 50–80 mg/dL). The sample was cultured on aerobic blood agar, anaerobic blood agar, chocolate, and MacConkey agar; the plates showed delayed growth at the end of the third day (72 hours incubation according to CSF standard operating procedures (SOPs) of our microbiology lab). It was a minute whitish milky colony, which was highly suggestive of fungal infection, confirmed by further subculture, the sample on Sabouraud's dextrose agar (SDA) plates (Figures 2(d)–2(f)). Indian ink stain and positive biochemical reactions were confirmatory for the diagnosis of Cryptococcus infection (Figures 3 and 4). Additionally, antifungal susceptibility testing was performed which was positive for both amphotericin B and flucytosine.
Despite that, the child manifested obvious clinical signs and symptoms of meningitis. Magnetic resonance imaging (MRI) brain with contrast showed findings within normal limits, and blood culture was negative for microbiological growth after 7 days incubation.
Based on the available laboratory results, treatment for disseminated cryptococcosis was initiated immediately upon laboratory notification, prednisone was further decreased to 20 mg/day, and fluconazole was discontinued. Amphotericin B was started at a dose of 0.7 mg/kg/day with an infusion time of 6 hours, since the patient had repeated reactions (fever, chills, and nausea) with a shorter infusion time. Concerning flucytosine, which is indicated as the drug of choice in cryptococcal meningitis treatment, it was not used for treatment of our presented case due to financial aspects and nonavailability in our country, Egypt. Repeated lumber tapping was performed to relieve persistent increased intracranial tension as a consequence of severe meningitis; in addition, plasmapheresis was performed to remove lupus autoantibodies.
The child was subjected for further workup to rule out pneumonia and other organs affection, and for follow up purpose, chest X-ray was ordered, which revealed normal findings, ESR, CRP, complete blood count (CBC), and sepsis marker, neutrophil CD64. These laboratory tests were performed every 3 days on a routine base for monitoring the medical progress which showed dramatic gradual improvement (Table 1 and Figure 5); in conjugation with clinical signs and symptoms improvement evident by regaining her mental and motor skills, besides healing of the leg ulcers, pus draining stopped and swelling disappeared (Figure 6). In this setting, a lumbar puncture was intended to be performed upon this obvious clinical and laboratory improvement preparing the patient to be discharged, but the child refused at her own request and was discharged on her demand after almost 30 days since amphotericin B infusion was first prescribed.
At the time of discharge, the patient had no pulmonary sequelae, but she had residual weakness in her lower limbs. The laboratory results at the time of discharge were hemoglobin 9.2 g/dL, WBC 16.700 cells per mm³, platelet 303.000 cells per mm³, AST 10 U/L, ALT 4 U/L, CRP 6 mg/L, and ESR 53 mm/h. The child was instructed to continue fluconazole (400 mg/day) at home for 8 weeks and then reduced its dose to 200 mg/day for 1 year. And she was weaned gradually from corticosteroid therapy.
One month later, the child was brought to the emergency department complaining of severe headache, projectile vomiting, and blurred vision. She was admitted for the 3rd time. An MRI brain was ordered, and a lumbar puncture was performed urgently to relieve intracranial tension, and for chemical, cytological, and microbiological analyses, all were negative for infection except for CRP slightly positive (12 mg/L). So, lupus flare-up was suspected, and pulse steroid therapy was started, in addition to antifungal (fluconazole) and antibiotic (amikacin and cefepime) coverage. The patient was subjected for plasmapheresis; upon it, she manifested dramatical improvement and discharge. She started to attend the immunotherapy clinic every two weeks for follow up purpose; she did well for 5 months and regained her functions except for difficulty in talking and walking abilities as she could not walk without support; so, the mother was advised to bring her for regular physiotherapy sessions every week.
Five months later, the patient complained of shivering in her legs and hands followed by seizures attacks which were gradually increasing in frequency and duration till her mother brought her to the E/R. She was admitted for the 4th time. Phenytoin was prescribed, initial dose 2.5 mg/kg/dose twice a day and increased gradually to maximum 5 mg/kg/dose twice daily, and intensive work up profile was conducted searching for the cause of the seizures which included electroencephalogram (EEG), MRI brain, full lab evaluation, and CSF chemical analysis and microbiological examination. EEG revealed normal electric impulses without focal activities (Figure 7). MRI brain showed mildly dilated 3rd ventricles, CSF chemistry analysis revealed protein level 82 mg/dL (normal range 15–60 mg/dL), and glucose levels of 35 mg/dL (normal range 50–80 mg/dL). Upon receiving the sample in our microbiology lab, the sample physical criteria were very similar to the previous one, clear colorless, and cell count was 15 cell/cm3. A direct wet film examination was positive for budding yeast cells which were suspected and notified immediately to the pediatric team, and protocol of treatment was decided rapidly. CSF culture results were again confirmatory for C. neoformans.
An intensive course of antifungal therapy was initiated which included amphotericin B (0.7 mg/kg/day) with an infusion time of 6 hours, and fluconazole. Resolution of patient signs and symptoms of infection was clinically evident in addition to negative culture results and improved laboratory sepsis parameters. The child general condition improved, but at this setting, she complained of poor visual acuity. The pediatric team immediately consulted the specialist neurosurgeon, ophthalmologist, and an MRI brain urgently performed which showed evidence of brain cell atrophy with subsequent increased intracranial ventricular sizes and evidence of optic nerve atrophy; the ophthalmologist confirmed bilateral optic nerve degeneration which was more evident on the left side (Figure 8).
After almost one month and, however, signs and symptoms of infection were resolved, cryptococcosis longstanding course with brain cell atrophy as a sequel of cryptococcal meningitis resulted in the child's death after almost one year from her first attack.
3. Discussion and Conclusion
Cryptococcus is an opportunistic fungal pathogen that leads to rare life-threatening infection. Meningoencephalitis and disseminated cryptococcosis are usually common complications reported in immunocompromised hosts [7, 8]. In the presented case, we reported a pediatric systemic lupus erythematosus patient complicated by rapidly disseminating cryptococcal infection which exhibited a latency in the child CNS followed by an attack of infection flare-up which was successfully treated, but slowly progressive brain cell atrophy due to longstanding disease resulted in her death.
Infections and sepsis are major causes of hospitalization, mortality, and morbidity in immunosuppressed patients [9]. Cryptococcosis is one of the fatal fungal infections reported mainly in immunocompromised hosts; however, several reported cases point to its incidence also in immunocompetent patients [10–12]. Cryptococcosis has a low incidence in non-HIV patients, approximately 1 : 100.000 [5, 13]. Patients with SLE are highly susceptible to infections due to the combined effects of their immunosuppressive therapy and the abnormalities of the immune system that the disease itself causes [14]. Concerning our presented case, prolonged corticosteroid therapy and immunosuppressants due to her underlying disease (SLE) were the major risk factors for disseminated cryptococcosis with poor outcomes.
The patient had a progressive renal course complicated by lupus nephritis class IV for which immunosuppressants was given. Lupus nephritis is clinically evident in 50–60% of patients with SLE [15]. Both mycophenolate mofetil and cyclophosphamide were prescribed to our case. Mycophenolate mofetil depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation [16]. While, cyclophosphamide inhibits protein synthesis through DNA and RNA crosslinking [17].
By discussing Cryptococcus as the causative pathogen, C. neoformans is the most common strain causing infections in humans, and it is an encapsulated yeast that has been isolated from chickens' droppings and grows readily in soil contaminated with avian excreta particularly that of pigeons. In humans, it can colonize the upper airway system. Nevertheless, no animal-to-human nor person-to-person respiratory transmission has been documented [9]. Our presented case lived in low socioeconomic and hygienic status, and she denied contact with pigeon or birds. However, the fungus might have been indirectly transmitted via other sources such as vegetables, fruits, and dairy products [8].
C. neoformans generally cause three types of infections: cryptococcal meningitis, pulmonary, and cutaneous cryptococcosis [18]. The dissemination of this disease occurs when at least two noncontiguous sites are affected, which is unusual and mostly observed in HIV patients [4, 19]. In our case, only pulmonary involvement was not present while cutaneous manifestations were the first presenting symptoms followed by cryptococcal meningitis. Some studies support the importance of lumbar puncture in patients with cryptococcosis, even when CNS symptoms are not observed because asymptomatic meningitis is reported to be an early stage of the disease [20].
Systemic lupus erythematosus disease activity index (SLEDAI) was calculated for our presented case in order to be used as a predictor for SLE mortality and as a measure of global disease activity, and it was achieving high values (79) which reflect why the patient underwent into cryptococcal meningitis with poor clinical course. Eventhough, for patients with low SLE activity, the possibility of cryptococcal meningitis should not be underestimated [21].
Skin involvement is a rare presenting symptom of Cryptococcus infection, but it is usually a sign of disseminated disease; it may precede the systemic symptoms even eight months earlier [5, 18]. It is important to stress the rarity and polymorphism of the skin conditions, with the possible development of vesicles or blisters and the potential progression to ulceration [1, 4].
Cryptococcal cellulitis is a rare specific cutaneous manifestation, which was developed in our case. It was initially suspected to be a bacterial infection for which antibiotics were prescribed until its failure and microbiological results confirmed the fungal diagnosis. Although rare, the present case, cryptococcal cellulitis was restricted mainly to the lower body, particularly to the lower extremities, and this was reported in other rare reported cases [1, 2]. Despite that, cryptococcal cellulitis is uncommon and undistinguishable from acute bacterial cellulitis for appearance and presentation [6], but high suspicion especially in a risky patient should be considered.
More than 80% of patients manifested cryptococcal cellulitis and are expected to survive in immunocompetent status when they receive the appropriate antifungal therapy [6]. According to the current guidelines of the American Society of Infectious Diseases for disseminated cryptococcosis management, amphotericin B combined with flucytosine is recommended as the primary therapy, followed by fluconazole as a consolidation therapy [4, 18]. Flucytosine is expensive and was not available in our country; so, it was not considered for the treatment. Instead, it was replaced by the addition of fluconazole to amphotericin B regimen.
Cryptococcal laboratory diagnosis relies on three main methods: latex agglutination test, fungal culture, and direct microscopic examination [22]. In the present case, both the microscopic examination and microbiological cultures were the cornerstone for the diagnosis. C. neoformans was differentiated from other fungal species especially Candida spp. by the characterized morphology in the Gram-stained smear, microbiological culture characters, Indian ink stain positivity, and biochemical reactions.
Indian ink stain was positive in our case. In HIV-positive patients, its sensitivity increases up to 80% due to higher fungal loads in the CSF, while in HIV negative patients, the sensitivity is only 30–50% [8, 23]. CSF culture is considered the gold standard for cryptococcal diagnosis, but it has several diagnostic obstacles as long time is needed for fungus to grow, while time is very critical for management of meningitis cases with evolving lifetime neurological complications [24]. Besides, fungal cultures are not available in all medical facilities and therefore may not be performed. It is also associated with false-negative results, especially in cases with low fungal load, and this may be the attributed cause of negative blood culture result in our case.
Regarding management of cryptococcosis, the prolonged course (6–10 weeks) of IV amphotericin B monotherapy, together with the reduction of chemotherapy to improve immune status, was the main target. Caution was taken while reducing immunosuppressive therapy, since a rapid reduction is reported to be associated with immune reconstitution inflammatory syndrome (IRIS) in some patients [9]. There is evidence that supports the requirement for maintenance therapy with fluconazole administered as indefinite secondary prophylaxis, since the rate of recurrence exceeds 50% after apparently successful treatment [25].
Differential diagnosis of the present case must be addressed which includes besides to what was mentioned, infection versus flare-up attacks in lupus patients; several sepsis markers including CRP increase significantly in SLE patients with concomitant infection but increase only slightly or not at all in patients with a lupus flare without infection [14, 26] which is exactly encountered in our presented case. Additionally, decreased visual acuity due to increased intracranial tension (papilledema) was differentiated from decreased visual acuity due to optic nerve atrophy. For the presented case, papilledema was evident on fundus examination at the time of cryptococcal meningitis first diagnosed, while optic nerve atrophy was evident on fundus examination at the end.
Finally, we highlight the importance of clinicians' awareness about such infection among non-HIV immunocompromised patients including those who are diagnosed with autoimmune diseases. The latency of Cryptococcus should be considered and suspected during the management of such cases which necessitate early recognition and proper management.
For preparing Indian ink-stained film, take two drops from the examined CSF sample directly or a small part of the growing colony from the plate, mix it well with the ink, put a cover slide, and leave the slide for an hour to give a chance for the cells to be settled, and for better contrast view, lower the condenser and reduce the microscopic light and examine the film by using the lens with magnification power (40x). Cryptococcus will be evident as shiny spherical budding in a dark background.
4. Conclusion
Cryptococcal meningitis should be considered as one of the possible diagnoses in a patient with altered sensorium and neck stiffness, especially those who are immunocompromised. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening complications.
Early management of cryptococcal meningitis is associated with better prognosis and lower neurological complications. Despite that, flucytosine is being described as the best antifungal medication for cryptococcal infections. Amphotericin B still gives good results in such cases.
Negative bacterial growth from a skin lesion does not necessitate that it is a sterile lesion; it may be an atypical microorganism or microorganism that needs special media to grow or longer duration to be cultivated. Clinical pathologists should be aware of Cryptococcus laboratory diagnosis and how to differentiate it from Candida spp. Microbiological culture is a confirmatory step for Cryptococcus diagnosis; however, Gram-stained and Indian ink-stained films are rapid and informative diagnostic methods especially in limited resources facilities. The communication between laboratory staff members and treating medical team is very crucial for better clinical judgment specifically in a circumstance where an unusual diagnostic result is released or diagnosing a rare disease.
CSF examination may show low cell count; however, infection presents; this is commonly seen in immunocompromised patients as no adequate inflammation. Cryptococcal infection associated with CNS latency which should to be suspected; hence, meticulous follow-up is an essential step in cryptococcal management. The second activation of cryptococcal latency is usually life-threatening and mostly fatal.
Acknowledgments
The authors would like to thank all members of Immunology Unit-Pediatric Department and Microbiology Unit-Clinical Pathology Department of Ain Shams University Hospital. The authors gratefully acknowledge Professor Dalia Helmy El-Ghoneimy and Professor Malaka Zakaria Amer for their efforts to diagnose and follow up severe medical cases including this presented case and special gratitude to the mother of the child for supporting with detailed medical information and for her medical awareness and patience throughout her daughter's longstanding disease.
Abbreviations
ALT:Alanine transaminase
ANA:Antinuclear antibody
AST:Aspartate transaminase
C. neoformans:
Cryptococcus neoformans
CBC:Complete blood count
CNS:Central nervous system
CRP:C-reactive protein
CSF:Cerebrospinal fluid
DNA:Deoxyribonucleic acid
dsDNA:Double-strand DNA
E.R:Emergency room
EEG:Electroencephalogram
eGFR:Estimated glomerular filtration rate
ESR:Erythrocyte sedimentation rate
HIV:Human immunodeficiency virus
IgG:Immunoglobulin G
IRIS:Immune reconstitution inflammatory syndrome
IV:Intravenous
MPA:Mycophenolic acid
MRI:Magnetic resonance imaging
PC ratio:Protein creatinine ratio
RF:Rheumatoid factor
RNA:Ribonucleic acid
RNP:Ribonucleoprotein antibodies
SDA:Sabouraud's dextrose agar
SLE:Systemic lupus erythematosus
SOPs:Standard operating procedures
WBC:White blood cell.
Data Availability
The data underlying the findings of this research are publicly available.
Ethical Approval
Compliance with ethics guidelines, all procedures followed the ethical standards of the responsible committee on human experimentation (institutional and national).
Consent
Written informed consent for publication of clinical details was obtained from the mother of the patient.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
Authors' Contributions
Heba Ezzat Hashem contributed to acquisition, analysis, and interpretation of data, drafting of paper, conception and design, revision for critical intellectual content, final approval, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Zakaria Hamza Ibrahim involved in revision for critical intellectual content, final approval, and financial support.
Figure 1 A simplified chart representing the sequence of the disease in our case.
Figure 2 (a) Clear colorless CSF sample; other etiological causes of meningitis especially viral meningitis versus fungal meningitis must be differentiated, specifically in the presence of clear colorless CSF samples with low cell count and minimal changes of CSF parameters. (b) Spherical budding yeast in the CSF; it should be differentiated from the elliptical budding yeast cells of Candida spp. which is more commonly encountered during CSF examination as a fungal cause of meningitis. (c) Gram-stained film; direct film from CSF shows spherical budding yeast cells with surrounding translucent haloes due to capsular structure. (d) Blood agar shows small white colonies, after 72 hours of incubation. (e) Sabouraud dextrose agar (SDA) shows pasty colonies that were confirmed to be Cryptococcus neoformans. (f) Gram from culture shows spherical yeast cells with surrounding translucent haloes.
Figure 3 Biochemical reaction; the urease test was positive.
Figure 4
Cryptococcus as shiny spherical budding in a dark background.
Figure 5 Laboratory course of the present case and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation; the patient improved clinically and discharged after almost one month with minimal residual weakness in her lower limbs. The nCD64 test was available in our hospital as a sepsis biomarker, and it was performed for our case for follow-up purposes.
Figure 6 Patient developed extensive skin ulceration with serous oozing from both lower limbs; this image was taken upon her clinical improvement on amphotericin B. The local edema resolved leaving the skin redundant, cracked, and the oozing discharge was first serous-like followed by purulent discharge then pus draining stopped.
Figure 7 EEG at the 4th admission, seizures, and other CNS manifestations in patients who had previous cryptococcal meningitis is very essential to be distinguished; it is due to reactivation of latent infection or due to seizures attributed to other medical causes. For the present case, EEG showed normal electric activates without focal localization.
Figure 8 MRI brain performed at the time of 3rd admission; dilated third ventricles were evident due to brain cell atrophy; at this occasion, signs of increase intracranial tension were negative which excluded it as a cause for cerebral ventricles dilatations.
Table 1 Laboratory course of the present case, and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation.
Hb TLC ANC ALC AMC PLT CRP CD64% CD64 MFI
08/05/2016 10.6 12.2 11.2 0.6 0.4 44 6 98.5 2.87
11/05/2016 9 10.9 9.2 1.1 0.51 81 6 91.5 1.91
15/05/2016 7.7 14.8 12.72 1.57 0.48 209 4 80.1 1.56
22/05/2016 7.2 10 7.6 1.1 0.5 238 4 68.9 1.45
Hb, hemoglobin (g/dl); TLC, total leukocytic count (X109/L); ANC, absolute neutrophil count (X109/L); ALC, absolute lymphocyte count (X109/L); AMC, absolute monocyte count (X109/L); PLT, platelet (X109/L); CRP, C-reactive protein (mg/L); nCD64%, neutrophil CD64%; nCD64MFI, nCD64 mean fluorescence intensity. | Fatal | ReactionOutcome | CC BY | 33628263 | 19,577,937 | 2021 |
What was the outcome of reaction 'Optic atrophy'? | Atypical Presentation of Pediatric Systemic Lupus Erythematosus Complicated by Cryptococcal Meningitis.
Cryptococcus is an opportunistic fungal pathogen that leads to life-threatening infections. Cryptococcal infections are mainly reported in HIV patients and less commonly encountered in non-HIV immunocompromised host. Cryptococcus neoformans (C. neoformans) is the most common Cryptococcus species causing diseases in humans which can be presented as pulmonary, meningitis, cutaneous, and/or disseminated cryptococcosis. Case Presentation. A 12-year-old female girl from Cairo, Egypt, presented to the pediatric hospital with signs of systemic lupus erythematosus (SLE). She had an aggressive lupus nephritis course for which corticosteroids, mycophenolate mofetil, and cyclophosphamide were prescribed, and the child gradually improved and was discharged. Two months later, the patient exhibited skin lesions involved both in her legs, massive ulcers were developed and extended rapidly through the entire legs followed by deterioration in her conscious level, and signs of meningitis were documented. Cerebrospinal fluid (CSF) examination and microbiological workup were confirmatory for C. neoformans infection, and mental and motor functions were rapidly deteriorated. Treatment with amphotericin B in addition to supportive treatment and close follow-up of the patient's medical condition result in obvious clinical improvement and patient discharge with minimal residual weakness in her legs after almost a one-month duration. After six months, the patient was brought to the emergency department complaining of repeated attacks of seizures, a lumbar puncture was performed, and culture results were again confirmatory for C. neoformans. An intensive course of antifungal therapy was prescribed which was successful, evident by resolution of the signs and symptoms of infection in addition to negative culture results and negative sepsis biomarkers. The child clinically improved, but unfortunately, gradual optic nerve degeneration and brain cell atrophy as a sequel of severe and longstanding cryptococcal infection resulted in her death after almost one year from her first attack.
Cryptococcal infection among non-HIV patients is a rare disease but can result in advanced medical complications which may be fatal. The disease should be suspected to be reliably diagnosed. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening consequences. Amphotericin B can be used effectively in cryptococcosis management in the settings where flucytosine is not available. Signs of cryptococcal meningitis can be manifested again after a period of remission and clinical cure which signifies the latency of Cryptococcus in the central nervous system. The second activation of Cryptococcus after its latency is usually life-threatening and mostly fatal.
1. Background
Immunocompromised individuals including HIV, SLE, and patients on prolonged corticosteroid and immunosuppressant therapy are more prone to various bacterial, viral, and fungal opportunistic infections. One of the most important fatal fungal infections is cryptococcal infection [1–4]. C. neoformans is the most frequent cryptococcal species infect humans, and it is an encapsulated yeast microorganism, which is commonly transmitted through bird feces, plants, dust, soil, and contaminated food [2, 3]. Cryptococcosis can cause disseminated infection reaching to the lungs, central nervous system (CNS), and skin [2, 3, 5]. Dermal manifestations can present in different clinical morphologies including ulcers, acneiform papules, subcutaneous nodules, and rarely, cellulitis [4, 6].
2. Case Presentation
A 12-years-old Egyptian female student presented to Ain Shams University Pediatric Hospital complaining of generalized body edema, frothy urine, and proteinuria (3.7 g/day). The child was diagnosed as nephrotic syndrome, with repeated albumin infusions, and steroid therapy was initiated, but the child was nonresponding; instead, her medical condition deteriorated. Laboratory profile was in concordance with serologically quiescent SLE which included antinuclear antibody titer 1: 1280 finely speckled, elevated rheumatoid factor (RF) of 456 IU/ml (N: 0–20 IU/ml), positive SS-A/Ro > 8.0 and SS-B/La > 8.0 antibodies, anti-beta-2 glycoprotein IgM Ab > 100 U/ml, C-reactive protein (CRP) level 3.9 mg/l (N: 0–5 mg/l), and erythrocyte sedimentation rate (ESR) 51 mm/hour (N: 0–10 mm/hour). The serologic tests that were negative included anti-dsDNA Abs, complement C3 level 154 mg/dl (N: 106–194 mg/dl), complement C4 level 38 mg/dl (N: 19–50 mg/dl), cyclic citrullinated peptide IgG, cryoglobulin, serum immunofixation, Scl-70 scleroderma, Smith, RNP, cardiolipin antibodies, and lupus anticoagulant. Urine studies at the time revealed 3 + proteinuria, no hematuria or pyuria, a creatinine level of 0.93 mg/dl, and eGFR > 60 ml/min/1.73 m2. The diagnosis of SLE with nephrotic presentation was established, upon which the child received a medical regimen for lupus management including corticosteroids, mycophenolate mofetil, and cyclophosphamide which resulted in patient clinical improvement.
Two months later, the child was admitted complaining of poor appetite, nausea and vomiting, tiredness, swollen ankles, and shortness of breath, and deteriorated renal functions were evident in her laboratory profile: creatinine increased to 1.92 mg/dl, 4 + protein on urinalysis, worsening urine protein to creatinine (PC) ratio of 1.9 (N: 0.0–0.1), and 24-hour urine protein of 1170 mg/24 hours (N: 50–150 mg/24 hours). Lupus nephritis grade IV was confirmed. Therefore, the child received intermittent hemodialysis; in addition, the doses of the prescribed immunosuppressant was increased: prednisone (40 mg/day), hydroxychloroquine (6 mg/kg/day), and mycophenolate mofetil (2 g/day). The patient was kept under this protocol; she gradually improved and was discharged. A simplified chart representing the sequence of the disease in the presented case is illustrated in Figure 1.
After two months, the child manifested skin ulcers in her lower extremities which were progressive in course. Drug allergies, insect bites, and family history were excluded. First, these lesions were nonwell-demarcated, erythematous, painful on palpation, nonpruritic with increasing local edema, and bullae formation. A few days later, lesions spread to involve entire her legs up to the groin area, the bullae began to coalescence together, ruptured, and a huge amount of serous discharge was drained from the lesions; no corresponding lesions appeared on the face, trunk, or upper extremities, and fever was not present at first, but with worsening of the lesions, the patient became feverish, hematuric, anemic, and hypotensive with deteriorated general condition; hence, she was admitted for the 2nd time.
At the time of admission, laboratory profile revealed hemoglobin 8.2 g/dL, white blood cell (WBC) count 10,800/mm³, platelet count 129,000 cells/mm³, serum aspartate transaminase (AST) 10 U/L, serum alanine transaminase (ALT) 17 U/L, CRP 12 mg/L, and ESR 60 mm. Upon worsening the skin lesions, bacterial skin infection was suspected; so empirical treatment with amikacin and cefepime was started and the dose of prednisone decreased to 30 mg/day; microbiological cultures revealed no microorganism growth after 48 hours of incubation. Upon suspicion of bacterial cellulitis and due to the lack of improvements of the skin lesions, vancomycin was added to the treatment regimen.
After three days, the patient medical condition deteriorated rapidly. She complained of severe headache, altered memory, continuous agitation, neck rigidity, stiffness, photophobia, and total loss of appetite; so, meningitis was suspected; hence, lumbar puncture was performed, and a CSF sample was sent for cytological examination in addition to culture procedures. The sample was clear colorless on physical inspection (Figure 2)(a), and cell count was 25 cells/HPF.
Direct Gram examination of CSF showed spherical budding encapsulated yeast cells surrounded by translucent hallow around the cells (Figures 2(b) and 2)(c). CSF chemical examination revealed protein level 74 mg/dL (normal range 15–60 mg/dL) and glucose levels 41 mg/dL (normal range 50–80 mg/dL). The sample was cultured on aerobic blood agar, anaerobic blood agar, chocolate, and MacConkey agar; the plates showed delayed growth at the end of the third day (72 hours incubation according to CSF standard operating procedures (SOPs) of our microbiology lab). It was a minute whitish milky colony, which was highly suggestive of fungal infection, confirmed by further subculture, the sample on Sabouraud's dextrose agar (SDA) plates (Figures 2(d)–2(f)). Indian ink stain and positive biochemical reactions were confirmatory for the diagnosis of Cryptococcus infection (Figures 3 and 4). Additionally, antifungal susceptibility testing was performed which was positive for both amphotericin B and flucytosine.
Despite that, the child manifested obvious clinical signs and symptoms of meningitis. Magnetic resonance imaging (MRI) brain with contrast showed findings within normal limits, and blood culture was negative for microbiological growth after 7 days incubation.
Based on the available laboratory results, treatment for disseminated cryptococcosis was initiated immediately upon laboratory notification, prednisone was further decreased to 20 mg/day, and fluconazole was discontinued. Amphotericin B was started at a dose of 0.7 mg/kg/day with an infusion time of 6 hours, since the patient had repeated reactions (fever, chills, and nausea) with a shorter infusion time. Concerning flucytosine, which is indicated as the drug of choice in cryptococcal meningitis treatment, it was not used for treatment of our presented case due to financial aspects and nonavailability in our country, Egypt. Repeated lumber tapping was performed to relieve persistent increased intracranial tension as a consequence of severe meningitis; in addition, plasmapheresis was performed to remove lupus autoantibodies.
The child was subjected for further workup to rule out pneumonia and other organs affection, and for follow up purpose, chest X-ray was ordered, which revealed normal findings, ESR, CRP, complete blood count (CBC), and sepsis marker, neutrophil CD64. These laboratory tests were performed every 3 days on a routine base for monitoring the medical progress which showed dramatic gradual improvement (Table 1 and Figure 5); in conjugation with clinical signs and symptoms improvement evident by regaining her mental and motor skills, besides healing of the leg ulcers, pus draining stopped and swelling disappeared (Figure 6). In this setting, a lumbar puncture was intended to be performed upon this obvious clinical and laboratory improvement preparing the patient to be discharged, but the child refused at her own request and was discharged on her demand after almost 30 days since amphotericin B infusion was first prescribed.
At the time of discharge, the patient had no pulmonary sequelae, but she had residual weakness in her lower limbs. The laboratory results at the time of discharge were hemoglobin 9.2 g/dL, WBC 16.700 cells per mm³, platelet 303.000 cells per mm³, AST 10 U/L, ALT 4 U/L, CRP 6 mg/L, and ESR 53 mm/h. The child was instructed to continue fluconazole (400 mg/day) at home for 8 weeks and then reduced its dose to 200 mg/day for 1 year. And she was weaned gradually from corticosteroid therapy.
One month later, the child was brought to the emergency department complaining of severe headache, projectile vomiting, and blurred vision. She was admitted for the 3rd time. An MRI brain was ordered, and a lumbar puncture was performed urgently to relieve intracranial tension, and for chemical, cytological, and microbiological analyses, all were negative for infection except for CRP slightly positive (12 mg/L). So, lupus flare-up was suspected, and pulse steroid therapy was started, in addition to antifungal (fluconazole) and antibiotic (amikacin and cefepime) coverage. The patient was subjected for plasmapheresis; upon it, she manifested dramatical improvement and discharge. She started to attend the immunotherapy clinic every two weeks for follow up purpose; she did well for 5 months and regained her functions except for difficulty in talking and walking abilities as she could not walk without support; so, the mother was advised to bring her for regular physiotherapy sessions every week.
Five months later, the patient complained of shivering in her legs and hands followed by seizures attacks which were gradually increasing in frequency and duration till her mother brought her to the E/R. She was admitted for the 4th time. Phenytoin was prescribed, initial dose 2.5 mg/kg/dose twice a day and increased gradually to maximum 5 mg/kg/dose twice daily, and intensive work up profile was conducted searching for the cause of the seizures which included electroencephalogram (EEG), MRI brain, full lab evaluation, and CSF chemical analysis and microbiological examination. EEG revealed normal electric impulses without focal activities (Figure 7). MRI brain showed mildly dilated 3rd ventricles, CSF chemistry analysis revealed protein level 82 mg/dL (normal range 15–60 mg/dL), and glucose levels of 35 mg/dL (normal range 50–80 mg/dL). Upon receiving the sample in our microbiology lab, the sample physical criteria were very similar to the previous one, clear colorless, and cell count was 15 cell/cm3. A direct wet film examination was positive for budding yeast cells which were suspected and notified immediately to the pediatric team, and protocol of treatment was decided rapidly. CSF culture results were again confirmatory for C. neoformans.
An intensive course of antifungal therapy was initiated which included amphotericin B (0.7 mg/kg/day) with an infusion time of 6 hours, and fluconazole. Resolution of patient signs and symptoms of infection was clinically evident in addition to negative culture results and improved laboratory sepsis parameters. The child general condition improved, but at this setting, she complained of poor visual acuity. The pediatric team immediately consulted the specialist neurosurgeon, ophthalmologist, and an MRI brain urgently performed which showed evidence of brain cell atrophy with subsequent increased intracranial ventricular sizes and evidence of optic nerve atrophy; the ophthalmologist confirmed bilateral optic nerve degeneration which was more evident on the left side (Figure 8).
After almost one month and, however, signs and symptoms of infection were resolved, cryptococcosis longstanding course with brain cell atrophy as a sequel of cryptococcal meningitis resulted in the child's death after almost one year from her first attack.
3. Discussion and Conclusion
Cryptococcus is an opportunistic fungal pathogen that leads to rare life-threatening infection. Meningoencephalitis and disseminated cryptococcosis are usually common complications reported in immunocompromised hosts [7, 8]. In the presented case, we reported a pediatric systemic lupus erythematosus patient complicated by rapidly disseminating cryptococcal infection which exhibited a latency in the child CNS followed by an attack of infection flare-up which was successfully treated, but slowly progressive brain cell atrophy due to longstanding disease resulted in her death.
Infections and sepsis are major causes of hospitalization, mortality, and morbidity in immunosuppressed patients [9]. Cryptococcosis is one of the fatal fungal infections reported mainly in immunocompromised hosts; however, several reported cases point to its incidence also in immunocompetent patients [10–12]. Cryptococcosis has a low incidence in non-HIV patients, approximately 1 : 100.000 [5, 13]. Patients with SLE are highly susceptible to infections due to the combined effects of their immunosuppressive therapy and the abnormalities of the immune system that the disease itself causes [14]. Concerning our presented case, prolonged corticosteroid therapy and immunosuppressants due to her underlying disease (SLE) were the major risk factors for disseminated cryptococcosis with poor outcomes.
The patient had a progressive renal course complicated by lupus nephritis class IV for which immunosuppressants was given. Lupus nephritis is clinically evident in 50–60% of patients with SLE [15]. Both mycophenolate mofetil and cyclophosphamide were prescribed to our case. Mycophenolate mofetil depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation [16]. While, cyclophosphamide inhibits protein synthesis through DNA and RNA crosslinking [17].
By discussing Cryptococcus as the causative pathogen, C. neoformans is the most common strain causing infections in humans, and it is an encapsulated yeast that has been isolated from chickens' droppings and grows readily in soil contaminated with avian excreta particularly that of pigeons. In humans, it can colonize the upper airway system. Nevertheless, no animal-to-human nor person-to-person respiratory transmission has been documented [9]. Our presented case lived in low socioeconomic and hygienic status, and she denied contact with pigeon or birds. However, the fungus might have been indirectly transmitted via other sources such as vegetables, fruits, and dairy products [8].
C. neoformans generally cause three types of infections: cryptococcal meningitis, pulmonary, and cutaneous cryptococcosis [18]. The dissemination of this disease occurs when at least two noncontiguous sites are affected, which is unusual and mostly observed in HIV patients [4, 19]. In our case, only pulmonary involvement was not present while cutaneous manifestations were the first presenting symptoms followed by cryptococcal meningitis. Some studies support the importance of lumbar puncture in patients with cryptococcosis, even when CNS symptoms are not observed because asymptomatic meningitis is reported to be an early stage of the disease [20].
Systemic lupus erythematosus disease activity index (SLEDAI) was calculated for our presented case in order to be used as a predictor for SLE mortality and as a measure of global disease activity, and it was achieving high values (79) which reflect why the patient underwent into cryptococcal meningitis with poor clinical course. Eventhough, for patients with low SLE activity, the possibility of cryptococcal meningitis should not be underestimated [21].
Skin involvement is a rare presenting symptom of Cryptococcus infection, but it is usually a sign of disseminated disease; it may precede the systemic symptoms even eight months earlier [5, 18]. It is important to stress the rarity and polymorphism of the skin conditions, with the possible development of vesicles or blisters and the potential progression to ulceration [1, 4].
Cryptococcal cellulitis is a rare specific cutaneous manifestation, which was developed in our case. It was initially suspected to be a bacterial infection for which antibiotics were prescribed until its failure and microbiological results confirmed the fungal diagnosis. Although rare, the present case, cryptococcal cellulitis was restricted mainly to the lower body, particularly to the lower extremities, and this was reported in other rare reported cases [1, 2]. Despite that, cryptococcal cellulitis is uncommon and undistinguishable from acute bacterial cellulitis for appearance and presentation [6], but high suspicion especially in a risky patient should be considered.
More than 80% of patients manifested cryptococcal cellulitis and are expected to survive in immunocompetent status when they receive the appropriate antifungal therapy [6]. According to the current guidelines of the American Society of Infectious Diseases for disseminated cryptococcosis management, amphotericin B combined with flucytosine is recommended as the primary therapy, followed by fluconazole as a consolidation therapy [4, 18]. Flucytosine is expensive and was not available in our country; so, it was not considered for the treatment. Instead, it was replaced by the addition of fluconazole to amphotericin B regimen.
Cryptococcal laboratory diagnosis relies on three main methods: latex agglutination test, fungal culture, and direct microscopic examination [22]. In the present case, both the microscopic examination and microbiological cultures were the cornerstone for the diagnosis. C. neoformans was differentiated from other fungal species especially Candida spp. by the characterized morphology in the Gram-stained smear, microbiological culture characters, Indian ink stain positivity, and biochemical reactions.
Indian ink stain was positive in our case. In HIV-positive patients, its sensitivity increases up to 80% due to higher fungal loads in the CSF, while in HIV negative patients, the sensitivity is only 30–50% [8, 23]. CSF culture is considered the gold standard for cryptococcal diagnosis, but it has several diagnostic obstacles as long time is needed for fungus to grow, while time is very critical for management of meningitis cases with evolving lifetime neurological complications [24]. Besides, fungal cultures are not available in all medical facilities and therefore may not be performed. It is also associated with false-negative results, especially in cases with low fungal load, and this may be the attributed cause of negative blood culture result in our case.
Regarding management of cryptococcosis, the prolonged course (6–10 weeks) of IV amphotericin B monotherapy, together with the reduction of chemotherapy to improve immune status, was the main target. Caution was taken while reducing immunosuppressive therapy, since a rapid reduction is reported to be associated with immune reconstitution inflammatory syndrome (IRIS) in some patients [9]. There is evidence that supports the requirement for maintenance therapy with fluconazole administered as indefinite secondary prophylaxis, since the rate of recurrence exceeds 50% after apparently successful treatment [25].
Differential diagnosis of the present case must be addressed which includes besides to what was mentioned, infection versus flare-up attacks in lupus patients; several sepsis markers including CRP increase significantly in SLE patients with concomitant infection but increase only slightly or not at all in patients with a lupus flare without infection [14, 26] which is exactly encountered in our presented case. Additionally, decreased visual acuity due to increased intracranial tension (papilledema) was differentiated from decreased visual acuity due to optic nerve atrophy. For the presented case, papilledema was evident on fundus examination at the time of cryptococcal meningitis first diagnosed, while optic nerve atrophy was evident on fundus examination at the end.
Finally, we highlight the importance of clinicians' awareness about such infection among non-HIV immunocompromised patients including those who are diagnosed with autoimmune diseases. The latency of Cryptococcus should be considered and suspected during the management of such cases which necessitate early recognition and proper management.
For preparing Indian ink-stained film, take two drops from the examined CSF sample directly or a small part of the growing colony from the plate, mix it well with the ink, put a cover slide, and leave the slide for an hour to give a chance for the cells to be settled, and for better contrast view, lower the condenser and reduce the microscopic light and examine the film by using the lens with magnification power (40x). Cryptococcus will be evident as shiny spherical budding in a dark background.
4. Conclusion
Cryptococcal meningitis should be considered as one of the possible diagnoses in a patient with altered sensorium and neck stiffness, especially those who are immunocompromised. Cryptococcus infection can be presented as a skin lesion which, if not treated properly at an earlier time, can result in dissemination and life-threatening complications.
Early management of cryptococcal meningitis is associated with better prognosis and lower neurological complications. Despite that, flucytosine is being described as the best antifungal medication for cryptococcal infections. Amphotericin B still gives good results in such cases.
Negative bacterial growth from a skin lesion does not necessitate that it is a sterile lesion; it may be an atypical microorganism or microorganism that needs special media to grow or longer duration to be cultivated. Clinical pathologists should be aware of Cryptococcus laboratory diagnosis and how to differentiate it from Candida spp. Microbiological culture is a confirmatory step for Cryptococcus diagnosis; however, Gram-stained and Indian ink-stained films are rapid and informative diagnostic methods especially in limited resources facilities. The communication between laboratory staff members and treating medical team is very crucial for better clinical judgment specifically in a circumstance where an unusual diagnostic result is released or diagnosing a rare disease.
CSF examination may show low cell count; however, infection presents; this is commonly seen in immunocompromised patients as no adequate inflammation. Cryptococcal infection associated with CNS latency which should to be suspected; hence, meticulous follow-up is an essential step in cryptococcal management. The second activation of cryptococcal latency is usually life-threatening and mostly fatal.
Acknowledgments
The authors would like to thank all members of Immunology Unit-Pediatric Department and Microbiology Unit-Clinical Pathology Department of Ain Shams University Hospital. The authors gratefully acknowledge Professor Dalia Helmy El-Ghoneimy and Professor Malaka Zakaria Amer for their efforts to diagnose and follow up severe medical cases including this presented case and special gratitude to the mother of the child for supporting with detailed medical information and for her medical awareness and patience throughout her daughter's longstanding disease.
Abbreviations
ALT:Alanine transaminase
ANA:Antinuclear antibody
AST:Aspartate transaminase
C. neoformans:
Cryptococcus neoformans
CBC:Complete blood count
CNS:Central nervous system
CRP:C-reactive protein
CSF:Cerebrospinal fluid
DNA:Deoxyribonucleic acid
dsDNA:Double-strand DNA
E.R:Emergency room
EEG:Electroencephalogram
eGFR:Estimated glomerular filtration rate
ESR:Erythrocyte sedimentation rate
HIV:Human immunodeficiency virus
IgG:Immunoglobulin G
IRIS:Immune reconstitution inflammatory syndrome
IV:Intravenous
MPA:Mycophenolic acid
MRI:Magnetic resonance imaging
PC ratio:Protein creatinine ratio
RF:Rheumatoid factor
RNA:Ribonucleic acid
RNP:Ribonucleoprotein antibodies
SDA:Sabouraud's dextrose agar
SLE:Systemic lupus erythematosus
SOPs:Standard operating procedures
WBC:White blood cell.
Data Availability
The data underlying the findings of this research are publicly available.
Ethical Approval
Compliance with ethics guidelines, all procedures followed the ethical standards of the responsible committee on human experimentation (institutional and national).
Consent
Written informed consent for publication of clinical details was obtained from the mother of the patient.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
Authors' Contributions
Heba Ezzat Hashem contributed to acquisition, analysis, and interpretation of data, drafting of paper, conception and design, revision for critical intellectual content, final approval, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Zakaria Hamza Ibrahim involved in revision for critical intellectual content, final approval, and financial support.
Figure 1 A simplified chart representing the sequence of the disease in our case.
Figure 2 (a) Clear colorless CSF sample; other etiological causes of meningitis especially viral meningitis versus fungal meningitis must be differentiated, specifically in the presence of clear colorless CSF samples with low cell count and minimal changes of CSF parameters. (b) Spherical budding yeast in the CSF; it should be differentiated from the elliptical budding yeast cells of Candida spp. which is more commonly encountered during CSF examination as a fungal cause of meningitis. (c) Gram-stained film; direct film from CSF shows spherical budding yeast cells with surrounding translucent haloes due to capsular structure. (d) Blood agar shows small white colonies, after 72 hours of incubation. (e) Sabouraud dextrose agar (SDA) shows pasty colonies that were confirmed to be Cryptococcus neoformans. (f) Gram from culture shows spherical yeast cells with surrounding translucent haloes.
Figure 3 Biochemical reaction; the urease test was positive.
Figure 4
Cryptococcus as shiny spherical budding in a dark background.
Figure 5 Laboratory course of the present case and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation; the patient improved clinically and discharged after almost one month with minimal residual weakness in her lower limbs. The nCD64 test was available in our hospital as a sepsis biomarker, and it was performed for our case for follow-up purposes.
Figure 6 Patient developed extensive skin ulceration with serous oozing from both lower limbs; this image was taken upon her clinical improvement on amphotericin B. The local edema resolved leaving the skin redundant, cracked, and the oozing discharge was first serous-like followed by purulent discharge then pus draining stopped.
Figure 7 EEG at the 4th admission, seizures, and other CNS manifestations in patients who had previous cryptococcal meningitis is very essential to be distinguished; it is due to reactivation of latent infection or due to seizures attributed to other medical causes. For the present case, EEG showed normal electric activates without focal localization.
Figure 8 MRI brain performed at the time of 3rd admission; dilated third ventricles were evident due to brain cell atrophy; at this occasion, signs of increase intracranial tension were negative which excluded it as a cause for cerebral ventricles dilatations.
Table 1 Laboratory course of the present case, and serial changes of sepsis markers in context with patient clinical improvement upon administration of amphotericin B at the time of meningitis clinical manifestation.
Hb TLC ANC ALC AMC PLT CRP CD64% CD64 MFI
08/05/2016 10.6 12.2 11.2 0.6 0.4 44 6 98.5 2.87
11/05/2016 9 10.9 9.2 1.1 0.51 81 6 91.5 1.91
15/05/2016 7.7 14.8 12.72 1.57 0.48 209 4 80.1 1.56
22/05/2016 7.2 10 7.6 1.1 0.5 238 4 68.9 1.45
Hb, hemoglobin (g/dl); TLC, total leukocytic count (X109/L); ANC, absolute neutrophil count (X109/L); ALC, absolute lymphocyte count (X109/L); AMC, absolute monocyte count (X109/L); PLT, platelet (X109/L); CRP, C-reactive protein (mg/L); nCD64%, neutrophil CD64%; nCD64MFI, nCD64 mean fluorescence intensity. | Fatal | ReactionOutcome | CC BY | 33628263 | 19,577,937 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cerebral disorder'. | Case report: Manual therapies promote resolution of persistent post-concussion symptoms in a 24-year-old athlete.
This case report illustrates the treatment outcomes of a collegiate athlete presenting with an 18-month history of post-concussion syndrome who received a series of mixed manual therapies in isolation of other therapy. Persistent symptoms were self-reported as debilitating, contributing to self-removal from participation in school, work, and leisure activities. Patient and parent interviews captured the history of multiple concussions and other sports-related injuries. Neurological screening and activities of daily living were baseline measured. Post-Concussion Symptom Checklist and Headache Impact Test-6™ were utilized to track symptom severity. Treatments applied included craniosacral therapy, manual lymphatic drainage, and glymphatic techniques. Eleven treatment sessions were administered over 3 months. Results indicated restoration of oxygen saturation, normalized pupil reactivity, and satisfactory sleep. Post-concussion syndrome symptom severity was reduced by 87% as reflected by accumulative Post-Concussion Symptom Checklist scores. Relief from chronic headaches was achieved, reflected by Headache Impact Test-6 scores. Restoration of mood and quality of life were reported. A 6-month follow-up revealed symptoms remained abated with full re-engagement of daily activities. The author hypothesized that post-concussion syndrome symptoms were related to compression of craniosacral system structures and lymphatic fluid stagnation that contributed to head pressure pain, severe sleep deprivation, and multiple neurological and psychological symptoms. Positive outcomes over a relatively short period of time without adverse effects suggest these therapies may offer viable options for the treatment of post-concussion syndrome.
Introduction
Serious awareness over the past decade of the short- and long-term effects of
traumatic head trauma leading to concussion has prompted rigorous diagnostic
and clinical management endeavors.1,2 Sources report the
number of sports-related concussions receiving medical attention in the
United States ranged between 1.6 million and 3.8 million annually.3,4
Persistent symptoms following concussions may not reflect a single
pathophysiological entity and likely describes individualized patterns of
non-specific, post-traumatic symptoms that may be linked to coexisting
and/or confounding issues.1,5 Subtypes of
post-concussion syndrome (PCS) are now recognized by physiological,
cervicogenic, and neuropsychological manifestations.2,4,6–9
A fluid model: glymphatic and meningeal lymphatic systems
The existence of a cerebral fluid-exchange system (different than blood
vessels) has been long debated but new discoveries have intensified research
into fluid dynamics within the brain parenchyma.10 Glial cells have been shown to create a possible architectural system
among the microvasculature which appears to match blood flow with neuronal firing.11 Pathways formed by glial cells and endothelial walls of penetrating
blood vessels have been suggested to serve as a physiological cleansing
mechanism called the “glymphatic system.”10,12,13 These pathways
appear to form perivascular channels by astroglia end-feet where monitoring
and active clearing of the neuronal terrain may occur.14–16
Furthermore, it is theorized that this cellular transportation network also
serves to distribute nutritional compounds and neuromodulators.15 Brain-wide perivascular pathways, believed to facilitate
cerebrospinal fluid (CSF) flow through the parenchyma and the movement of
interstitial solutes, have been captured by contrast-enhanced magnetic
resonance imaging (MRI) scan.13 The theoretical function then of this proposed glymphatic system
serves to support perfusion of CSF and interstitial fluids as a means of
pseudo-lymphatic function of the nervous system, elucidating a possible
mechanism of how the brain cleans itself through elimination of soluble
proteins and metabolites.10,13,17–19
However, there are also proponents who argue a glymphatic system as proposed
needs to be re-evaluated, accounting for more specifics to cerebrovascular
fluid transport.20 Regardless, there is within the brain a mechanism that moves fluids
through a cleansing process, shown to be active during restorative sleep and
rather inactive during wakefulness.15
Lymphatic system discovery
In addition, a recent identification of lymphatic projections into meningeal
membranes within the cranial vault suggests a functional proximity and/or
connection between the brain pseudo-lymphatic and the whole-body lymphatic
network.21,22 Furthermore, lymphatic vessels were discovered
lining the dura sinuses of the meninges and in turn have been shown to carry
both fluid and immune cells from the CSF, connecting to deep cervical lymph
nodes and into the peripheral venous return system.17,21
Magnetic resonance images provide supporting evidence of glymphatic drainage
from human brain to cervical lymph nodes.23 Other emerging data from both animal models and human studies support
this theory that the brain fluid-exchange and body lymphatics system share
an intimacy and work together for homeostasis, though we are only at the
beginning of understanding how this works.12,22–24
Structural impact and pathology of fluid transport systems
Chronic symptoms associated with PCS have been theorized to be a result of
“gliopathy,” a dysregulation of glial function and drainage in the central
and peripheral nervous system.25 Murine models of glial and glymphatic system function following head
injury has begun to shed light on the effect of brain trauma upon astrocytes
and the effect upon intracranial edema and resolution.26,27
Impaired functioning of the meningeal lymphatic vessels has been theorized
to accelerate the accumulation of toxic amyloid beta protein in the brain parenchyma.28
Upledger illuminated and confirmed the existence of the function and physiology
of the craniosacral system (meninges housing the brain, spinal cord, and
cerebral spinal fluids).29,30 Bodywork
professionals are guided by the premise that structural compressions such as
osseous and/or fascial restrictions can impede fluid movement and exchange,
leading to an array of symptomology.30–34 It is understood
that vertebral bone compression into spinal cord space will create various
neurological symptoms theorized, in part, by the obstruction of cerebral
spinal fluid.35,36 One animal model has demonstrated that blocking
the normal physiologic cerebral spinal fluid drainage sites in the
cribriform plate increases resting intracranial pressure.37
Manual therapies for the central nervous system
Craniosacral therapy
Manual therapies such as craniosacral therapy (CST) emerged from the
science that explored the physiological motion of the central nervous
system.30,38,39 The core
intent of CST is the theoretic interactions with connective tissue at
osseous sites and, using a sustained low-force stretch, elicit a
softening or relaxation response of soft tissues. In turn, a positive
effect upon fluid exchange and the body’s self-correcting actions can occur.30 Studies have illuminated the natural motion of cranial bones,
organ movement, and fluid exchange, depicting and measuring the
dynamic nature of the physiology of the craniosacral system.33,40,41 Based on observations of one animal study on
the structural effects of applying CST, no discernible length
difference was found at cranial bone sutures. However, this study
concluded that perhaps a different biological basis for such treatment
could be at play.42 In a now classic study, changes in the length of the
intracranial falx cerebri membrane were demonstrated with the
application of CST on an embalmed cadaver skull. Recorded relative
change in tissue length ranged between .28 and 1.44 mm at different
sites of the membrane with different CST techniques applied. This
study offers some validation that sustained, gentle, and external
forces have a measurable effect upon the intracranial membrane system.43
Manual lymphatic drainage
Various methods of manual lymphatic drainage (LD) exist, but a
contemporary version aligns with discoveries of anatomical pathways
and lymph tissue mapping, the depths of lymph flow throughout the
body, and using specific rhythms in fluid evacuation.44 Hand pressure used in the Chikly method is extremely light,
matching the tissue dynamics unique to each patient, and only enough
to stimulate the movement of fluid to enhance flow through specific
lymph pathways. This is theorized to activate contractions of the
functional unit of lymph vessels, called lymphangions, which assist
fluid exchange without increasing blood filtration or lymph node
collapse from too great of manually imposed pressure. There exists
extensive innervation from the autonomic nervous system of these
contractile units of the lymphatic system and the conceptualization of
the movement of lymphatic fluids.45,46 LD is believed to influence the whole-body
system through gentle manual evacuation, creating a system-wide
siphoning effect to enhance fluid exchange in multiple systems.45
The use of manual LD by qualified professionals is a treatment option for
lymphedema, sports injuries, and fibromyalgia.44,47–49 Manual LD was first suggested as a specific
treatment of post-contusion and PCS for its anti-edematous effects.50 The evolution and addition of glymphatic treatment methods have
only recently emerged and are based on the practical application of
the combination of methods such as CST, LD, and non-invasive intention
of therapeutic touch.16,45
Existing studies on manual therapies for concussions and brain
injuries
In clinical application, CST has been shown to have positive effect for a
number of chronic syndromes that parallel PCS subtypes, but the body
of data is limited to observational designs and low to moderate
quality of randomized controlled methods.51,52 The credibility of a sham control protocol for
future study of CST was reported.53 A recent study of former pro-football players with PCS showed
statistically greater improvements in range of motion, pain, sleep,
and cognitive function after a series of combined manual therapies.54 A pilot study of 10 active military members had a reduction of
symptoms of post-traumatic stress and head injury through the
application of mixed light touch manual therapies.55 A single blind case series measured clinical outcomes of
soldiers with combat-related head injuries receiving CST and other
manipulation techniques. Results showed statistically greater
improvements in objective and subjective measurements pre- and post-treatment.56 Case studies report positive outcomes of varied uses of manual
therapies for the treatment of PCS.57,58 One case of an athlete with PCS compared brain
scans before and after 15 isolated CST treatments using quantitative
electroencephalogram comparing symptom reduction to changes in
neurological activity.59
Headaches
Headaches are a common symptom of concussion and PCS.7,60 CST and
other manual methods have been shown to have positive effect in the
treatment of headaches, migraines, and trigeminal neuralgia.61–64
Sleep
Sleep has a critical function in ensuring metabolic homeostasis and
clearance of metabolites and is but one important way for the nervous
system to heal from trauma and injury.13,18,65 The
glymphatic system functions mainly during sleep and is largely
disengaged during wakefulness. Sleep debt and a glymphatic system
disruption have been proposed as a mediator of brain trauma, chronic
traumatic encephalopathy, and other neurological disorders.15,66,67
Concussion symptom assessments
Subjective data —from patient
Self-reporting symptom scales are vital for assisting in the medical
management of PCS. Several tracking tools hold substantial overlap
with one another in capturing various pains and neurological
infirmaries, functional impairment, and quality of life.68–70 Although
only some have been empirically studied, clinical users need to be
aware that these scales have evolved rather than being developed scientifically.71 Nonetheless, patient reports of subjective levels of pain,
sensory, and psychological symptoms are crucial to aid in the clinical
search for effective treatments.
Post-Concussion Symptom Checklist (PCSC)
The PCSC was utilized to track outcomes and re-administered periodically
throughout the treatment process with care given to avoid coaching the
patient on symptom manifestations.70,72 Symptoms were also tracked through open-ended
self-reporting by the patient at the onset of each session if he
wished to share them.
Headache Impact Test™ (HIT-6)
The HIT-6 was designed to screen and monitor patients’ severity of
headache pain and the impact on function and quality of life.73 Utilizing six items with a severity rating scale, the HIT-6 has
been shown to be a reliable and valid tool for discriminating the
effect of headache on daily living.74,75 A possible point range of 36–78 reflects the
severity of impact that headaches are interfering with daily quality
of life and function. The HIT-6 was chosen for this particular patient
to track headache symptoms which was also a chief complaint, second
only to sleep disturbances.
Measurement of sleep
Sleep function was tracked through a sleep diary and the patient’s
perception of restfulness and daily energy.
Subjective data —from the clinician
Neurological screenings occurred each session per standard of care,
including pupil and oculomotor status, balance reactions, and general
cognitive assessments conducted through observations of behavior.
Palpation findings from full body assessment of musculoskeletal,
fascia and fluid fields were conducted at the beginning of each
treatment session. Inquiry about mood and stress were made at the
beginning of each session.
Objective data
Quantifiable neurological soft sign and biomarkers not captured on the
PCSC included fixed and dilated pupils, oxygen saturation, and
frequency of urination and thirst.
Case report
The subject, a 24-year-old male, presented with an 18-month history of
persistent neurological and behavioral symptoms reportedly related to
one sports-induced concussion. Onset was in October 2017, following a
head injury while playing in a collegiate-level sport. He reported
being screened by an athletic trainer and having a follow-up medical
assessment. No hospitalization was required. Prolonged rest was
prescribed and adhered to for several months. An eventual referral to
a local academic-medicine concussion clinic was made several months
post-injury due to escalation of unresolved symptoms where
psychological services addressing anxiety and depression and
medications for pain and concentration were prescribed. Medications
reported on patient intake included Prozac, Xanax, and Adderall. He
reported his ability to focus on job tasks improved by the Adderall
but the medications generally worsened “brain fog” and memory. He also
participated in a physical therapy program for vestibular
rehabilitation. Symptoms persisted to the point of full debilitation
by sleep deprivation, increasing dizziness, sensory overload, and
brain fatigue. Suicidal ideation prompted his parents to seek other
recommendations and services.
In the interview with the patient and one of his parents, it was
discovered that he sustained a total of six sports-related concussions
dating back several years. History also included several orthopedic
injuries long since healed (fractures to a foot and nose, and several
bone contusions). The patient affirmed that a whiplash occurred with
the most recent concussion and had originally sought chiropractic care
for neck pain post-injury.
Since symptoms began to intensify, he was forced to take a medical leave
from attending school and working a job that required much traveling.
He stated he could perform job duties, enjoyed them, and felt capable
of the job. However, the sensory intolerances created significant
anxiety and began to reduce his confidence in his job performance. His
tolerance and engagement in favorite activities were at 10% of normal
participation level. He frequently isolated himself to cope with the
sensory overload which added to a sense of helplessness.
Based upon client report and clinical observations, functional problems
were noted on intake (see Figure 1). Initial clinical
findings were also noted (see Figure 2).
Figure 1. Post-concussion symptoms (18 month duration) reported on
intake questionnaire by patient and in personal and parent
interviews.
Figure 2. Initial clinical findings.
Treatment methods employed included the following: (incorporated into
each session as the need arose).
Manual LD techniques (Chikly).45
CST techniques (Upledger).30
Glial and Glymphatic system techniques (Wanveer).16
Goals for series of therapy encounters
Reduce and eliminate stagnant and congested edema of spine,
neck, and head.
Soft tissue mobilization and fascial release methods to
increase general soft tissue flexibility and subtleness
through body to reduce sympathetic tone (through CST).
Facilitate exchange of fluid through all body fluid systems;
reduce interstitial congestion to promote healing and
self-correction of nervous system (through LD).
Neurological rehabilitation strategies to reduce and adapt to
sensory challenges; environmental structuring. (These
methods were not required due to the speed in which
positive changes were experienced and observed with manual
therapies.)
Achieve freedom from pain and neurological dysfunction,
restore/raise quality of life.
Community and work re-entry, adaptations, and modifications
assistance where needed.
Patient and family education on the concepts of manual
therapies.
Client stated just one personal goal: “I just want to be able
to sleep.”
Treatment process
Treatment was conducted in isolation of any other (new) therapy over the
course of three months. The patient participated in eleven, 1-h
sessions. Scheduling sessions were recommended at 2–3 times per week
initially. Following the first session, he requested daily treatment
but was advised to allow his system to acclimate and integrate
treatment effects. The first four sessions were scheduled 3 days
apart. After the fourth session, scheduling was left to his
discretion. Six more appointments were scheduled with 1 week spacing,
and the eleventh session was as a follow-up at the patient’s
discretion 5 weeks later. Each session was an improvisational process
of applying the various manual therapies and techniques, based upon
whole-body assessment of primary and secondary structural and fluid
findings.
Results and treatment outcomes
Quantitative data were collected through self-reporting of severity of
symptoms using the PCSC, the HIT-6, and clinical observations.
Sessions began most often with an invitation for him to report
whatever symptom(s) felt most pressing. Quality of life measurements
were self-reporting of sleep function, brain fog, ability to “get
through the day,” ability to tolerate sensory aspects of daily events,
and endurance for mental and physical activities. All were recorded in
the daily notes. A total of five recordings of the PCSC and three
recordings of the HIT-6 were captured over the course of the treatment
series (see Figure
3). Based upon both verbal responses from the patient as
well as observation, some particular treatment techniques demonstrated
a direct correlation to a reduction of a specific symptom (see Figure 4).
Figure 3. Self-reported changes of persistent concussion symptoms
related to treatment intervention; measured through
symptom tracking methods.
Figure 4. Based upon patient’s verbal responses and direct observation
in treatment, several techniques had a direct correlation
to a reduction of specific symptoms.
Sleep was restored following the first treatment as he reported sleeping
12 h each night between session one and two. Sleep continued to remain
at normalized levels throughout the treatment process.
Sessions were not based upon following specific protocol sequence. A
narrative summary of this improvisational and experiential treatment
process is reflected in a summary of the daily notes (see Figure 5).
Figure 5. Treatment Progression Depicted through Daily Notes.
Abbreviated daily notes to reflect the full therapeutic
process of applying CST and LD to treat symptoms of
concussion. See KEY for term definitions.
Six month follow-up
A 6-month follow-up (via telephone conversation) revealed sustained
abatement of PCS symptoms and the patient resumed educational pursuits
and gainful employment. His parents recommended that he continue to
receive maintenance therapy but he voiced concerned over his mounting
financial debt. He denied that symptoms were interfering with daily
activities and quality of life. The patient’s perspective about these
therapies was highly positive.
Discussion
This article offers a hypothesis that persistent symptoms of PCS could be, in
part, a result of compromised glymphatic and lymphatic pathway flow stemming
from restrictions of movement and balanced position of osseous and soft
tissue structures. The theoretical constructs of CST suggest when fascial
membranes such as the dura and other meningeal layers and/or cranial plates
and vertebral column may be in a compressive state, leading to neurological
and/or behavioral symptoms.30,32,76 The theoretical
constructs of LD is that gentle, manual evacuation of lymphatic channels
following anatomical mapping enhances a whole-body fluid exchange and
removal of cellular wastes between interconnecting fluid systems.45,49
Only through whole-body palpation assessment was the first clinical discoveries
made in this patient. Asymmetrical rib cage alignment, with sub-optimal
breath expansion and lowered oxygen saturation, was subjectively assessed
and CST techniques were immediately employed. The second discovery was
persistent edema through anterior and lateral cervical chains, over the
expanse of scalp lymphatics, and engorged in bilateral occipital nodes at
the cranial base. It is a reasonable assumption that edema may have occurred
at the time of injury but after 18 months, edema and interstitial fluid
stagnation would be expected to have resolved. That was not the case for
this athlete. Palpation for (chronic) edema is a skill set learned through
specific LD training methods.
Sleep was the first of the chronic symptoms to demonstrate an effect from
treatment, after just one, 1-h treatment session. It could be suggested that
fluid stagnation in and around the central nervous system contributed to the
adverse head pressure pain with impact on the lack of restorative sleep (as
surmised by the patient’s insights). It could be suggested that quality of
breathing function may also have had a negative effect upon sleep. It is
apparent through the stream of daily notes that the first treatment in and
around the thoracic body and rib cage (consisting of fascia mobilization
following CST methods) produced immediate elevation in oxygen saturation. It
was also immediately apparent that LD through the central spinal lymph node
confluences and pathways produced an immediate response of head pressure
relief. Sleep resolved to satisfactory levels for the patient and remained
so for the remainder of the treatment series, and at the 6-month
follow-up.
Other neurological symptoms resolved at different, but steady rates, as
reflected on the periodic scoring of the PCSC. To avoid or minimize effects
of coaching or influencing the patient on symptom reporting, freely
expressed symptom declarations were documented prior to the administration
of repeated PCSC scoring. It is with a high rate of certainty that the PCSC
yielded an accurate expression of the patient’s self-reported experiences in
symptom status through the treatment process.
Therapeutic touch and emotional support are aspects of most forms of manual
therapies. It is possible that any placebo or autonomic calming effect of
therapeutic touch contributed to the reduction of symptoms. However,
resolution of certain chronic symptoms did correlate with the application of
only specific treatment techniques (see Figure 4). Mood, cognitive
function, and emotional well-being improved and the patient attributed this
to reduction and elimination of head pain, brain fatigue, and sensory
sensitivities. Quality of life improved and he returned to his occupational
tasks of completing college and finding a less stressful, yet meaningful,
job.
The literature supports interventions for PCS which include psychological,
cervical, and vestibular rehabilitation.5 The differential methods of CST and LD as distinct manual therapies
have yet to be fully explored as options for PCS, though emerging studies
indicate CST being used clinically with functional PCS subtypes. One
contraindication for CST is not to apply during acute stages of brain injury
when increased intracranial pressure is present.30 Contraindications for LD have been cited and include acute infection
or inflammatory disease process, thrombosis or phlebitis, acute hemorrhage,
active malignant ailments, and acute heart problems as LD increases cardiac
load.44,45
Future study could possibly isolate the impact CST and LD modalities have upon
sleep in PCS. Research of the fluid exchange models of the nervous system
could explore possible correlations to persistent symptoms of PCS.
Furthermore, efficacy studies into therapies such as CST and LD might be
aided by advancements of proving and measuring the exchange of fluids where
glymphatic and lymphatic structures merge.
Conclusions
This case report reflects one collegiate athlete’s unique constellation of PCS
and the self-reported reduction of persistent symptoms through the
experiential process of CST and LD intervention. There is little published
evidence of the efficacy of CST and/or LD on the symptoms of PCS, though
both have been utilized in clinics internationally for over 3 decades. Rest
allowance and other therapy interventions had been previously trialed for
18 months, though no concussion symptom tracking was completed or available
from previous records for comparative purposes. Previous pharmacologic
treatment and vestibular rehabilitation for this patient were self-reported
to have reduced symptoms of attention deficits and balance in climbing
stairs, respectively. Other psychology and physical medicine endeavors had
been trialed over the year and a half, and per his declaration, “Did not
help heal me. Medications only helped me get through the work day; they did
not take away the symptoms.”
The author, an occupational therapist with 20 years of experience applying CST
and LD in clinical practice, admits to a strong inherent bias. The strength
of this case study, however, is that treatment was provided in isolation of
any intervention other than his established medication usage. It could be
said that placebo effect had been controlled for where specific treatment
techniques clearly resolved some specific symptoms, but not all. Other
symptoms resolved over time and may reflect effects of the restoration of
sleep and elevation of mood. Though generalization of the findings in this
case cannot be applied to the greater population of patients with
concussions and brain injuries, this case does suggest that CST and LD are
valuable treatment options for PCS and worthy of future study.
We thank all the clients and their families who trust the wisdom of structural
medicine as we continue to merge theory with day-to-day clinical practices.
We are forever indebted to your tenacity and steadfastness to find and
secure appropriate help.
Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article: Any conflicts of interests are implied by the author being an
active clinician where these techniques and therapeutic strategies are
utilized in the clinic setting.
Ethical approval: Our institution does not require ethical approval for reporting
individual cases or case series.
Funding: The author(s) received no financial support for the research, authorship,
and/or publication of this article.
Informed consent: Written informed consent was obtained from the patient(s) for their
anonymized information to be published in this article. This informed
consent is maintained in the medical records for this patient.
ORCID iD: Susan Vaughan Kratz https://orcid.org/0000-0003-2018-8365 | ALPRAZOLAM, AMPHETAMINE ASPARTATE\AMPHETAMINE SULFATE\DEXTROAMPHETAMINE SACCHARATE\DEXTROAMPHETAMINE SULFATE, FLUOXETINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33628444 | 18,976,097 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Case report: Manual therapies promote resolution of persistent post-concussion symptoms in a 24-year-old athlete.
This case report illustrates the treatment outcomes of a collegiate athlete presenting with an 18-month history of post-concussion syndrome who received a series of mixed manual therapies in isolation of other therapy. Persistent symptoms were self-reported as debilitating, contributing to self-removal from participation in school, work, and leisure activities. Patient and parent interviews captured the history of multiple concussions and other sports-related injuries. Neurological screening and activities of daily living were baseline measured. Post-Concussion Symptom Checklist and Headache Impact Test-6™ were utilized to track symptom severity. Treatments applied included craniosacral therapy, manual lymphatic drainage, and glymphatic techniques. Eleven treatment sessions were administered over 3 months. Results indicated restoration of oxygen saturation, normalized pupil reactivity, and satisfactory sleep. Post-concussion syndrome symptom severity was reduced by 87% as reflected by accumulative Post-Concussion Symptom Checklist scores. Relief from chronic headaches was achieved, reflected by Headache Impact Test-6 scores. Restoration of mood and quality of life were reported. A 6-month follow-up revealed symptoms remained abated with full re-engagement of daily activities. The author hypothesized that post-concussion syndrome symptoms were related to compression of craniosacral system structures and lymphatic fluid stagnation that contributed to head pressure pain, severe sleep deprivation, and multiple neurological and psychological symptoms. Positive outcomes over a relatively short period of time without adverse effects suggest these therapies may offer viable options for the treatment of post-concussion syndrome.
Introduction
Serious awareness over the past decade of the short- and long-term effects of
traumatic head trauma leading to concussion has prompted rigorous diagnostic
and clinical management endeavors.1,2 Sources report the
number of sports-related concussions receiving medical attention in the
United States ranged between 1.6 million and 3.8 million annually.3,4
Persistent symptoms following concussions may not reflect a single
pathophysiological entity and likely describes individualized patterns of
non-specific, post-traumatic symptoms that may be linked to coexisting
and/or confounding issues.1,5 Subtypes of
post-concussion syndrome (PCS) are now recognized by physiological,
cervicogenic, and neuropsychological manifestations.2,4,6–9
A fluid model: glymphatic and meningeal lymphatic systems
The existence of a cerebral fluid-exchange system (different than blood
vessels) has been long debated but new discoveries have intensified research
into fluid dynamics within the brain parenchyma.10 Glial cells have been shown to create a possible architectural system
among the microvasculature which appears to match blood flow with neuronal firing.11 Pathways formed by glial cells and endothelial walls of penetrating
blood vessels have been suggested to serve as a physiological cleansing
mechanism called the “glymphatic system.”10,12,13 These pathways
appear to form perivascular channels by astroglia end-feet where monitoring
and active clearing of the neuronal terrain may occur.14–16
Furthermore, it is theorized that this cellular transportation network also
serves to distribute nutritional compounds and neuromodulators.15 Brain-wide perivascular pathways, believed to facilitate
cerebrospinal fluid (CSF) flow through the parenchyma and the movement of
interstitial solutes, have been captured by contrast-enhanced magnetic
resonance imaging (MRI) scan.13 The theoretical function then of this proposed glymphatic system
serves to support perfusion of CSF and interstitial fluids as a means of
pseudo-lymphatic function of the nervous system, elucidating a possible
mechanism of how the brain cleans itself through elimination of soluble
proteins and metabolites.10,13,17–19
However, there are also proponents who argue a glymphatic system as proposed
needs to be re-evaluated, accounting for more specifics to cerebrovascular
fluid transport.20 Regardless, there is within the brain a mechanism that moves fluids
through a cleansing process, shown to be active during restorative sleep and
rather inactive during wakefulness.15
Lymphatic system discovery
In addition, a recent identification of lymphatic projections into meningeal
membranes within the cranial vault suggests a functional proximity and/or
connection between the brain pseudo-lymphatic and the whole-body lymphatic
network.21,22 Furthermore, lymphatic vessels were discovered
lining the dura sinuses of the meninges and in turn have been shown to carry
both fluid and immune cells from the CSF, connecting to deep cervical lymph
nodes and into the peripheral venous return system.17,21
Magnetic resonance images provide supporting evidence of glymphatic drainage
from human brain to cervical lymph nodes.23 Other emerging data from both animal models and human studies support
this theory that the brain fluid-exchange and body lymphatics system share
an intimacy and work together for homeostasis, though we are only at the
beginning of understanding how this works.12,22–24
Structural impact and pathology of fluid transport systems
Chronic symptoms associated with PCS have been theorized to be a result of
“gliopathy,” a dysregulation of glial function and drainage in the central
and peripheral nervous system.25 Murine models of glial and glymphatic system function following head
injury has begun to shed light on the effect of brain trauma upon astrocytes
and the effect upon intracranial edema and resolution.26,27
Impaired functioning of the meningeal lymphatic vessels has been theorized
to accelerate the accumulation of toxic amyloid beta protein in the brain parenchyma.28
Upledger illuminated and confirmed the existence of the function and physiology
of the craniosacral system (meninges housing the brain, spinal cord, and
cerebral spinal fluids).29,30 Bodywork
professionals are guided by the premise that structural compressions such as
osseous and/or fascial restrictions can impede fluid movement and exchange,
leading to an array of symptomology.30–34 It is understood
that vertebral bone compression into spinal cord space will create various
neurological symptoms theorized, in part, by the obstruction of cerebral
spinal fluid.35,36 One animal model has demonstrated that blocking
the normal physiologic cerebral spinal fluid drainage sites in the
cribriform plate increases resting intracranial pressure.37
Manual therapies for the central nervous system
Craniosacral therapy
Manual therapies such as craniosacral therapy (CST) emerged from the
science that explored the physiological motion of the central nervous
system.30,38,39 The core
intent of CST is the theoretic interactions with connective tissue at
osseous sites and, using a sustained low-force stretch, elicit a
softening or relaxation response of soft tissues. In turn, a positive
effect upon fluid exchange and the body’s self-correcting actions can occur.30 Studies have illuminated the natural motion of cranial bones,
organ movement, and fluid exchange, depicting and measuring the
dynamic nature of the physiology of the craniosacral system.33,40,41 Based on observations of one animal study on
the structural effects of applying CST, no discernible length
difference was found at cranial bone sutures. However, this study
concluded that perhaps a different biological basis for such treatment
could be at play.42 In a now classic study, changes in the length of the
intracranial falx cerebri membrane were demonstrated with the
application of CST on an embalmed cadaver skull. Recorded relative
change in tissue length ranged between .28 and 1.44 mm at different
sites of the membrane with different CST techniques applied. This
study offers some validation that sustained, gentle, and external
forces have a measurable effect upon the intracranial membrane system.43
Manual lymphatic drainage
Various methods of manual lymphatic drainage (LD) exist, but a
contemporary version aligns with discoveries of anatomical pathways
and lymph tissue mapping, the depths of lymph flow throughout the
body, and using specific rhythms in fluid evacuation.44 Hand pressure used in the Chikly method is extremely light,
matching the tissue dynamics unique to each patient, and only enough
to stimulate the movement of fluid to enhance flow through specific
lymph pathways. This is theorized to activate contractions of the
functional unit of lymph vessels, called lymphangions, which assist
fluid exchange without increasing blood filtration or lymph node
collapse from too great of manually imposed pressure. There exists
extensive innervation from the autonomic nervous system of these
contractile units of the lymphatic system and the conceptualization of
the movement of lymphatic fluids.45,46 LD is believed to influence the whole-body
system through gentle manual evacuation, creating a system-wide
siphoning effect to enhance fluid exchange in multiple systems.45
The use of manual LD by qualified professionals is a treatment option for
lymphedema, sports injuries, and fibromyalgia.44,47–49 Manual LD was first suggested as a specific
treatment of post-contusion and PCS for its anti-edematous effects.50 The evolution and addition of glymphatic treatment methods have
only recently emerged and are based on the practical application of
the combination of methods such as CST, LD, and non-invasive intention
of therapeutic touch.16,45
Existing studies on manual therapies for concussions and brain
injuries
In clinical application, CST has been shown to have positive effect for a
number of chronic syndromes that parallel PCS subtypes, but the body
of data is limited to observational designs and low to moderate
quality of randomized controlled methods.51,52 The credibility of a sham control protocol for
future study of CST was reported.53 A recent study of former pro-football players with PCS showed
statistically greater improvements in range of motion, pain, sleep,
and cognitive function after a series of combined manual therapies.54 A pilot study of 10 active military members had a reduction of
symptoms of post-traumatic stress and head injury through the
application of mixed light touch manual therapies.55 A single blind case series measured clinical outcomes of
soldiers with combat-related head injuries receiving CST and other
manipulation techniques. Results showed statistically greater
improvements in objective and subjective measurements pre- and post-treatment.56 Case studies report positive outcomes of varied uses of manual
therapies for the treatment of PCS.57,58 One case of an athlete with PCS compared brain
scans before and after 15 isolated CST treatments using quantitative
electroencephalogram comparing symptom reduction to changes in
neurological activity.59
Headaches
Headaches are a common symptom of concussion and PCS.7,60 CST and
other manual methods have been shown to have positive effect in the
treatment of headaches, migraines, and trigeminal neuralgia.61–64
Sleep
Sleep has a critical function in ensuring metabolic homeostasis and
clearance of metabolites and is but one important way for the nervous
system to heal from trauma and injury.13,18,65 The
glymphatic system functions mainly during sleep and is largely
disengaged during wakefulness. Sleep debt and a glymphatic system
disruption have been proposed as a mediator of brain trauma, chronic
traumatic encephalopathy, and other neurological disorders.15,66,67
Concussion symptom assessments
Subjective data —from patient
Self-reporting symptom scales are vital for assisting in the medical
management of PCS. Several tracking tools hold substantial overlap
with one another in capturing various pains and neurological
infirmaries, functional impairment, and quality of life.68–70 Although
only some have been empirically studied, clinical users need to be
aware that these scales have evolved rather than being developed scientifically.71 Nonetheless, patient reports of subjective levels of pain,
sensory, and psychological symptoms are crucial to aid in the clinical
search for effective treatments.
Post-Concussion Symptom Checklist (PCSC)
The PCSC was utilized to track outcomes and re-administered periodically
throughout the treatment process with care given to avoid coaching the
patient on symptom manifestations.70,72 Symptoms were also tracked through open-ended
self-reporting by the patient at the onset of each session if he
wished to share them.
Headache Impact Test™ (HIT-6)
The HIT-6 was designed to screen and monitor patients’ severity of
headache pain and the impact on function and quality of life.73 Utilizing six items with a severity rating scale, the HIT-6 has
been shown to be a reliable and valid tool for discriminating the
effect of headache on daily living.74,75 A possible point range of 36–78 reflects the
severity of impact that headaches are interfering with daily quality
of life and function. The HIT-6 was chosen for this particular patient
to track headache symptoms which was also a chief complaint, second
only to sleep disturbances.
Measurement of sleep
Sleep function was tracked through a sleep diary and the patient’s
perception of restfulness and daily energy.
Subjective data —from the clinician
Neurological screenings occurred each session per standard of care,
including pupil and oculomotor status, balance reactions, and general
cognitive assessments conducted through observations of behavior.
Palpation findings from full body assessment of musculoskeletal,
fascia and fluid fields were conducted at the beginning of each
treatment session. Inquiry about mood and stress were made at the
beginning of each session.
Objective data
Quantifiable neurological soft sign and biomarkers not captured on the
PCSC included fixed and dilated pupils, oxygen saturation, and
frequency of urination and thirst.
Case report
The subject, a 24-year-old male, presented with an 18-month history of
persistent neurological and behavioral symptoms reportedly related to
one sports-induced concussion. Onset was in October 2017, following a
head injury while playing in a collegiate-level sport. He reported
being screened by an athletic trainer and having a follow-up medical
assessment. No hospitalization was required. Prolonged rest was
prescribed and adhered to for several months. An eventual referral to
a local academic-medicine concussion clinic was made several months
post-injury due to escalation of unresolved symptoms where
psychological services addressing anxiety and depression and
medications for pain and concentration were prescribed. Medications
reported on patient intake included Prozac, Xanax, and Adderall. He
reported his ability to focus on job tasks improved by the Adderall
but the medications generally worsened “brain fog” and memory. He also
participated in a physical therapy program for vestibular
rehabilitation. Symptoms persisted to the point of full debilitation
by sleep deprivation, increasing dizziness, sensory overload, and
brain fatigue. Suicidal ideation prompted his parents to seek other
recommendations and services.
In the interview with the patient and one of his parents, it was
discovered that he sustained a total of six sports-related concussions
dating back several years. History also included several orthopedic
injuries long since healed (fractures to a foot and nose, and several
bone contusions). The patient affirmed that a whiplash occurred with
the most recent concussion and had originally sought chiropractic care
for neck pain post-injury.
Since symptoms began to intensify, he was forced to take a medical leave
from attending school and working a job that required much traveling.
He stated he could perform job duties, enjoyed them, and felt capable
of the job. However, the sensory intolerances created significant
anxiety and began to reduce his confidence in his job performance. His
tolerance and engagement in favorite activities were at 10% of normal
participation level. He frequently isolated himself to cope with the
sensory overload which added to a sense of helplessness.
Based upon client report and clinical observations, functional problems
were noted on intake (see Figure 1). Initial clinical
findings were also noted (see Figure 2).
Figure 1. Post-concussion symptoms (18 month duration) reported on
intake questionnaire by patient and in personal and parent
interviews.
Figure 2. Initial clinical findings.
Treatment methods employed included the following: (incorporated into
each session as the need arose).
Manual LD techniques (Chikly).45
CST techniques (Upledger).30
Glial and Glymphatic system techniques (Wanveer).16
Goals for series of therapy encounters
Reduce and eliminate stagnant and congested edema of spine,
neck, and head.
Soft tissue mobilization and fascial release methods to
increase general soft tissue flexibility and subtleness
through body to reduce sympathetic tone (through CST).
Facilitate exchange of fluid through all body fluid systems;
reduce interstitial congestion to promote healing and
self-correction of nervous system (through LD).
Neurological rehabilitation strategies to reduce and adapt to
sensory challenges; environmental structuring. (These
methods were not required due to the speed in which
positive changes were experienced and observed with manual
therapies.)
Achieve freedom from pain and neurological dysfunction,
restore/raise quality of life.
Community and work re-entry, adaptations, and modifications
assistance where needed.
Patient and family education on the concepts of manual
therapies.
Client stated just one personal goal: “I just want to be able
to sleep.”
Treatment process
Treatment was conducted in isolation of any other (new) therapy over the
course of three months. The patient participated in eleven, 1-h
sessions. Scheduling sessions were recommended at 2–3 times per week
initially. Following the first session, he requested daily treatment
but was advised to allow his system to acclimate and integrate
treatment effects. The first four sessions were scheduled 3 days
apart. After the fourth session, scheduling was left to his
discretion. Six more appointments were scheduled with 1 week spacing,
and the eleventh session was as a follow-up at the patient’s
discretion 5 weeks later. Each session was an improvisational process
of applying the various manual therapies and techniques, based upon
whole-body assessment of primary and secondary structural and fluid
findings.
Results and treatment outcomes
Quantitative data were collected through self-reporting of severity of
symptoms using the PCSC, the HIT-6, and clinical observations.
Sessions began most often with an invitation for him to report
whatever symptom(s) felt most pressing. Quality of life measurements
were self-reporting of sleep function, brain fog, ability to “get
through the day,” ability to tolerate sensory aspects of daily events,
and endurance for mental and physical activities. All were recorded in
the daily notes. A total of five recordings of the PCSC and three
recordings of the HIT-6 were captured over the course of the treatment
series (see Figure
3). Based upon both verbal responses from the patient as
well as observation, some particular treatment techniques demonstrated
a direct correlation to a reduction of a specific symptom (see Figure 4).
Figure 3. Self-reported changes of persistent concussion symptoms
related to treatment intervention; measured through
symptom tracking methods.
Figure 4. Based upon patient’s verbal responses and direct observation
in treatment, several techniques had a direct correlation
to a reduction of specific symptoms.
Sleep was restored following the first treatment as he reported sleeping
12 h each night between session one and two. Sleep continued to remain
at normalized levels throughout the treatment process.
Sessions were not based upon following specific protocol sequence. A
narrative summary of this improvisational and experiential treatment
process is reflected in a summary of the daily notes (see Figure 5).
Figure 5. Treatment Progression Depicted through Daily Notes.
Abbreviated daily notes to reflect the full therapeutic
process of applying CST and LD to treat symptoms of
concussion. See KEY for term definitions.
Six month follow-up
A 6-month follow-up (via telephone conversation) revealed sustained
abatement of PCS symptoms and the patient resumed educational pursuits
and gainful employment. His parents recommended that he continue to
receive maintenance therapy but he voiced concerned over his mounting
financial debt. He denied that symptoms were interfering with daily
activities and quality of life. The patient’s perspective about these
therapies was highly positive.
Discussion
This article offers a hypothesis that persistent symptoms of PCS could be, in
part, a result of compromised glymphatic and lymphatic pathway flow stemming
from restrictions of movement and balanced position of osseous and soft
tissue structures. The theoretical constructs of CST suggest when fascial
membranes such as the dura and other meningeal layers and/or cranial plates
and vertebral column may be in a compressive state, leading to neurological
and/or behavioral symptoms.30,32,76 The theoretical
constructs of LD is that gentle, manual evacuation of lymphatic channels
following anatomical mapping enhances a whole-body fluid exchange and
removal of cellular wastes between interconnecting fluid systems.45,49
Only through whole-body palpation assessment was the first clinical discoveries
made in this patient. Asymmetrical rib cage alignment, with sub-optimal
breath expansion and lowered oxygen saturation, was subjectively assessed
and CST techniques were immediately employed. The second discovery was
persistent edema through anterior and lateral cervical chains, over the
expanse of scalp lymphatics, and engorged in bilateral occipital nodes at
the cranial base. It is a reasonable assumption that edema may have occurred
at the time of injury but after 18 months, edema and interstitial fluid
stagnation would be expected to have resolved. That was not the case for
this athlete. Palpation for (chronic) edema is a skill set learned through
specific LD training methods.
Sleep was the first of the chronic symptoms to demonstrate an effect from
treatment, after just one, 1-h treatment session. It could be suggested that
fluid stagnation in and around the central nervous system contributed to the
adverse head pressure pain with impact on the lack of restorative sleep (as
surmised by the patient’s insights). It could be suggested that quality of
breathing function may also have had a negative effect upon sleep. It is
apparent through the stream of daily notes that the first treatment in and
around the thoracic body and rib cage (consisting of fascia mobilization
following CST methods) produced immediate elevation in oxygen saturation. It
was also immediately apparent that LD through the central spinal lymph node
confluences and pathways produced an immediate response of head pressure
relief. Sleep resolved to satisfactory levels for the patient and remained
so for the remainder of the treatment series, and at the 6-month
follow-up.
Other neurological symptoms resolved at different, but steady rates, as
reflected on the periodic scoring of the PCSC. To avoid or minimize effects
of coaching or influencing the patient on symptom reporting, freely
expressed symptom declarations were documented prior to the administration
of repeated PCSC scoring. It is with a high rate of certainty that the PCSC
yielded an accurate expression of the patient’s self-reported experiences in
symptom status through the treatment process.
Therapeutic touch and emotional support are aspects of most forms of manual
therapies. It is possible that any placebo or autonomic calming effect of
therapeutic touch contributed to the reduction of symptoms. However,
resolution of certain chronic symptoms did correlate with the application of
only specific treatment techniques (see Figure 4). Mood, cognitive
function, and emotional well-being improved and the patient attributed this
to reduction and elimination of head pain, brain fatigue, and sensory
sensitivities. Quality of life improved and he returned to his occupational
tasks of completing college and finding a less stressful, yet meaningful,
job.
The literature supports interventions for PCS which include psychological,
cervical, and vestibular rehabilitation.5 The differential methods of CST and LD as distinct manual therapies
have yet to be fully explored as options for PCS, though emerging studies
indicate CST being used clinically with functional PCS subtypes. One
contraindication for CST is not to apply during acute stages of brain injury
when increased intracranial pressure is present.30 Contraindications for LD have been cited and include acute infection
or inflammatory disease process, thrombosis or phlebitis, acute hemorrhage,
active malignant ailments, and acute heart problems as LD increases cardiac
load.44,45
Future study could possibly isolate the impact CST and LD modalities have upon
sleep in PCS. Research of the fluid exchange models of the nervous system
could explore possible correlations to persistent symptoms of PCS.
Furthermore, efficacy studies into therapies such as CST and LD might be
aided by advancements of proving and measuring the exchange of fluids where
glymphatic and lymphatic structures merge.
Conclusions
This case report reflects one collegiate athlete’s unique constellation of PCS
and the self-reported reduction of persistent symptoms through the
experiential process of CST and LD intervention. There is little published
evidence of the efficacy of CST and/or LD on the symptoms of PCS, though
both have been utilized in clinics internationally for over 3 decades. Rest
allowance and other therapy interventions had been previously trialed for
18 months, though no concussion symptom tracking was completed or available
from previous records for comparative purposes. Previous pharmacologic
treatment and vestibular rehabilitation for this patient were self-reported
to have reduced symptoms of attention deficits and balance in climbing
stairs, respectively. Other psychology and physical medicine endeavors had
been trialed over the year and a half, and per his declaration, “Did not
help heal me. Medications only helped me get through the work day; they did
not take away the symptoms.”
The author, an occupational therapist with 20 years of experience applying CST
and LD in clinical practice, admits to a strong inherent bias. The strength
of this case study, however, is that treatment was provided in isolation of
any intervention other than his established medication usage. It could be
said that placebo effect had been controlled for where specific treatment
techniques clearly resolved some specific symptoms, but not all. Other
symptoms resolved over time and may reflect effects of the restoration of
sleep and elevation of mood. Though generalization of the findings in this
case cannot be applied to the greater population of patients with
concussions and brain injuries, this case does suggest that CST and LD are
valuable treatment options for PCS and worthy of future study.
We thank all the clients and their families who trust the wisdom of structural
medicine as we continue to merge theory with day-to-day clinical practices.
We are forever indebted to your tenacity and steadfastness to find and
secure appropriate help.
Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article: Any conflicts of interests are implied by the author being an
active clinician where these techniques and therapeutic strategies are
utilized in the clinic setting.
Ethical approval: Our institution does not require ethical approval for reporting
individual cases or case series.
Funding: The author(s) received no financial support for the research, authorship,
and/or publication of this article.
Informed consent: Written informed consent was obtained from the patient(s) for their
anonymized information to be published in this article. This informed
consent is maintained in the medical records for this patient.
ORCID iD: Susan Vaughan Kratz https://orcid.org/0000-0003-2018-8365 | ALPRAZOLAM, AMPHETAMINE ASPARTATE\AMPHETAMINE SULFATE\DEXTROAMPHETAMINE SACCHARATE\DEXTROAMPHETAMINE SULFATE, FLUOXETINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33628444 | 18,976,097 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Feeling abnormal'. | Case report: Manual therapies promote resolution of persistent post-concussion symptoms in a 24-year-old athlete.
This case report illustrates the treatment outcomes of a collegiate athlete presenting with an 18-month history of post-concussion syndrome who received a series of mixed manual therapies in isolation of other therapy. Persistent symptoms were self-reported as debilitating, contributing to self-removal from participation in school, work, and leisure activities. Patient and parent interviews captured the history of multiple concussions and other sports-related injuries. Neurological screening and activities of daily living were baseline measured. Post-Concussion Symptom Checklist and Headache Impact Test-6™ were utilized to track symptom severity. Treatments applied included craniosacral therapy, manual lymphatic drainage, and glymphatic techniques. Eleven treatment sessions were administered over 3 months. Results indicated restoration of oxygen saturation, normalized pupil reactivity, and satisfactory sleep. Post-concussion syndrome symptom severity was reduced by 87% as reflected by accumulative Post-Concussion Symptom Checklist scores. Relief from chronic headaches was achieved, reflected by Headache Impact Test-6 scores. Restoration of mood and quality of life were reported. A 6-month follow-up revealed symptoms remained abated with full re-engagement of daily activities. The author hypothesized that post-concussion syndrome symptoms were related to compression of craniosacral system structures and lymphatic fluid stagnation that contributed to head pressure pain, severe sleep deprivation, and multiple neurological and psychological symptoms. Positive outcomes over a relatively short period of time without adverse effects suggest these therapies may offer viable options for the treatment of post-concussion syndrome.
Introduction
Serious awareness over the past decade of the short- and long-term effects of
traumatic head trauma leading to concussion has prompted rigorous diagnostic
and clinical management endeavors.1,2 Sources report the
number of sports-related concussions receiving medical attention in the
United States ranged between 1.6 million and 3.8 million annually.3,4
Persistent symptoms following concussions may not reflect a single
pathophysiological entity and likely describes individualized patterns of
non-specific, post-traumatic symptoms that may be linked to coexisting
and/or confounding issues.1,5 Subtypes of
post-concussion syndrome (PCS) are now recognized by physiological,
cervicogenic, and neuropsychological manifestations.2,4,6–9
A fluid model: glymphatic and meningeal lymphatic systems
The existence of a cerebral fluid-exchange system (different than blood
vessels) has been long debated but new discoveries have intensified research
into fluid dynamics within the brain parenchyma.10 Glial cells have been shown to create a possible architectural system
among the microvasculature which appears to match blood flow with neuronal firing.11 Pathways formed by glial cells and endothelial walls of penetrating
blood vessels have been suggested to serve as a physiological cleansing
mechanism called the “glymphatic system.”10,12,13 These pathways
appear to form perivascular channels by astroglia end-feet where monitoring
and active clearing of the neuronal terrain may occur.14–16
Furthermore, it is theorized that this cellular transportation network also
serves to distribute nutritional compounds and neuromodulators.15 Brain-wide perivascular pathways, believed to facilitate
cerebrospinal fluid (CSF) flow through the parenchyma and the movement of
interstitial solutes, have been captured by contrast-enhanced magnetic
resonance imaging (MRI) scan.13 The theoretical function then of this proposed glymphatic system
serves to support perfusion of CSF and interstitial fluids as a means of
pseudo-lymphatic function of the nervous system, elucidating a possible
mechanism of how the brain cleans itself through elimination of soluble
proteins and metabolites.10,13,17–19
However, there are also proponents who argue a glymphatic system as proposed
needs to be re-evaluated, accounting for more specifics to cerebrovascular
fluid transport.20 Regardless, there is within the brain a mechanism that moves fluids
through a cleansing process, shown to be active during restorative sleep and
rather inactive during wakefulness.15
Lymphatic system discovery
In addition, a recent identification of lymphatic projections into meningeal
membranes within the cranial vault suggests a functional proximity and/or
connection between the brain pseudo-lymphatic and the whole-body lymphatic
network.21,22 Furthermore, lymphatic vessels were discovered
lining the dura sinuses of the meninges and in turn have been shown to carry
both fluid and immune cells from the CSF, connecting to deep cervical lymph
nodes and into the peripheral venous return system.17,21
Magnetic resonance images provide supporting evidence of glymphatic drainage
from human brain to cervical lymph nodes.23 Other emerging data from both animal models and human studies support
this theory that the brain fluid-exchange and body lymphatics system share
an intimacy and work together for homeostasis, though we are only at the
beginning of understanding how this works.12,22–24
Structural impact and pathology of fluid transport systems
Chronic symptoms associated with PCS have been theorized to be a result of
“gliopathy,” a dysregulation of glial function and drainage in the central
and peripheral nervous system.25 Murine models of glial and glymphatic system function following head
injury has begun to shed light on the effect of brain trauma upon astrocytes
and the effect upon intracranial edema and resolution.26,27
Impaired functioning of the meningeal lymphatic vessels has been theorized
to accelerate the accumulation of toxic amyloid beta protein in the brain parenchyma.28
Upledger illuminated and confirmed the existence of the function and physiology
of the craniosacral system (meninges housing the brain, spinal cord, and
cerebral spinal fluids).29,30 Bodywork
professionals are guided by the premise that structural compressions such as
osseous and/or fascial restrictions can impede fluid movement and exchange,
leading to an array of symptomology.30–34 It is understood
that vertebral bone compression into spinal cord space will create various
neurological symptoms theorized, in part, by the obstruction of cerebral
spinal fluid.35,36 One animal model has demonstrated that blocking
the normal physiologic cerebral spinal fluid drainage sites in the
cribriform plate increases resting intracranial pressure.37
Manual therapies for the central nervous system
Craniosacral therapy
Manual therapies such as craniosacral therapy (CST) emerged from the
science that explored the physiological motion of the central nervous
system.30,38,39 The core
intent of CST is the theoretic interactions with connective tissue at
osseous sites and, using a sustained low-force stretch, elicit a
softening or relaxation response of soft tissues. In turn, a positive
effect upon fluid exchange and the body’s self-correcting actions can occur.30 Studies have illuminated the natural motion of cranial bones,
organ movement, and fluid exchange, depicting and measuring the
dynamic nature of the physiology of the craniosacral system.33,40,41 Based on observations of one animal study on
the structural effects of applying CST, no discernible length
difference was found at cranial bone sutures. However, this study
concluded that perhaps a different biological basis for such treatment
could be at play.42 In a now classic study, changes in the length of the
intracranial falx cerebri membrane were demonstrated with the
application of CST on an embalmed cadaver skull. Recorded relative
change in tissue length ranged between .28 and 1.44 mm at different
sites of the membrane with different CST techniques applied. This
study offers some validation that sustained, gentle, and external
forces have a measurable effect upon the intracranial membrane system.43
Manual lymphatic drainage
Various methods of manual lymphatic drainage (LD) exist, but a
contemporary version aligns with discoveries of anatomical pathways
and lymph tissue mapping, the depths of lymph flow throughout the
body, and using specific rhythms in fluid evacuation.44 Hand pressure used in the Chikly method is extremely light,
matching the tissue dynamics unique to each patient, and only enough
to stimulate the movement of fluid to enhance flow through specific
lymph pathways. This is theorized to activate contractions of the
functional unit of lymph vessels, called lymphangions, which assist
fluid exchange without increasing blood filtration or lymph node
collapse from too great of manually imposed pressure. There exists
extensive innervation from the autonomic nervous system of these
contractile units of the lymphatic system and the conceptualization of
the movement of lymphatic fluids.45,46 LD is believed to influence the whole-body
system through gentle manual evacuation, creating a system-wide
siphoning effect to enhance fluid exchange in multiple systems.45
The use of manual LD by qualified professionals is a treatment option for
lymphedema, sports injuries, and fibromyalgia.44,47–49 Manual LD was first suggested as a specific
treatment of post-contusion and PCS for its anti-edematous effects.50 The evolution and addition of glymphatic treatment methods have
only recently emerged and are based on the practical application of
the combination of methods such as CST, LD, and non-invasive intention
of therapeutic touch.16,45
Existing studies on manual therapies for concussions and brain
injuries
In clinical application, CST has been shown to have positive effect for a
number of chronic syndromes that parallel PCS subtypes, but the body
of data is limited to observational designs and low to moderate
quality of randomized controlled methods.51,52 The credibility of a sham control protocol for
future study of CST was reported.53 A recent study of former pro-football players with PCS showed
statistically greater improvements in range of motion, pain, sleep,
and cognitive function after a series of combined manual therapies.54 A pilot study of 10 active military members had a reduction of
symptoms of post-traumatic stress and head injury through the
application of mixed light touch manual therapies.55 A single blind case series measured clinical outcomes of
soldiers with combat-related head injuries receiving CST and other
manipulation techniques. Results showed statistically greater
improvements in objective and subjective measurements pre- and post-treatment.56 Case studies report positive outcomes of varied uses of manual
therapies for the treatment of PCS.57,58 One case of an athlete with PCS compared brain
scans before and after 15 isolated CST treatments using quantitative
electroencephalogram comparing symptom reduction to changes in
neurological activity.59
Headaches
Headaches are a common symptom of concussion and PCS.7,60 CST and
other manual methods have been shown to have positive effect in the
treatment of headaches, migraines, and trigeminal neuralgia.61–64
Sleep
Sleep has a critical function in ensuring metabolic homeostasis and
clearance of metabolites and is but one important way for the nervous
system to heal from trauma and injury.13,18,65 The
glymphatic system functions mainly during sleep and is largely
disengaged during wakefulness. Sleep debt and a glymphatic system
disruption have been proposed as a mediator of brain trauma, chronic
traumatic encephalopathy, and other neurological disorders.15,66,67
Concussion symptom assessments
Subjective data —from patient
Self-reporting symptom scales are vital for assisting in the medical
management of PCS. Several tracking tools hold substantial overlap
with one another in capturing various pains and neurological
infirmaries, functional impairment, and quality of life.68–70 Although
only some have been empirically studied, clinical users need to be
aware that these scales have evolved rather than being developed scientifically.71 Nonetheless, patient reports of subjective levels of pain,
sensory, and psychological symptoms are crucial to aid in the clinical
search for effective treatments.
Post-Concussion Symptom Checklist (PCSC)
The PCSC was utilized to track outcomes and re-administered periodically
throughout the treatment process with care given to avoid coaching the
patient on symptom manifestations.70,72 Symptoms were also tracked through open-ended
self-reporting by the patient at the onset of each session if he
wished to share them.
Headache Impact Test™ (HIT-6)
The HIT-6 was designed to screen and monitor patients’ severity of
headache pain and the impact on function and quality of life.73 Utilizing six items with a severity rating scale, the HIT-6 has
been shown to be a reliable and valid tool for discriminating the
effect of headache on daily living.74,75 A possible point range of 36–78 reflects the
severity of impact that headaches are interfering with daily quality
of life and function. The HIT-6 was chosen for this particular patient
to track headache symptoms which was also a chief complaint, second
only to sleep disturbances.
Measurement of sleep
Sleep function was tracked through a sleep diary and the patient’s
perception of restfulness and daily energy.
Subjective data —from the clinician
Neurological screenings occurred each session per standard of care,
including pupil and oculomotor status, balance reactions, and general
cognitive assessments conducted through observations of behavior.
Palpation findings from full body assessment of musculoskeletal,
fascia and fluid fields were conducted at the beginning of each
treatment session. Inquiry about mood and stress were made at the
beginning of each session.
Objective data
Quantifiable neurological soft sign and biomarkers not captured on the
PCSC included fixed and dilated pupils, oxygen saturation, and
frequency of urination and thirst.
Case report
The subject, a 24-year-old male, presented with an 18-month history of
persistent neurological and behavioral symptoms reportedly related to
one sports-induced concussion. Onset was in October 2017, following a
head injury while playing in a collegiate-level sport. He reported
being screened by an athletic trainer and having a follow-up medical
assessment. No hospitalization was required. Prolonged rest was
prescribed and adhered to for several months. An eventual referral to
a local academic-medicine concussion clinic was made several months
post-injury due to escalation of unresolved symptoms where
psychological services addressing anxiety and depression and
medications for pain and concentration were prescribed. Medications
reported on patient intake included Prozac, Xanax, and Adderall. He
reported his ability to focus on job tasks improved by the Adderall
but the medications generally worsened “brain fog” and memory. He also
participated in a physical therapy program for vestibular
rehabilitation. Symptoms persisted to the point of full debilitation
by sleep deprivation, increasing dizziness, sensory overload, and
brain fatigue. Suicidal ideation prompted his parents to seek other
recommendations and services.
In the interview with the patient and one of his parents, it was
discovered that he sustained a total of six sports-related concussions
dating back several years. History also included several orthopedic
injuries long since healed (fractures to a foot and nose, and several
bone contusions). The patient affirmed that a whiplash occurred with
the most recent concussion and had originally sought chiropractic care
for neck pain post-injury.
Since symptoms began to intensify, he was forced to take a medical leave
from attending school and working a job that required much traveling.
He stated he could perform job duties, enjoyed them, and felt capable
of the job. However, the sensory intolerances created significant
anxiety and began to reduce his confidence in his job performance. His
tolerance and engagement in favorite activities were at 10% of normal
participation level. He frequently isolated himself to cope with the
sensory overload which added to a sense of helplessness.
Based upon client report and clinical observations, functional problems
were noted on intake (see Figure 1). Initial clinical
findings were also noted (see Figure 2).
Figure 1. Post-concussion symptoms (18 month duration) reported on
intake questionnaire by patient and in personal and parent
interviews.
Figure 2. Initial clinical findings.
Treatment methods employed included the following: (incorporated into
each session as the need arose).
Manual LD techniques (Chikly).45
CST techniques (Upledger).30
Glial and Glymphatic system techniques (Wanveer).16
Goals for series of therapy encounters
Reduce and eliminate stagnant and congested edema of spine,
neck, and head.
Soft tissue mobilization and fascial release methods to
increase general soft tissue flexibility and subtleness
through body to reduce sympathetic tone (through CST).
Facilitate exchange of fluid through all body fluid systems;
reduce interstitial congestion to promote healing and
self-correction of nervous system (through LD).
Neurological rehabilitation strategies to reduce and adapt to
sensory challenges; environmental structuring. (These
methods were not required due to the speed in which
positive changes were experienced and observed with manual
therapies.)
Achieve freedom from pain and neurological dysfunction,
restore/raise quality of life.
Community and work re-entry, adaptations, and modifications
assistance where needed.
Patient and family education on the concepts of manual
therapies.
Client stated just one personal goal: “I just want to be able
to sleep.”
Treatment process
Treatment was conducted in isolation of any other (new) therapy over the
course of three months. The patient participated in eleven, 1-h
sessions. Scheduling sessions were recommended at 2–3 times per week
initially. Following the first session, he requested daily treatment
but was advised to allow his system to acclimate and integrate
treatment effects. The first four sessions were scheduled 3 days
apart. After the fourth session, scheduling was left to his
discretion. Six more appointments were scheduled with 1 week spacing,
and the eleventh session was as a follow-up at the patient’s
discretion 5 weeks later. Each session was an improvisational process
of applying the various manual therapies and techniques, based upon
whole-body assessment of primary and secondary structural and fluid
findings.
Results and treatment outcomes
Quantitative data were collected through self-reporting of severity of
symptoms using the PCSC, the HIT-6, and clinical observations.
Sessions began most often with an invitation for him to report
whatever symptom(s) felt most pressing. Quality of life measurements
were self-reporting of sleep function, brain fog, ability to “get
through the day,” ability to tolerate sensory aspects of daily events,
and endurance for mental and physical activities. All were recorded in
the daily notes. A total of five recordings of the PCSC and three
recordings of the HIT-6 were captured over the course of the treatment
series (see Figure
3). Based upon both verbal responses from the patient as
well as observation, some particular treatment techniques demonstrated
a direct correlation to a reduction of a specific symptom (see Figure 4).
Figure 3. Self-reported changes of persistent concussion symptoms
related to treatment intervention; measured through
symptom tracking methods.
Figure 4. Based upon patient’s verbal responses and direct observation
in treatment, several techniques had a direct correlation
to a reduction of specific symptoms.
Sleep was restored following the first treatment as he reported sleeping
12 h each night between session one and two. Sleep continued to remain
at normalized levels throughout the treatment process.
Sessions were not based upon following specific protocol sequence. A
narrative summary of this improvisational and experiential treatment
process is reflected in a summary of the daily notes (see Figure 5).
Figure 5. Treatment Progression Depicted through Daily Notes.
Abbreviated daily notes to reflect the full therapeutic
process of applying CST and LD to treat symptoms of
concussion. See KEY for term definitions.
Six month follow-up
A 6-month follow-up (via telephone conversation) revealed sustained
abatement of PCS symptoms and the patient resumed educational pursuits
and gainful employment. His parents recommended that he continue to
receive maintenance therapy but he voiced concerned over his mounting
financial debt. He denied that symptoms were interfering with daily
activities and quality of life. The patient’s perspective about these
therapies was highly positive.
Discussion
This article offers a hypothesis that persistent symptoms of PCS could be, in
part, a result of compromised glymphatic and lymphatic pathway flow stemming
from restrictions of movement and balanced position of osseous and soft
tissue structures. The theoretical constructs of CST suggest when fascial
membranes such as the dura and other meningeal layers and/or cranial plates
and vertebral column may be in a compressive state, leading to neurological
and/or behavioral symptoms.30,32,76 The theoretical
constructs of LD is that gentle, manual evacuation of lymphatic channels
following anatomical mapping enhances a whole-body fluid exchange and
removal of cellular wastes between interconnecting fluid systems.45,49
Only through whole-body palpation assessment was the first clinical discoveries
made in this patient. Asymmetrical rib cage alignment, with sub-optimal
breath expansion and lowered oxygen saturation, was subjectively assessed
and CST techniques were immediately employed. The second discovery was
persistent edema through anterior and lateral cervical chains, over the
expanse of scalp lymphatics, and engorged in bilateral occipital nodes at
the cranial base. It is a reasonable assumption that edema may have occurred
at the time of injury but after 18 months, edema and interstitial fluid
stagnation would be expected to have resolved. That was not the case for
this athlete. Palpation for (chronic) edema is a skill set learned through
specific LD training methods.
Sleep was the first of the chronic symptoms to demonstrate an effect from
treatment, after just one, 1-h treatment session. It could be suggested that
fluid stagnation in and around the central nervous system contributed to the
adverse head pressure pain with impact on the lack of restorative sleep (as
surmised by the patient’s insights). It could be suggested that quality of
breathing function may also have had a negative effect upon sleep. It is
apparent through the stream of daily notes that the first treatment in and
around the thoracic body and rib cage (consisting of fascia mobilization
following CST methods) produced immediate elevation in oxygen saturation. It
was also immediately apparent that LD through the central spinal lymph node
confluences and pathways produced an immediate response of head pressure
relief. Sleep resolved to satisfactory levels for the patient and remained
so for the remainder of the treatment series, and at the 6-month
follow-up.
Other neurological symptoms resolved at different, but steady rates, as
reflected on the periodic scoring of the PCSC. To avoid or minimize effects
of coaching or influencing the patient on symptom reporting, freely
expressed symptom declarations were documented prior to the administration
of repeated PCSC scoring. It is with a high rate of certainty that the PCSC
yielded an accurate expression of the patient’s self-reported experiences in
symptom status through the treatment process.
Therapeutic touch and emotional support are aspects of most forms of manual
therapies. It is possible that any placebo or autonomic calming effect of
therapeutic touch contributed to the reduction of symptoms. However,
resolution of certain chronic symptoms did correlate with the application of
only specific treatment techniques (see Figure 4). Mood, cognitive
function, and emotional well-being improved and the patient attributed this
to reduction and elimination of head pain, brain fatigue, and sensory
sensitivities. Quality of life improved and he returned to his occupational
tasks of completing college and finding a less stressful, yet meaningful,
job.
The literature supports interventions for PCS which include psychological,
cervical, and vestibular rehabilitation.5 The differential methods of CST and LD as distinct manual therapies
have yet to be fully explored as options for PCS, though emerging studies
indicate CST being used clinically with functional PCS subtypes. One
contraindication for CST is not to apply during acute stages of brain injury
when increased intracranial pressure is present.30 Contraindications for LD have been cited and include acute infection
or inflammatory disease process, thrombosis or phlebitis, acute hemorrhage,
active malignant ailments, and acute heart problems as LD increases cardiac
load.44,45
Future study could possibly isolate the impact CST and LD modalities have upon
sleep in PCS. Research of the fluid exchange models of the nervous system
could explore possible correlations to persistent symptoms of PCS.
Furthermore, efficacy studies into therapies such as CST and LD might be
aided by advancements of proving and measuring the exchange of fluids where
glymphatic and lymphatic structures merge.
Conclusions
This case report reflects one collegiate athlete’s unique constellation of PCS
and the self-reported reduction of persistent symptoms through the
experiential process of CST and LD intervention. There is little published
evidence of the efficacy of CST and/or LD on the symptoms of PCS, though
both have been utilized in clinics internationally for over 3 decades. Rest
allowance and other therapy interventions had been previously trialed for
18 months, though no concussion symptom tracking was completed or available
from previous records for comparative purposes. Previous pharmacologic
treatment and vestibular rehabilitation for this patient were self-reported
to have reduced symptoms of attention deficits and balance in climbing
stairs, respectively. Other psychology and physical medicine endeavors had
been trialed over the year and a half, and per his declaration, “Did not
help heal me. Medications only helped me get through the work day; they did
not take away the symptoms.”
The author, an occupational therapist with 20 years of experience applying CST
and LD in clinical practice, admits to a strong inherent bias. The strength
of this case study, however, is that treatment was provided in isolation of
any intervention other than his established medication usage. It could be
said that placebo effect had been controlled for where specific treatment
techniques clearly resolved some specific symptoms, but not all. Other
symptoms resolved over time and may reflect effects of the restoration of
sleep and elevation of mood. Though generalization of the findings in this
case cannot be applied to the greater population of patients with
concussions and brain injuries, this case does suggest that CST and LD are
valuable treatment options for PCS and worthy of future study.
We thank all the clients and their families who trust the wisdom of structural
medicine as we continue to merge theory with day-to-day clinical practices.
We are forever indebted to your tenacity and steadfastness to find and
secure appropriate help.
Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article: Any conflicts of interests are implied by the author being an
active clinician where these techniques and therapeutic strategies are
utilized in the clinic setting.
Ethical approval: Our institution does not require ethical approval for reporting
individual cases or case series.
Funding: The author(s) received no financial support for the research, authorship,
and/or publication of this article.
Informed consent: Written informed consent was obtained from the patient(s) for their
anonymized information to be published in this article. This informed
consent is maintained in the medical records for this patient.
ORCID iD: Susan Vaughan Kratz https://orcid.org/0000-0003-2018-8365 | ALPRAZOLAM, AMPHETAMINE ASPARTATE\AMPHETAMINE SULFATE\DEXTROAMPHETAMINE SACCHARATE\DEXTROAMPHETAMINE SULFATE, FLUOXETINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33628444 | 18,976,097 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Memory impairment'. | Case report: Manual therapies promote resolution of persistent post-concussion symptoms in a 24-year-old athlete.
This case report illustrates the treatment outcomes of a collegiate athlete presenting with an 18-month history of post-concussion syndrome who received a series of mixed manual therapies in isolation of other therapy. Persistent symptoms were self-reported as debilitating, contributing to self-removal from participation in school, work, and leisure activities. Patient and parent interviews captured the history of multiple concussions and other sports-related injuries. Neurological screening and activities of daily living were baseline measured. Post-Concussion Symptom Checklist and Headache Impact Test-6™ were utilized to track symptom severity. Treatments applied included craniosacral therapy, manual lymphatic drainage, and glymphatic techniques. Eleven treatment sessions were administered over 3 months. Results indicated restoration of oxygen saturation, normalized pupil reactivity, and satisfactory sleep. Post-concussion syndrome symptom severity was reduced by 87% as reflected by accumulative Post-Concussion Symptom Checklist scores. Relief from chronic headaches was achieved, reflected by Headache Impact Test-6 scores. Restoration of mood and quality of life were reported. A 6-month follow-up revealed symptoms remained abated with full re-engagement of daily activities. The author hypothesized that post-concussion syndrome symptoms were related to compression of craniosacral system structures and lymphatic fluid stagnation that contributed to head pressure pain, severe sleep deprivation, and multiple neurological and psychological symptoms. Positive outcomes over a relatively short period of time without adverse effects suggest these therapies may offer viable options for the treatment of post-concussion syndrome.
Introduction
Serious awareness over the past decade of the short- and long-term effects of
traumatic head trauma leading to concussion has prompted rigorous diagnostic
and clinical management endeavors.1,2 Sources report the
number of sports-related concussions receiving medical attention in the
United States ranged between 1.6 million and 3.8 million annually.3,4
Persistent symptoms following concussions may not reflect a single
pathophysiological entity and likely describes individualized patterns of
non-specific, post-traumatic symptoms that may be linked to coexisting
and/or confounding issues.1,5 Subtypes of
post-concussion syndrome (PCS) are now recognized by physiological,
cervicogenic, and neuropsychological manifestations.2,4,6–9
A fluid model: glymphatic and meningeal lymphatic systems
The existence of a cerebral fluid-exchange system (different than blood
vessels) has been long debated but new discoveries have intensified research
into fluid dynamics within the brain parenchyma.10 Glial cells have been shown to create a possible architectural system
among the microvasculature which appears to match blood flow with neuronal firing.11 Pathways formed by glial cells and endothelial walls of penetrating
blood vessels have been suggested to serve as a physiological cleansing
mechanism called the “glymphatic system.”10,12,13 These pathways
appear to form perivascular channels by astroglia end-feet where monitoring
and active clearing of the neuronal terrain may occur.14–16
Furthermore, it is theorized that this cellular transportation network also
serves to distribute nutritional compounds and neuromodulators.15 Brain-wide perivascular pathways, believed to facilitate
cerebrospinal fluid (CSF) flow through the parenchyma and the movement of
interstitial solutes, have been captured by contrast-enhanced magnetic
resonance imaging (MRI) scan.13 The theoretical function then of this proposed glymphatic system
serves to support perfusion of CSF and interstitial fluids as a means of
pseudo-lymphatic function of the nervous system, elucidating a possible
mechanism of how the brain cleans itself through elimination of soluble
proteins and metabolites.10,13,17–19
However, there are also proponents who argue a glymphatic system as proposed
needs to be re-evaluated, accounting for more specifics to cerebrovascular
fluid transport.20 Regardless, there is within the brain a mechanism that moves fluids
through a cleansing process, shown to be active during restorative sleep and
rather inactive during wakefulness.15
Lymphatic system discovery
In addition, a recent identification of lymphatic projections into meningeal
membranes within the cranial vault suggests a functional proximity and/or
connection between the brain pseudo-lymphatic and the whole-body lymphatic
network.21,22 Furthermore, lymphatic vessels were discovered
lining the dura sinuses of the meninges and in turn have been shown to carry
both fluid and immune cells from the CSF, connecting to deep cervical lymph
nodes and into the peripheral venous return system.17,21
Magnetic resonance images provide supporting evidence of glymphatic drainage
from human brain to cervical lymph nodes.23 Other emerging data from both animal models and human studies support
this theory that the brain fluid-exchange and body lymphatics system share
an intimacy and work together for homeostasis, though we are only at the
beginning of understanding how this works.12,22–24
Structural impact and pathology of fluid transport systems
Chronic symptoms associated with PCS have been theorized to be a result of
“gliopathy,” a dysregulation of glial function and drainage in the central
and peripheral nervous system.25 Murine models of glial and glymphatic system function following head
injury has begun to shed light on the effect of brain trauma upon astrocytes
and the effect upon intracranial edema and resolution.26,27
Impaired functioning of the meningeal lymphatic vessels has been theorized
to accelerate the accumulation of toxic amyloid beta protein in the brain parenchyma.28
Upledger illuminated and confirmed the existence of the function and physiology
of the craniosacral system (meninges housing the brain, spinal cord, and
cerebral spinal fluids).29,30 Bodywork
professionals are guided by the premise that structural compressions such as
osseous and/or fascial restrictions can impede fluid movement and exchange,
leading to an array of symptomology.30–34 It is understood
that vertebral bone compression into spinal cord space will create various
neurological symptoms theorized, in part, by the obstruction of cerebral
spinal fluid.35,36 One animal model has demonstrated that blocking
the normal physiologic cerebral spinal fluid drainage sites in the
cribriform plate increases resting intracranial pressure.37
Manual therapies for the central nervous system
Craniosacral therapy
Manual therapies such as craniosacral therapy (CST) emerged from the
science that explored the physiological motion of the central nervous
system.30,38,39 The core
intent of CST is the theoretic interactions with connective tissue at
osseous sites and, using a sustained low-force stretch, elicit a
softening or relaxation response of soft tissues. In turn, a positive
effect upon fluid exchange and the body’s self-correcting actions can occur.30 Studies have illuminated the natural motion of cranial bones,
organ movement, and fluid exchange, depicting and measuring the
dynamic nature of the physiology of the craniosacral system.33,40,41 Based on observations of one animal study on
the structural effects of applying CST, no discernible length
difference was found at cranial bone sutures. However, this study
concluded that perhaps a different biological basis for such treatment
could be at play.42 In a now classic study, changes in the length of the
intracranial falx cerebri membrane were demonstrated with the
application of CST on an embalmed cadaver skull. Recorded relative
change in tissue length ranged between .28 and 1.44 mm at different
sites of the membrane with different CST techniques applied. This
study offers some validation that sustained, gentle, and external
forces have a measurable effect upon the intracranial membrane system.43
Manual lymphatic drainage
Various methods of manual lymphatic drainage (LD) exist, but a
contemporary version aligns with discoveries of anatomical pathways
and lymph tissue mapping, the depths of lymph flow throughout the
body, and using specific rhythms in fluid evacuation.44 Hand pressure used in the Chikly method is extremely light,
matching the tissue dynamics unique to each patient, and only enough
to stimulate the movement of fluid to enhance flow through specific
lymph pathways. This is theorized to activate contractions of the
functional unit of lymph vessels, called lymphangions, which assist
fluid exchange without increasing blood filtration or lymph node
collapse from too great of manually imposed pressure. There exists
extensive innervation from the autonomic nervous system of these
contractile units of the lymphatic system and the conceptualization of
the movement of lymphatic fluids.45,46 LD is believed to influence the whole-body
system through gentle manual evacuation, creating a system-wide
siphoning effect to enhance fluid exchange in multiple systems.45
The use of manual LD by qualified professionals is a treatment option for
lymphedema, sports injuries, and fibromyalgia.44,47–49 Manual LD was first suggested as a specific
treatment of post-contusion and PCS for its anti-edematous effects.50 The evolution and addition of glymphatic treatment methods have
only recently emerged and are based on the practical application of
the combination of methods such as CST, LD, and non-invasive intention
of therapeutic touch.16,45
Existing studies on manual therapies for concussions and brain
injuries
In clinical application, CST has been shown to have positive effect for a
number of chronic syndromes that parallel PCS subtypes, but the body
of data is limited to observational designs and low to moderate
quality of randomized controlled methods.51,52 The credibility of a sham control protocol for
future study of CST was reported.53 A recent study of former pro-football players with PCS showed
statistically greater improvements in range of motion, pain, sleep,
and cognitive function after a series of combined manual therapies.54 A pilot study of 10 active military members had a reduction of
symptoms of post-traumatic stress and head injury through the
application of mixed light touch manual therapies.55 A single blind case series measured clinical outcomes of
soldiers with combat-related head injuries receiving CST and other
manipulation techniques. Results showed statistically greater
improvements in objective and subjective measurements pre- and post-treatment.56 Case studies report positive outcomes of varied uses of manual
therapies for the treatment of PCS.57,58 One case of an athlete with PCS compared brain
scans before and after 15 isolated CST treatments using quantitative
electroencephalogram comparing symptom reduction to changes in
neurological activity.59
Headaches
Headaches are a common symptom of concussion and PCS.7,60 CST and
other manual methods have been shown to have positive effect in the
treatment of headaches, migraines, and trigeminal neuralgia.61–64
Sleep
Sleep has a critical function in ensuring metabolic homeostasis and
clearance of metabolites and is but one important way for the nervous
system to heal from trauma and injury.13,18,65 The
glymphatic system functions mainly during sleep and is largely
disengaged during wakefulness. Sleep debt and a glymphatic system
disruption have been proposed as a mediator of brain trauma, chronic
traumatic encephalopathy, and other neurological disorders.15,66,67
Concussion symptom assessments
Subjective data —from patient
Self-reporting symptom scales are vital for assisting in the medical
management of PCS. Several tracking tools hold substantial overlap
with one another in capturing various pains and neurological
infirmaries, functional impairment, and quality of life.68–70 Although
only some have been empirically studied, clinical users need to be
aware that these scales have evolved rather than being developed scientifically.71 Nonetheless, patient reports of subjective levels of pain,
sensory, and psychological symptoms are crucial to aid in the clinical
search for effective treatments.
Post-Concussion Symptom Checklist (PCSC)
The PCSC was utilized to track outcomes and re-administered periodically
throughout the treatment process with care given to avoid coaching the
patient on symptom manifestations.70,72 Symptoms were also tracked through open-ended
self-reporting by the patient at the onset of each session if he
wished to share them.
Headache Impact Test™ (HIT-6)
The HIT-6 was designed to screen and monitor patients’ severity of
headache pain and the impact on function and quality of life.73 Utilizing six items with a severity rating scale, the HIT-6 has
been shown to be a reliable and valid tool for discriminating the
effect of headache on daily living.74,75 A possible point range of 36–78 reflects the
severity of impact that headaches are interfering with daily quality
of life and function. The HIT-6 was chosen for this particular patient
to track headache symptoms which was also a chief complaint, second
only to sleep disturbances.
Measurement of sleep
Sleep function was tracked through a sleep diary and the patient’s
perception of restfulness and daily energy.
Subjective data —from the clinician
Neurological screenings occurred each session per standard of care,
including pupil and oculomotor status, balance reactions, and general
cognitive assessments conducted through observations of behavior.
Palpation findings from full body assessment of musculoskeletal,
fascia and fluid fields were conducted at the beginning of each
treatment session. Inquiry about mood and stress were made at the
beginning of each session.
Objective data
Quantifiable neurological soft sign and biomarkers not captured on the
PCSC included fixed and dilated pupils, oxygen saturation, and
frequency of urination and thirst.
Case report
The subject, a 24-year-old male, presented with an 18-month history of
persistent neurological and behavioral symptoms reportedly related to
one sports-induced concussion. Onset was in October 2017, following a
head injury while playing in a collegiate-level sport. He reported
being screened by an athletic trainer and having a follow-up medical
assessment. No hospitalization was required. Prolonged rest was
prescribed and adhered to for several months. An eventual referral to
a local academic-medicine concussion clinic was made several months
post-injury due to escalation of unresolved symptoms where
psychological services addressing anxiety and depression and
medications for pain and concentration were prescribed. Medications
reported on patient intake included Prozac, Xanax, and Adderall. He
reported his ability to focus on job tasks improved by the Adderall
but the medications generally worsened “brain fog” and memory. He also
participated in a physical therapy program for vestibular
rehabilitation. Symptoms persisted to the point of full debilitation
by sleep deprivation, increasing dizziness, sensory overload, and
brain fatigue. Suicidal ideation prompted his parents to seek other
recommendations and services.
In the interview with the patient and one of his parents, it was
discovered that he sustained a total of six sports-related concussions
dating back several years. History also included several orthopedic
injuries long since healed (fractures to a foot and nose, and several
bone contusions). The patient affirmed that a whiplash occurred with
the most recent concussion and had originally sought chiropractic care
for neck pain post-injury.
Since symptoms began to intensify, he was forced to take a medical leave
from attending school and working a job that required much traveling.
He stated he could perform job duties, enjoyed them, and felt capable
of the job. However, the sensory intolerances created significant
anxiety and began to reduce his confidence in his job performance. His
tolerance and engagement in favorite activities were at 10% of normal
participation level. He frequently isolated himself to cope with the
sensory overload which added to a sense of helplessness.
Based upon client report and clinical observations, functional problems
were noted on intake (see Figure 1). Initial clinical
findings were also noted (see Figure 2).
Figure 1. Post-concussion symptoms (18 month duration) reported on
intake questionnaire by patient and in personal and parent
interviews.
Figure 2. Initial clinical findings.
Treatment methods employed included the following: (incorporated into
each session as the need arose).
Manual LD techniques (Chikly).45
CST techniques (Upledger).30
Glial and Glymphatic system techniques (Wanveer).16
Goals for series of therapy encounters
Reduce and eliminate stagnant and congested edema of spine,
neck, and head.
Soft tissue mobilization and fascial release methods to
increase general soft tissue flexibility and subtleness
through body to reduce sympathetic tone (through CST).
Facilitate exchange of fluid through all body fluid systems;
reduce interstitial congestion to promote healing and
self-correction of nervous system (through LD).
Neurological rehabilitation strategies to reduce and adapt to
sensory challenges; environmental structuring. (These
methods were not required due to the speed in which
positive changes were experienced and observed with manual
therapies.)
Achieve freedom from pain and neurological dysfunction,
restore/raise quality of life.
Community and work re-entry, adaptations, and modifications
assistance where needed.
Patient and family education on the concepts of manual
therapies.
Client stated just one personal goal: “I just want to be able
to sleep.”
Treatment process
Treatment was conducted in isolation of any other (new) therapy over the
course of three months. The patient participated in eleven, 1-h
sessions. Scheduling sessions were recommended at 2–3 times per week
initially. Following the first session, he requested daily treatment
but was advised to allow his system to acclimate and integrate
treatment effects. The first four sessions were scheduled 3 days
apart. After the fourth session, scheduling was left to his
discretion. Six more appointments were scheduled with 1 week spacing,
and the eleventh session was as a follow-up at the patient’s
discretion 5 weeks later. Each session was an improvisational process
of applying the various manual therapies and techniques, based upon
whole-body assessment of primary and secondary structural and fluid
findings.
Results and treatment outcomes
Quantitative data were collected through self-reporting of severity of
symptoms using the PCSC, the HIT-6, and clinical observations.
Sessions began most often with an invitation for him to report
whatever symptom(s) felt most pressing. Quality of life measurements
were self-reporting of sleep function, brain fog, ability to “get
through the day,” ability to tolerate sensory aspects of daily events,
and endurance for mental and physical activities. All were recorded in
the daily notes. A total of five recordings of the PCSC and three
recordings of the HIT-6 were captured over the course of the treatment
series (see Figure
3). Based upon both verbal responses from the patient as
well as observation, some particular treatment techniques demonstrated
a direct correlation to a reduction of a specific symptom (see Figure 4).
Figure 3. Self-reported changes of persistent concussion symptoms
related to treatment intervention; measured through
symptom tracking methods.
Figure 4. Based upon patient’s verbal responses and direct observation
in treatment, several techniques had a direct correlation
to a reduction of specific symptoms.
Sleep was restored following the first treatment as he reported sleeping
12 h each night between session one and two. Sleep continued to remain
at normalized levels throughout the treatment process.
Sessions were not based upon following specific protocol sequence. A
narrative summary of this improvisational and experiential treatment
process is reflected in a summary of the daily notes (see Figure 5).
Figure 5. Treatment Progression Depicted through Daily Notes.
Abbreviated daily notes to reflect the full therapeutic
process of applying CST and LD to treat symptoms of
concussion. See KEY for term definitions.
Six month follow-up
A 6-month follow-up (via telephone conversation) revealed sustained
abatement of PCS symptoms and the patient resumed educational pursuits
and gainful employment. His parents recommended that he continue to
receive maintenance therapy but he voiced concerned over his mounting
financial debt. He denied that symptoms were interfering with daily
activities and quality of life. The patient’s perspective about these
therapies was highly positive.
Discussion
This article offers a hypothesis that persistent symptoms of PCS could be, in
part, a result of compromised glymphatic and lymphatic pathway flow stemming
from restrictions of movement and balanced position of osseous and soft
tissue structures. The theoretical constructs of CST suggest when fascial
membranes such as the dura and other meningeal layers and/or cranial plates
and vertebral column may be in a compressive state, leading to neurological
and/or behavioral symptoms.30,32,76 The theoretical
constructs of LD is that gentle, manual evacuation of lymphatic channels
following anatomical mapping enhances a whole-body fluid exchange and
removal of cellular wastes between interconnecting fluid systems.45,49
Only through whole-body palpation assessment was the first clinical discoveries
made in this patient. Asymmetrical rib cage alignment, with sub-optimal
breath expansion and lowered oxygen saturation, was subjectively assessed
and CST techniques were immediately employed. The second discovery was
persistent edema through anterior and lateral cervical chains, over the
expanse of scalp lymphatics, and engorged in bilateral occipital nodes at
the cranial base. It is a reasonable assumption that edema may have occurred
at the time of injury but after 18 months, edema and interstitial fluid
stagnation would be expected to have resolved. That was not the case for
this athlete. Palpation for (chronic) edema is a skill set learned through
specific LD training methods.
Sleep was the first of the chronic symptoms to demonstrate an effect from
treatment, after just one, 1-h treatment session. It could be suggested that
fluid stagnation in and around the central nervous system contributed to the
adverse head pressure pain with impact on the lack of restorative sleep (as
surmised by the patient’s insights). It could be suggested that quality of
breathing function may also have had a negative effect upon sleep. It is
apparent through the stream of daily notes that the first treatment in and
around the thoracic body and rib cage (consisting of fascia mobilization
following CST methods) produced immediate elevation in oxygen saturation. It
was also immediately apparent that LD through the central spinal lymph node
confluences and pathways produced an immediate response of head pressure
relief. Sleep resolved to satisfactory levels for the patient and remained
so for the remainder of the treatment series, and at the 6-month
follow-up.
Other neurological symptoms resolved at different, but steady rates, as
reflected on the periodic scoring of the PCSC. To avoid or minimize effects
of coaching or influencing the patient on symptom reporting, freely
expressed symptom declarations were documented prior to the administration
of repeated PCSC scoring. It is with a high rate of certainty that the PCSC
yielded an accurate expression of the patient’s self-reported experiences in
symptom status through the treatment process.
Therapeutic touch and emotional support are aspects of most forms of manual
therapies. It is possible that any placebo or autonomic calming effect of
therapeutic touch contributed to the reduction of symptoms. However,
resolution of certain chronic symptoms did correlate with the application of
only specific treatment techniques (see Figure 4). Mood, cognitive
function, and emotional well-being improved and the patient attributed this
to reduction and elimination of head pain, brain fatigue, and sensory
sensitivities. Quality of life improved and he returned to his occupational
tasks of completing college and finding a less stressful, yet meaningful,
job.
The literature supports interventions for PCS which include psychological,
cervical, and vestibular rehabilitation.5 The differential methods of CST and LD as distinct manual therapies
have yet to be fully explored as options for PCS, though emerging studies
indicate CST being used clinically with functional PCS subtypes. One
contraindication for CST is not to apply during acute stages of brain injury
when increased intracranial pressure is present.30 Contraindications for LD have been cited and include acute infection
or inflammatory disease process, thrombosis or phlebitis, acute hemorrhage,
active malignant ailments, and acute heart problems as LD increases cardiac
load.44,45
Future study could possibly isolate the impact CST and LD modalities have upon
sleep in PCS. Research of the fluid exchange models of the nervous system
could explore possible correlations to persistent symptoms of PCS.
Furthermore, efficacy studies into therapies such as CST and LD might be
aided by advancements of proving and measuring the exchange of fluids where
glymphatic and lymphatic structures merge.
Conclusions
This case report reflects one collegiate athlete’s unique constellation of PCS
and the self-reported reduction of persistent symptoms through the
experiential process of CST and LD intervention. There is little published
evidence of the efficacy of CST and/or LD on the symptoms of PCS, though
both have been utilized in clinics internationally for over 3 decades. Rest
allowance and other therapy interventions had been previously trialed for
18 months, though no concussion symptom tracking was completed or available
from previous records for comparative purposes. Previous pharmacologic
treatment and vestibular rehabilitation for this patient were self-reported
to have reduced symptoms of attention deficits and balance in climbing
stairs, respectively. Other psychology and physical medicine endeavors had
been trialed over the year and a half, and per his declaration, “Did not
help heal me. Medications only helped me get through the work day; they did
not take away the symptoms.”
The author, an occupational therapist with 20 years of experience applying CST
and LD in clinical practice, admits to a strong inherent bias. The strength
of this case study, however, is that treatment was provided in isolation of
any intervention other than his established medication usage. It could be
said that placebo effect had been controlled for where specific treatment
techniques clearly resolved some specific symptoms, but not all. Other
symptoms resolved over time and may reflect effects of the restoration of
sleep and elevation of mood. Though generalization of the findings in this
case cannot be applied to the greater population of patients with
concussions and brain injuries, this case does suggest that CST and LD are
valuable treatment options for PCS and worthy of future study.
We thank all the clients and their families who trust the wisdom of structural
medicine as we continue to merge theory with day-to-day clinical practices.
We are forever indebted to your tenacity and steadfastness to find and
secure appropriate help.
Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article: Any conflicts of interests are implied by the author being an
active clinician where these techniques and therapeutic strategies are
utilized in the clinic setting.
Ethical approval: Our institution does not require ethical approval for reporting
individual cases or case series.
Funding: The author(s) received no financial support for the research, authorship,
and/or publication of this article.
Informed consent: Written informed consent was obtained from the patient(s) for their
anonymized information to be published in this article. This informed
consent is maintained in the medical records for this patient.
ORCID iD: Susan Vaughan Kratz https://orcid.org/0000-0003-2018-8365 | ALPRAZOLAM, AMPHETAMINE ASPARTATE\AMPHETAMINE SULFATE\DEXTROAMPHETAMINE SACCHARATE\DEXTROAMPHETAMINE SULFATE, FLUOXETINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33628444 | 18,976,097 | 2021 |
What was the outcome of reaction 'Cerebral disorder'? | Case report: Manual therapies promote resolution of persistent post-concussion symptoms in a 24-year-old athlete.
This case report illustrates the treatment outcomes of a collegiate athlete presenting with an 18-month history of post-concussion syndrome who received a series of mixed manual therapies in isolation of other therapy. Persistent symptoms were self-reported as debilitating, contributing to self-removal from participation in school, work, and leisure activities. Patient and parent interviews captured the history of multiple concussions and other sports-related injuries. Neurological screening and activities of daily living were baseline measured. Post-Concussion Symptom Checklist and Headache Impact Test-6™ were utilized to track symptom severity. Treatments applied included craniosacral therapy, manual lymphatic drainage, and glymphatic techniques. Eleven treatment sessions were administered over 3 months. Results indicated restoration of oxygen saturation, normalized pupil reactivity, and satisfactory sleep. Post-concussion syndrome symptom severity was reduced by 87% as reflected by accumulative Post-Concussion Symptom Checklist scores. Relief from chronic headaches was achieved, reflected by Headache Impact Test-6 scores. Restoration of mood and quality of life were reported. A 6-month follow-up revealed symptoms remained abated with full re-engagement of daily activities. The author hypothesized that post-concussion syndrome symptoms were related to compression of craniosacral system structures and lymphatic fluid stagnation that contributed to head pressure pain, severe sleep deprivation, and multiple neurological and psychological symptoms. Positive outcomes over a relatively short period of time without adverse effects suggest these therapies may offer viable options for the treatment of post-concussion syndrome.
Introduction
Serious awareness over the past decade of the short- and long-term effects of
traumatic head trauma leading to concussion has prompted rigorous diagnostic
and clinical management endeavors.1,2 Sources report the
number of sports-related concussions receiving medical attention in the
United States ranged between 1.6 million and 3.8 million annually.3,4
Persistent symptoms following concussions may not reflect a single
pathophysiological entity and likely describes individualized patterns of
non-specific, post-traumatic symptoms that may be linked to coexisting
and/or confounding issues.1,5 Subtypes of
post-concussion syndrome (PCS) are now recognized by physiological,
cervicogenic, and neuropsychological manifestations.2,4,6–9
A fluid model: glymphatic and meningeal lymphatic systems
The existence of a cerebral fluid-exchange system (different than blood
vessels) has been long debated but new discoveries have intensified research
into fluid dynamics within the brain parenchyma.10 Glial cells have been shown to create a possible architectural system
among the microvasculature which appears to match blood flow with neuronal firing.11 Pathways formed by glial cells and endothelial walls of penetrating
blood vessels have been suggested to serve as a physiological cleansing
mechanism called the “glymphatic system.”10,12,13 These pathways
appear to form perivascular channels by astroglia end-feet where monitoring
and active clearing of the neuronal terrain may occur.14–16
Furthermore, it is theorized that this cellular transportation network also
serves to distribute nutritional compounds and neuromodulators.15 Brain-wide perivascular pathways, believed to facilitate
cerebrospinal fluid (CSF) flow through the parenchyma and the movement of
interstitial solutes, have been captured by contrast-enhanced magnetic
resonance imaging (MRI) scan.13 The theoretical function then of this proposed glymphatic system
serves to support perfusion of CSF and interstitial fluids as a means of
pseudo-lymphatic function of the nervous system, elucidating a possible
mechanism of how the brain cleans itself through elimination of soluble
proteins and metabolites.10,13,17–19
However, there are also proponents who argue a glymphatic system as proposed
needs to be re-evaluated, accounting for more specifics to cerebrovascular
fluid transport.20 Regardless, there is within the brain a mechanism that moves fluids
through a cleansing process, shown to be active during restorative sleep and
rather inactive during wakefulness.15
Lymphatic system discovery
In addition, a recent identification of lymphatic projections into meningeal
membranes within the cranial vault suggests a functional proximity and/or
connection between the brain pseudo-lymphatic and the whole-body lymphatic
network.21,22 Furthermore, lymphatic vessels were discovered
lining the dura sinuses of the meninges and in turn have been shown to carry
both fluid and immune cells from the CSF, connecting to deep cervical lymph
nodes and into the peripheral venous return system.17,21
Magnetic resonance images provide supporting evidence of glymphatic drainage
from human brain to cervical lymph nodes.23 Other emerging data from both animal models and human studies support
this theory that the brain fluid-exchange and body lymphatics system share
an intimacy and work together for homeostasis, though we are only at the
beginning of understanding how this works.12,22–24
Structural impact and pathology of fluid transport systems
Chronic symptoms associated with PCS have been theorized to be a result of
“gliopathy,” a dysregulation of glial function and drainage in the central
and peripheral nervous system.25 Murine models of glial and glymphatic system function following head
injury has begun to shed light on the effect of brain trauma upon astrocytes
and the effect upon intracranial edema and resolution.26,27
Impaired functioning of the meningeal lymphatic vessels has been theorized
to accelerate the accumulation of toxic amyloid beta protein in the brain parenchyma.28
Upledger illuminated and confirmed the existence of the function and physiology
of the craniosacral system (meninges housing the brain, spinal cord, and
cerebral spinal fluids).29,30 Bodywork
professionals are guided by the premise that structural compressions such as
osseous and/or fascial restrictions can impede fluid movement and exchange,
leading to an array of symptomology.30–34 It is understood
that vertebral bone compression into spinal cord space will create various
neurological symptoms theorized, in part, by the obstruction of cerebral
spinal fluid.35,36 One animal model has demonstrated that blocking
the normal physiologic cerebral spinal fluid drainage sites in the
cribriform plate increases resting intracranial pressure.37
Manual therapies for the central nervous system
Craniosacral therapy
Manual therapies such as craniosacral therapy (CST) emerged from the
science that explored the physiological motion of the central nervous
system.30,38,39 The core
intent of CST is the theoretic interactions with connective tissue at
osseous sites and, using a sustained low-force stretch, elicit a
softening or relaxation response of soft tissues. In turn, a positive
effect upon fluid exchange and the body’s self-correcting actions can occur.30 Studies have illuminated the natural motion of cranial bones,
organ movement, and fluid exchange, depicting and measuring the
dynamic nature of the physiology of the craniosacral system.33,40,41 Based on observations of one animal study on
the structural effects of applying CST, no discernible length
difference was found at cranial bone sutures. However, this study
concluded that perhaps a different biological basis for such treatment
could be at play.42 In a now classic study, changes in the length of the
intracranial falx cerebri membrane were demonstrated with the
application of CST on an embalmed cadaver skull. Recorded relative
change in tissue length ranged between .28 and 1.44 mm at different
sites of the membrane with different CST techniques applied. This
study offers some validation that sustained, gentle, and external
forces have a measurable effect upon the intracranial membrane system.43
Manual lymphatic drainage
Various methods of manual lymphatic drainage (LD) exist, but a
contemporary version aligns with discoveries of anatomical pathways
and lymph tissue mapping, the depths of lymph flow throughout the
body, and using specific rhythms in fluid evacuation.44 Hand pressure used in the Chikly method is extremely light,
matching the tissue dynamics unique to each patient, and only enough
to stimulate the movement of fluid to enhance flow through specific
lymph pathways. This is theorized to activate contractions of the
functional unit of lymph vessels, called lymphangions, which assist
fluid exchange without increasing blood filtration or lymph node
collapse from too great of manually imposed pressure. There exists
extensive innervation from the autonomic nervous system of these
contractile units of the lymphatic system and the conceptualization of
the movement of lymphatic fluids.45,46 LD is believed to influence the whole-body
system through gentle manual evacuation, creating a system-wide
siphoning effect to enhance fluid exchange in multiple systems.45
The use of manual LD by qualified professionals is a treatment option for
lymphedema, sports injuries, and fibromyalgia.44,47–49 Manual LD was first suggested as a specific
treatment of post-contusion and PCS for its anti-edematous effects.50 The evolution and addition of glymphatic treatment methods have
only recently emerged and are based on the practical application of
the combination of methods such as CST, LD, and non-invasive intention
of therapeutic touch.16,45
Existing studies on manual therapies for concussions and brain
injuries
In clinical application, CST has been shown to have positive effect for a
number of chronic syndromes that parallel PCS subtypes, but the body
of data is limited to observational designs and low to moderate
quality of randomized controlled methods.51,52 The credibility of a sham control protocol for
future study of CST was reported.53 A recent study of former pro-football players with PCS showed
statistically greater improvements in range of motion, pain, sleep,
and cognitive function after a series of combined manual therapies.54 A pilot study of 10 active military members had a reduction of
symptoms of post-traumatic stress and head injury through the
application of mixed light touch manual therapies.55 A single blind case series measured clinical outcomes of
soldiers with combat-related head injuries receiving CST and other
manipulation techniques. Results showed statistically greater
improvements in objective and subjective measurements pre- and post-treatment.56 Case studies report positive outcomes of varied uses of manual
therapies for the treatment of PCS.57,58 One case of an athlete with PCS compared brain
scans before and after 15 isolated CST treatments using quantitative
electroencephalogram comparing symptom reduction to changes in
neurological activity.59
Headaches
Headaches are a common symptom of concussion and PCS.7,60 CST and
other manual methods have been shown to have positive effect in the
treatment of headaches, migraines, and trigeminal neuralgia.61–64
Sleep
Sleep has a critical function in ensuring metabolic homeostasis and
clearance of metabolites and is but one important way for the nervous
system to heal from trauma and injury.13,18,65 The
glymphatic system functions mainly during sleep and is largely
disengaged during wakefulness. Sleep debt and a glymphatic system
disruption have been proposed as a mediator of brain trauma, chronic
traumatic encephalopathy, and other neurological disorders.15,66,67
Concussion symptom assessments
Subjective data —from patient
Self-reporting symptom scales are vital for assisting in the medical
management of PCS. Several tracking tools hold substantial overlap
with one another in capturing various pains and neurological
infirmaries, functional impairment, and quality of life.68–70 Although
only some have been empirically studied, clinical users need to be
aware that these scales have evolved rather than being developed scientifically.71 Nonetheless, patient reports of subjective levels of pain,
sensory, and psychological symptoms are crucial to aid in the clinical
search for effective treatments.
Post-Concussion Symptom Checklist (PCSC)
The PCSC was utilized to track outcomes and re-administered periodically
throughout the treatment process with care given to avoid coaching the
patient on symptom manifestations.70,72 Symptoms were also tracked through open-ended
self-reporting by the patient at the onset of each session if he
wished to share them.
Headache Impact Test™ (HIT-6)
The HIT-6 was designed to screen and monitor patients’ severity of
headache pain and the impact on function and quality of life.73 Utilizing six items with a severity rating scale, the HIT-6 has
been shown to be a reliable and valid tool for discriminating the
effect of headache on daily living.74,75 A possible point range of 36–78 reflects the
severity of impact that headaches are interfering with daily quality
of life and function. The HIT-6 was chosen for this particular patient
to track headache symptoms which was also a chief complaint, second
only to sleep disturbances.
Measurement of sleep
Sleep function was tracked through a sleep diary and the patient’s
perception of restfulness and daily energy.
Subjective data —from the clinician
Neurological screenings occurred each session per standard of care,
including pupil and oculomotor status, balance reactions, and general
cognitive assessments conducted through observations of behavior.
Palpation findings from full body assessment of musculoskeletal,
fascia and fluid fields were conducted at the beginning of each
treatment session. Inquiry about mood and stress were made at the
beginning of each session.
Objective data
Quantifiable neurological soft sign and biomarkers not captured on the
PCSC included fixed and dilated pupils, oxygen saturation, and
frequency of urination and thirst.
Case report
The subject, a 24-year-old male, presented with an 18-month history of
persistent neurological and behavioral symptoms reportedly related to
one sports-induced concussion. Onset was in October 2017, following a
head injury while playing in a collegiate-level sport. He reported
being screened by an athletic trainer and having a follow-up medical
assessment. No hospitalization was required. Prolonged rest was
prescribed and adhered to for several months. An eventual referral to
a local academic-medicine concussion clinic was made several months
post-injury due to escalation of unresolved symptoms where
psychological services addressing anxiety and depression and
medications for pain and concentration were prescribed. Medications
reported on patient intake included Prozac, Xanax, and Adderall. He
reported his ability to focus on job tasks improved by the Adderall
but the medications generally worsened “brain fog” and memory. He also
participated in a physical therapy program for vestibular
rehabilitation. Symptoms persisted to the point of full debilitation
by sleep deprivation, increasing dizziness, sensory overload, and
brain fatigue. Suicidal ideation prompted his parents to seek other
recommendations and services.
In the interview with the patient and one of his parents, it was
discovered that he sustained a total of six sports-related concussions
dating back several years. History also included several orthopedic
injuries long since healed (fractures to a foot and nose, and several
bone contusions). The patient affirmed that a whiplash occurred with
the most recent concussion and had originally sought chiropractic care
for neck pain post-injury.
Since symptoms began to intensify, he was forced to take a medical leave
from attending school and working a job that required much traveling.
He stated he could perform job duties, enjoyed them, and felt capable
of the job. However, the sensory intolerances created significant
anxiety and began to reduce his confidence in his job performance. His
tolerance and engagement in favorite activities were at 10% of normal
participation level. He frequently isolated himself to cope with the
sensory overload which added to a sense of helplessness.
Based upon client report and clinical observations, functional problems
were noted on intake (see Figure 1). Initial clinical
findings were also noted (see Figure 2).
Figure 1. Post-concussion symptoms (18 month duration) reported on
intake questionnaire by patient and in personal and parent
interviews.
Figure 2. Initial clinical findings.
Treatment methods employed included the following: (incorporated into
each session as the need arose).
Manual LD techniques (Chikly).45
CST techniques (Upledger).30
Glial and Glymphatic system techniques (Wanveer).16
Goals for series of therapy encounters
Reduce and eliminate stagnant and congested edema of spine,
neck, and head.
Soft tissue mobilization and fascial release methods to
increase general soft tissue flexibility and subtleness
through body to reduce sympathetic tone (through CST).
Facilitate exchange of fluid through all body fluid systems;
reduce interstitial congestion to promote healing and
self-correction of nervous system (through LD).
Neurological rehabilitation strategies to reduce and adapt to
sensory challenges; environmental structuring. (These
methods were not required due to the speed in which
positive changes were experienced and observed with manual
therapies.)
Achieve freedom from pain and neurological dysfunction,
restore/raise quality of life.
Community and work re-entry, adaptations, and modifications
assistance where needed.
Patient and family education on the concepts of manual
therapies.
Client stated just one personal goal: “I just want to be able
to sleep.”
Treatment process
Treatment was conducted in isolation of any other (new) therapy over the
course of three months. The patient participated in eleven, 1-h
sessions. Scheduling sessions were recommended at 2–3 times per week
initially. Following the first session, he requested daily treatment
but was advised to allow his system to acclimate and integrate
treatment effects. The first four sessions were scheduled 3 days
apart. After the fourth session, scheduling was left to his
discretion. Six more appointments were scheduled with 1 week spacing,
and the eleventh session was as a follow-up at the patient’s
discretion 5 weeks later. Each session was an improvisational process
of applying the various manual therapies and techniques, based upon
whole-body assessment of primary and secondary structural and fluid
findings.
Results and treatment outcomes
Quantitative data were collected through self-reporting of severity of
symptoms using the PCSC, the HIT-6, and clinical observations.
Sessions began most often with an invitation for him to report
whatever symptom(s) felt most pressing. Quality of life measurements
were self-reporting of sleep function, brain fog, ability to “get
through the day,” ability to tolerate sensory aspects of daily events,
and endurance for mental and physical activities. All were recorded in
the daily notes. A total of five recordings of the PCSC and three
recordings of the HIT-6 were captured over the course of the treatment
series (see Figure
3). Based upon both verbal responses from the patient as
well as observation, some particular treatment techniques demonstrated
a direct correlation to a reduction of a specific symptom (see Figure 4).
Figure 3. Self-reported changes of persistent concussion symptoms
related to treatment intervention; measured through
symptom tracking methods.
Figure 4. Based upon patient’s verbal responses and direct observation
in treatment, several techniques had a direct correlation
to a reduction of specific symptoms.
Sleep was restored following the first treatment as he reported sleeping
12 h each night between session one and two. Sleep continued to remain
at normalized levels throughout the treatment process.
Sessions were not based upon following specific protocol sequence. A
narrative summary of this improvisational and experiential treatment
process is reflected in a summary of the daily notes (see Figure 5).
Figure 5. Treatment Progression Depicted through Daily Notes.
Abbreviated daily notes to reflect the full therapeutic
process of applying CST and LD to treat symptoms of
concussion. See KEY for term definitions.
Six month follow-up
A 6-month follow-up (via telephone conversation) revealed sustained
abatement of PCS symptoms and the patient resumed educational pursuits
and gainful employment. His parents recommended that he continue to
receive maintenance therapy but he voiced concerned over his mounting
financial debt. He denied that symptoms were interfering with daily
activities and quality of life. The patient’s perspective about these
therapies was highly positive.
Discussion
This article offers a hypothesis that persistent symptoms of PCS could be, in
part, a result of compromised glymphatic and lymphatic pathway flow stemming
from restrictions of movement and balanced position of osseous and soft
tissue structures. The theoretical constructs of CST suggest when fascial
membranes such as the dura and other meningeal layers and/or cranial plates
and vertebral column may be in a compressive state, leading to neurological
and/or behavioral symptoms.30,32,76 The theoretical
constructs of LD is that gentle, manual evacuation of lymphatic channels
following anatomical mapping enhances a whole-body fluid exchange and
removal of cellular wastes between interconnecting fluid systems.45,49
Only through whole-body palpation assessment was the first clinical discoveries
made in this patient. Asymmetrical rib cage alignment, with sub-optimal
breath expansion and lowered oxygen saturation, was subjectively assessed
and CST techniques were immediately employed. The second discovery was
persistent edema through anterior and lateral cervical chains, over the
expanse of scalp lymphatics, and engorged in bilateral occipital nodes at
the cranial base. It is a reasonable assumption that edema may have occurred
at the time of injury but after 18 months, edema and interstitial fluid
stagnation would be expected to have resolved. That was not the case for
this athlete. Palpation for (chronic) edema is a skill set learned through
specific LD training methods.
Sleep was the first of the chronic symptoms to demonstrate an effect from
treatment, after just one, 1-h treatment session. It could be suggested that
fluid stagnation in and around the central nervous system contributed to the
adverse head pressure pain with impact on the lack of restorative sleep (as
surmised by the patient’s insights). It could be suggested that quality of
breathing function may also have had a negative effect upon sleep. It is
apparent through the stream of daily notes that the first treatment in and
around the thoracic body and rib cage (consisting of fascia mobilization
following CST methods) produced immediate elevation in oxygen saturation. It
was also immediately apparent that LD through the central spinal lymph node
confluences and pathways produced an immediate response of head pressure
relief. Sleep resolved to satisfactory levels for the patient and remained
so for the remainder of the treatment series, and at the 6-month
follow-up.
Other neurological symptoms resolved at different, but steady rates, as
reflected on the periodic scoring of the PCSC. To avoid or minimize effects
of coaching or influencing the patient on symptom reporting, freely
expressed symptom declarations were documented prior to the administration
of repeated PCSC scoring. It is with a high rate of certainty that the PCSC
yielded an accurate expression of the patient’s self-reported experiences in
symptom status through the treatment process.
Therapeutic touch and emotional support are aspects of most forms of manual
therapies. It is possible that any placebo or autonomic calming effect of
therapeutic touch contributed to the reduction of symptoms. However,
resolution of certain chronic symptoms did correlate with the application of
only specific treatment techniques (see Figure 4). Mood, cognitive
function, and emotional well-being improved and the patient attributed this
to reduction and elimination of head pain, brain fatigue, and sensory
sensitivities. Quality of life improved and he returned to his occupational
tasks of completing college and finding a less stressful, yet meaningful,
job.
The literature supports interventions for PCS which include psychological,
cervical, and vestibular rehabilitation.5 The differential methods of CST and LD as distinct manual therapies
have yet to be fully explored as options for PCS, though emerging studies
indicate CST being used clinically with functional PCS subtypes. One
contraindication for CST is not to apply during acute stages of brain injury
when increased intracranial pressure is present.30 Contraindications for LD have been cited and include acute infection
or inflammatory disease process, thrombosis or phlebitis, acute hemorrhage,
active malignant ailments, and acute heart problems as LD increases cardiac
load.44,45
Future study could possibly isolate the impact CST and LD modalities have upon
sleep in PCS. Research of the fluid exchange models of the nervous system
could explore possible correlations to persistent symptoms of PCS.
Furthermore, efficacy studies into therapies such as CST and LD might be
aided by advancements of proving and measuring the exchange of fluids where
glymphatic and lymphatic structures merge.
Conclusions
This case report reflects one collegiate athlete’s unique constellation of PCS
and the self-reported reduction of persistent symptoms through the
experiential process of CST and LD intervention. There is little published
evidence of the efficacy of CST and/or LD on the symptoms of PCS, though
both have been utilized in clinics internationally for over 3 decades. Rest
allowance and other therapy interventions had been previously trialed for
18 months, though no concussion symptom tracking was completed or available
from previous records for comparative purposes. Previous pharmacologic
treatment and vestibular rehabilitation for this patient were self-reported
to have reduced symptoms of attention deficits and balance in climbing
stairs, respectively. Other psychology and physical medicine endeavors had
been trialed over the year and a half, and per his declaration, “Did not
help heal me. Medications only helped me get through the work day; they did
not take away the symptoms.”
The author, an occupational therapist with 20 years of experience applying CST
and LD in clinical practice, admits to a strong inherent bias. The strength
of this case study, however, is that treatment was provided in isolation of
any intervention other than his established medication usage. It could be
said that placebo effect had been controlled for where specific treatment
techniques clearly resolved some specific symptoms, but not all. Other
symptoms resolved over time and may reflect effects of the restoration of
sleep and elevation of mood. Though generalization of the findings in this
case cannot be applied to the greater population of patients with
concussions and brain injuries, this case does suggest that CST and LD are
valuable treatment options for PCS and worthy of future study.
We thank all the clients and their families who trust the wisdom of structural
medicine as we continue to merge theory with day-to-day clinical practices.
We are forever indebted to your tenacity and steadfastness to find and
secure appropriate help.
Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article: Any conflicts of interests are implied by the author being an
active clinician where these techniques and therapeutic strategies are
utilized in the clinic setting.
Ethical approval: Our institution does not require ethical approval for reporting
individual cases or case series.
Funding: The author(s) received no financial support for the research, authorship,
and/or publication of this article.
Informed consent: Written informed consent was obtained from the patient(s) for their
anonymized information to be published in this article. This informed
consent is maintained in the medical records for this patient.
ORCID iD: Susan Vaughan Kratz https://orcid.org/0000-0003-2018-8365 | Recovering | ReactionOutcome | CC BY-NC | 33628444 | 18,976,097 | 2021 |
What was the outcome of reaction 'Condition aggravated'? | Case report: Manual therapies promote resolution of persistent post-concussion symptoms in a 24-year-old athlete.
This case report illustrates the treatment outcomes of a collegiate athlete presenting with an 18-month history of post-concussion syndrome who received a series of mixed manual therapies in isolation of other therapy. Persistent symptoms were self-reported as debilitating, contributing to self-removal from participation in school, work, and leisure activities. Patient and parent interviews captured the history of multiple concussions and other sports-related injuries. Neurological screening and activities of daily living were baseline measured. Post-Concussion Symptom Checklist and Headache Impact Test-6™ were utilized to track symptom severity. Treatments applied included craniosacral therapy, manual lymphatic drainage, and glymphatic techniques. Eleven treatment sessions were administered over 3 months. Results indicated restoration of oxygen saturation, normalized pupil reactivity, and satisfactory sleep. Post-concussion syndrome symptom severity was reduced by 87% as reflected by accumulative Post-Concussion Symptom Checklist scores. Relief from chronic headaches was achieved, reflected by Headache Impact Test-6 scores. Restoration of mood and quality of life were reported. A 6-month follow-up revealed symptoms remained abated with full re-engagement of daily activities. The author hypothesized that post-concussion syndrome symptoms were related to compression of craniosacral system structures and lymphatic fluid stagnation that contributed to head pressure pain, severe sleep deprivation, and multiple neurological and psychological symptoms. Positive outcomes over a relatively short period of time without adverse effects suggest these therapies may offer viable options for the treatment of post-concussion syndrome.
Introduction
Serious awareness over the past decade of the short- and long-term effects of
traumatic head trauma leading to concussion has prompted rigorous diagnostic
and clinical management endeavors.1,2 Sources report the
number of sports-related concussions receiving medical attention in the
United States ranged between 1.6 million and 3.8 million annually.3,4
Persistent symptoms following concussions may not reflect a single
pathophysiological entity and likely describes individualized patterns of
non-specific, post-traumatic symptoms that may be linked to coexisting
and/or confounding issues.1,5 Subtypes of
post-concussion syndrome (PCS) are now recognized by physiological,
cervicogenic, and neuropsychological manifestations.2,4,6–9
A fluid model: glymphatic and meningeal lymphatic systems
The existence of a cerebral fluid-exchange system (different than blood
vessels) has been long debated but new discoveries have intensified research
into fluid dynamics within the brain parenchyma.10 Glial cells have been shown to create a possible architectural system
among the microvasculature which appears to match blood flow with neuronal firing.11 Pathways formed by glial cells and endothelial walls of penetrating
blood vessels have been suggested to serve as a physiological cleansing
mechanism called the “glymphatic system.”10,12,13 These pathways
appear to form perivascular channels by astroglia end-feet where monitoring
and active clearing of the neuronal terrain may occur.14–16
Furthermore, it is theorized that this cellular transportation network also
serves to distribute nutritional compounds and neuromodulators.15 Brain-wide perivascular pathways, believed to facilitate
cerebrospinal fluid (CSF) flow through the parenchyma and the movement of
interstitial solutes, have been captured by contrast-enhanced magnetic
resonance imaging (MRI) scan.13 The theoretical function then of this proposed glymphatic system
serves to support perfusion of CSF and interstitial fluids as a means of
pseudo-lymphatic function of the nervous system, elucidating a possible
mechanism of how the brain cleans itself through elimination of soluble
proteins and metabolites.10,13,17–19
However, there are also proponents who argue a glymphatic system as proposed
needs to be re-evaluated, accounting for more specifics to cerebrovascular
fluid transport.20 Regardless, there is within the brain a mechanism that moves fluids
through a cleansing process, shown to be active during restorative sleep and
rather inactive during wakefulness.15
Lymphatic system discovery
In addition, a recent identification of lymphatic projections into meningeal
membranes within the cranial vault suggests a functional proximity and/or
connection between the brain pseudo-lymphatic and the whole-body lymphatic
network.21,22 Furthermore, lymphatic vessels were discovered
lining the dura sinuses of the meninges and in turn have been shown to carry
both fluid and immune cells from the CSF, connecting to deep cervical lymph
nodes and into the peripheral venous return system.17,21
Magnetic resonance images provide supporting evidence of glymphatic drainage
from human brain to cervical lymph nodes.23 Other emerging data from both animal models and human studies support
this theory that the brain fluid-exchange and body lymphatics system share
an intimacy and work together for homeostasis, though we are only at the
beginning of understanding how this works.12,22–24
Structural impact and pathology of fluid transport systems
Chronic symptoms associated with PCS have been theorized to be a result of
“gliopathy,” a dysregulation of glial function and drainage in the central
and peripheral nervous system.25 Murine models of glial and glymphatic system function following head
injury has begun to shed light on the effect of brain trauma upon astrocytes
and the effect upon intracranial edema and resolution.26,27
Impaired functioning of the meningeal lymphatic vessels has been theorized
to accelerate the accumulation of toxic amyloid beta protein in the brain parenchyma.28
Upledger illuminated and confirmed the existence of the function and physiology
of the craniosacral system (meninges housing the brain, spinal cord, and
cerebral spinal fluids).29,30 Bodywork
professionals are guided by the premise that structural compressions such as
osseous and/or fascial restrictions can impede fluid movement and exchange,
leading to an array of symptomology.30–34 It is understood
that vertebral bone compression into spinal cord space will create various
neurological symptoms theorized, in part, by the obstruction of cerebral
spinal fluid.35,36 One animal model has demonstrated that blocking
the normal physiologic cerebral spinal fluid drainage sites in the
cribriform plate increases resting intracranial pressure.37
Manual therapies for the central nervous system
Craniosacral therapy
Manual therapies such as craniosacral therapy (CST) emerged from the
science that explored the physiological motion of the central nervous
system.30,38,39 The core
intent of CST is the theoretic interactions with connective tissue at
osseous sites and, using a sustained low-force stretch, elicit a
softening or relaxation response of soft tissues. In turn, a positive
effect upon fluid exchange and the body’s self-correcting actions can occur.30 Studies have illuminated the natural motion of cranial bones,
organ movement, and fluid exchange, depicting and measuring the
dynamic nature of the physiology of the craniosacral system.33,40,41 Based on observations of one animal study on
the structural effects of applying CST, no discernible length
difference was found at cranial bone sutures. However, this study
concluded that perhaps a different biological basis for such treatment
could be at play.42 In a now classic study, changes in the length of the
intracranial falx cerebri membrane were demonstrated with the
application of CST on an embalmed cadaver skull. Recorded relative
change in tissue length ranged between .28 and 1.44 mm at different
sites of the membrane with different CST techniques applied. This
study offers some validation that sustained, gentle, and external
forces have a measurable effect upon the intracranial membrane system.43
Manual lymphatic drainage
Various methods of manual lymphatic drainage (LD) exist, but a
contemporary version aligns with discoveries of anatomical pathways
and lymph tissue mapping, the depths of lymph flow throughout the
body, and using specific rhythms in fluid evacuation.44 Hand pressure used in the Chikly method is extremely light,
matching the tissue dynamics unique to each patient, and only enough
to stimulate the movement of fluid to enhance flow through specific
lymph pathways. This is theorized to activate contractions of the
functional unit of lymph vessels, called lymphangions, which assist
fluid exchange without increasing blood filtration or lymph node
collapse from too great of manually imposed pressure. There exists
extensive innervation from the autonomic nervous system of these
contractile units of the lymphatic system and the conceptualization of
the movement of lymphatic fluids.45,46 LD is believed to influence the whole-body
system through gentle manual evacuation, creating a system-wide
siphoning effect to enhance fluid exchange in multiple systems.45
The use of manual LD by qualified professionals is a treatment option for
lymphedema, sports injuries, and fibromyalgia.44,47–49 Manual LD was first suggested as a specific
treatment of post-contusion and PCS for its anti-edematous effects.50 The evolution and addition of glymphatic treatment methods have
only recently emerged and are based on the practical application of
the combination of methods such as CST, LD, and non-invasive intention
of therapeutic touch.16,45
Existing studies on manual therapies for concussions and brain
injuries
In clinical application, CST has been shown to have positive effect for a
number of chronic syndromes that parallel PCS subtypes, but the body
of data is limited to observational designs and low to moderate
quality of randomized controlled methods.51,52 The credibility of a sham control protocol for
future study of CST was reported.53 A recent study of former pro-football players with PCS showed
statistically greater improvements in range of motion, pain, sleep,
and cognitive function after a series of combined manual therapies.54 A pilot study of 10 active military members had a reduction of
symptoms of post-traumatic stress and head injury through the
application of mixed light touch manual therapies.55 A single blind case series measured clinical outcomes of
soldiers with combat-related head injuries receiving CST and other
manipulation techniques. Results showed statistically greater
improvements in objective and subjective measurements pre- and post-treatment.56 Case studies report positive outcomes of varied uses of manual
therapies for the treatment of PCS.57,58 One case of an athlete with PCS compared brain
scans before and after 15 isolated CST treatments using quantitative
electroencephalogram comparing symptom reduction to changes in
neurological activity.59
Headaches
Headaches are a common symptom of concussion and PCS.7,60 CST and
other manual methods have been shown to have positive effect in the
treatment of headaches, migraines, and trigeminal neuralgia.61–64
Sleep
Sleep has a critical function in ensuring metabolic homeostasis and
clearance of metabolites and is but one important way for the nervous
system to heal from trauma and injury.13,18,65 The
glymphatic system functions mainly during sleep and is largely
disengaged during wakefulness. Sleep debt and a glymphatic system
disruption have been proposed as a mediator of brain trauma, chronic
traumatic encephalopathy, and other neurological disorders.15,66,67
Concussion symptom assessments
Subjective data —from patient
Self-reporting symptom scales are vital for assisting in the medical
management of PCS. Several tracking tools hold substantial overlap
with one another in capturing various pains and neurological
infirmaries, functional impairment, and quality of life.68–70 Although
only some have been empirically studied, clinical users need to be
aware that these scales have evolved rather than being developed scientifically.71 Nonetheless, patient reports of subjective levels of pain,
sensory, and psychological symptoms are crucial to aid in the clinical
search for effective treatments.
Post-Concussion Symptom Checklist (PCSC)
The PCSC was utilized to track outcomes and re-administered periodically
throughout the treatment process with care given to avoid coaching the
patient on symptom manifestations.70,72 Symptoms were also tracked through open-ended
self-reporting by the patient at the onset of each session if he
wished to share them.
Headache Impact Test™ (HIT-6)
The HIT-6 was designed to screen and monitor patients’ severity of
headache pain and the impact on function and quality of life.73 Utilizing six items with a severity rating scale, the HIT-6 has
been shown to be a reliable and valid tool for discriminating the
effect of headache on daily living.74,75 A possible point range of 36–78 reflects the
severity of impact that headaches are interfering with daily quality
of life and function. The HIT-6 was chosen for this particular patient
to track headache symptoms which was also a chief complaint, second
only to sleep disturbances.
Measurement of sleep
Sleep function was tracked through a sleep diary and the patient’s
perception of restfulness and daily energy.
Subjective data —from the clinician
Neurological screenings occurred each session per standard of care,
including pupil and oculomotor status, balance reactions, and general
cognitive assessments conducted through observations of behavior.
Palpation findings from full body assessment of musculoskeletal,
fascia and fluid fields were conducted at the beginning of each
treatment session. Inquiry about mood and stress were made at the
beginning of each session.
Objective data
Quantifiable neurological soft sign and biomarkers not captured on the
PCSC included fixed and dilated pupils, oxygen saturation, and
frequency of urination and thirst.
Case report
The subject, a 24-year-old male, presented with an 18-month history of
persistent neurological and behavioral symptoms reportedly related to
one sports-induced concussion. Onset was in October 2017, following a
head injury while playing in a collegiate-level sport. He reported
being screened by an athletic trainer and having a follow-up medical
assessment. No hospitalization was required. Prolonged rest was
prescribed and adhered to for several months. An eventual referral to
a local academic-medicine concussion clinic was made several months
post-injury due to escalation of unresolved symptoms where
psychological services addressing anxiety and depression and
medications for pain and concentration were prescribed. Medications
reported on patient intake included Prozac, Xanax, and Adderall. He
reported his ability to focus on job tasks improved by the Adderall
but the medications generally worsened “brain fog” and memory. He also
participated in a physical therapy program for vestibular
rehabilitation. Symptoms persisted to the point of full debilitation
by sleep deprivation, increasing dizziness, sensory overload, and
brain fatigue. Suicidal ideation prompted his parents to seek other
recommendations and services.
In the interview with the patient and one of his parents, it was
discovered that he sustained a total of six sports-related concussions
dating back several years. History also included several orthopedic
injuries long since healed (fractures to a foot and nose, and several
bone contusions). The patient affirmed that a whiplash occurred with
the most recent concussion and had originally sought chiropractic care
for neck pain post-injury.
Since symptoms began to intensify, he was forced to take a medical leave
from attending school and working a job that required much traveling.
He stated he could perform job duties, enjoyed them, and felt capable
of the job. However, the sensory intolerances created significant
anxiety and began to reduce his confidence in his job performance. His
tolerance and engagement in favorite activities were at 10% of normal
participation level. He frequently isolated himself to cope with the
sensory overload which added to a sense of helplessness.
Based upon client report and clinical observations, functional problems
were noted on intake (see Figure 1). Initial clinical
findings were also noted (see Figure 2).
Figure 1. Post-concussion symptoms (18 month duration) reported on
intake questionnaire by patient and in personal and parent
interviews.
Figure 2. Initial clinical findings.
Treatment methods employed included the following: (incorporated into
each session as the need arose).
Manual LD techniques (Chikly).45
CST techniques (Upledger).30
Glial and Glymphatic system techniques (Wanveer).16
Goals for series of therapy encounters
Reduce and eliminate stagnant and congested edema of spine,
neck, and head.
Soft tissue mobilization and fascial release methods to
increase general soft tissue flexibility and subtleness
through body to reduce sympathetic tone (through CST).
Facilitate exchange of fluid through all body fluid systems;
reduce interstitial congestion to promote healing and
self-correction of nervous system (through LD).
Neurological rehabilitation strategies to reduce and adapt to
sensory challenges; environmental structuring. (These
methods were not required due to the speed in which
positive changes were experienced and observed with manual
therapies.)
Achieve freedom from pain and neurological dysfunction,
restore/raise quality of life.
Community and work re-entry, adaptations, and modifications
assistance where needed.
Patient and family education on the concepts of manual
therapies.
Client stated just one personal goal: “I just want to be able
to sleep.”
Treatment process
Treatment was conducted in isolation of any other (new) therapy over the
course of three months. The patient participated in eleven, 1-h
sessions. Scheduling sessions were recommended at 2–3 times per week
initially. Following the first session, he requested daily treatment
but was advised to allow his system to acclimate and integrate
treatment effects. The first four sessions were scheduled 3 days
apart. After the fourth session, scheduling was left to his
discretion. Six more appointments were scheduled with 1 week spacing,
and the eleventh session was as a follow-up at the patient’s
discretion 5 weeks later. Each session was an improvisational process
of applying the various manual therapies and techniques, based upon
whole-body assessment of primary and secondary structural and fluid
findings.
Results and treatment outcomes
Quantitative data were collected through self-reporting of severity of
symptoms using the PCSC, the HIT-6, and clinical observations.
Sessions began most often with an invitation for him to report
whatever symptom(s) felt most pressing. Quality of life measurements
were self-reporting of sleep function, brain fog, ability to “get
through the day,” ability to tolerate sensory aspects of daily events,
and endurance for mental and physical activities. All were recorded in
the daily notes. A total of five recordings of the PCSC and three
recordings of the HIT-6 were captured over the course of the treatment
series (see Figure
3). Based upon both verbal responses from the patient as
well as observation, some particular treatment techniques demonstrated
a direct correlation to a reduction of a specific symptom (see Figure 4).
Figure 3. Self-reported changes of persistent concussion symptoms
related to treatment intervention; measured through
symptom tracking methods.
Figure 4. Based upon patient’s verbal responses and direct observation
in treatment, several techniques had a direct correlation
to a reduction of specific symptoms.
Sleep was restored following the first treatment as he reported sleeping
12 h each night between session one and two. Sleep continued to remain
at normalized levels throughout the treatment process.
Sessions were not based upon following specific protocol sequence. A
narrative summary of this improvisational and experiential treatment
process is reflected in a summary of the daily notes (see Figure 5).
Figure 5. Treatment Progression Depicted through Daily Notes.
Abbreviated daily notes to reflect the full therapeutic
process of applying CST and LD to treat symptoms of
concussion. See KEY for term definitions.
Six month follow-up
A 6-month follow-up (via telephone conversation) revealed sustained
abatement of PCS symptoms and the patient resumed educational pursuits
and gainful employment. His parents recommended that he continue to
receive maintenance therapy but he voiced concerned over his mounting
financial debt. He denied that symptoms were interfering with daily
activities and quality of life. The patient’s perspective about these
therapies was highly positive.
Discussion
This article offers a hypothesis that persistent symptoms of PCS could be, in
part, a result of compromised glymphatic and lymphatic pathway flow stemming
from restrictions of movement and balanced position of osseous and soft
tissue structures. The theoretical constructs of CST suggest when fascial
membranes such as the dura and other meningeal layers and/or cranial plates
and vertebral column may be in a compressive state, leading to neurological
and/or behavioral symptoms.30,32,76 The theoretical
constructs of LD is that gentle, manual evacuation of lymphatic channels
following anatomical mapping enhances a whole-body fluid exchange and
removal of cellular wastes between interconnecting fluid systems.45,49
Only through whole-body palpation assessment was the first clinical discoveries
made in this patient. Asymmetrical rib cage alignment, with sub-optimal
breath expansion and lowered oxygen saturation, was subjectively assessed
and CST techniques were immediately employed. The second discovery was
persistent edema through anterior and lateral cervical chains, over the
expanse of scalp lymphatics, and engorged in bilateral occipital nodes at
the cranial base. It is a reasonable assumption that edema may have occurred
at the time of injury but after 18 months, edema and interstitial fluid
stagnation would be expected to have resolved. That was not the case for
this athlete. Palpation for (chronic) edema is a skill set learned through
specific LD training methods.
Sleep was the first of the chronic symptoms to demonstrate an effect from
treatment, after just one, 1-h treatment session. It could be suggested that
fluid stagnation in and around the central nervous system contributed to the
adverse head pressure pain with impact on the lack of restorative sleep (as
surmised by the patient’s insights). It could be suggested that quality of
breathing function may also have had a negative effect upon sleep. It is
apparent through the stream of daily notes that the first treatment in and
around the thoracic body and rib cage (consisting of fascia mobilization
following CST methods) produced immediate elevation in oxygen saturation. It
was also immediately apparent that LD through the central spinal lymph node
confluences and pathways produced an immediate response of head pressure
relief. Sleep resolved to satisfactory levels for the patient and remained
so for the remainder of the treatment series, and at the 6-month
follow-up.
Other neurological symptoms resolved at different, but steady rates, as
reflected on the periodic scoring of the PCSC. To avoid or minimize effects
of coaching or influencing the patient on symptom reporting, freely
expressed symptom declarations were documented prior to the administration
of repeated PCSC scoring. It is with a high rate of certainty that the PCSC
yielded an accurate expression of the patient’s self-reported experiences in
symptom status through the treatment process.
Therapeutic touch and emotional support are aspects of most forms of manual
therapies. It is possible that any placebo or autonomic calming effect of
therapeutic touch contributed to the reduction of symptoms. However,
resolution of certain chronic symptoms did correlate with the application of
only specific treatment techniques (see Figure 4). Mood, cognitive
function, and emotional well-being improved and the patient attributed this
to reduction and elimination of head pain, brain fatigue, and sensory
sensitivities. Quality of life improved and he returned to his occupational
tasks of completing college and finding a less stressful, yet meaningful,
job.
The literature supports interventions for PCS which include psychological,
cervical, and vestibular rehabilitation.5 The differential methods of CST and LD as distinct manual therapies
have yet to be fully explored as options for PCS, though emerging studies
indicate CST being used clinically with functional PCS subtypes. One
contraindication for CST is not to apply during acute stages of brain injury
when increased intracranial pressure is present.30 Contraindications for LD have been cited and include acute infection
or inflammatory disease process, thrombosis or phlebitis, acute hemorrhage,
active malignant ailments, and acute heart problems as LD increases cardiac
load.44,45
Future study could possibly isolate the impact CST and LD modalities have upon
sleep in PCS. Research of the fluid exchange models of the nervous system
could explore possible correlations to persistent symptoms of PCS.
Furthermore, efficacy studies into therapies such as CST and LD might be
aided by advancements of proving and measuring the exchange of fluids where
glymphatic and lymphatic structures merge.
Conclusions
This case report reflects one collegiate athlete’s unique constellation of PCS
and the self-reported reduction of persistent symptoms through the
experiential process of CST and LD intervention. There is little published
evidence of the efficacy of CST and/or LD on the symptoms of PCS, though
both have been utilized in clinics internationally for over 3 decades. Rest
allowance and other therapy interventions had been previously trialed for
18 months, though no concussion symptom tracking was completed or available
from previous records for comparative purposes. Previous pharmacologic
treatment and vestibular rehabilitation for this patient were self-reported
to have reduced symptoms of attention deficits and balance in climbing
stairs, respectively. Other psychology and physical medicine endeavors had
been trialed over the year and a half, and per his declaration, “Did not
help heal me. Medications only helped me get through the work day; they did
not take away the symptoms.”
The author, an occupational therapist with 20 years of experience applying CST
and LD in clinical practice, admits to a strong inherent bias. The strength
of this case study, however, is that treatment was provided in isolation of
any intervention other than his established medication usage. It could be
said that placebo effect had been controlled for where specific treatment
techniques clearly resolved some specific symptoms, but not all. Other
symptoms resolved over time and may reflect effects of the restoration of
sleep and elevation of mood. Though generalization of the findings in this
case cannot be applied to the greater population of patients with
concussions and brain injuries, this case does suggest that CST and LD are
valuable treatment options for PCS and worthy of future study.
We thank all the clients and their families who trust the wisdom of structural
medicine as we continue to merge theory with day-to-day clinical practices.
We are forever indebted to your tenacity and steadfastness to find and
secure appropriate help.
Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article: Any conflicts of interests are implied by the author being an
active clinician where these techniques and therapeutic strategies are
utilized in the clinic setting.
Ethical approval: Our institution does not require ethical approval for reporting
individual cases or case series.
Funding: The author(s) received no financial support for the research, authorship,
and/or publication of this article.
Informed consent: Written informed consent was obtained from the patient(s) for their
anonymized information to be published in this article. This informed
consent is maintained in the medical records for this patient.
ORCID iD: Susan Vaughan Kratz https://orcid.org/0000-0003-2018-8365 | Recovering | ReactionOutcome | CC BY-NC | 33628444 | 18,976,097 | 2021 |
What was the outcome of reaction 'Feeling abnormal'? | Case report: Manual therapies promote resolution of persistent post-concussion symptoms in a 24-year-old athlete.
This case report illustrates the treatment outcomes of a collegiate athlete presenting with an 18-month history of post-concussion syndrome who received a series of mixed manual therapies in isolation of other therapy. Persistent symptoms were self-reported as debilitating, contributing to self-removal from participation in school, work, and leisure activities. Patient and parent interviews captured the history of multiple concussions and other sports-related injuries. Neurological screening and activities of daily living were baseline measured. Post-Concussion Symptom Checklist and Headache Impact Test-6™ were utilized to track symptom severity. Treatments applied included craniosacral therapy, manual lymphatic drainage, and glymphatic techniques. Eleven treatment sessions were administered over 3 months. Results indicated restoration of oxygen saturation, normalized pupil reactivity, and satisfactory sleep. Post-concussion syndrome symptom severity was reduced by 87% as reflected by accumulative Post-Concussion Symptom Checklist scores. Relief from chronic headaches was achieved, reflected by Headache Impact Test-6 scores. Restoration of mood and quality of life were reported. A 6-month follow-up revealed symptoms remained abated with full re-engagement of daily activities. The author hypothesized that post-concussion syndrome symptoms were related to compression of craniosacral system structures and lymphatic fluid stagnation that contributed to head pressure pain, severe sleep deprivation, and multiple neurological and psychological symptoms. Positive outcomes over a relatively short period of time without adverse effects suggest these therapies may offer viable options for the treatment of post-concussion syndrome.
Introduction
Serious awareness over the past decade of the short- and long-term effects of
traumatic head trauma leading to concussion has prompted rigorous diagnostic
and clinical management endeavors.1,2 Sources report the
number of sports-related concussions receiving medical attention in the
United States ranged between 1.6 million and 3.8 million annually.3,4
Persistent symptoms following concussions may not reflect a single
pathophysiological entity and likely describes individualized patterns of
non-specific, post-traumatic symptoms that may be linked to coexisting
and/or confounding issues.1,5 Subtypes of
post-concussion syndrome (PCS) are now recognized by physiological,
cervicogenic, and neuropsychological manifestations.2,4,6–9
A fluid model: glymphatic and meningeal lymphatic systems
The existence of a cerebral fluid-exchange system (different than blood
vessels) has been long debated but new discoveries have intensified research
into fluid dynamics within the brain parenchyma.10 Glial cells have been shown to create a possible architectural system
among the microvasculature which appears to match blood flow with neuronal firing.11 Pathways formed by glial cells and endothelial walls of penetrating
blood vessels have been suggested to serve as a physiological cleansing
mechanism called the “glymphatic system.”10,12,13 These pathways
appear to form perivascular channels by astroglia end-feet where monitoring
and active clearing of the neuronal terrain may occur.14–16
Furthermore, it is theorized that this cellular transportation network also
serves to distribute nutritional compounds and neuromodulators.15 Brain-wide perivascular pathways, believed to facilitate
cerebrospinal fluid (CSF) flow through the parenchyma and the movement of
interstitial solutes, have been captured by contrast-enhanced magnetic
resonance imaging (MRI) scan.13 The theoretical function then of this proposed glymphatic system
serves to support perfusion of CSF and interstitial fluids as a means of
pseudo-lymphatic function of the nervous system, elucidating a possible
mechanism of how the brain cleans itself through elimination of soluble
proteins and metabolites.10,13,17–19
However, there are also proponents who argue a glymphatic system as proposed
needs to be re-evaluated, accounting for more specifics to cerebrovascular
fluid transport.20 Regardless, there is within the brain a mechanism that moves fluids
through a cleansing process, shown to be active during restorative sleep and
rather inactive during wakefulness.15
Lymphatic system discovery
In addition, a recent identification of lymphatic projections into meningeal
membranes within the cranial vault suggests a functional proximity and/or
connection between the brain pseudo-lymphatic and the whole-body lymphatic
network.21,22 Furthermore, lymphatic vessels were discovered
lining the dura sinuses of the meninges and in turn have been shown to carry
both fluid and immune cells from the CSF, connecting to deep cervical lymph
nodes and into the peripheral venous return system.17,21
Magnetic resonance images provide supporting evidence of glymphatic drainage
from human brain to cervical lymph nodes.23 Other emerging data from both animal models and human studies support
this theory that the brain fluid-exchange and body lymphatics system share
an intimacy and work together for homeostasis, though we are only at the
beginning of understanding how this works.12,22–24
Structural impact and pathology of fluid transport systems
Chronic symptoms associated with PCS have been theorized to be a result of
“gliopathy,” a dysregulation of glial function and drainage in the central
and peripheral nervous system.25 Murine models of glial and glymphatic system function following head
injury has begun to shed light on the effect of brain trauma upon astrocytes
and the effect upon intracranial edema and resolution.26,27
Impaired functioning of the meningeal lymphatic vessels has been theorized
to accelerate the accumulation of toxic amyloid beta protein in the brain parenchyma.28
Upledger illuminated and confirmed the existence of the function and physiology
of the craniosacral system (meninges housing the brain, spinal cord, and
cerebral spinal fluids).29,30 Bodywork
professionals are guided by the premise that structural compressions such as
osseous and/or fascial restrictions can impede fluid movement and exchange,
leading to an array of symptomology.30–34 It is understood
that vertebral bone compression into spinal cord space will create various
neurological symptoms theorized, in part, by the obstruction of cerebral
spinal fluid.35,36 One animal model has demonstrated that blocking
the normal physiologic cerebral spinal fluid drainage sites in the
cribriform plate increases resting intracranial pressure.37
Manual therapies for the central nervous system
Craniosacral therapy
Manual therapies such as craniosacral therapy (CST) emerged from the
science that explored the physiological motion of the central nervous
system.30,38,39 The core
intent of CST is the theoretic interactions with connective tissue at
osseous sites and, using a sustained low-force stretch, elicit a
softening or relaxation response of soft tissues. In turn, a positive
effect upon fluid exchange and the body’s self-correcting actions can occur.30 Studies have illuminated the natural motion of cranial bones,
organ movement, and fluid exchange, depicting and measuring the
dynamic nature of the physiology of the craniosacral system.33,40,41 Based on observations of one animal study on
the structural effects of applying CST, no discernible length
difference was found at cranial bone sutures. However, this study
concluded that perhaps a different biological basis for such treatment
could be at play.42 In a now classic study, changes in the length of the
intracranial falx cerebri membrane were demonstrated with the
application of CST on an embalmed cadaver skull. Recorded relative
change in tissue length ranged between .28 and 1.44 mm at different
sites of the membrane with different CST techniques applied. This
study offers some validation that sustained, gentle, and external
forces have a measurable effect upon the intracranial membrane system.43
Manual lymphatic drainage
Various methods of manual lymphatic drainage (LD) exist, but a
contemporary version aligns with discoveries of anatomical pathways
and lymph tissue mapping, the depths of lymph flow throughout the
body, and using specific rhythms in fluid evacuation.44 Hand pressure used in the Chikly method is extremely light,
matching the tissue dynamics unique to each patient, and only enough
to stimulate the movement of fluid to enhance flow through specific
lymph pathways. This is theorized to activate contractions of the
functional unit of lymph vessels, called lymphangions, which assist
fluid exchange without increasing blood filtration or lymph node
collapse from too great of manually imposed pressure. There exists
extensive innervation from the autonomic nervous system of these
contractile units of the lymphatic system and the conceptualization of
the movement of lymphatic fluids.45,46 LD is believed to influence the whole-body
system through gentle manual evacuation, creating a system-wide
siphoning effect to enhance fluid exchange in multiple systems.45
The use of manual LD by qualified professionals is a treatment option for
lymphedema, sports injuries, and fibromyalgia.44,47–49 Manual LD was first suggested as a specific
treatment of post-contusion and PCS for its anti-edematous effects.50 The evolution and addition of glymphatic treatment methods have
only recently emerged and are based on the practical application of
the combination of methods such as CST, LD, and non-invasive intention
of therapeutic touch.16,45
Existing studies on manual therapies for concussions and brain
injuries
In clinical application, CST has been shown to have positive effect for a
number of chronic syndromes that parallel PCS subtypes, but the body
of data is limited to observational designs and low to moderate
quality of randomized controlled methods.51,52 The credibility of a sham control protocol for
future study of CST was reported.53 A recent study of former pro-football players with PCS showed
statistically greater improvements in range of motion, pain, sleep,
and cognitive function after a series of combined manual therapies.54 A pilot study of 10 active military members had a reduction of
symptoms of post-traumatic stress and head injury through the
application of mixed light touch manual therapies.55 A single blind case series measured clinical outcomes of
soldiers with combat-related head injuries receiving CST and other
manipulation techniques. Results showed statistically greater
improvements in objective and subjective measurements pre- and post-treatment.56 Case studies report positive outcomes of varied uses of manual
therapies for the treatment of PCS.57,58 One case of an athlete with PCS compared brain
scans before and after 15 isolated CST treatments using quantitative
electroencephalogram comparing symptom reduction to changes in
neurological activity.59
Headaches
Headaches are a common symptom of concussion and PCS.7,60 CST and
other manual methods have been shown to have positive effect in the
treatment of headaches, migraines, and trigeminal neuralgia.61–64
Sleep
Sleep has a critical function in ensuring metabolic homeostasis and
clearance of metabolites and is but one important way for the nervous
system to heal from trauma and injury.13,18,65 The
glymphatic system functions mainly during sleep and is largely
disengaged during wakefulness. Sleep debt and a glymphatic system
disruption have been proposed as a mediator of brain trauma, chronic
traumatic encephalopathy, and other neurological disorders.15,66,67
Concussion symptom assessments
Subjective data —from patient
Self-reporting symptom scales are vital for assisting in the medical
management of PCS. Several tracking tools hold substantial overlap
with one another in capturing various pains and neurological
infirmaries, functional impairment, and quality of life.68–70 Although
only some have been empirically studied, clinical users need to be
aware that these scales have evolved rather than being developed scientifically.71 Nonetheless, patient reports of subjective levels of pain,
sensory, and psychological symptoms are crucial to aid in the clinical
search for effective treatments.
Post-Concussion Symptom Checklist (PCSC)
The PCSC was utilized to track outcomes and re-administered periodically
throughout the treatment process with care given to avoid coaching the
patient on symptom manifestations.70,72 Symptoms were also tracked through open-ended
self-reporting by the patient at the onset of each session if he
wished to share them.
Headache Impact Test™ (HIT-6)
The HIT-6 was designed to screen and monitor patients’ severity of
headache pain and the impact on function and quality of life.73 Utilizing six items with a severity rating scale, the HIT-6 has
been shown to be a reliable and valid tool for discriminating the
effect of headache on daily living.74,75 A possible point range of 36–78 reflects the
severity of impact that headaches are interfering with daily quality
of life and function. The HIT-6 was chosen for this particular patient
to track headache symptoms which was also a chief complaint, second
only to sleep disturbances.
Measurement of sleep
Sleep function was tracked through a sleep diary and the patient’s
perception of restfulness and daily energy.
Subjective data —from the clinician
Neurological screenings occurred each session per standard of care,
including pupil and oculomotor status, balance reactions, and general
cognitive assessments conducted through observations of behavior.
Palpation findings from full body assessment of musculoskeletal,
fascia and fluid fields were conducted at the beginning of each
treatment session. Inquiry about mood and stress were made at the
beginning of each session.
Objective data
Quantifiable neurological soft sign and biomarkers not captured on the
PCSC included fixed and dilated pupils, oxygen saturation, and
frequency of urination and thirst.
Case report
The subject, a 24-year-old male, presented with an 18-month history of
persistent neurological and behavioral symptoms reportedly related to
one sports-induced concussion. Onset was in October 2017, following a
head injury while playing in a collegiate-level sport. He reported
being screened by an athletic trainer and having a follow-up medical
assessment. No hospitalization was required. Prolonged rest was
prescribed and adhered to for several months. An eventual referral to
a local academic-medicine concussion clinic was made several months
post-injury due to escalation of unresolved symptoms where
psychological services addressing anxiety and depression and
medications for pain and concentration were prescribed. Medications
reported on patient intake included Prozac, Xanax, and Adderall. He
reported his ability to focus on job tasks improved by the Adderall
but the medications generally worsened “brain fog” and memory. He also
participated in a physical therapy program for vestibular
rehabilitation. Symptoms persisted to the point of full debilitation
by sleep deprivation, increasing dizziness, sensory overload, and
brain fatigue. Suicidal ideation prompted his parents to seek other
recommendations and services.
In the interview with the patient and one of his parents, it was
discovered that he sustained a total of six sports-related concussions
dating back several years. History also included several orthopedic
injuries long since healed (fractures to a foot and nose, and several
bone contusions). The patient affirmed that a whiplash occurred with
the most recent concussion and had originally sought chiropractic care
for neck pain post-injury.
Since symptoms began to intensify, he was forced to take a medical leave
from attending school and working a job that required much traveling.
He stated he could perform job duties, enjoyed them, and felt capable
of the job. However, the sensory intolerances created significant
anxiety and began to reduce his confidence in his job performance. His
tolerance and engagement in favorite activities were at 10% of normal
participation level. He frequently isolated himself to cope with the
sensory overload which added to a sense of helplessness.
Based upon client report and clinical observations, functional problems
were noted on intake (see Figure 1). Initial clinical
findings were also noted (see Figure 2).
Figure 1. Post-concussion symptoms (18 month duration) reported on
intake questionnaire by patient and in personal and parent
interviews.
Figure 2. Initial clinical findings.
Treatment methods employed included the following: (incorporated into
each session as the need arose).
Manual LD techniques (Chikly).45
CST techniques (Upledger).30
Glial and Glymphatic system techniques (Wanveer).16
Goals for series of therapy encounters
Reduce and eliminate stagnant and congested edema of spine,
neck, and head.
Soft tissue mobilization and fascial release methods to
increase general soft tissue flexibility and subtleness
through body to reduce sympathetic tone (through CST).
Facilitate exchange of fluid through all body fluid systems;
reduce interstitial congestion to promote healing and
self-correction of nervous system (through LD).
Neurological rehabilitation strategies to reduce and adapt to
sensory challenges; environmental structuring. (These
methods were not required due to the speed in which
positive changes were experienced and observed with manual
therapies.)
Achieve freedom from pain and neurological dysfunction,
restore/raise quality of life.
Community and work re-entry, adaptations, and modifications
assistance where needed.
Patient and family education on the concepts of manual
therapies.
Client stated just one personal goal: “I just want to be able
to sleep.”
Treatment process
Treatment was conducted in isolation of any other (new) therapy over the
course of three months. The patient participated in eleven, 1-h
sessions. Scheduling sessions were recommended at 2–3 times per week
initially. Following the first session, he requested daily treatment
but was advised to allow his system to acclimate and integrate
treatment effects. The first four sessions were scheduled 3 days
apart. After the fourth session, scheduling was left to his
discretion. Six more appointments were scheduled with 1 week spacing,
and the eleventh session was as a follow-up at the patient’s
discretion 5 weeks later. Each session was an improvisational process
of applying the various manual therapies and techniques, based upon
whole-body assessment of primary and secondary structural and fluid
findings.
Results and treatment outcomes
Quantitative data were collected through self-reporting of severity of
symptoms using the PCSC, the HIT-6, and clinical observations.
Sessions began most often with an invitation for him to report
whatever symptom(s) felt most pressing. Quality of life measurements
were self-reporting of sleep function, brain fog, ability to “get
through the day,” ability to tolerate sensory aspects of daily events,
and endurance for mental and physical activities. All were recorded in
the daily notes. A total of five recordings of the PCSC and three
recordings of the HIT-6 were captured over the course of the treatment
series (see Figure
3). Based upon both verbal responses from the patient as
well as observation, some particular treatment techniques demonstrated
a direct correlation to a reduction of a specific symptom (see Figure 4).
Figure 3. Self-reported changes of persistent concussion symptoms
related to treatment intervention; measured through
symptom tracking methods.
Figure 4. Based upon patient’s verbal responses and direct observation
in treatment, several techniques had a direct correlation
to a reduction of specific symptoms.
Sleep was restored following the first treatment as he reported sleeping
12 h each night between session one and two. Sleep continued to remain
at normalized levels throughout the treatment process.
Sessions were not based upon following specific protocol sequence. A
narrative summary of this improvisational and experiential treatment
process is reflected in a summary of the daily notes (see Figure 5).
Figure 5. Treatment Progression Depicted through Daily Notes.
Abbreviated daily notes to reflect the full therapeutic
process of applying CST and LD to treat symptoms of
concussion. See KEY for term definitions.
Six month follow-up
A 6-month follow-up (via telephone conversation) revealed sustained
abatement of PCS symptoms and the patient resumed educational pursuits
and gainful employment. His parents recommended that he continue to
receive maintenance therapy but he voiced concerned over his mounting
financial debt. He denied that symptoms were interfering with daily
activities and quality of life. The patient’s perspective about these
therapies was highly positive.
Discussion
This article offers a hypothesis that persistent symptoms of PCS could be, in
part, a result of compromised glymphatic and lymphatic pathway flow stemming
from restrictions of movement and balanced position of osseous and soft
tissue structures. The theoretical constructs of CST suggest when fascial
membranes such as the dura and other meningeal layers and/or cranial plates
and vertebral column may be in a compressive state, leading to neurological
and/or behavioral symptoms.30,32,76 The theoretical
constructs of LD is that gentle, manual evacuation of lymphatic channels
following anatomical mapping enhances a whole-body fluid exchange and
removal of cellular wastes between interconnecting fluid systems.45,49
Only through whole-body palpation assessment was the first clinical discoveries
made in this patient. Asymmetrical rib cage alignment, with sub-optimal
breath expansion and lowered oxygen saturation, was subjectively assessed
and CST techniques were immediately employed. The second discovery was
persistent edema through anterior and lateral cervical chains, over the
expanse of scalp lymphatics, and engorged in bilateral occipital nodes at
the cranial base. It is a reasonable assumption that edema may have occurred
at the time of injury but after 18 months, edema and interstitial fluid
stagnation would be expected to have resolved. That was not the case for
this athlete. Palpation for (chronic) edema is a skill set learned through
specific LD training methods.
Sleep was the first of the chronic symptoms to demonstrate an effect from
treatment, after just one, 1-h treatment session. It could be suggested that
fluid stagnation in and around the central nervous system contributed to the
adverse head pressure pain with impact on the lack of restorative sleep (as
surmised by the patient’s insights). It could be suggested that quality of
breathing function may also have had a negative effect upon sleep. It is
apparent through the stream of daily notes that the first treatment in and
around the thoracic body and rib cage (consisting of fascia mobilization
following CST methods) produced immediate elevation in oxygen saturation. It
was also immediately apparent that LD through the central spinal lymph node
confluences and pathways produced an immediate response of head pressure
relief. Sleep resolved to satisfactory levels for the patient and remained
so for the remainder of the treatment series, and at the 6-month
follow-up.
Other neurological symptoms resolved at different, but steady rates, as
reflected on the periodic scoring of the PCSC. To avoid or minimize effects
of coaching or influencing the patient on symptom reporting, freely
expressed symptom declarations were documented prior to the administration
of repeated PCSC scoring. It is with a high rate of certainty that the PCSC
yielded an accurate expression of the patient’s self-reported experiences in
symptom status through the treatment process.
Therapeutic touch and emotional support are aspects of most forms of manual
therapies. It is possible that any placebo or autonomic calming effect of
therapeutic touch contributed to the reduction of symptoms. However,
resolution of certain chronic symptoms did correlate with the application of
only specific treatment techniques (see Figure 4). Mood, cognitive
function, and emotional well-being improved and the patient attributed this
to reduction and elimination of head pain, brain fatigue, and sensory
sensitivities. Quality of life improved and he returned to his occupational
tasks of completing college and finding a less stressful, yet meaningful,
job.
The literature supports interventions for PCS which include psychological,
cervical, and vestibular rehabilitation.5 The differential methods of CST and LD as distinct manual therapies
have yet to be fully explored as options for PCS, though emerging studies
indicate CST being used clinically with functional PCS subtypes. One
contraindication for CST is not to apply during acute stages of brain injury
when increased intracranial pressure is present.30 Contraindications for LD have been cited and include acute infection
or inflammatory disease process, thrombosis or phlebitis, acute hemorrhage,
active malignant ailments, and acute heart problems as LD increases cardiac
load.44,45
Future study could possibly isolate the impact CST and LD modalities have upon
sleep in PCS. Research of the fluid exchange models of the nervous system
could explore possible correlations to persistent symptoms of PCS.
Furthermore, efficacy studies into therapies such as CST and LD might be
aided by advancements of proving and measuring the exchange of fluids where
glymphatic and lymphatic structures merge.
Conclusions
This case report reflects one collegiate athlete’s unique constellation of PCS
and the self-reported reduction of persistent symptoms through the
experiential process of CST and LD intervention. There is little published
evidence of the efficacy of CST and/or LD on the symptoms of PCS, though
both have been utilized in clinics internationally for over 3 decades. Rest
allowance and other therapy interventions had been previously trialed for
18 months, though no concussion symptom tracking was completed or available
from previous records for comparative purposes. Previous pharmacologic
treatment and vestibular rehabilitation for this patient were self-reported
to have reduced symptoms of attention deficits and balance in climbing
stairs, respectively. Other psychology and physical medicine endeavors had
been trialed over the year and a half, and per his declaration, “Did not
help heal me. Medications only helped me get through the work day; they did
not take away the symptoms.”
The author, an occupational therapist with 20 years of experience applying CST
and LD in clinical practice, admits to a strong inherent bias. The strength
of this case study, however, is that treatment was provided in isolation of
any intervention other than his established medication usage. It could be
said that placebo effect had been controlled for where specific treatment
techniques clearly resolved some specific symptoms, but not all. Other
symptoms resolved over time and may reflect effects of the restoration of
sleep and elevation of mood. Though generalization of the findings in this
case cannot be applied to the greater population of patients with
concussions and brain injuries, this case does suggest that CST and LD are
valuable treatment options for PCS and worthy of future study.
We thank all the clients and their families who trust the wisdom of structural
medicine as we continue to merge theory with day-to-day clinical practices.
We are forever indebted to your tenacity and steadfastness to find and
secure appropriate help.
Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article: Any conflicts of interests are implied by the author being an
active clinician where these techniques and therapeutic strategies are
utilized in the clinic setting.
Ethical approval: Our institution does not require ethical approval for reporting
individual cases or case series.
Funding: The author(s) received no financial support for the research, authorship,
and/or publication of this article.
Informed consent: Written informed consent was obtained from the patient(s) for their
anonymized information to be published in this article. This informed
consent is maintained in the medical records for this patient.
ORCID iD: Susan Vaughan Kratz https://orcid.org/0000-0003-2018-8365 | Recovering | ReactionOutcome | CC BY-NC | 33628444 | 18,976,097 | 2021 |
What was the outcome of reaction 'Memory impairment'? | Case report: Manual therapies promote resolution of persistent post-concussion symptoms in a 24-year-old athlete.
This case report illustrates the treatment outcomes of a collegiate athlete presenting with an 18-month history of post-concussion syndrome who received a series of mixed manual therapies in isolation of other therapy. Persistent symptoms were self-reported as debilitating, contributing to self-removal from participation in school, work, and leisure activities. Patient and parent interviews captured the history of multiple concussions and other sports-related injuries. Neurological screening and activities of daily living were baseline measured. Post-Concussion Symptom Checklist and Headache Impact Test-6™ were utilized to track symptom severity. Treatments applied included craniosacral therapy, manual lymphatic drainage, and glymphatic techniques. Eleven treatment sessions were administered over 3 months. Results indicated restoration of oxygen saturation, normalized pupil reactivity, and satisfactory sleep. Post-concussion syndrome symptom severity was reduced by 87% as reflected by accumulative Post-Concussion Symptom Checklist scores. Relief from chronic headaches was achieved, reflected by Headache Impact Test-6 scores. Restoration of mood and quality of life were reported. A 6-month follow-up revealed symptoms remained abated with full re-engagement of daily activities. The author hypothesized that post-concussion syndrome symptoms were related to compression of craniosacral system structures and lymphatic fluid stagnation that contributed to head pressure pain, severe sleep deprivation, and multiple neurological and psychological symptoms. Positive outcomes over a relatively short period of time without adverse effects suggest these therapies may offer viable options for the treatment of post-concussion syndrome.
Introduction
Serious awareness over the past decade of the short- and long-term effects of
traumatic head trauma leading to concussion has prompted rigorous diagnostic
and clinical management endeavors.1,2 Sources report the
number of sports-related concussions receiving medical attention in the
United States ranged between 1.6 million and 3.8 million annually.3,4
Persistent symptoms following concussions may not reflect a single
pathophysiological entity and likely describes individualized patterns of
non-specific, post-traumatic symptoms that may be linked to coexisting
and/or confounding issues.1,5 Subtypes of
post-concussion syndrome (PCS) are now recognized by physiological,
cervicogenic, and neuropsychological manifestations.2,4,6–9
A fluid model: glymphatic and meningeal lymphatic systems
The existence of a cerebral fluid-exchange system (different than blood
vessels) has been long debated but new discoveries have intensified research
into fluid dynamics within the brain parenchyma.10 Glial cells have been shown to create a possible architectural system
among the microvasculature which appears to match blood flow with neuronal firing.11 Pathways formed by glial cells and endothelial walls of penetrating
blood vessels have been suggested to serve as a physiological cleansing
mechanism called the “glymphatic system.”10,12,13 These pathways
appear to form perivascular channels by astroglia end-feet where monitoring
and active clearing of the neuronal terrain may occur.14–16
Furthermore, it is theorized that this cellular transportation network also
serves to distribute nutritional compounds and neuromodulators.15 Brain-wide perivascular pathways, believed to facilitate
cerebrospinal fluid (CSF) flow through the parenchyma and the movement of
interstitial solutes, have been captured by contrast-enhanced magnetic
resonance imaging (MRI) scan.13 The theoretical function then of this proposed glymphatic system
serves to support perfusion of CSF and interstitial fluids as a means of
pseudo-lymphatic function of the nervous system, elucidating a possible
mechanism of how the brain cleans itself through elimination of soluble
proteins and metabolites.10,13,17–19
However, there are also proponents who argue a glymphatic system as proposed
needs to be re-evaluated, accounting for more specifics to cerebrovascular
fluid transport.20 Regardless, there is within the brain a mechanism that moves fluids
through a cleansing process, shown to be active during restorative sleep and
rather inactive during wakefulness.15
Lymphatic system discovery
In addition, a recent identification of lymphatic projections into meningeal
membranes within the cranial vault suggests a functional proximity and/or
connection between the brain pseudo-lymphatic and the whole-body lymphatic
network.21,22 Furthermore, lymphatic vessels were discovered
lining the dura sinuses of the meninges and in turn have been shown to carry
both fluid and immune cells from the CSF, connecting to deep cervical lymph
nodes and into the peripheral venous return system.17,21
Magnetic resonance images provide supporting evidence of glymphatic drainage
from human brain to cervical lymph nodes.23 Other emerging data from both animal models and human studies support
this theory that the brain fluid-exchange and body lymphatics system share
an intimacy and work together for homeostasis, though we are only at the
beginning of understanding how this works.12,22–24
Structural impact and pathology of fluid transport systems
Chronic symptoms associated with PCS have been theorized to be a result of
“gliopathy,” a dysregulation of glial function and drainage in the central
and peripheral nervous system.25 Murine models of glial and glymphatic system function following head
injury has begun to shed light on the effect of brain trauma upon astrocytes
and the effect upon intracranial edema and resolution.26,27
Impaired functioning of the meningeal lymphatic vessels has been theorized
to accelerate the accumulation of toxic amyloid beta protein in the brain parenchyma.28
Upledger illuminated and confirmed the existence of the function and physiology
of the craniosacral system (meninges housing the brain, spinal cord, and
cerebral spinal fluids).29,30 Bodywork
professionals are guided by the premise that structural compressions such as
osseous and/or fascial restrictions can impede fluid movement and exchange,
leading to an array of symptomology.30–34 It is understood
that vertebral bone compression into spinal cord space will create various
neurological symptoms theorized, in part, by the obstruction of cerebral
spinal fluid.35,36 One animal model has demonstrated that blocking
the normal physiologic cerebral spinal fluid drainage sites in the
cribriform plate increases resting intracranial pressure.37
Manual therapies for the central nervous system
Craniosacral therapy
Manual therapies such as craniosacral therapy (CST) emerged from the
science that explored the physiological motion of the central nervous
system.30,38,39 The core
intent of CST is the theoretic interactions with connective tissue at
osseous sites and, using a sustained low-force stretch, elicit a
softening or relaxation response of soft tissues. In turn, a positive
effect upon fluid exchange and the body’s self-correcting actions can occur.30 Studies have illuminated the natural motion of cranial bones,
organ movement, and fluid exchange, depicting and measuring the
dynamic nature of the physiology of the craniosacral system.33,40,41 Based on observations of one animal study on
the structural effects of applying CST, no discernible length
difference was found at cranial bone sutures. However, this study
concluded that perhaps a different biological basis for such treatment
could be at play.42 In a now classic study, changes in the length of the
intracranial falx cerebri membrane were demonstrated with the
application of CST on an embalmed cadaver skull. Recorded relative
change in tissue length ranged between .28 and 1.44 mm at different
sites of the membrane with different CST techniques applied. This
study offers some validation that sustained, gentle, and external
forces have a measurable effect upon the intracranial membrane system.43
Manual lymphatic drainage
Various methods of manual lymphatic drainage (LD) exist, but a
contemporary version aligns with discoveries of anatomical pathways
and lymph tissue mapping, the depths of lymph flow throughout the
body, and using specific rhythms in fluid evacuation.44 Hand pressure used in the Chikly method is extremely light,
matching the tissue dynamics unique to each patient, and only enough
to stimulate the movement of fluid to enhance flow through specific
lymph pathways. This is theorized to activate contractions of the
functional unit of lymph vessels, called lymphangions, which assist
fluid exchange without increasing blood filtration or lymph node
collapse from too great of manually imposed pressure. There exists
extensive innervation from the autonomic nervous system of these
contractile units of the lymphatic system and the conceptualization of
the movement of lymphatic fluids.45,46 LD is believed to influence the whole-body
system through gentle manual evacuation, creating a system-wide
siphoning effect to enhance fluid exchange in multiple systems.45
The use of manual LD by qualified professionals is a treatment option for
lymphedema, sports injuries, and fibromyalgia.44,47–49 Manual LD was first suggested as a specific
treatment of post-contusion and PCS for its anti-edematous effects.50 The evolution and addition of glymphatic treatment methods have
only recently emerged and are based on the practical application of
the combination of methods such as CST, LD, and non-invasive intention
of therapeutic touch.16,45
Existing studies on manual therapies for concussions and brain
injuries
In clinical application, CST has been shown to have positive effect for a
number of chronic syndromes that parallel PCS subtypes, but the body
of data is limited to observational designs and low to moderate
quality of randomized controlled methods.51,52 The credibility of a sham control protocol for
future study of CST was reported.53 A recent study of former pro-football players with PCS showed
statistically greater improvements in range of motion, pain, sleep,
and cognitive function after a series of combined manual therapies.54 A pilot study of 10 active military members had a reduction of
symptoms of post-traumatic stress and head injury through the
application of mixed light touch manual therapies.55 A single blind case series measured clinical outcomes of
soldiers with combat-related head injuries receiving CST and other
manipulation techniques. Results showed statistically greater
improvements in objective and subjective measurements pre- and post-treatment.56 Case studies report positive outcomes of varied uses of manual
therapies for the treatment of PCS.57,58 One case of an athlete with PCS compared brain
scans before and after 15 isolated CST treatments using quantitative
electroencephalogram comparing symptom reduction to changes in
neurological activity.59
Headaches
Headaches are a common symptom of concussion and PCS.7,60 CST and
other manual methods have been shown to have positive effect in the
treatment of headaches, migraines, and trigeminal neuralgia.61–64
Sleep
Sleep has a critical function in ensuring metabolic homeostasis and
clearance of metabolites and is but one important way for the nervous
system to heal from trauma and injury.13,18,65 The
glymphatic system functions mainly during sleep and is largely
disengaged during wakefulness. Sleep debt and a glymphatic system
disruption have been proposed as a mediator of brain trauma, chronic
traumatic encephalopathy, and other neurological disorders.15,66,67
Concussion symptom assessments
Subjective data —from patient
Self-reporting symptom scales are vital for assisting in the medical
management of PCS. Several tracking tools hold substantial overlap
with one another in capturing various pains and neurological
infirmaries, functional impairment, and quality of life.68–70 Although
only some have been empirically studied, clinical users need to be
aware that these scales have evolved rather than being developed scientifically.71 Nonetheless, patient reports of subjective levels of pain,
sensory, and psychological symptoms are crucial to aid in the clinical
search for effective treatments.
Post-Concussion Symptom Checklist (PCSC)
The PCSC was utilized to track outcomes and re-administered periodically
throughout the treatment process with care given to avoid coaching the
patient on symptom manifestations.70,72 Symptoms were also tracked through open-ended
self-reporting by the patient at the onset of each session if he
wished to share them.
Headache Impact Test™ (HIT-6)
The HIT-6 was designed to screen and monitor patients’ severity of
headache pain and the impact on function and quality of life.73 Utilizing six items with a severity rating scale, the HIT-6 has
been shown to be a reliable and valid tool for discriminating the
effect of headache on daily living.74,75 A possible point range of 36–78 reflects the
severity of impact that headaches are interfering with daily quality
of life and function. The HIT-6 was chosen for this particular patient
to track headache symptoms which was also a chief complaint, second
only to sleep disturbances.
Measurement of sleep
Sleep function was tracked through a sleep diary and the patient’s
perception of restfulness and daily energy.
Subjective data —from the clinician
Neurological screenings occurred each session per standard of care,
including pupil and oculomotor status, balance reactions, and general
cognitive assessments conducted through observations of behavior.
Palpation findings from full body assessment of musculoskeletal,
fascia and fluid fields were conducted at the beginning of each
treatment session. Inquiry about mood and stress were made at the
beginning of each session.
Objective data
Quantifiable neurological soft sign and biomarkers not captured on the
PCSC included fixed and dilated pupils, oxygen saturation, and
frequency of urination and thirst.
Case report
The subject, a 24-year-old male, presented with an 18-month history of
persistent neurological and behavioral symptoms reportedly related to
one sports-induced concussion. Onset was in October 2017, following a
head injury while playing in a collegiate-level sport. He reported
being screened by an athletic trainer and having a follow-up medical
assessment. No hospitalization was required. Prolonged rest was
prescribed and adhered to for several months. An eventual referral to
a local academic-medicine concussion clinic was made several months
post-injury due to escalation of unresolved symptoms where
psychological services addressing anxiety and depression and
medications for pain and concentration were prescribed. Medications
reported on patient intake included Prozac, Xanax, and Adderall. He
reported his ability to focus on job tasks improved by the Adderall
but the medications generally worsened “brain fog” and memory. He also
participated in a physical therapy program for vestibular
rehabilitation. Symptoms persisted to the point of full debilitation
by sleep deprivation, increasing dizziness, sensory overload, and
brain fatigue. Suicidal ideation prompted his parents to seek other
recommendations and services.
In the interview with the patient and one of his parents, it was
discovered that he sustained a total of six sports-related concussions
dating back several years. History also included several orthopedic
injuries long since healed (fractures to a foot and nose, and several
bone contusions). The patient affirmed that a whiplash occurred with
the most recent concussion and had originally sought chiropractic care
for neck pain post-injury.
Since symptoms began to intensify, he was forced to take a medical leave
from attending school and working a job that required much traveling.
He stated he could perform job duties, enjoyed them, and felt capable
of the job. However, the sensory intolerances created significant
anxiety and began to reduce his confidence in his job performance. His
tolerance and engagement in favorite activities were at 10% of normal
participation level. He frequently isolated himself to cope with the
sensory overload which added to a sense of helplessness.
Based upon client report and clinical observations, functional problems
were noted on intake (see Figure 1). Initial clinical
findings were also noted (see Figure 2).
Figure 1. Post-concussion symptoms (18 month duration) reported on
intake questionnaire by patient and in personal and parent
interviews.
Figure 2. Initial clinical findings.
Treatment methods employed included the following: (incorporated into
each session as the need arose).
Manual LD techniques (Chikly).45
CST techniques (Upledger).30
Glial and Glymphatic system techniques (Wanveer).16
Goals for series of therapy encounters
Reduce and eliminate stagnant and congested edema of spine,
neck, and head.
Soft tissue mobilization and fascial release methods to
increase general soft tissue flexibility and subtleness
through body to reduce sympathetic tone (through CST).
Facilitate exchange of fluid through all body fluid systems;
reduce interstitial congestion to promote healing and
self-correction of nervous system (through LD).
Neurological rehabilitation strategies to reduce and adapt to
sensory challenges; environmental structuring. (These
methods were not required due to the speed in which
positive changes were experienced and observed with manual
therapies.)
Achieve freedom from pain and neurological dysfunction,
restore/raise quality of life.
Community and work re-entry, adaptations, and modifications
assistance where needed.
Patient and family education on the concepts of manual
therapies.
Client stated just one personal goal: “I just want to be able
to sleep.”
Treatment process
Treatment was conducted in isolation of any other (new) therapy over the
course of three months. The patient participated in eleven, 1-h
sessions. Scheduling sessions were recommended at 2–3 times per week
initially. Following the first session, he requested daily treatment
but was advised to allow his system to acclimate and integrate
treatment effects. The first four sessions were scheduled 3 days
apart. After the fourth session, scheduling was left to his
discretion. Six more appointments were scheduled with 1 week spacing,
and the eleventh session was as a follow-up at the patient’s
discretion 5 weeks later. Each session was an improvisational process
of applying the various manual therapies and techniques, based upon
whole-body assessment of primary and secondary structural and fluid
findings.
Results and treatment outcomes
Quantitative data were collected through self-reporting of severity of
symptoms using the PCSC, the HIT-6, and clinical observations.
Sessions began most often with an invitation for him to report
whatever symptom(s) felt most pressing. Quality of life measurements
were self-reporting of sleep function, brain fog, ability to “get
through the day,” ability to tolerate sensory aspects of daily events,
and endurance for mental and physical activities. All were recorded in
the daily notes. A total of five recordings of the PCSC and three
recordings of the HIT-6 were captured over the course of the treatment
series (see Figure
3). Based upon both verbal responses from the patient as
well as observation, some particular treatment techniques demonstrated
a direct correlation to a reduction of a specific symptom (see Figure 4).
Figure 3. Self-reported changes of persistent concussion symptoms
related to treatment intervention; measured through
symptom tracking methods.
Figure 4. Based upon patient’s verbal responses and direct observation
in treatment, several techniques had a direct correlation
to a reduction of specific symptoms.
Sleep was restored following the first treatment as he reported sleeping
12 h each night between session one and two. Sleep continued to remain
at normalized levels throughout the treatment process.
Sessions were not based upon following specific protocol sequence. A
narrative summary of this improvisational and experiential treatment
process is reflected in a summary of the daily notes (see Figure 5).
Figure 5. Treatment Progression Depicted through Daily Notes.
Abbreviated daily notes to reflect the full therapeutic
process of applying CST and LD to treat symptoms of
concussion. See KEY for term definitions.
Six month follow-up
A 6-month follow-up (via telephone conversation) revealed sustained
abatement of PCS symptoms and the patient resumed educational pursuits
and gainful employment. His parents recommended that he continue to
receive maintenance therapy but he voiced concerned over his mounting
financial debt. He denied that symptoms were interfering with daily
activities and quality of life. The patient’s perspective about these
therapies was highly positive.
Discussion
This article offers a hypothesis that persistent symptoms of PCS could be, in
part, a result of compromised glymphatic and lymphatic pathway flow stemming
from restrictions of movement and balanced position of osseous and soft
tissue structures. The theoretical constructs of CST suggest when fascial
membranes such as the dura and other meningeal layers and/or cranial plates
and vertebral column may be in a compressive state, leading to neurological
and/or behavioral symptoms.30,32,76 The theoretical
constructs of LD is that gentle, manual evacuation of lymphatic channels
following anatomical mapping enhances a whole-body fluid exchange and
removal of cellular wastes between interconnecting fluid systems.45,49
Only through whole-body palpation assessment was the first clinical discoveries
made in this patient. Asymmetrical rib cage alignment, with sub-optimal
breath expansion and lowered oxygen saturation, was subjectively assessed
and CST techniques were immediately employed. The second discovery was
persistent edema through anterior and lateral cervical chains, over the
expanse of scalp lymphatics, and engorged in bilateral occipital nodes at
the cranial base. It is a reasonable assumption that edema may have occurred
at the time of injury but after 18 months, edema and interstitial fluid
stagnation would be expected to have resolved. That was not the case for
this athlete. Palpation for (chronic) edema is a skill set learned through
specific LD training methods.
Sleep was the first of the chronic symptoms to demonstrate an effect from
treatment, after just one, 1-h treatment session. It could be suggested that
fluid stagnation in and around the central nervous system contributed to the
adverse head pressure pain with impact on the lack of restorative sleep (as
surmised by the patient’s insights). It could be suggested that quality of
breathing function may also have had a negative effect upon sleep. It is
apparent through the stream of daily notes that the first treatment in and
around the thoracic body and rib cage (consisting of fascia mobilization
following CST methods) produced immediate elevation in oxygen saturation. It
was also immediately apparent that LD through the central spinal lymph node
confluences and pathways produced an immediate response of head pressure
relief. Sleep resolved to satisfactory levels for the patient and remained
so for the remainder of the treatment series, and at the 6-month
follow-up.
Other neurological symptoms resolved at different, but steady rates, as
reflected on the periodic scoring of the PCSC. To avoid or minimize effects
of coaching or influencing the patient on symptom reporting, freely
expressed symptom declarations were documented prior to the administration
of repeated PCSC scoring. It is with a high rate of certainty that the PCSC
yielded an accurate expression of the patient’s self-reported experiences in
symptom status through the treatment process.
Therapeutic touch and emotional support are aspects of most forms of manual
therapies. It is possible that any placebo or autonomic calming effect of
therapeutic touch contributed to the reduction of symptoms. However,
resolution of certain chronic symptoms did correlate with the application of
only specific treatment techniques (see Figure 4). Mood, cognitive
function, and emotional well-being improved and the patient attributed this
to reduction and elimination of head pain, brain fatigue, and sensory
sensitivities. Quality of life improved and he returned to his occupational
tasks of completing college and finding a less stressful, yet meaningful,
job.
The literature supports interventions for PCS which include psychological,
cervical, and vestibular rehabilitation.5 The differential methods of CST and LD as distinct manual therapies
have yet to be fully explored as options for PCS, though emerging studies
indicate CST being used clinically with functional PCS subtypes. One
contraindication for CST is not to apply during acute stages of brain injury
when increased intracranial pressure is present.30 Contraindications for LD have been cited and include acute infection
or inflammatory disease process, thrombosis or phlebitis, acute hemorrhage,
active malignant ailments, and acute heart problems as LD increases cardiac
load.44,45
Future study could possibly isolate the impact CST and LD modalities have upon
sleep in PCS. Research of the fluid exchange models of the nervous system
could explore possible correlations to persistent symptoms of PCS.
Furthermore, efficacy studies into therapies such as CST and LD might be
aided by advancements of proving and measuring the exchange of fluids where
glymphatic and lymphatic structures merge.
Conclusions
This case report reflects one collegiate athlete’s unique constellation of PCS
and the self-reported reduction of persistent symptoms through the
experiential process of CST and LD intervention. There is little published
evidence of the efficacy of CST and/or LD on the symptoms of PCS, though
both have been utilized in clinics internationally for over 3 decades. Rest
allowance and other therapy interventions had been previously trialed for
18 months, though no concussion symptom tracking was completed or available
from previous records for comparative purposes. Previous pharmacologic
treatment and vestibular rehabilitation for this patient were self-reported
to have reduced symptoms of attention deficits and balance in climbing
stairs, respectively. Other psychology and physical medicine endeavors had
been trialed over the year and a half, and per his declaration, “Did not
help heal me. Medications only helped me get through the work day; they did
not take away the symptoms.”
The author, an occupational therapist with 20 years of experience applying CST
and LD in clinical practice, admits to a strong inherent bias. The strength
of this case study, however, is that treatment was provided in isolation of
any intervention other than his established medication usage. It could be
said that placebo effect had been controlled for where specific treatment
techniques clearly resolved some specific symptoms, but not all. Other
symptoms resolved over time and may reflect effects of the restoration of
sleep and elevation of mood. Though generalization of the findings in this
case cannot be applied to the greater population of patients with
concussions and brain injuries, this case does suggest that CST and LD are
valuable treatment options for PCS and worthy of future study.
We thank all the clients and their families who trust the wisdom of structural
medicine as we continue to merge theory with day-to-day clinical practices.
We are forever indebted to your tenacity and steadfastness to find and
secure appropriate help.
Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article: Any conflicts of interests are implied by the author being an
active clinician where these techniques and therapeutic strategies are
utilized in the clinic setting.
Ethical approval: Our institution does not require ethical approval for reporting
individual cases or case series.
Funding: The author(s) received no financial support for the research, authorship,
and/or publication of this article.
Informed consent: Written informed consent was obtained from the patient(s) for their
anonymized information to be published in this article. This informed
consent is maintained in the medical records for this patient.
ORCID iD: Susan Vaughan Kratz https://orcid.org/0000-0003-2018-8365 | Recovering | ReactionOutcome | CC BY-NC | 33628444 | 18,976,097 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Calcific Uremic Arteriolopathy: A Case Series and Review from an Inner-City Tertiary University Center in End-Stage Renal Disease Patients on Renal Replacement Therapy.
24 patients with CUA and on RRT were evaluated at Detroit Medical Center from 2007 to 2016. Skin biopsy was used in almost all patients, along with the radiological and clinical findings. The patient's clinical and paraclinical data were retrieved from the electronic medical records. The effect of treatment modalities and the underlying hyperparathyroidism management were compared to the clinical outcomes using appropriate statistical tests.
Twenty-one patients were on hemodialysis, two patients received renal transplants, and one patient was on peritoneal dialysis. Diabetes mellitus was the most prevalent cause of ESRD. The parathyroid hormone level (PTH) was elevated in 22 patients. Fifteen patients were diagnosed 2 weeks or more prior to skin lesion onset. Twenty-two and thirteen patients received sodium thiosulphate and cinacalcet, respectively. Patients with lower PTH and the calcium-phosphate product levels had a relatively better outcome of CUA.
A multifaceted approach may play a role in treating CUA. Referral to a nephrologist may aid in the early diagnosis and prompt management of CUA.
1. Introduction
Calcific uremic arteriolopathy, formerly called calciphylaxis, is an uncommon wrecking condition seen often in patients with advanced CKD, predominantly in patients on some form of renal replacement therapy (RRT) [1, 2]. It is initially characterized by livedo reticularis that advances to patches of ischemic necrosis, predominantly over the legs, thighs, gluteal region, abdomen, and breasts. It was first described in 1898 by Bryant and White [3]. The expression “calciphylaxis” was introduced by Selye in 1962 when he observed that inducing hyperparathyroidism or hypervitaminosis D in rodents could potentially lead to the progress of soft tissue calcification when exposed to injury or metallic salts, particularly iron therapy [4, 5]. The condition is also known as “metastatic calcinosis cutis” and “necrotizing or calcifying panniculitis.” Although it was thought to be uncommon in the past, the rate of CUA seems to rise, as proposed by an analysis of the United States Renal Data System [6]. A cross-sectional study of 242 patients undergoing hemodialysis in an outpatient setting presented a prevalence of 4 percent [7]. It was recently found that hypersensitivity or IgE release has no role in its development; subsequently, this eventually led to a significant change in the terminology to CUA, which was proposed as a better description of the underlying pathological process. A plethora of case reports published in the literature in the past addressed the same condition in patients without severe renal failure; a systematic review of 36 case reports discussed the development of nonuremic calciphylaxis [8]. CUA is characterized by regions of painful ischemic necrosis [9, 10]. As far as we can tell, in certain patients, pain may be the initial symptom before the development of the ulcerative lesions by numerous days. The exact mechanism of pain in CUA is a debatable issue and is believed to be ischemic in origin, yet, there might be a neuropathic element [11]. Skin lesions may have a particular preference for areas with abundant fat distribution. This has been shown in one of the most massive CUA reviews, including the leg, abdomen, and buttocks in 60, 23, and 9 percent of cases, respectively [12]. The variety of the lesions can be quite polymorphic and could be related to the stage of presentation. For instance, one of the most distinctive lesions is violaceous, painful, plaque-like subcutaneous nodules that may advance into frankly ischemic/necrotic ulcerative lesions with eschars once vascular thrombosis has been superimposed [13]. The risk of infection in eschars is relatively high [14]. Ischemic changes may appear early as livedo reticularis [15]. Less commonly, painful proximal muscle weakness can be the only presenting symptom shortly followed by skin lesions [16]. Both morbidity and mortality are quite unfavorable in this condition, with the most frequent cause of death being overwhelming sepsis because of compromised integrity of both epidermis and dermis [17].
Inducing hyperparathyroidism in animals was shown to increase the risk of ischemic skin necrosis [18]. Furthermore, parathyroidectomy has led to clinical improvement in many cases [1, 19]. Poorly controlled secondary hyperparathyroidism has been associated with significant complications like soft tissue and vascular calcification [20].
Many studies and case reports have linked warfarin as an essential risk factor for the precipitation of CUA. Iron administration has also been proposed as a risk factor for calciphylaxis. Iron deposits have been demonstrated in tissue samples from patients with calciphylaxis [21]. Moreover, excessive consumption of vitamin D was associated with an increased risk of subsequent development of CUA [2]. Skin biopsy is the gold standard with the other tools, including radiological scanning, which may show calcific radiopaque deposits at the same site of the skin lesions. Furthermore, clinical bedside diagnosis is remarkably helpful in the initial suspicion of this disorder.
Superimposed infections and sepsis are the leading cause of mortality [22]. Patients who survive severe ulcerative lesions might end up with significant scarring and disfigurement. Few cases might end up with extremity amputations at multiple levels.
The degree of skin involvement has been shown to directly proportionate with the one-year mortality rate that reaches up to 67% in deeper ulcerative lesions [23]. Earlier timing to the diagnosis and initiation of therapy has a significant impact on the final outcome, as well as the location of the lesions (proximal vs. distal), which has not been well examined.
2. Materials and Methods
The study was conducted in a tertiary inner-city university center, both retrospective as well as prospective over a 9-year period (2007–2016), and a total of 24 patients were enrolled in the study.
Following the Wayne State University/Detroit medical center's IRB approval, the ICD coding 9/10 systems were used to find patients admitted with CUA to the DMC hospitals, with no restriction on sample size or study duration. Inclusion criteria included age group of 18–80 years, patients with RRT for at least three months, and patients with a diagnosis of calcific uremic arteriolopathy. Exclusion criteria included loss of follow-up.
Demographic features of the patients including age, ethnicity, RRT modality, as well as the history of diabetes mellitus (DM), hypertension (HTN), peripheral artery disease (PAD), coronary artery disease (CAD), congestive heart failure (CHF), and cerebrovascular disease (CVA) were collected from their medical records.
The following variables were collected: serum calcium, phosphorus, calcium-phosphate product, and intact parathyroid hormone (iPTH). We also recorded serum ferritin, transferrin saturation%, protein C/S levels, and antiphospholipid antibody levels if available. Different renal osteodystrophy therapy methods were also recorded, including vitamin D therapy, oral calcimimetics, and subtotal parathyroidectomy. We examined the diagnosis methods of calciphylaxis, including clinical bedside evaluation, radiological imaging, and skin biopsy. Timing of the diagnosis, early (<2 weeks) vs. delayed (>2 weeks), and the anatomical site (proximal vs. distal) of the lesions were also noted. Components of multifaceted regimens that our patients received are sodium thiosulphate, hyperbaric O2, wound care, and/or modes of hyperthyroidism management, which were examined. Disease course and the final outcome of the lesions were categorized into complete resolution, partial resolution, or amputation and death. A critical guide to case series reporting was used to improve the quality of the study. We summarized the categorical variables using the number and percentage of the patients included in the study. Comparisons of the clinical characteristics of our patients were made using Fisher's exact test. All statistical tests were two-sided. The statistically significant P value was set to be less than 0.05. Our data were analyzed using SPSS version 27.
3. Results
As shown in Table 1, 24 patients were diagnosed with calcific uremic arteriolopathy (CUA). The results showed a female predominance of 18 patients as compared to 6 male patients. The mean age was 56.3 ± 14.6 years, ranging from 28 to 81. Ten patients were above 60 years of age, ten patients were aged between 40 and 60 years, and only four patients were less than 40 years. Among those cases, 22 were of African American descent, whereas only 2 cases were Caucasians. Twenty-one of our patients were on hemodialysis, only one patient managed through peritoneal dialysis, and the remaining 2 had a renal transplant. Diabetes mellitus (DM) was the most common etiology of end-stage renal disease (ESRD) with 13 cases being identified, while 8 cases had hypertension (HTN), with the three remaining reported etiologies as polycystic kidney disease (PKD), systemic lupus erythematosus (SLE), and focal segmental glomerulosclerosis. Seventeen patients had higher serum calcium of more than 8.5 mg/dl, and only seven patients had lower serum calcium of less than 8.5 mg/dl at the time of the diagnosis. Fifteen patients had lower serum phosphorus levels of less than 6.5 mg/dl, while nine patients had higher serum phosphorus levels of more than 6.5 mg/dl.
Moreover, 10 cases were diagnosed with a higher calcium-phosphate product of more than 55 mg2/dl2, and 14 patients had a lower calcium-phosphate product of less than 55 mg2/dl2. Most cases (N = 22 cases) had an elevated iPTH level compared to only 2 cases with normal iPTH levels. Nine patients had a serum PTH of more than 600 pg/ml, while 15 patients had a lower iPTH level of less than 600 pg/ml. Fourteen patients had a ferritin level of more than 500 μg/l, while six patients had a ferritin level of less than 500 μg/l. Fourteen patients had more than 20% transferrin saturation, while six patients had transferrin saturation less than 20%.
As Table 2 shows, 17 patients had histopathological evidence of CUA, while 4 cases were diagnosed based on bedside clinical examination, and only 3 cases were diagnosed based on radiological scanning. Regarding the time of diagnosis, 15 patients were diagnosed late (i.e., more than two weeks from the onset of the lesions), and nine patients were diagnosed earlier (i.e., less than two weeks from the onset of the lesions). From the anatomical standpoint, 13 patients had CUA lesions distal to the knee, whereas 11 patients had proximal lesions (above the knee).
As Table 3 shows, regarding the treatment of hyperparathyroidism, 13 patients were on cinacalcet, while only 3 received vitamin D analogs, alendronate, and parathyroidectomy in each arm, respectively. Eight out of our case series did not receive any mode of therapy for hyperparathyroidism. Only 2 cases received treatment with the HBO2. The majority of our case series were on sodium thiosulphate treatment (n = 22). 21 out of our cases received wound care management of their lesions. Regarding the outcome and progression of CUA lesions, 12 of our patients improved entirely or partially, while the other half of the cases ended up with amputation or died.
As shown in Table 4, patients with a lower PTH level of less than 600 pg/ml had an improvement in the outcome of their lesions (7/10: 70%). Nevertheless, patients who underwent amputation or died were more likely (7/12: 58.3%) to have PTH of less than 600 pg/ml. Of the two patients who showed partial improvement, one patient had a PTH level of more than 600 pg/ml, while the other had a PTH less than 600 pg/ml. Patients with a lower calcium-phosphate product (of less than 55 mg2/dl2) were found to have much more improvement (7/10: 70%), while patients who had calcium-phosphate products of more than 55 mg2/dl2 were less likely to survive or end up with more amputations (7/12: 58.3%). Only two patients with a lower calcium-phosphate product of less than 55 mg2/dl2 showed partial improvement. 8/10 (80%) of our patients with a lower phosphate level of less than 6.5 mg/dl were more likely to show improvement in the outcome, while 7/12 (58.3%) of our patients with a severely elevated phosphate level of more than 6.5 mg/dl were more likely to die or have an amputated limb. Only two patients showed partial improvement and had a phosphate level of less than 6.5 mg/dl. Significant differences were observed regarding the timing of the diagnosis and the final outcome of the lesions. Seven out of ten patients (70%) who had an improvement in the final outcome of their lesions were diagnosed in less than 2 weeks. Ten out of twelve patients (83.3%) who had a poor outcome, i.e., had amputated limb or expired, had a late diagnosis in their course. P value = 0.019.
As illustrated in Table 5, notably, patients who did not receive any parathyroid treatment were more likely (5/8: 62.5%) to have a lower phosphate level of less than 6.5 mg/dl. In comparison, patients who received cinacalcet as a form of therapy were more likely (8/13: 62%) to have a lower phosphate level of less than 6.5 mg/dl. Patients who were on Doxercalciferol and Alendronate were found to have a lower phosphate level of less than 6.5 mg/dl as well. One patient underwent parathyroidectomy and had a phosphate level of more than 6.5 mg/dl. Patients who did not receive any form of parathyroid therapy were more likely (7/8 : 85.5%) to have a lower PTH level of less than 600 pg/ml, as well as patients who were on cinacalcet therapy, who also more likely (7/13: 53.8%) had a PTH level of less than 600 pg/ml. Only one patient received Doxercalciferol and had severely elevated PTH levels of more than 600 pg/ml. One patient underwent parathyroid gland resection and had an elevated PTH level of more than 600 pg/ml as well. Finally, only one patient received Alendronate and had a PTH level of less than 600 pg/ml.
As Table 6 shows, the use of multifaceted treatment and its relation to the outcome, 14 patients received three different regimens for the management of CUA, while 9 received two regimens, and one patient received wound care only as a mode of management.
4. Discussion
CUA is a syndrome characterized by both thrombosis and small vessel calcification that significantly burdens patients with end-stage renal disease resulting in high morbidity and mortality. It is well known to be multifactorial in etiology. Our findings from this study suggest that many risk factors may predispose patients to the development of CUA. A significant number of patients have shown improvement with the multidisciplinary approach of those lesions. Our study has shown that most of the patients affected were of the female sex, which is in line with numerous previous studies in the past [14, 24]. The fat distribution pattern might explain the prevalence of CUA lesions in females, particularly those with an average BMI of more than 30 [3]. Our study has demonstrated that most of our patients were of African American descent compared to other studies in which patients were predominantly Caucasians [13, 25–27]. However, our tertiary hospital demographically deals with patients who are predominantly of African American origin, which may explain those findings. Most of our patients were aged above 55, which is similar to other studies in the literature that suggested advanced age as a contributing factor [25]. Most of our patients had multiple comorbidities. As reported in previous studies, diabetes mellitus was the commonest contributing factor that may play a role in the development and progression of the lesions making management quite difficult in these subtypes of patients [2, 3, 24]. Early skin lesions like subcutaneous nodules in patients with end-stage renal disease, secondary hyperparathyroidism, calcium, and phosphorus abnormalities should raise the clinicians' suspicion about the possibility of CUA diagnosis. CUA lesions can mimic a wide variety of skin pathologies, including atherosclerosis, cholesterol embolization, warfarin skin necrosis, endarteritis obliterans, vasculitis, cellulitis, purpura fulminans, oxalate vasculopathy, antiphospholipid antibody syndrome, radiation arteritis, Martorell hypertensive ischemic ulcer, cardiac myxoma, and in early nephrogenic systemic fibrosis skin lesions [11, 28].
Ghosh et al. [29] have shown that CUA may be misdiagnosed in its early stages. An appropriate skin biopsy remains the gold standard to confirm a CUA diagnosis to distinguish it from other conditions. 17 of our patients were diagnosed by skin biopsy, and only three were identified via radiological imaging based on the patterns of calcium deposits in the site of CUA lesions. However, the diagnostic utility is not established yet [30, 31], while 4 cases were diagnosed based on bedside clinical examination only.
Most of the patients in this cohort were treated with hemodialysis, which suggests more incidence of CUA with this modality of renal replacement therapy. However, one single-center study had shown a higher incidence in patients on peritoneal dialysis [32]. The high incidence of CUA lesions may be explained by a heavier calcium exposure in this subset of patients.
In our study, we identified only seven patients who were hypercalcemic at the time of diagnosis; this is in contrast to a study published by Nigwekar et al. [26], which had found that hypercalcemia was common in most of their patients with an OR of 1.83 (P: 0.02).
Most of our patients' lab values were within the normal range at the time of diagnosis, and this is a major shortcoming in accurately addressing the immediate risk factor to predispose patients to the development of CUA lesions. Although many studies had implicated the role of hyperphosphatemia in the development of CUA (3) [33], 15 of our patients had serum phosphorous levels of less than 6.5 mg/dl.
In our case series, almost all of our patients (n = 22) had significant hyperparathyroidism, which is in keeping with many previous studies showing its major role in the development of CUA lesions (3) [33]. We believed that moderate to severe hyperparathyroidism predispose renal failure patients to the development of CUA lesions. A high parathyroid hormone level induces high-turnover bone disease, which is significantly associated with vascular calcification in renal failure patients and eventually may lead to the development of CUA lesions; however, a low level (<100 pg/ml) induces adynamic bone disease, which is less associated with the development of CUA lesions. Abnormalities in calcium, phosphorus, or PTH may be noted in patients with calciphylaxis, but it is not always the case, as these patients may present with normal lab values. In our study, the most notable abnormality is the elevated parathyroid hormone levels.
This study found that the majority of our patients with improved outcomes had PTH levels of less than 600 pg/ml; nevertheless, when considering patients who expired or had amputations with similar PTH levels, this observation was statistically insignificant. P value = 0.79.
The majority of our patients (7/10: 70%) who had an improvement in the final outcome of their lesions were diagnosed in less than 2 weeks. Most of the patients (10/12: 83.3%) who had a poor outcome, i.e., had amputated limb or expired, had a late diagnosis in their course. This relationship showed statistical significance. P = 0.019.
Many reports had addressed the beneficial role of reducing phosphate and calcium-phosphate product in the outcome of CUA lesions [34–36]; this is well shown in our study, which has found better outcomes in patients with a lower calcium-phosphorus product of less than 55 mg2/dl2. Block et al. have shown that patients with a calcium-phosphate product of higher than 72 mg2/dl2 had a relatively higher risk of mortality [37].
A paper published by Farah et al. [38] has found, in 12 histological tissue samples of CUA lesions, significant iron deposits affecting the microvasculature but otherwise absent in other tissues. This finding raises the hypothesis that iron-inducing oxidative stress in patients with uremia and iron-chelating therapy might play a role in the treatment of CUA.
Zarjou et al. [39] concluded that ferritin might help to prevent vascular calcification by the induction of a heme-oxygenase-1/ferritin system that prevents inorganic phosphate mediated calcification and osteoblastic differentiation of human smooth muscle cells mainly via ferroxidase activity of ferritin. In our study, 14 of our patients had elevated ferritin of more than 500 μg/l and transferrin saturation of >20%.
We cannot overemphasize the importance of a high index of CUA suspicion in patients with deranged bone and mineral profiles on renal replacement therapy. This subset of the patient needs an urgent referral to a nephrologist to reach a final diagnosis. Out of 24 patients, only 9 cases (37.5%) were diagnosed earlier than two weeks with CUA from the development of the lesions, which is in keeping with the same results by Ghosh et al. [29], who identified only two out of five patients early in their course of the development of the lesions, and hence receiving prompt treatment is associated with less grievous complications.
With the use of multifaceted interventions, 10 of our patients showed complete recovery from CUA lesions, while two patients have made a partial recovery. However, 12 patients have taken a relatively steep downhill course with amputation of an extremity as well as death. This particular subset could have a heavier comorbid load. Unfortunately, it is difficult to track the exact cause of their death due to a lack of information in our medical record. From our case series, there was no specific combination of therapies that pointed toward the improvement of CUA lesions.
A literature review on 104 cases was conducted and showed that parathyroidectomy remains the most important modality to improve patients with severe hyperparathyroidism and CUA, as suggested by Hafner et al. [40]. The vast majority of our patients did not receive parathyroidectomy as a form of parathyroid treatment (only one patient did), and this might be explained by the availability of more potent medical therapy such as cinacalcet. Patients who received cinacalcet were more likely to have PTH of less than 600 pg/ml. Higgins et al. pointed out that the recurrence of severe hyperparathyroidism is less likely to occur following parathyroid surgery [41].
To our knowledge, no study significantly addressed in detail a therapy for CUA. The management of such a condition depends mainly on the multifaceted interventions to treat CUA lesions as suggested by many other studies, leading to favorable outcomes [42–44]. Thirteen of our patients received cinacalcet as a treatment for hyperparathyroidism and CUA. Several case reports showed the benefits of cinacalcet [45–47]; however, a meta-analysis for the use of cinacalcet in the management of patients with CUA has shown no association with a lower risk of mortality, wound progressions, and amputation [48]. Sodium thiosulphate is an inorganic salt with significant antioxidant properties and a vasodilatory effect [49]. Twenty-two of our patients received STS in addition to the other therapy modes, with 12 patients showing a significant response. Hyperbaric oxygen therapy involves administering 100% oxygen in a pressurized environment (hyperbaric chamber) (>1.4 absolute atmosphere ATA). In this way, oxygen transport is increased 27 times compared with the O2 transport in plasma. This type of therapy favors the healing of CUA lesions with remarkable improvement in pain control. In addition, HBO2 therapy increases host and cellular immune responses and fibroblast-mediated collagen production and enhances the action of antibiotic therapy. In our study, only two patients could be enrolled in this therapy type due to our institution's logistic restrictions. The two patients showed a significant improvement in wound healing and less pain, which is in keeping with few studies published in the past [50–52]. A meta-analysis examining a few cohorts has failed to show its risk-reducing effect in the progression of skin lesions, amputation, or death [48].
5. Conclusion
CUA is associated with a high rate of morbidity and mortality in patients with end-stage renal disease. The lesions associated with this disorder are usually misdiagnosed by the clinicians, which leads to a significant delay in therapy initiation. Early diagnosis and referral to a nephrologist will guarantee to deliver prompt treatment and prevent lethal complications. Overall, the importance of good control of mineral and bone profile is a cornerstone of preventing CUA. Based on our results, we strongly recommend a multidisciplinary approach to both diagnosis and therapy of CUA, which can lead to a less unfavorable outcome. CUA multifaceted therapy may play a role in the final outcome of the lesions, and clearly, from our case series, no single patient has received all the modalities of CUA therapy. It must be borne in mind that this study was only conducted in a small group of patients. More case-control multicenter clinical trials are required to unravel numerous mysterious issues regarding CUA.
Data Availability
The data used to support this article will be provided upon reasonable request from the corresponding author.
Conflicts of Interest
All authors declare that they have no conflicts of interest.
Table 1 Baseline characteristics and biochemical lab values: (n = 24) unless noted.
Patient variables Frequency (%)
Gender
Male 6 (25%)
Female 18 (75%)
Age group (years)
<40 4 (16.7%)
40–60 10 (41.7%)
>60 10 (41.7%)
Ethnicity
African american 22 (91.7%)
Caucasian 2 (2.3%)
Mode of renal replacement therapy
Hemodialysis 21 (87.5%)
Peritoneal dialysis 1 (4.2%)
Renal transplant 2 (8.3%)
ESRD etiology
Diabetes 13 (54.2%)
Hypertension 8 (33.3%)
Others 3 (12.3%)
Calcium level (mg/dl)
Ca > 8.5 17 (70.8%)
Ca < 8.5 7 (29.2%)
Phosphate level (mg/dl)
Ph > 6.5 9(37.5%)
Ph < 6.5 15(62.5%)
Calcium-phosphate product level (mg2/dl2)
CaPP > 55 10 (41.7%)
CaPP < 55 14 (58.3%)
Parathyroid hormone level (pg/ml)
PTH > 600 9 (37.5%)
PTH < 600 15 (62.5%)
Ferritin level (μg/l) (n = 20)∗
Ferritin > 500 14 (58.3%)
Ferritin < 500 6 (25%)
Transferrin saturation (%) (n = 20)∗
T.sat > 20% 14 (58.3%)
T.sat < 20% 6 (25%)
Ca: serum calcium, Ph: serum phosphorus, CaPP: serum calcium-phosphorus products, PTH: serum parathyroid hormone, T.Sat: transferrin saturation. ∗4 cases were missed to follow-up of transferrin saturation and ferritin levels.
Table 2 The mode, the timing of the diagnosis, and site of the lesions.
Mode of the diagnosis
Skin biopsy 17 (70.8%)
Imaging 3 (12.5%)
Clinical 4 (16.7%)
Timing of the diagnosis
Early (<2 weeks) 9 (37.5%)
Late (>2 weeks) 15 (62.5%)
Site of the lesion
Proximal (above the knee) 11 (45.8%)
Distal (below the knee) 13 (54.2%)
Table 3 Types of therapy to manage hyperparathyroidism and the outcome of the CUA lesions.
Patient variables Frequency (%)
Therapy of hyperparathyroidism
Vitamin D 1 (4.2%)
Cinacalcet 13 (54.2%)
Parathyroidectomy 1 (4.2%)
Alendronate 1 (4.2%)
No treatment 8 (33.3%)
Therapy of calcific uremic arteriolopathy∗
Received Did not receive
HBO2 2 (8.3%) 22 (91.7%)
Cinacalcet 13 (54.1%) 11 (45.9%)
Wound care 21 (87.5%) 3 (12.5%)
NaTSO4 22 (91.7%) 2 (8.3%)
PTHx 1 (4.2%) 23 (95.8%)
The outcome of the lesion
Improved 10 (41.7%)
Partially improved 2 (8.3%)
Expired or amputation 12 (50%)
HBO: hyperbaric oxygen therapy, NaTSO4: sodium thiosulphate, PTHx: parathyroidectomy. ∗Patients may be enrolled in multiple types of treatment for calcific uremic arteriolopathy.
Table 4 The outcome of calcific uremic arteriolopathy lesions in relation to the severity of hyperparathyroidism, levels of calcium-phosphate products, the degree of hyperphosphatemia, and the timing of the diagnosis.
Outcome Parathyroid hormone levels
P value
<600 >/=600 Total
Improved 7 (70%) 3 (30%) 10 (100%) 0.79
Partial improvement 1 (50.00%) 1 (50.00%) 2 (100%)
Expired or amputation 7 (58.3%) 5 (41.7%) 12 (100%)
Total 15 9 24
Outcome Calcium-phosphate product levels
<55 >/=55 Total
Improved 7 (70%) 3 (30%) 10 (100%) 0.18
Partial improvement 2 (100%) 0 (0.00%) 2 (100%)
Expired/Amputated 5 (41.7%) 7 (58.3%) 12 (100%)
Total 14 10 24
Outcome Phosphate levels
<6.5 >6.5 Total
Improved 8 (80%) 2 (20%) 10 (100%) 0.94
Partial improvement 2 (100%) 0 (0.00%) 2 (100%)
Expired/Amputated 5 (41.7%) 7 (58.3%) 12 (100%)
Total 15 9 24 (100%)
Outcome Timing of diagnosis
Early Late Total
Improved 7 (70%) 3 (30%) 10 (100%) 0.019
Partial improvement 0 (0.00%) 2 (100%) 2 (100%)
Expired/Amputated 2 (16.7%) 10 (83.3%) 12(100%)
Total 9 (37.5%) 15 (62.5%) 24 (100%)
Table 5 The relation of parathyroid treatment to the degree of hyperphosphatemia and parathyroid hormone levels.
Parathyroid treatment Phosphate levels
P value
<6.5 >/= 6.5 Total
No treatment 5(62.5%) 3(37.5%) 8(100%) 0.58
Cinacalcet 8(62%) 5(38%) 13(100%)
Doxercalciferol 1(100%) 0(0.00%) 1(100%)
Parathyroidectomy 0(0.00%) 1(100%) 1(100%)
Alendronate 1(100%) 0(0.00%) 1(100%)
Total 15 9 24
Parathyroid treatment Parathyroid hormone levels
<600 >/= 600 Total
No treatment 7(85.5%) 1(12.5%) 8(100%) 0.16
Cinacalcet 7(53.8%) 6(46.2%) 13(100%)
Doxercalciferol 0(0.00%) 1(100%) 1(100%)
Parathyroidectomy 0(0.00%) 1(100%) 1(100%)
Alendronate 1(100%) 0(0.00%) 1(100%)
Total 15 9 24
Table 6 The relationship of multifaceted regimens of our patients and their final outcomes.
Patients Sodium thiosulfate Hyperbaric oxygen Wound care Hyperparathyroidism management Outcome
Patient no. 1 √ — √ Cinacalcet Improved
Patient no. 2 √ — √ Cinacalcet Improved
Patient no. 3 √ — √ Cinacalcet Amputated/Died
Patient no. 4 √ — — Cinacalcet Partially improved
Patient no. 5 √ — √ — Amputated/Died
Patient no. 6 √ — — Cinacalcet Amputated/Died
Patient no. 7 √ — √ — Amputated/Died
Patient no. 8 √ — √ Cinacalcet Amputated/Died
Patient no. 9 √ — √ Cinacalcet Amputated/Died
Patient no. 10 √ — √ Doxercalciferol Improved
Patient no. 11 √ √ √ — Amputated/Died
Patient no. 12 √ — √ — Improved
Patient no. 13 √ — √ — Amputated/Died
Patient no. 14 √ — √ Parathyroidectomy Amputated/Died
Patient no. 15 √ — √ Cinacalcet Amputated/Died
Patient no. 16 √ — √ Cinacalcet Partially improved
Patient no. 17 √ — — Cinacalcet Improved
Patient no. 18 √ — √ Cinacalcet Improved
Patient no. 19 √ — √ Alendronate Amputated/Died
Patient no. 20 — — √ — Improved
Patient no. 21 √ — √ Cinacalcet Improved
Patient no. 22 √ — √ Cinacalcet Amputated/Died
Patient no. 23 √ — √ — Improved
Patient no. 24 — √ √ — Improved | ALENDRONATE SODIUM, SODIUM THIOSULFATE | DrugsGivenReaction | CC BY | 33628505 | 19,686,266 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapeutic product effect incomplete'. | Calcific Uremic Arteriolopathy: A Case Series and Review from an Inner-City Tertiary University Center in End-Stage Renal Disease Patients on Renal Replacement Therapy.
24 patients with CUA and on RRT were evaluated at Detroit Medical Center from 2007 to 2016. Skin biopsy was used in almost all patients, along with the radiological and clinical findings. The patient's clinical and paraclinical data were retrieved from the electronic medical records. The effect of treatment modalities and the underlying hyperparathyroidism management were compared to the clinical outcomes using appropriate statistical tests.
Twenty-one patients were on hemodialysis, two patients received renal transplants, and one patient was on peritoneal dialysis. Diabetes mellitus was the most prevalent cause of ESRD. The parathyroid hormone level (PTH) was elevated in 22 patients. Fifteen patients were diagnosed 2 weeks or more prior to skin lesion onset. Twenty-two and thirteen patients received sodium thiosulphate and cinacalcet, respectively. Patients with lower PTH and the calcium-phosphate product levels had a relatively better outcome of CUA.
A multifaceted approach may play a role in treating CUA. Referral to a nephrologist may aid in the early diagnosis and prompt management of CUA.
1. Introduction
Calcific uremic arteriolopathy, formerly called calciphylaxis, is an uncommon wrecking condition seen often in patients with advanced CKD, predominantly in patients on some form of renal replacement therapy (RRT) [1, 2]. It is initially characterized by livedo reticularis that advances to patches of ischemic necrosis, predominantly over the legs, thighs, gluteal region, abdomen, and breasts. It was first described in 1898 by Bryant and White [3]. The expression “calciphylaxis” was introduced by Selye in 1962 when he observed that inducing hyperparathyroidism or hypervitaminosis D in rodents could potentially lead to the progress of soft tissue calcification when exposed to injury or metallic salts, particularly iron therapy [4, 5]. The condition is also known as “metastatic calcinosis cutis” and “necrotizing or calcifying panniculitis.” Although it was thought to be uncommon in the past, the rate of CUA seems to rise, as proposed by an analysis of the United States Renal Data System [6]. A cross-sectional study of 242 patients undergoing hemodialysis in an outpatient setting presented a prevalence of 4 percent [7]. It was recently found that hypersensitivity or IgE release has no role in its development; subsequently, this eventually led to a significant change in the terminology to CUA, which was proposed as a better description of the underlying pathological process. A plethora of case reports published in the literature in the past addressed the same condition in patients without severe renal failure; a systematic review of 36 case reports discussed the development of nonuremic calciphylaxis [8]. CUA is characterized by regions of painful ischemic necrosis [9, 10]. As far as we can tell, in certain patients, pain may be the initial symptom before the development of the ulcerative lesions by numerous days. The exact mechanism of pain in CUA is a debatable issue and is believed to be ischemic in origin, yet, there might be a neuropathic element [11]. Skin lesions may have a particular preference for areas with abundant fat distribution. This has been shown in one of the most massive CUA reviews, including the leg, abdomen, and buttocks in 60, 23, and 9 percent of cases, respectively [12]. The variety of the lesions can be quite polymorphic and could be related to the stage of presentation. For instance, one of the most distinctive lesions is violaceous, painful, plaque-like subcutaneous nodules that may advance into frankly ischemic/necrotic ulcerative lesions with eschars once vascular thrombosis has been superimposed [13]. The risk of infection in eschars is relatively high [14]. Ischemic changes may appear early as livedo reticularis [15]. Less commonly, painful proximal muscle weakness can be the only presenting symptom shortly followed by skin lesions [16]. Both morbidity and mortality are quite unfavorable in this condition, with the most frequent cause of death being overwhelming sepsis because of compromised integrity of both epidermis and dermis [17].
Inducing hyperparathyroidism in animals was shown to increase the risk of ischemic skin necrosis [18]. Furthermore, parathyroidectomy has led to clinical improvement in many cases [1, 19]. Poorly controlled secondary hyperparathyroidism has been associated with significant complications like soft tissue and vascular calcification [20].
Many studies and case reports have linked warfarin as an essential risk factor for the precipitation of CUA. Iron administration has also been proposed as a risk factor for calciphylaxis. Iron deposits have been demonstrated in tissue samples from patients with calciphylaxis [21]. Moreover, excessive consumption of vitamin D was associated with an increased risk of subsequent development of CUA [2]. Skin biopsy is the gold standard with the other tools, including radiological scanning, which may show calcific radiopaque deposits at the same site of the skin lesions. Furthermore, clinical bedside diagnosis is remarkably helpful in the initial suspicion of this disorder.
Superimposed infections and sepsis are the leading cause of mortality [22]. Patients who survive severe ulcerative lesions might end up with significant scarring and disfigurement. Few cases might end up with extremity amputations at multiple levels.
The degree of skin involvement has been shown to directly proportionate with the one-year mortality rate that reaches up to 67% in deeper ulcerative lesions [23]. Earlier timing to the diagnosis and initiation of therapy has a significant impact on the final outcome, as well as the location of the lesions (proximal vs. distal), which has not been well examined.
2. Materials and Methods
The study was conducted in a tertiary inner-city university center, both retrospective as well as prospective over a 9-year period (2007–2016), and a total of 24 patients were enrolled in the study.
Following the Wayne State University/Detroit medical center's IRB approval, the ICD coding 9/10 systems were used to find patients admitted with CUA to the DMC hospitals, with no restriction on sample size or study duration. Inclusion criteria included age group of 18–80 years, patients with RRT for at least three months, and patients with a diagnosis of calcific uremic arteriolopathy. Exclusion criteria included loss of follow-up.
Demographic features of the patients including age, ethnicity, RRT modality, as well as the history of diabetes mellitus (DM), hypertension (HTN), peripheral artery disease (PAD), coronary artery disease (CAD), congestive heart failure (CHF), and cerebrovascular disease (CVA) were collected from their medical records.
The following variables were collected: serum calcium, phosphorus, calcium-phosphate product, and intact parathyroid hormone (iPTH). We also recorded serum ferritin, transferrin saturation%, protein C/S levels, and antiphospholipid antibody levels if available. Different renal osteodystrophy therapy methods were also recorded, including vitamin D therapy, oral calcimimetics, and subtotal parathyroidectomy. We examined the diagnosis methods of calciphylaxis, including clinical bedside evaluation, radiological imaging, and skin biopsy. Timing of the diagnosis, early (<2 weeks) vs. delayed (>2 weeks), and the anatomical site (proximal vs. distal) of the lesions were also noted. Components of multifaceted regimens that our patients received are sodium thiosulphate, hyperbaric O2, wound care, and/or modes of hyperthyroidism management, which were examined. Disease course and the final outcome of the lesions were categorized into complete resolution, partial resolution, or amputation and death. A critical guide to case series reporting was used to improve the quality of the study. We summarized the categorical variables using the number and percentage of the patients included in the study. Comparisons of the clinical characteristics of our patients were made using Fisher's exact test. All statistical tests were two-sided. The statistically significant P value was set to be less than 0.05. Our data were analyzed using SPSS version 27.
3. Results
As shown in Table 1, 24 patients were diagnosed with calcific uremic arteriolopathy (CUA). The results showed a female predominance of 18 patients as compared to 6 male patients. The mean age was 56.3 ± 14.6 years, ranging from 28 to 81. Ten patients were above 60 years of age, ten patients were aged between 40 and 60 years, and only four patients were less than 40 years. Among those cases, 22 were of African American descent, whereas only 2 cases were Caucasians. Twenty-one of our patients were on hemodialysis, only one patient managed through peritoneal dialysis, and the remaining 2 had a renal transplant. Diabetes mellitus (DM) was the most common etiology of end-stage renal disease (ESRD) with 13 cases being identified, while 8 cases had hypertension (HTN), with the three remaining reported etiologies as polycystic kidney disease (PKD), systemic lupus erythematosus (SLE), and focal segmental glomerulosclerosis. Seventeen patients had higher serum calcium of more than 8.5 mg/dl, and only seven patients had lower serum calcium of less than 8.5 mg/dl at the time of the diagnosis. Fifteen patients had lower serum phosphorus levels of less than 6.5 mg/dl, while nine patients had higher serum phosphorus levels of more than 6.5 mg/dl.
Moreover, 10 cases were diagnosed with a higher calcium-phosphate product of more than 55 mg2/dl2, and 14 patients had a lower calcium-phosphate product of less than 55 mg2/dl2. Most cases (N = 22 cases) had an elevated iPTH level compared to only 2 cases with normal iPTH levels. Nine patients had a serum PTH of more than 600 pg/ml, while 15 patients had a lower iPTH level of less than 600 pg/ml. Fourteen patients had a ferritin level of more than 500 μg/l, while six patients had a ferritin level of less than 500 μg/l. Fourteen patients had more than 20% transferrin saturation, while six patients had transferrin saturation less than 20%.
As Table 2 shows, 17 patients had histopathological evidence of CUA, while 4 cases were diagnosed based on bedside clinical examination, and only 3 cases were diagnosed based on radiological scanning. Regarding the time of diagnosis, 15 patients were diagnosed late (i.e., more than two weeks from the onset of the lesions), and nine patients were diagnosed earlier (i.e., less than two weeks from the onset of the lesions). From the anatomical standpoint, 13 patients had CUA lesions distal to the knee, whereas 11 patients had proximal lesions (above the knee).
As Table 3 shows, regarding the treatment of hyperparathyroidism, 13 patients were on cinacalcet, while only 3 received vitamin D analogs, alendronate, and parathyroidectomy in each arm, respectively. Eight out of our case series did not receive any mode of therapy for hyperparathyroidism. Only 2 cases received treatment with the HBO2. The majority of our case series were on sodium thiosulphate treatment (n = 22). 21 out of our cases received wound care management of their lesions. Regarding the outcome and progression of CUA lesions, 12 of our patients improved entirely or partially, while the other half of the cases ended up with amputation or died.
As shown in Table 4, patients with a lower PTH level of less than 600 pg/ml had an improvement in the outcome of their lesions (7/10: 70%). Nevertheless, patients who underwent amputation or died were more likely (7/12: 58.3%) to have PTH of less than 600 pg/ml. Of the two patients who showed partial improvement, one patient had a PTH level of more than 600 pg/ml, while the other had a PTH less than 600 pg/ml. Patients with a lower calcium-phosphate product (of less than 55 mg2/dl2) were found to have much more improvement (7/10: 70%), while patients who had calcium-phosphate products of more than 55 mg2/dl2 were less likely to survive or end up with more amputations (7/12: 58.3%). Only two patients with a lower calcium-phosphate product of less than 55 mg2/dl2 showed partial improvement. 8/10 (80%) of our patients with a lower phosphate level of less than 6.5 mg/dl were more likely to show improvement in the outcome, while 7/12 (58.3%) of our patients with a severely elevated phosphate level of more than 6.5 mg/dl were more likely to die or have an amputated limb. Only two patients showed partial improvement and had a phosphate level of less than 6.5 mg/dl. Significant differences were observed regarding the timing of the diagnosis and the final outcome of the lesions. Seven out of ten patients (70%) who had an improvement in the final outcome of their lesions were diagnosed in less than 2 weeks. Ten out of twelve patients (83.3%) who had a poor outcome, i.e., had amputated limb or expired, had a late diagnosis in their course. P value = 0.019.
As illustrated in Table 5, notably, patients who did not receive any parathyroid treatment were more likely (5/8: 62.5%) to have a lower phosphate level of less than 6.5 mg/dl. In comparison, patients who received cinacalcet as a form of therapy were more likely (8/13: 62%) to have a lower phosphate level of less than 6.5 mg/dl. Patients who were on Doxercalciferol and Alendronate were found to have a lower phosphate level of less than 6.5 mg/dl as well. One patient underwent parathyroidectomy and had a phosphate level of more than 6.5 mg/dl. Patients who did not receive any form of parathyroid therapy were more likely (7/8 : 85.5%) to have a lower PTH level of less than 600 pg/ml, as well as patients who were on cinacalcet therapy, who also more likely (7/13: 53.8%) had a PTH level of less than 600 pg/ml. Only one patient received Doxercalciferol and had severely elevated PTH levels of more than 600 pg/ml. One patient underwent parathyroid gland resection and had an elevated PTH level of more than 600 pg/ml as well. Finally, only one patient received Alendronate and had a PTH level of less than 600 pg/ml.
As Table 6 shows, the use of multifaceted treatment and its relation to the outcome, 14 patients received three different regimens for the management of CUA, while 9 received two regimens, and one patient received wound care only as a mode of management.
4. Discussion
CUA is a syndrome characterized by both thrombosis and small vessel calcification that significantly burdens patients with end-stage renal disease resulting in high morbidity and mortality. It is well known to be multifactorial in etiology. Our findings from this study suggest that many risk factors may predispose patients to the development of CUA. A significant number of patients have shown improvement with the multidisciplinary approach of those lesions. Our study has shown that most of the patients affected were of the female sex, which is in line with numerous previous studies in the past [14, 24]. The fat distribution pattern might explain the prevalence of CUA lesions in females, particularly those with an average BMI of more than 30 [3]. Our study has demonstrated that most of our patients were of African American descent compared to other studies in which patients were predominantly Caucasians [13, 25–27]. However, our tertiary hospital demographically deals with patients who are predominantly of African American origin, which may explain those findings. Most of our patients were aged above 55, which is similar to other studies in the literature that suggested advanced age as a contributing factor [25]. Most of our patients had multiple comorbidities. As reported in previous studies, diabetes mellitus was the commonest contributing factor that may play a role in the development and progression of the lesions making management quite difficult in these subtypes of patients [2, 3, 24]. Early skin lesions like subcutaneous nodules in patients with end-stage renal disease, secondary hyperparathyroidism, calcium, and phosphorus abnormalities should raise the clinicians' suspicion about the possibility of CUA diagnosis. CUA lesions can mimic a wide variety of skin pathologies, including atherosclerosis, cholesterol embolization, warfarin skin necrosis, endarteritis obliterans, vasculitis, cellulitis, purpura fulminans, oxalate vasculopathy, antiphospholipid antibody syndrome, radiation arteritis, Martorell hypertensive ischemic ulcer, cardiac myxoma, and in early nephrogenic systemic fibrosis skin lesions [11, 28].
Ghosh et al. [29] have shown that CUA may be misdiagnosed in its early stages. An appropriate skin biopsy remains the gold standard to confirm a CUA diagnosis to distinguish it from other conditions. 17 of our patients were diagnosed by skin biopsy, and only three were identified via radiological imaging based on the patterns of calcium deposits in the site of CUA lesions. However, the diagnostic utility is not established yet [30, 31], while 4 cases were diagnosed based on bedside clinical examination only.
Most of the patients in this cohort were treated with hemodialysis, which suggests more incidence of CUA with this modality of renal replacement therapy. However, one single-center study had shown a higher incidence in patients on peritoneal dialysis [32]. The high incidence of CUA lesions may be explained by a heavier calcium exposure in this subset of patients.
In our study, we identified only seven patients who were hypercalcemic at the time of diagnosis; this is in contrast to a study published by Nigwekar et al. [26], which had found that hypercalcemia was common in most of their patients with an OR of 1.83 (P: 0.02).
Most of our patients' lab values were within the normal range at the time of diagnosis, and this is a major shortcoming in accurately addressing the immediate risk factor to predispose patients to the development of CUA lesions. Although many studies had implicated the role of hyperphosphatemia in the development of CUA (3) [33], 15 of our patients had serum phosphorous levels of less than 6.5 mg/dl.
In our case series, almost all of our patients (n = 22) had significant hyperparathyroidism, which is in keeping with many previous studies showing its major role in the development of CUA lesions (3) [33]. We believed that moderate to severe hyperparathyroidism predispose renal failure patients to the development of CUA lesions. A high parathyroid hormone level induces high-turnover bone disease, which is significantly associated with vascular calcification in renal failure patients and eventually may lead to the development of CUA lesions; however, a low level (<100 pg/ml) induces adynamic bone disease, which is less associated with the development of CUA lesions. Abnormalities in calcium, phosphorus, or PTH may be noted in patients with calciphylaxis, but it is not always the case, as these patients may present with normal lab values. In our study, the most notable abnormality is the elevated parathyroid hormone levels.
This study found that the majority of our patients with improved outcomes had PTH levels of less than 600 pg/ml; nevertheless, when considering patients who expired or had amputations with similar PTH levels, this observation was statistically insignificant. P value = 0.79.
The majority of our patients (7/10: 70%) who had an improvement in the final outcome of their lesions were diagnosed in less than 2 weeks. Most of the patients (10/12: 83.3%) who had a poor outcome, i.e., had amputated limb or expired, had a late diagnosis in their course. This relationship showed statistical significance. P = 0.019.
Many reports had addressed the beneficial role of reducing phosphate and calcium-phosphate product in the outcome of CUA lesions [34–36]; this is well shown in our study, which has found better outcomes in patients with a lower calcium-phosphorus product of less than 55 mg2/dl2. Block et al. have shown that patients with a calcium-phosphate product of higher than 72 mg2/dl2 had a relatively higher risk of mortality [37].
A paper published by Farah et al. [38] has found, in 12 histological tissue samples of CUA lesions, significant iron deposits affecting the microvasculature but otherwise absent in other tissues. This finding raises the hypothesis that iron-inducing oxidative stress in patients with uremia and iron-chelating therapy might play a role in the treatment of CUA.
Zarjou et al. [39] concluded that ferritin might help to prevent vascular calcification by the induction of a heme-oxygenase-1/ferritin system that prevents inorganic phosphate mediated calcification and osteoblastic differentiation of human smooth muscle cells mainly via ferroxidase activity of ferritin. In our study, 14 of our patients had elevated ferritin of more than 500 μg/l and transferrin saturation of >20%.
We cannot overemphasize the importance of a high index of CUA suspicion in patients with deranged bone and mineral profiles on renal replacement therapy. This subset of the patient needs an urgent referral to a nephrologist to reach a final diagnosis. Out of 24 patients, only 9 cases (37.5%) were diagnosed earlier than two weeks with CUA from the development of the lesions, which is in keeping with the same results by Ghosh et al. [29], who identified only two out of five patients early in their course of the development of the lesions, and hence receiving prompt treatment is associated with less grievous complications.
With the use of multifaceted interventions, 10 of our patients showed complete recovery from CUA lesions, while two patients have made a partial recovery. However, 12 patients have taken a relatively steep downhill course with amputation of an extremity as well as death. This particular subset could have a heavier comorbid load. Unfortunately, it is difficult to track the exact cause of their death due to a lack of information in our medical record. From our case series, there was no specific combination of therapies that pointed toward the improvement of CUA lesions.
A literature review on 104 cases was conducted and showed that parathyroidectomy remains the most important modality to improve patients with severe hyperparathyroidism and CUA, as suggested by Hafner et al. [40]. The vast majority of our patients did not receive parathyroidectomy as a form of parathyroid treatment (only one patient did), and this might be explained by the availability of more potent medical therapy such as cinacalcet. Patients who received cinacalcet were more likely to have PTH of less than 600 pg/ml. Higgins et al. pointed out that the recurrence of severe hyperparathyroidism is less likely to occur following parathyroid surgery [41].
To our knowledge, no study significantly addressed in detail a therapy for CUA. The management of such a condition depends mainly on the multifaceted interventions to treat CUA lesions as suggested by many other studies, leading to favorable outcomes [42–44]. Thirteen of our patients received cinacalcet as a treatment for hyperparathyroidism and CUA. Several case reports showed the benefits of cinacalcet [45–47]; however, a meta-analysis for the use of cinacalcet in the management of patients with CUA has shown no association with a lower risk of mortality, wound progressions, and amputation [48]. Sodium thiosulphate is an inorganic salt with significant antioxidant properties and a vasodilatory effect [49]. Twenty-two of our patients received STS in addition to the other therapy modes, with 12 patients showing a significant response. Hyperbaric oxygen therapy involves administering 100% oxygen in a pressurized environment (hyperbaric chamber) (>1.4 absolute atmosphere ATA). In this way, oxygen transport is increased 27 times compared with the O2 transport in plasma. This type of therapy favors the healing of CUA lesions with remarkable improvement in pain control. In addition, HBO2 therapy increases host and cellular immune responses and fibroblast-mediated collagen production and enhances the action of antibiotic therapy. In our study, only two patients could be enrolled in this therapy type due to our institution's logistic restrictions. The two patients showed a significant improvement in wound healing and less pain, which is in keeping with few studies published in the past [50–52]. A meta-analysis examining a few cohorts has failed to show its risk-reducing effect in the progression of skin lesions, amputation, or death [48].
5. Conclusion
CUA is associated with a high rate of morbidity and mortality in patients with end-stage renal disease. The lesions associated with this disorder are usually misdiagnosed by the clinicians, which leads to a significant delay in therapy initiation. Early diagnosis and referral to a nephrologist will guarantee to deliver prompt treatment and prevent lethal complications. Overall, the importance of good control of mineral and bone profile is a cornerstone of preventing CUA. Based on our results, we strongly recommend a multidisciplinary approach to both diagnosis and therapy of CUA, which can lead to a less unfavorable outcome. CUA multifaceted therapy may play a role in the final outcome of the lesions, and clearly, from our case series, no single patient has received all the modalities of CUA therapy. It must be borne in mind that this study was only conducted in a small group of patients. More case-control multicenter clinical trials are required to unravel numerous mysterious issues regarding CUA.
Data Availability
The data used to support this article will be provided upon reasonable request from the corresponding author.
Conflicts of Interest
All authors declare that they have no conflicts of interest.
Table 1 Baseline characteristics and biochemical lab values: (n = 24) unless noted.
Patient variables Frequency (%)
Gender
Male 6 (25%)
Female 18 (75%)
Age group (years)
<40 4 (16.7%)
40–60 10 (41.7%)
>60 10 (41.7%)
Ethnicity
African american 22 (91.7%)
Caucasian 2 (2.3%)
Mode of renal replacement therapy
Hemodialysis 21 (87.5%)
Peritoneal dialysis 1 (4.2%)
Renal transplant 2 (8.3%)
ESRD etiology
Diabetes 13 (54.2%)
Hypertension 8 (33.3%)
Others 3 (12.3%)
Calcium level (mg/dl)
Ca > 8.5 17 (70.8%)
Ca < 8.5 7 (29.2%)
Phosphate level (mg/dl)
Ph > 6.5 9(37.5%)
Ph < 6.5 15(62.5%)
Calcium-phosphate product level (mg2/dl2)
CaPP > 55 10 (41.7%)
CaPP < 55 14 (58.3%)
Parathyroid hormone level (pg/ml)
PTH > 600 9 (37.5%)
PTH < 600 15 (62.5%)
Ferritin level (μg/l) (n = 20)∗
Ferritin > 500 14 (58.3%)
Ferritin < 500 6 (25%)
Transferrin saturation (%) (n = 20)∗
T.sat > 20% 14 (58.3%)
T.sat < 20% 6 (25%)
Ca: serum calcium, Ph: serum phosphorus, CaPP: serum calcium-phosphorus products, PTH: serum parathyroid hormone, T.Sat: transferrin saturation. ∗4 cases were missed to follow-up of transferrin saturation and ferritin levels.
Table 2 The mode, the timing of the diagnosis, and site of the lesions.
Mode of the diagnosis
Skin biopsy 17 (70.8%)
Imaging 3 (12.5%)
Clinical 4 (16.7%)
Timing of the diagnosis
Early (<2 weeks) 9 (37.5%)
Late (>2 weeks) 15 (62.5%)
Site of the lesion
Proximal (above the knee) 11 (45.8%)
Distal (below the knee) 13 (54.2%)
Table 3 Types of therapy to manage hyperparathyroidism and the outcome of the CUA lesions.
Patient variables Frequency (%)
Therapy of hyperparathyroidism
Vitamin D 1 (4.2%)
Cinacalcet 13 (54.2%)
Parathyroidectomy 1 (4.2%)
Alendronate 1 (4.2%)
No treatment 8 (33.3%)
Therapy of calcific uremic arteriolopathy∗
Received Did not receive
HBO2 2 (8.3%) 22 (91.7%)
Cinacalcet 13 (54.1%) 11 (45.9%)
Wound care 21 (87.5%) 3 (12.5%)
NaTSO4 22 (91.7%) 2 (8.3%)
PTHx 1 (4.2%) 23 (95.8%)
The outcome of the lesion
Improved 10 (41.7%)
Partially improved 2 (8.3%)
Expired or amputation 12 (50%)
HBO: hyperbaric oxygen therapy, NaTSO4: sodium thiosulphate, PTHx: parathyroidectomy. ∗Patients may be enrolled in multiple types of treatment for calcific uremic arteriolopathy.
Table 4 The outcome of calcific uremic arteriolopathy lesions in relation to the severity of hyperparathyroidism, levels of calcium-phosphate products, the degree of hyperphosphatemia, and the timing of the diagnosis.
Outcome Parathyroid hormone levels
P value
<600 >/=600 Total
Improved 7 (70%) 3 (30%) 10 (100%) 0.79
Partial improvement 1 (50.00%) 1 (50.00%) 2 (100%)
Expired or amputation 7 (58.3%) 5 (41.7%) 12 (100%)
Total 15 9 24
Outcome Calcium-phosphate product levels
<55 >/=55 Total
Improved 7 (70%) 3 (30%) 10 (100%) 0.18
Partial improvement 2 (100%) 0 (0.00%) 2 (100%)
Expired/Amputated 5 (41.7%) 7 (58.3%) 12 (100%)
Total 14 10 24
Outcome Phosphate levels
<6.5 >6.5 Total
Improved 8 (80%) 2 (20%) 10 (100%) 0.94
Partial improvement 2 (100%) 0 (0.00%) 2 (100%)
Expired/Amputated 5 (41.7%) 7 (58.3%) 12 (100%)
Total 15 9 24 (100%)
Outcome Timing of diagnosis
Early Late Total
Improved 7 (70%) 3 (30%) 10 (100%) 0.019
Partial improvement 0 (0.00%) 2 (100%) 2 (100%)
Expired/Amputated 2 (16.7%) 10 (83.3%) 12(100%)
Total 9 (37.5%) 15 (62.5%) 24 (100%)
Table 5 The relation of parathyroid treatment to the degree of hyperphosphatemia and parathyroid hormone levels.
Parathyroid treatment Phosphate levels
P value
<6.5 >/= 6.5 Total
No treatment 5(62.5%) 3(37.5%) 8(100%) 0.58
Cinacalcet 8(62%) 5(38%) 13(100%)
Doxercalciferol 1(100%) 0(0.00%) 1(100%)
Parathyroidectomy 0(0.00%) 1(100%) 1(100%)
Alendronate 1(100%) 0(0.00%) 1(100%)
Total 15 9 24
Parathyroid treatment Parathyroid hormone levels
<600 >/= 600 Total
No treatment 7(85.5%) 1(12.5%) 8(100%) 0.16
Cinacalcet 7(53.8%) 6(46.2%) 13(100%)
Doxercalciferol 0(0.00%) 1(100%) 1(100%)
Parathyroidectomy 0(0.00%) 1(100%) 1(100%)
Alendronate 1(100%) 0(0.00%) 1(100%)
Total 15 9 24
Table 6 The relationship of multifaceted regimens of our patients and their final outcomes.
Patients Sodium thiosulfate Hyperbaric oxygen Wound care Hyperparathyroidism management Outcome
Patient no. 1 √ — √ Cinacalcet Improved
Patient no. 2 √ — √ Cinacalcet Improved
Patient no. 3 √ — √ Cinacalcet Amputated/Died
Patient no. 4 √ — — Cinacalcet Partially improved
Patient no. 5 √ — √ — Amputated/Died
Patient no. 6 √ — — Cinacalcet Amputated/Died
Patient no. 7 √ — √ — Amputated/Died
Patient no. 8 √ — √ Cinacalcet Amputated/Died
Patient no. 9 √ — √ Cinacalcet Amputated/Died
Patient no. 10 √ — √ Doxercalciferol Improved
Patient no. 11 √ √ √ — Amputated/Died
Patient no. 12 √ — √ — Improved
Patient no. 13 √ — √ — Amputated/Died
Patient no. 14 √ — √ Parathyroidectomy Amputated/Died
Patient no. 15 √ — √ Cinacalcet Amputated/Died
Patient no. 16 √ — √ Cinacalcet Partially improved
Patient no. 17 √ — — Cinacalcet Improved
Patient no. 18 √ — √ Cinacalcet Improved
Patient no. 19 √ — √ Alendronate Amputated/Died
Patient no. 20 — — √ — Improved
Patient no. 21 √ — √ Cinacalcet Improved
Patient no. 22 √ — √ Cinacalcet Amputated/Died
Patient no. 23 √ — √ — Improved
Patient no. 24 — √ √ — Improved | CINACALCET HYDROCHLORIDE, SODIUM THIOSULFATE | DrugsGivenReaction | CC BY | 33628505 | 18,989,445 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Arthralgia'. | Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.
Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.
1. Introduction
Multiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.
2. Case Presentation
A 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).
On examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.
3. Types of Bisphosphonates and Mechanism of Action
Bisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.
Chemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.
Once absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].
4. Pathophysiology of Ocular Inflammation
Bisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].
The exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].
The acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].
5. Discussion
Myeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.
Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].
Although most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].
The decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.
6. Conclusion
Bisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Right eyelid and periorbital swelling and redness.
Figure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe. | BORTEZOMIB, DEXAMETHASONE, LENALIDOMIDE, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY | 33628538 | 19,053,189 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cellulitis orbital'. | Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.
Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.
1. Introduction
Multiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.
2. Case Presentation
A 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).
On examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.
3. Types of Bisphosphonates and Mechanism of Action
Bisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.
Chemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.
Once absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].
4. Pathophysiology of Ocular Inflammation
Bisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].
The exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].
The acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].
5. Discussion
Myeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.
Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].
Although most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].
The decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.
6. Conclusion
Bisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Right eyelid and periorbital swelling and redness.
Figure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe. | BORTEZOMIB, DEXAMETHASONE, LENALIDOMIDE, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY | 33628538 | 19,053,189 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Conjunctival oedema'. | Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.
Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.
1. Introduction
Multiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.
2. Case Presentation
A 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).
On examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.
3. Types of Bisphosphonates and Mechanism of Action
Bisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.
Chemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.
Once absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].
4. Pathophysiology of Ocular Inflammation
Bisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].
The exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].
The acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].
5. Discussion
Myeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.
Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].
Although most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].
The decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.
6. Conclusion
Bisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Right eyelid and periorbital swelling and redness.
Figure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe. | BORTEZOMIB, DEXAMETHASONE, LENALIDOMIDE, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY | 33628538 | 19,034,472 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Erythema'. | Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.
Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.
1. Introduction
Multiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.
2. Case Presentation
A 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).
On examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.
3. Types of Bisphosphonates and Mechanism of Action
Bisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.
Chemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.
Once absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].
4. Pathophysiology of Ocular Inflammation
Bisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].
The exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].
The acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].
5. Discussion
Myeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.
Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].
Although most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].
The decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.
6. Conclusion
Bisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Right eyelid and periorbital swelling and redness.
Figure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe. | BORTEZOMIB, DEXAMETHASONE, LENALIDOMIDE, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY | 33628538 | 19,034,472 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Eye inflammation'. | Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.
Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.
1. Introduction
Multiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.
2. Case Presentation
A 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).
On examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.
3. Types of Bisphosphonates and Mechanism of Action
Bisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.
Chemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.
Once absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].
4. Pathophysiology of Ocular Inflammation
Bisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].
The exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].
The acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].
5. Discussion
Myeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.
Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].
Although most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].
The decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.
6. Conclusion
Bisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Right eyelid and periorbital swelling and redness.
Figure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe. | BORTEZOMIB, DEXAMETHASONE, LENALIDOMIDE, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY | 33628538 | 19,053,189 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Eye pain'. | Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.
Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.
1. Introduction
Multiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.
2. Case Presentation
A 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).
On examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.
3. Types of Bisphosphonates and Mechanism of Action
Bisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.
Chemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.
Once absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].
4. Pathophysiology of Ocular Inflammation
Bisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].
The exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].
The acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].
5. Discussion
Myeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.
Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].
Although most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].
The decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.
6. Conclusion
Bisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Right eyelid and periorbital swelling and redness.
Figure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe. | BORTEZOMIB, DEXAMETHASONE, LENALIDOMIDE, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY | 33628538 | 19,034,472 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Influenza like illness'. | Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.
Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.
1. Introduction
Multiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.
2. Case Presentation
A 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).
On examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.
3. Types of Bisphosphonates and Mechanism of Action
Bisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.
Chemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.
Once absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].
4. Pathophysiology of Ocular Inflammation
Bisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].
The exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].
The acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].
5. Discussion
Myeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.
Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].
Although most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].
The decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.
6. Conclusion
Bisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Right eyelid and periorbital swelling and redness.
Figure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe. | BORTEZOMIB, DEXAMETHASONE, LENALIDOMIDE, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY | 33628538 | 19,053,189 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lacrimation increased'. | Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.
Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.
1. Introduction
Multiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.
2. Case Presentation
A 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).
On examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.
3. Types of Bisphosphonates and Mechanism of Action
Bisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.
Chemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.
Once absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].
4. Pathophysiology of Ocular Inflammation
Bisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].
The exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].
The acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].
5. Discussion
Myeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.
Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].
Although most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].
The decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.
6. Conclusion
Bisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Right eyelid and periorbital swelling and redness.
Figure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe. | BORTEZOMIB, DEXAMETHASONE, LENALIDOMIDE, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY | 33628538 | 19,034,472 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Parophthalmia'. | Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.
Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.
1. Introduction
Multiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.
2. Case Presentation
A 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).
On examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.
3. Types of Bisphosphonates and Mechanism of Action
Bisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.
Chemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.
Once absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].
4. Pathophysiology of Ocular Inflammation
Bisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].
The exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].
The acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].
5. Discussion
Myeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.
Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].
Although most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].
The decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.
6. Conclusion
Bisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Right eyelid and periorbital swelling and redness.
Figure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe. | BORTEZOMIB, DEXAMETHASONE, LENALIDOMIDE, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY | 33628538 | 19,042,285 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Periorbital swelling'. | Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.
Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.
1. Introduction
Multiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.
2. Case Presentation
A 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).
On examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.
3. Types of Bisphosphonates and Mechanism of Action
Bisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.
Chemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.
Once absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].
4. Pathophysiology of Ocular Inflammation
Bisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].
The exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].
The acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].
5. Discussion
Myeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.
Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].
Although most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].
The decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.
6. Conclusion
Bisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Right eyelid and periorbital swelling and redness.
Figure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe. | BORTEZOMIB, DEXAMETHASONE, LENALIDOMIDE, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY | 33628538 | 19,034,472 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.
Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.
1. Introduction
Multiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.
2. Case Presentation
A 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).
On examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.
3. Types of Bisphosphonates and Mechanism of Action
Bisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.
Chemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.
Once absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].
4. Pathophysiology of Ocular Inflammation
Bisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].
The exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].
The acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].
5. Discussion
Myeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.
Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].
Although most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].
The decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.
6. Conclusion
Bisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Right eyelid and periorbital swelling and redness.
Figure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe. | BORTEZOMIB, DEXAMETHASONE, LENALIDOMIDE, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY | 33628538 | 19,034,472 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Visual acuity reduced'. | Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.
Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.
1. Introduction
Multiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.
2. Case Presentation
A 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).
On examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.
3. Types of Bisphosphonates and Mechanism of Action
Bisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.
Chemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.
Once absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].
4. Pathophysiology of Ocular Inflammation
Bisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].
The exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].
The acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].
5. Discussion
Myeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.
Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].
Although most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].
The decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.
6. Conclusion
Bisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Right eyelid and periorbital swelling and redness.
Figure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe. | BORTEZOMIB, DEXAMETHASONE, LENALIDOMIDE, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY | 33628538 | 19,053,189 | 2021 |
What was the administration route of drug 'DEXAMETHASONE'? | Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.
Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.
1. Introduction
Multiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.
2. Case Presentation
A 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).
On examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.
3. Types of Bisphosphonates and Mechanism of Action
Bisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.
Chemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.
Once absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].
4. Pathophysiology of Ocular Inflammation
Bisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].
The exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].
The acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].
5. Discussion
Myeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.
Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].
Although most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].
The decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.
6. Conclusion
Bisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Right eyelid and periorbital swelling and redness.
Figure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe. | Oral | DrugAdministrationRoute | CC BY | 33628538 | 19,034,472 | 2021 |
What was the administration route of drug 'LENALIDOMIDE'? | Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.
Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.
1. Introduction
Multiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.
2. Case Presentation
A 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).
On examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.
3. Types of Bisphosphonates and Mechanism of Action
Bisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.
Chemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.
Once absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].
4. Pathophysiology of Ocular Inflammation
Bisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].
The exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].
The acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].
5. Discussion
Myeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.
Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].
Although most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].
The decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.
6. Conclusion
Bisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Right eyelid and periorbital swelling and redness.
Figure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe. | Oral | DrugAdministrationRoute | CC BY | 33628538 | 19,034,472 | 2021 |
What was the dosage of drug 'BORTEZOMIB'? | Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.
Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.
1. Introduction
Multiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.
2. Case Presentation
A 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).
On examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.
3. Types of Bisphosphonates and Mechanism of Action
Bisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.
Chemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.
Once absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].
4. Pathophysiology of Ocular Inflammation
Bisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].
The exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].
The acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].
5. Discussion
Myeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.
Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].
Although most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].
The decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.
6. Conclusion
Bisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Right eyelid and periorbital swelling and redness.
Figure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe. | UNK UNK, QW | DrugDosageText | CC BY | 33628538 | 19,034,472 | 2021 |
What was the outcome of reaction 'Arthralgia'? | Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.
Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.
1. Introduction
Multiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.
2. Case Presentation
A 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).
On examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.
3. Types of Bisphosphonates and Mechanism of Action
Bisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.
Chemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.
Once absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].
4. Pathophysiology of Ocular Inflammation
Bisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].
The exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].
The acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].
5. Discussion
Myeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.
Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].
Although most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].
The decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.
6. Conclusion
Bisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Right eyelid and periorbital swelling and redness.
Figure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe. | Recovered | ReactionOutcome | CC BY | 33628538 | 19,053,189 | 2021 |
What was the outcome of reaction 'Cellulitis orbital'? | Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.
Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.
1. Introduction
Multiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.
2. Case Presentation
A 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).
On examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.
3. Types of Bisphosphonates and Mechanism of Action
Bisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.
Chemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.
Once absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].
4. Pathophysiology of Ocular Inflammation
Bisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].
The exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].
The acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].
5. Discussion
Myeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.
Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].
Although most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].
The decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.
6. Conclusion
Bisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Right eyelid and periorbital swelling and redness.
Figure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe. | Recovered | ReactionOutcome | CC BY | 33628538 | 19,053,189 | 2021 |
What was the outcome of reaction 'Conjunctival oedema'? | Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.
Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.
1. Introduction
Multiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.
2. Case Presentation
A 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).
On examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.
3. Types of Bisphosphonates and Mechanism of Action
Bisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.
Chemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.
Once absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].
4. Pathophysiology of Ocular Inflammation
Bisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].
The exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].
The acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].
5. Discussion
Myeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.
Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].
Although most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].
The decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.
6. Conclusion
Bisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Right eyelid and periorbital swelling and redness.
Figure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe. | Recovered | ReactionOutcome | CC BY | 33628538 | 19,034,472 | 2021 |
What was the outcome of reaction 'Erythema'? | Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.
Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.
1. Introduction
Multiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.
2. Case Presentation
A 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).
On examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.
3. Types of Bisphosphonates and Mechanism of Action
Bisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.
Chemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.
Once absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].
4. Pathophysiology of Ocular Inflammation
Bisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].
The exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].
The acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].
5. Discussion
Myeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.
Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].
Although most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].
The decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.
6. Conclusion
Bisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Right eyelid and periorbital swelling and redness.
Figure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe. | Recovered | ReactionOutcome | CC BY | 33628538 | 19,034,472 | 2021 |
What was the outcome of reaction 'Eye inflammation'? | Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.
Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.
1. Introduction
Multiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.
2. Case Presentation
A 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).
On examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.
3. Types of Bisphosphonates and Mechanism of Action
Bisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.
Chemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.
Once absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].
4. Pathophysiology of Ocular Inflammation
Bisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].
The exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].
The acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].
5. Discussion
Myeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.
Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].
Although most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].
The decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.
6. Conclusion
Bisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Right eyelid and periorbital swelling and redness.
Figure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe. | Recovered | ReactionOutcome | CC BY | 33628538 | 19,053,189 | 2021 |
What was the outcome of reaction 'Eye pain'? | Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.
Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.
1. Introduction
Multiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.
2. Case Presentation
A 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).
On examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.
3. Types of Bisphosphonates and Mechanism of Action
Bisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.
Chemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.
Once absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].
4. Pathophysiology of Ocular Inflammation
Bisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].
The exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].
The acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].
5. Discussion
Myeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.
Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].
Although most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].
The decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.
6. Conclusion
Bisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Right eyelid and periorbital swelling and redness.
Figure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe. | Recovered | ReactionOutcome | CC BY | 33628538 | 19,034,472 | 2021 |
What was the outcome of reaction 'Influenza like illness'? | Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.
Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.
1. Introduction
Multiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.
2. Case Presentation
A 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).
On examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.
3. Types of Bisphosphonates and Mechanism of Action
Bisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.
Chemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.
Once absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].
4. Pathophysiology of Ocular Inflammation
Bisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].
The exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].
The acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].
5. Discussion
Myeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.
Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].
Although most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].
The decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.
6. Conclusion
Bisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Right eyelid and periorbital swelling and redness.
Figure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe. | Recovered | ReactionOutcome | CC BY | 33628538 | 19,053,189 | 2021 |
What was the outcome of reaction 'Lacrimation increased'? | Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.
Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.
1. Introduction
Multiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.
2. Case Presentation
A 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).
On examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.
3. Types of Bisphosphonates and Mechanism of Action
Bisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.
Chemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.
Once absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].
4. Pathophysiology of Ocular Inflammation
Bisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].
The exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].
The acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].
5. Discussion
Myeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.
Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].
Although most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].
The decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.
6. Conclusion
Bisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Right eyelid and periorbital swelling and redness.
Figure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe. | Recovered | ReactionOutcome | CC BY | 33628538 | 19,034,472 | 2021 |
What was the outcome of reaction 'Parophthalmia'? | Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.
Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.
1. Introduction
Multiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.
2. Case Presentation
A 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).
On examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.
3. Types of Bisphosphonates and Mechanism of Action
Bisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.
Chemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.
Once absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].
4. Pathophysiology of Ocular Inflammation
Bisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].
The exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].
The acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].
5. Discussion
Myeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.
Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].
Although most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].
The decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.
6. Conclusion
Bisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Right eyelid and periorbital swelling and redness.
Figure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe. | Recovered | ReactionOutcome | CC BY | 33628538 | 19,042,285 | 2021 |
What was the outcome of reaction 'Periorbital swelling'? | Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.
Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.
1. Introduction
Multiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.
2. Case Presentation
A 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).
On examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.
3. Types of Bisphosphonates and Mechanism of Action
Bisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.
Chemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.
Once absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].
4. Pathophysiology of Ocular Inflammation
Bisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].
The exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].
The acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].
5. Discussion
Myeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.
Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].
Although most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].
The decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.
6. Conclusion
Bisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Right eyelid and periorbital swelling and redness.
Figure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe. | Recovered | ReactionOutcome | CC BY | 33628538 | 19,034,472 | 2021 |
What was the outcome of reaction 'Visual acuity reduced'? | Keeping an Eye on Bisphosphonate Therapy in Myeloma: A Case Report of Ocular Inflammation Postzoledronic Acid Infusion.
Bisphosphonates have evolved over the past decades from oral to more potent intravenous preparations. Along with significant paradigm shift in the management of myeloma over the past years, stronger nitrogen-containing bisphosphonates, due to their antiresorptive action on the bones, have found their way as a key and integral part in the management of bone disease in myeloma. Multiple randomized controlled trials have established efficacy of bisphosphonates in reducing skeletal-related events in myeloma. Some well-documented adverse events include acute-phase reactions, esophageal irritation, and osteonecrosis of the jaw. Across all clinical indications, the incidence of inflammatory eye reactions after bisphosphonate infusion ranges from 0.046% to 1%. However, data from myeloma patients are extrapolated from few reported cases in literature with varying management strategies including discontinuation, switching to different forms, and rechallenging with steroid cover. Inflammatory eye reactions can vary from self-limiting conjunctivitis and episcleritis to serious uveitis and vision-threatening orbital inflammation. We present a similar case of a patient with IgG kappa myeloma who developed flu-like symptoms followed by severe orbital inflammation within 48-72 hours after receiving zoledronic acid infusion. The patient was successfully managed with intravenous methyl prednisolone followed by oral tapering dose of steroids and discontinuation of further bisphosphonate therapy. A complete recovery was noted in a week's time.
1. Introduction
Multiple myeloma is a disorder of clonal plasma cells which are derived from postgerminal B cells. It accounts for around 1% of all cancers and 13% of hematological malignancies. Median age of diagnosis is around 70 years with 37% of myeloma patients younger than 65 years [1]. Alongside anemia, hypercalcemia, and renal impairment, lytic bone lesions are an important feature of myeloma, which can complicate the course of disease with severe pain and skeletal-related events (SREs) including pathological fractures and cord compression. Approximately 80% of multiple myeloma patients experience a pathological fracture over the course of their disease [2]. Introduction of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies into the treatment algorithms have translated into better survival outcomes. Over the past decades, bisphosphonates have found central role in osteoporosis, malignancies, and Paget's disease, and now they are an integral part of the management of bone disease in myeloma. Bisphosphonates have evolved from oral therapies to more potent, dose-convenient, intravenous therapies. Generally, well tolerated, they are known to cause side effects ranging from mild acute-phase reactions, esophageal irritation, hypocalcemia, and atrial fibrillation to rare serious adverse events such as osteonecrosis of the jaw. Relatively rare adverse effects of bisphosphonate therapy are inflammatory eye reactions (IERs) ranging from conjunctivitis and episcleritis to vision-threatening uveitis, scleritis, and severe orbital inflammation. Due to their increasing indications, usage, and previously underreporting, more cases of ophthalmological adverse events have come to light in recent years.
2. Case Presentation
A 45-year-old man presented to the eye casualty with right-sided periorbital swelling, pain, epiphora, and chemosis three days after receiving zoledronic acid in hematology day ward. He had a history of recently diagnosis of IgG kappa myeloma, R-ISS stage I, with multiple lytic lesions on the ribs, and a bone-related plasmacytoma on the left-sided ninth rib. He was an ex-smoker with a smoking history of 15 pack years. He had no other significantly past medical history and was not on any regular medications prior to his diagnosis. He was started on bortezomib/lenalidomide/dexamethasone (VRD) therapy. At the start of the second cycle, he received zoledronic acid 4 mg intravenously. He started noticing flu-like symptoms 24 hours after infusion, along with mild joint pains and minimal right eyelid swelling. Over the next 48 hours, he reported worsening right eye swelling, pain, redness, and difficulty in opening his eye (Figure 1).
On examination, his visual acuity was 6/9 bilaterally. A computed tomography (CT) scan of both orbits was requested to assess any possible retrobulbar inflammation. CT findings were suggestive of right-sided orbital cellulitis (Figure 2). On suspicion of a possible infective episode, he was empirically started on IV antibiotics. His symptoms continued to worsen over the next 12 hours, and it was decided to start on IV methyl prednisolone 500 mg once daily. By day three of IV steroids, there was a significant resolution of swelling and pain. He was discharged on oral prednisolone 60 mg which was tapered down every third day. He was followed up in day ward after a week where he reported complete recovery. Based on severity of the event and ophthalmology opinion, it was agreed to discontinue any further bisphosphonate therapy.
3. Types of Bisphosphonates and Mechanism of Action
Bisphosphonates are structural analogues of naturally occurring inorganic pyrophosphates, which bind to the hydroxyapatite binding site on the exposed areas of the bone, undergoing active resorption. During the resorptive process, bisphosphonates are absorbed by the osteoclasts, eventually leading to apoptosis.
Chemically, they are classified into two categories: nonnitrogen-containing bisphosphonates that include early first-generation bisphosphonates such as clodronate and etidronate. They are structurally very similar to naturally occurring inorganic pyrophosphates. The second category consists of nitrogen-containing bisphosphonates which include second- and third-generation compounds such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. The addition of nitrogen/amine group to the bisphosphonate upgrades its antiresorptive potency by 10–10,000 compared to nonnitrogen-containing bisphosphonates [3, 4]. It is important to know that, along with the antiresorptive effect, pyrophosphates (including naturally occurring inorganic pyrophosphates and bisphosphonates) also inhibit calcification and mineralization of the bone. However, the potential to inhibit mineralization differs among the bisphosphonates, for example, risedronate inhibits bone resorption and mineralization at the same concentration (therapeutic index 1 : 1). In contrast, for nitrogen-containing bisphosphonates, the potential to inhibit mineralization is 1000 times less than its antiresorptive effect at the same concentration of the drug. Therefore, it renders a favorable therapeutic index to treat conditions such as myeloma-related bone disease.
Once absorbed by the osteoclasts, nonnitrogen-containing bisphosphonates are metabolized and incorporated into newly formed adenosine triphosphate (ATP) molecules. These nonhydrolysable ATPs accumulate and are unable to drive ATP-dependent cellular processes, resulting in osteoclast apoptosis. In comparison, nitrogen-containing bisphosphonates, once absorbed by the osteoclasts, inhibit the activity of farnesyl pyrophosphate synthase, a key regulatory enzyme in the mevalonic acid pathway resulting in posttranslational modifications of key proteins and eventually resulting in osteoclast apoptosis [4].
4. Pathophysiology of Ocular Inflammation
Bisphosphonate treatment has been known to trigger the release of cytokines, IL-1 and IL-6, and other acute-phase proteins. In one study, it is suggested that nitrogen-containing bisphosphonates stimulate gamma/delta T cells (γ/δ T cells) in peripheral blood. Furthermore, it is suggested that the intensity of the acute-phase reaction seemed to correlate with the magnitude of increase in γ/δ T cells [5].
The exact mechanism of underlying ocular inflammatory response largely remains unknown. One suggested mechanism is that the drug is secreted into the tears by the lacrimal gland triggering a transitory localized irritation leading to the release of cytokines and other acute-phase proteins in the eye or cause activation of gamma/delta T cells within the orbit [6–8]. Preclinical animal studies reported conjunctivitis and episcleral congestion in rabbits with very supratherapeutic doses of pamidronate (daily dose of 30 mg/kg for 6 months), and it was identified that, at these doses, pamidronate secrets tears [9, 10].
The acute cytokines or T-cell response could explain the immediate eye reactions that take place within a short window. However, it is difficult to explain very delayed reactions occurring after weeks or months. It is uncertain whether the type of bisphosphonates used or disease-related factors such as background inflammatory conditions, immune dysregulation, or progressive accumulation of bisphosphonates overtime within the eye play any possible role to illicit these delayed reactions [6].
5. Discussion
Myeloma represents a subsegment of the patients receiving bisphosphonate therapies. Over the past years, multiple randomized placebo trials have demonstrated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing bone pains and skeletal-related events. One study showed zoledronic acid was found to be as effective as pamidronate in reducing pain and incidence of SREs [11]. In another study, Medical Research Council (MRC) Myeloma IX trial, it not only shows zoledronic acid to be better than clodronate in reduction of SREs but also demonstrates that addition of zoledronic acid to standard first-line myeloma treatment reduced the risk of death by 16% and prolonged median overall survival by 5.5 months compared to clodronate [12]. However, a meta-analysis from Cochrane database was not able to confirm superiority of one bisphosphonate over another, but it is important to note that zoledronic acid is the only bisphosphonate to show survival benefit in placebo-controlled trials [13, 14]. Most experts and myeloma groups recommend a 2-year duration of bisphosphonate therapy, which is extrapolated from all placebo-controlled trials, in which the maximum duration of bisphosphonate therapy was 2 years.
Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%, with onset occurring from a few hours after exposure up to more than 3 years, with a median of 3 weeks [9]. Around 1 in 10 patients receiving bisphosphonates have flu-like symptoms such as fever, arthralgia, and myalgia following the first dose. The rate of reactions reduces to half following subsequent infusions. In one study, HORIZON trial, the rate of acute-phase reactions after the third dose was suggested to be around 2.8% [9].
Although most of the data around ocular adverse effects of bisphosphonates comes from its use in broader categories of indications such as osteoporosis, Paget's disease, and solid cancers such as breast, prostate, and lung cancers, the data of myeloma patients come from few case reports in literature with variability in the management ranging from discontinuation of bisphosphonate therapy to rechallenging with the same or different forms of bisphosphonate. Maniel et al. report a recurrence of ocular symptoms including eyelid swelling, chemosis, and diplopia on rechallenging 4 months after the first episode with the same bisphosphonate (pamidronate) [15]. Similarly, Benderson et al. reports recurrence of milder symptoms after switching from zoledronic acid to pamidronate infusion with methyl prednisolone support and continued monthly pamidronate with steroid cover thereafter with minimal symptoms [16]. Gathering data from other indications for bisphosphonate, Fraunfelder and Fraunfelder reported 17 cases of unilateral scleritis associated with intravenous pamidronate which required discontinuation of the pamidronate therapy [17].
The decisions to rechallenge should be based on the severity of the adverse event and accurate diagnosis with formal evaluation by ophthalmology. Isolated conjunctivitis or episcleritis, having good prognosis, often experiences complete resolution without specific treatment after few days. Nonspecific conjunctivitis usually decreases in intensity during subsequent exposure to a bisphosphonate [17]. In context of myeloma where benefits clearly outweigh the risks in such circumstances, retreatment with or without steroid cover is generally safe. Patients presenting with severe orbital inflammation, once septic elements are excluded, should be promptly initiated on intravenous steroids. More severe adverse events such as uveitis, scleritis, and orbital inflammation can have serious and long-lasting consequences. In case of scleritis to fully resolve, bisphosphonate must be discontinued [17]. Cases such as these should be dealt with utmost care in conjunction with ophthalmology before a decision to rechallenge is made.
6. Conclusion
Bisphosphonate therapy for myeloma patients continues to be an integral part of myeloma management. Physicians and hematologists should be aware of these uncommon adverse events, and based on the severity of the events and in collaboration with ophthalmology support, a well-informed decision should be made in best interest of the patient.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Right eyelid and periorbital swelling and redness.
Figure 2 Mild right eye proptosis and soft tissue thickening overlying the right orbit (arrow). Edema of the medial and superior rectus muscles. Postseptal involvement with inflammatory fat stranding in the intraconal fat posterior to the globe. | Recovered | ReactionOutcome | CC BY | 33628538 | 19,053,189 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | The Tale of Stridor and Wheezing in an Infant.
Recurrent respiratory papillomatosis is a respiratory disease caused by human papillomavirus and can infect any part of the aerodigestive tract, but the larynx is most involved (Derkay et al. 2010). This report is a discussion about a 7-month-old male that presented to our institution for respiratory distress. He was admitted to the Pediatric Intensive Care Unit (PICU) for stabilization, observation, and further treatment and management due to an acute RSV infection. Initial efforts failed to improve his respiratory failure. A bronchoscopy was performed and showed various flesh-colored lesions throughout the larynx, vocal cords, and tracheal tree just above the carina. Pediatric otolaryngology performed an emergent debulking surgery to alleviate his respiratory failure. He has had multiple exacerbations of his condition since then and has required frequent debulking procedures with a few trials of intralesional bevacizumab therapies.
1. Introduction
Recurrent respiratory papillomatosis (RRP) is a result of an infection caused by the human papilloma virus (HPV) [1]. The virus causes abnormal proliferation of the normal squamous epithelium leading to complications such as airway obstruction, mucus plug formation, and airway compromise, which may recur over time. In the pediatric population, it is typically diagnosed around the age of 2 to 3 years but earlier onset of the disease may be attributed to infections caused by more aggressive genotypes of HPV, vertical transmission during birth, or transplacental infection acquired from an infected mother [2].
Pathology into HPV DNA subtype analysis helps determine the HPV genotype such as 6 and 11 vs. 16, 18, and 31 [3]. This is essential since HPV 16 has been associated with the more aggressive forms of papillomatosis with possible risk for distal airway involvement and malignant transformation [4]. Involvement of extralaryngeal sites such as the trachea, bronchial epithelium, and mucous glands usually occurs in addition with upper airway involvement and is also more common in children vs. adults, occurring in 3–15% of cases [5, 6]. The overall risk of malignant transformation is low in children (<1%), since majority of infections are caused by HPV genotypes 6 and 11. However, genotype analysis helps predict the recurrence and aggressiveness of the disease process [3]. Histopathology may reveal koilocytes (HPV-infected dysplastic squamous cells with a “raisinlike” nucleus).
Tracheostomy is usually avoided as it can increase the risk of recurrence and development of lower airway papillomas from distal spread. But, the need for a tracheostomy may vary based upon individual case circumstances such as upper airway obstruction [3].
2. Case Presentation
A 7-month-old male with a history of NICU admission for neonatal asbstinence syndrome for 3 weeks after in utero drug and tobacco exposure (opioids, benzodiazepines, and marijuana) was transferred from an outlying institution due to respiratory distress, hypoxemia, and stridor. He received oxygen via mask delivery, dexamethasone, and several racemic epinephrine treatments prior to his transfer for stabilization. However, his respiratory distress did not improve with the above interventions.
Upon presentation to the emergency room, he had worsening respiratory distress. He was started on oxygen supplementation after a trial of nebulization treatment. However, he progressed into respiratory failure. A viral panel was positive for RSV. Hisrespiratory failure worsened, and he required endotracheal intubation with invasive mechanical ventilation. Although his respiratory status improved, he continued to have intermittent episodes of hypoxemia. A chest X-ray showed multifocal opacities typical of a RSV infection. He had a similar episode of respiratory failure two months prior that required endotracheal intubation.
His intermittent respiratory failure with worsening hypoxemia while on invasive mechanical ventilation prompted an evaluation by pediatric pulmonology. It was decided that the patient have a more thorough airway evaluation via flexible bronchoscopy.
3. Diagnostic Focus and Assessment
During flexible bronchoscopy, widespread, sessile, 3–5 mm mucosal lesions resembling verruca were noted throughout the larynx, vocal cords, and trachea approximately 3 cm above the carina; images recorded are shown in Figure 1. However, the procedure was aborted after the patient experienced multiple severe hypoxemic episodes due to tracheal obstruction from these lesions. Pediatric otolaryngology was consulted for surgical management. An emergent debulking surgery was performed.
4. Therapeutic Focus and Assessment
The debulking surgery was performed using a microdebrider blade. Many lesions were excised, and images were obtained for preoperative and postoperative comparison (Figure 2). The patient tolerated the procedure well, and his respiratory distress improved significantly in the postoperative period leading to extubation shortly thereafter.
5. Follow-Up and Outcome
He was discharged home with follow-up for planned debulking procedures. Unfortunately, he presented several more times forrespiratory failure, each requiring intubation and bronchoscopic evaluation of his airway with debulking surgeries. Due to the recurrence of papillomatosis obstructing the vocal cords, a tracheostomy was performed. The patient has had a total of four debulking surgeries from January 2020 to March 2020. Multimodality treatment with intralesional vs. systemic administration of bevacizumab has also been considered as an adjunctive measure to minimize the number of debulking surgeries and to potentially increase the time interval between subsequent procedures. However, the patient had only a modest response to similar treatments in the past. Due to disease progression, the patient has developed bilateral true vocal cord fixation and subglottic stenosis, recently requiring a laryngoplasty approach for debulking procedures.
6. Discussion
RRP is the most common cause of benign laryngeal neoplasm in children [1]. The disease process may affect any part of the aerodigestive tract; the larynx is the most involved anatomical location [1]. The lesions are usually multiple, stemlike protrusion or “cauliflowerlike” in appearance and may bleed with manipulation. Suspected tracheobronchial involvement- or recurrence-related complications are further investigated with imaging of the chest and bronchoscopy. Chest X-ray is usually normal unless there is lung parenchymal involvement. The CT scan may show walled cysts with nodules, atelectasis, and bronchiectasis with mucus plugging [2]. Airway visualization (i.e., flexible or rigid bronchoscopy) remains superior, as it may aid with direct visualization of lesions and biopsies for further analysis.
The recurrent nature of the disease course warrants repeated surgical procedures, and the mean number of surgeries required can be as high as 4.4 procedures per year [8]. Consequently, this exposes patients to various complications such as anesthesia-related complications, damage to healthy tissue, tracheal stenosis, perforation, and socioeconomical burdens on families [9].
In addition, adjunct treatments with alpha-interferon and antiviral medications such as cidofovir have shown to be effective as well. These agents may increase the length of the time intervals between surgeries or decrease the total number of surgeries that the patients may require [9]. Vascular endothelial growth factor (VEGF) inhibitor, such as bevacizumab, is another feasible choice for adjunct treatment therapies for recurrent respiratory papillomatosis [10, 11]. However, these agents are prone to limitations due to dosing recommendations, systemic vs. intralesional mode of administration, and minimal response to therapies [7, 12]. HPV vaccinations may also be an effective measure to prevent the overall risk of disease transmission in the pediatric population as majority of these infections are vertically transmitted from a high-risk mother [9].
7. Conclusion
Recurrent respiratory papillomatosis infections in children are typically acquired during vertical transmission at birth or transplacental infections. The risk factors for recurrence, aggressive nature of the disease with distal spread, and malignant potential include firstborn child, vaginal delivery, women with a history of HPV infection (subtype 16), and history of prior invasive interventions. However, among infants born to women with such a history, the risk of RRP is <1% [4]. The prognosis of disease also varies based upon the risk factors mentioned above with less aggressive types of infections having a good outcome and more aggressive types of infections requiring frequent debulking surgeries and tracheostomy [8].
Data Availability
The academic and clinical percentile data used to support and discuss the findings of this case report are included within the article.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Images collected during flexible bronchoscopy. (a) Lesions protruding from the tracheal wall mucosal. (b) Narrowing of the trachea secondary to multiple lesions. (c) Normal-appearing area ∼3 cm above the carina.
Figure 2 Images collected s/p debulking surgery via rigid bronchoscopy. (a) Lesions obscuring the vocal cord(s) [7]. (b) Lesions in the distal trachea. (c) Tracheal lumen. | BEVACIZUMAB | DrugsGivenReaction | CC BY | 33628559 | 18,983,482 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Respiratory papilloma'. | The Tale of Stridor and Wheezing in an Infant.
Recurrent respiratory papillomatosis is a respiratory disease caused by human papillomavirus and can infect any part of the aerodigestive tract, but the larynx is most involved (Derkay et al. 2010). This report is a discussion about a 7-month-old male that presented to our institution for respiratory distress. He was admitted to the Pediatric Intensive Care Unit (PICU) for stabilization, observation, and further treatment and management due to an acute RSV infection. Initial efforts failed to improve his respiratory failure. A bronchoscopy was performed and showed various flesh-colored lesions throughout the larynx, vocal cords, and tracheal tree just above the carina. Pediatric otolaryngology performed an emergent debulking surgery to alleviate his respiratory failure. He has had multiple exacerbations of his condition since then and has required frequent debulking procedures with a few trials of intralesional bevacizumab therapies.
1. Introduction
Recurrent respiratory papillomatosis (RRP) is a result of an infection caused by the human papilloma virus (HPV) [1]. The virus causes abnormal proliferation of the normal squamous epithelium leading to complications such as airway obstruction, mucus plug formation, and airway compromise, which may recur over time. In the pediatric population, it is typically diagnosed around the age of 2 to 3 years but earlier onset of the disease may be attributed to infections caused by more aggressive genotypes of HPV, vertical transmission during birth, or transplacental infection acquired from an infected mother [2].
Pathology into HPV DNA subtype analysis helps determine the HPV genotype such as 6 and 11 vs. 16, 18, and 31 [3]. This is essential since HPV 16 has been associated with the more aggressive forms of papillomatosis with possible risk for distal airway involvement and malignant transformation [4]. Involvement of extralaryngeal sites such as the trachea, bronchial epithelium, and mucous glands usually occurs in addition with upper airway involvement and is also more common in children vs. adults, occurring in 3–15% of cases [5, 6]. The overall risk of malignant transformation is low in children (<1%), since majority of infections are caused by HPV genotypes 6 and 11. However, genotype analysis helps predict the recurrence and aggressiveness of the disease process [3]. Histopathology may reveal koilocytes (HPV-infected dysplastic squamous cells with a “raisinlike” nucleus).
Tracheostomy is usually avoided as it can increase the risk of recurrence and development of lower airway papillomas from distal spread. But, the need for a tracheostomy may vary based upon individual case circumstances such as upper airway obstruction [3].
2. Case Presentation
A 7-month-old male with a history of NICU admission for neonatal asbstinence syndrome for 3 weeks after in utero drug and tobacco exposure (opioids, benzodiazepines, and marijuana) was transferred from an outlying institution due to respiratory distress, hypoxemia, and stridor. He received oxygen via mask delivery, dexamethasone, and several racemic epinephrine treatments prior to his transfer for stabilization. However, his respiratory distress did not improve with the above interventions.
Upon presentation to the emergency room, he had worsening respiratory distress. He was started on oxygen supplementation after a trial of nebulization treatment. However, he progressed into respiratory failure. A viral panel was positive for RSV. Hisrespiratory failure worsened, and he required endotracheal intubation with invasive mechanical ventilation. Although his respiratory status improved, he continued to have intermittent episodes of hypoxemia. A chest X-ray showed multifocal opacities typical of a RSV infection. He had a similar episode of respiratory failure two months prior that required endotracheal intubation.
His intermittent respiratory failure with worsening hypoxemia while on invasive mechanical ventilation prompted an evaluation by pediatric pulmonology. It was decided that the patient have a more thorough airway evaluation via flexible bronchoscopy.
3. Diagnostic Focus and Assessment
During flexible bronchoscopy, widespread, sessile, 3–5 mm mucosal lesions resembling verruca were noted throughout the larynx, vocal cords, and trachea approximately 3 cm above the carina; images recorded are shown in Figure 1. However, the procedure was aborted after the patient experienced multiple severe hypoxemic episodes due to tracheal obstruction from these lesions. Pediatric otolaryngology was consulted for surgical management. An emergent debulking surgery was performed.
4. Therapeutic Focus and Assessment
The debulking surgery was performed using a microdebrider blade. Many lesions were excised, and images were obtained for preoperative and postoperative comparison (Figure 2). The patient tolerated the procedure well, and his respiratory distress improved significantly in the postoperative period leading to extubation shortly thereafter.
5. Follow-Up and Outcome
He was discharged home with follow-up for planned debulking procedures. Unfortunately, he presented several more times forrespiratory failure, each requiring intubation and bronchoscopic evaluation of his airway with debulking surgeries. Due to the recurrence of papillomatosis obstructing the vocal cords, a tracheostomy was performed. The patient has had a total of four debulking surgeries from January 2020 to March 2020. Multimodality treatment with intralesional vs. systemic administration of bevacizumab has also been considered as an adjunctive measure to minimize the number of debulking surgeries and to potentially increase the time interval between subsequent procedures. However, the patient had only a modest response to similar treatments in the past. Due to disease progression, the patient has developed bilateral true vocal cord fixation and subglottic stenosis, recently requiring a laryngoplasty approach for debulking procedures.
6. Discussion
RRP is the most common cause of benign laryngeal neoplasm in children [1]. The disease process may affect any part of the aerodigestive tract; the larynx is the most involved anatomical location [1]. The lesions are usually multiple, stemlike protrusion or “cauliflowerlike” in appearance and may bleed with manipulation. Suspected tracheobronchial involvement- or recurrence-related complications are further investigated with imaging of the chest and bronchoscopy. Chest X-ray is usually normal unless there is lung parenchymal involvement. The CT scan may show walled cysts with nodules, atelectasis, and bronchiectasis with mucus plugging [2]. Airway visualization (i.e., flexible or rigid bronchoscopy) remains superior, as it may aid with direct visualization of lesions and biopsies for further analysis.
The recurrent nature of the disease course warrants repeated surgical procedures, and the mean number of surgeries required can be as high as 4.4 procedures per year [8]. Consequently, this exposes patients to various complications such as anesthesia-related complications, damage to healthy tissue, tracheal stenosis, perforation, and socioeconomical burdens on families [9].
In addition, adjunct treatments with alpha-interferon and antiviral medications such as cidofovir have shown to be effective as well. These agents may increase the length of the time intervals between surgeries or decrease the total number of surgeries that the patients may require [9]. Vascular endothelial growth factor (VEGF) inhibitor, such as bevacizumab, is another feasible choice for adjunct treatment therapies for recurrent respiratory papillomatosis [10, 11]. However, these agents are prone to limitations due to dosing recommendations, systemic vs. intralesional mode of administration, and minimal response to therapies [7, 12]. HPV vaccinations may also be an effective measure to prevent the overall risk of disease transmission in the pediatric population as majority of these infections are vertically transmitted from a high-risk mother [9].
7. Conclusion
Recurrent respiratory papillomatosis infections in children are typically acquired during vertical transmission at birth or transplacental infections. The risk factors for recurrence, aggressive nature of the disease with distal spread, and malignant potential include firstborn child, vaginal delivery, women with a history of HPV infection (subtype 16), and history of prior invasive interventions. However, among infants born to women with such a history, the risk of RRP is <1% [4]. The prognosis of disease also varies based upon the risk factors mentioned above with less aggressive types of infections having a good outcome and more aggressive types of infections requiring frequent debulking surgeries and tracheostomy [8].
Data Availability
The academic and clinical percentile data used to support and discuss the findings of this case report are included within the article.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Images collected during flexible bronchoscopy. (a) Lesions protruding from the tracheal wall mucosal. (b) Narrowing of the trachea secondary to multiple lesions. (c) Normal-appearing area ∼3 cm above the carina.
Figure 2 Images collected s/p debulking surgery via rigid bronchoscopy. (a) Lesions obscuring the vocal cord(s) [7]. (b) Lesions in the distal trachea. (c) Tracheal lumen. | BEVACIZUMAB | DrugsGivenReaction | CC BY | 33628559 | 18,983,482 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypersensitivity vasculitis'. | Drug-Induced Lupus with Leukocytoclastic Vasculitis Associated with Apixaban.
Drug-induced lupus is an iatrogenic-induced autoimmune disease with common offending agents well documented in the literature. To our knowledge, there are no prior case reports of drug-induced lupus associated with apixaban or any other direct oral anticoagulant. We describe a case of drug-induced lupus with leukocytoclastic vasculitis associated with apixaban started 15 days prior, after a WATCHMAN procedure for atrial fibrillation in an 86-year-old male previously anticoagulated on rivaroxaban.
1. Introduction
Drug-induced lupus (DIL) is an iatrogenic-induced autoimmune disease that can present systemically or cutaneously and varies in presentation based on the offending drug. Common systemic features include arthralgia and myalgia, while cutaneous lesions generally involving the lower extremity can include purpura or necrotizing vasculitis [1]. Leukocytoclastic vasculitis (LCV) is a histopathologic diagnosis with immune complex deposition into the vessel walls. Although LCV can be systemic, it most commonly is limited to cutaneous manifestations with palpable purpura in the lower extremities at 7–14 days after exposure to drug or infection [2]. DIL and LCV are not commonly described together nor commonly associated with apixaban.
2. Method
2.1. Case Report and Review of Literature
2.1.1. Case
An 86-year-old male presented with generalized weakness and dyspnea on exertion, additionally noted to have a new petechial rash on both of his feet without pruritus. The patient recently underwent placement of WATCHMAN left atrial appendage occlusion device and was converted from rivaroxaban to apixaban and aspirin, as well as from flecainide to amiodarone. Past medical history was significant for diverticulosis with partial bowel resection, paroxysmal atrial fibrillation complicated by multiple gastrointestinal bleeds, hypertension, type 2 diabetes mellitus, chronic kidney disease stage IIIb, major depressive disorder, and obstructive sleep apnea. Other medications include trazodone, citalopram, sitagliptin, metoprolol, pravastatin, oxybutynin, and tamsulosin. The patient denied chemical exposure, insect bites, or prior allergic reactions. On day 15 after starting apixaban, the patient noted nonpruritic petechial rash on his feet, followed by weakness and dyspnea on exertion leading to hospital admission (Figure 1). On physical exam, the patient had stable vitals on room air with an irregularly irregular rhythm, as well as a nonpruritic nonpainful nonblanching petechial rash beginning on the feet and later spread to his thighs and arms with associated diffuse myalgias. Laboratory data showed a white blood cell count of 11.3 with 0.3% eosinophil (0.3–5.0%), platelet count of 289, hemoglobin 12.1, creatinine 2.14 (baseline 1.5), erythrocyte sedimentation rate 63, C-reactive protein 11.7, borderline antinuclear antibody 1 : 40, strongly positive antihistone antibodies 4.4, positive hepatitis B core antibody, and C3 of 147 (75–152 mg/dL) with C4 of 72 (14–48 mg/dL). Further workup included negative double-stranded DNA, antineutrophil cytoplasmic antibodies, glomerular basement membrane antibodies, COVID-19, Rocky Mountain spotted fever, syphilis, coxsackie, and ehrlichia. A skin biopsy was performed. Apixaban was stopped, and the patient was started on prednisone 30 mg twice daily while waiting for skin biopsy results.
Skin biopsy showed superficial and deep perivascular neutrophilic infiltration consistent with LCV (Figure 2). During the hospitalization, the patient was bridged onto warfarin with heparin and discharged with a prednisone taper. The rash and associated symptoms were resolved when seen at 2-week outpatient follow-up.
3. Discussion
Drug-induced lupus (DIL) is an iatrogenic-induced autoimmune disease that is typically suspected when the patient presents with systemic or cutaneous lupus-like symptoms in the context of a known DIL offender. None of the patient's existing or new medications are common offenders of DIL [3]. Combining the patient's cutaneous manifestations and recent change of medication, our initial clinical diagnosis was of apixaban-related leukocytoclastic vasculitis (LCV), of which there are four preceding case reports [4–7].
LCV is a small-vessel vasculitis with immune complex deposition into vessel walls with neutrophil activation, small vessel vasculature destruction, and red blood cell extravasation, resulting in palpable purpura preferentially seen in dependent areas, typically 7–14 days after initiation of the offending drug. When small vessel vasculitis is suspected, skin biopsy of fresh lesions within 24–48 hours should be obtained for histopathologic evaluation, looking for evidence of neutrophilic infiltrate of small vessels with evidence of granulocytic debris and nuclear dust, endothelial swelling, fibrinoid necrosis of vessel walls, and extravasation of red blood cells. Although skin biopsy is required for the diagnosis of LCV, positive findings do not rule out the possibility of extracutaneous involvement, and additional testing to exclude systemic involvement should be pursued. Management of LCV involves discontinuing the offending agent, with or without the addition of systemic immunosuppression. For severe cases involving widespread, ulcerative, or necrotic lesions, corticosteroids with a 4–8 week taper is appropriate [8].
As part of the workup to exclude systemic involvement, the rheumatologic panel revealed a strongly positive antihistone antibody titer [9]. After apixaban was discontinued and prednisone initiated, the symptoms dramatically improved without another likely causative agent. This supports that the patient had apixaban-related DIL. DIL typically presents with mild lupus-like symptoms including arthralgia, myalgia, fever, and cutaneous manifestations, with additional symptoms varying based on the offending drug. Skin lesions of note include photodistributed erythema and annular plaques, purpura, urticarial lesions, and necrotizing vasculitis. The management of DIL is similar to LCV, with discontinuing the offending drug, and initiation of corticosteroids for patients with end organ damage.
It is our impression that this patient had apixaban-related DIL with cutaneous manifestation consistent with LCV. To our knowledge, this is the first case report of DIL associated with a direct oral anticoagulant. This is the fifth case report of LCV associated with apixaban. There is one other case report of DIL with LCV, and it is documented in association with adalimumab [10].
4. Conclusion
Apixaban is a potential precipitant of drug-induced lupus that was not previously described in the literature. While leukocytoclastic vasculitis may have a similar cutaneous presentation, it is important to remember that it is a diagnosis of exclusion and to keep a wide differential. Fortunately, the general treatment direction for both diagnoses is similar, and in most cases, symptoms should improve and resolve after stopping the offending medication.
Data Availability
The data used to support the findings of this study are available from the corresponding author upon request.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Rash of the left lower extremity.
Figure 2 Excisional biopsy demonstrating superficial and deep perivascular neutrophil infiltration consistent with leukocytoclastic vasculitis. | AMIODARONE, APIXABAN, ASPIRIN, CITALOPRAM HYDROBROMIDE, METOPROLOL, OXYBUTYNIN CHLORIDE, PRAVASTATIN, SITAGLIPTIN PHOSPHATE, TAMSULOSIN HYDROCHLORIDE, TRAZODONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33628568 | 19,001,114 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lupus-like syndrome'. | Drug-Induced Lupus with Leukocytoclastic Vasculitis Associated with Apixaban.
Drug-induced lupus is an iatrogenic-induced autoimmune disease with common offending agents well documented in the literature. To our knowledge, there are no prior case reports of drug-induced lupus associated with apixaban or any other direct oral anticoagulant. We describe a case of drug-induced lupus with leukocytoclastic vasculitis associated with apixaban started 15 days prior, after a WATCHMAN procedure for atrial fibrillation in an 86-year-old male previously anticoagulated on rivaroxaban.
1. Introduction
Drug-induced lupus (DIL) is an iatrogenic-induced autoimmune disease that can present systemically or cutaneously and varies in presentation based on the offending drug. Common systemic features include arthralgia and myalgia, while cutaneous lesions generally involving the lower extremity can include purpura or necrotizing vasculitis [1]. Leukocytoclastic vasculitis (LCV) is a histopathologic diagnosis with immune complex deposition into the vessel walls. Although LCV can be systemic, it most commonly is limited to cutaneous manifestations with palpable purpura in the lower extremities at 7–14 days after exposure to drug or infection [2]. DIL and LCV are not commonly described together nor commonly associated with apixaban.
2. Method
2.1. Case Report and Review of Literature
2.1.1. Case
An 86-year-old male presented with generalized weakness and dyspnea on exertion, additionally noted to have a new petechial rash on both of his feet without pruritus. The patient recently underwent placement of WATCHMAN left atrial appendage occlusion device and was converted from rivaroxaban to apixaban and aspirin, as well as from flecainide to amiodarone. Past medical history was significant for diverticulosis with partial bowel resection, paroxysmal atrial fibrillation complicated by multiple gastrointestinal bleeds, hypertension, type 2 diabetes mellitus, chronic kidney disease stage IIIb, major depressive disorder, and obstructive sleep apnea. Other medications include trazodone, citalopram, sitagliptin, metoprolol, pravastatin, oxybutynin, and tamsulosin. The patient denied chemical exposure, insect bites, or prior allergic reactions. On day 15 after starting apixaban, the patient noted nonpruritic petechial rash on his feet, followed by weakness and dyspnea on exertion leading to hospital admission (Figure 1). On physical exam, the patient had stable vitals on room air with an irregularly irregular rhythm, as well as a nonpruritic nonpainful nonblanching petechial rash beginning on the feet and later spread to his thighs and arms with associated diffuse myalgias. Laboratory data showed a white blood cell count of 11.3 with 0.3% eosinophil (0.3–5.0%), platelet count of 289, hemoglobin 12.1, creatinine 2.14 (baseline 1.5), erythrocyte sedimentation rate 63, C-reactive protein 11.7, borderline antinuclear antibody 1 : 40, strongly positive antihistone antibodies 4.4, positive hepatitis B core antibody, and C3 of 147 (75–152 mg/dL) with C4 of 72 (14–48 mg/dL). Further workup included negative double-stranded DNA, antineutrophil cytoplasmic antibodies, glomerular basement membrane antibodies, COVID-19, Rocky Mountain spotted fever, syphilis, coxsackie, and ehrlichia. A skin biopsy was performed. Apixaban was stopped, and the patient was started on prednisone 30 mg twice daily while waiting for skin biopsy results.
Skin biopsy showed superficial and deep perivascular neutrophilic infiltration consistent with LCV (Figure 2). During the hospitalization, the patient was bridged onto warfarin with heparin and discharged with a prednisone taper. The rash and associated symptoms were resolved when seen at 2-week outpatient follow-up.
3. Discussion
Drug-induced lupus (DIL) is an iatrogenic-induced autoimmune disease that is typically suspected when the patient presents with systemic or cutaneous lupus-like symptoms in the context of a known DIL offender. None of the patient's existing or new medications are common offenders of DIL [3]. Combining the patient's cutaneous manifestations and recent change of medication, our initial clinical diagnosis was of apixaban-related leukocytoclastic vasculitis (LCV), of which there are four preceding case reports [4–7].
LCV is a small-vessel vasculitis with immune complex deposition into vessel walls with neutrophil activation, small vessel vasculature destruction, and red blood cell extravasation, resulting in palpable purpura preferentially seen in dependent areas, typically 7–14 days after initiation of the offending drug. When small vessel vasculitis is suspected, skin biopsy of fresh lesions within 24–48 hours should be obtained for histopathologic evaluation, looking for evidence of neutrophilic infiltrate of small vessels with evidence of granulocytic debris and nuclear dust, endothelial swelling, fibrinoid necrosis of vessel walls, and extravasation of red blood cells. Although skin biopsy is required for the diagnosis of LCV, positive findings do not rule out the possibility of extracutaneous involvement, and additional testing to exclude systemic involvement should be pursued. Management of LCV involves discontinuing the offending agent, with or without the addition of systemic immunosuppression. For severe cases involving widespread, ulcerative, or necrotic lesions, corticosteroids with a 4–8 week taper is appropriate [8].
As part of the workup to exclude systemic involvement, the rheumatologic panel revealed a strongly positive antihistone antibody titer [9]. After apixaban was discontinued and prednisone initiated, the symptoms dramatically improved without another likely causative agent. This supports that the patient had apixaban-related DIL. DIL typically presents with mild lupus-like symptoms including arthralgia, myalgia, fever, and cutaneous manifestations, with additional symptoms varying based on the offending drug. Skin lesions of note include photodistributed erythema and annular plaques, purpura, urticarial lesions, and necrotizing vasculitis. The management of DIL is similar to LCV, with discontinuing the offending drug, and initiation of corticosteroids for patients with end organ damage.
It is our impression that this patient had apixaban-related DIL with cutaneous manifestation consistent with LCV. To our knowledge, this is the first case report of DIL associated with a direct oral anticoagulant. This is the fifth case report of LCV associated with apixaban. There is one other case report of DIL with LCV, and it is documented in association with adalimumab [10].
4. Conclusion
Apixaban is a potential precipitant of drug-induced lupus that was not previously described in the literature. While leukocytoclastic vasculitis may have a similar cutaneous presentation, it is important to remember that it is a diagnosis of exclusion and to keep a wide differential. Fortunately, the general treatment direction for both diagnoses is similar, and in most cases, symptoms should improve and resolve after stopping the offending medication.
Data Availability
The data used to support the findings of this study are available from the corresponding author upon request.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Rash of the left lower extremity.
Figure 2 Excisional biopsy demonstrating superficial and deep perivascular neutrophil infiltration consistent with leukocytoclastic vasculitis. | AMIODARONE, APIXABAN, ASPIRIN, CITALOPRAM HYDROBROMIDE, METOPROLOL, OXYBUTYNIN CHLORIDE, PRAVASTATIN, SITAGLIPTIN PHOSPHATE, TAMSULOSIN HYDROCHLORIDE, TRAZODONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33628568 | 19,001,114 | 2021 |
What was the administration route of drug 'APIXABAN'? | Drug-Induced Lupus with Leukocytoclastic Vasculitis Associated with Apixaban.
Drug-induced lupus is an iatrogenic-induced autoimmune disease with common offending agents well documented in the literature. To our knowledge, there are no prior case reports of drug-induced lupus associated with apixaban or any other direct oral anticoagulant. We describe a case of drug-induced lupus with leukocytoclastic vasculitis associated with apixaban started 15 days prior, after a WATCHMAN procedure for atrial fibrillation in an 86-year-old male previously anticoagulated on rivaroxaban.
1. Introduction
Drug-induced lupus (DIL) is an iatrogenic-induced autoimmune disease that can present systemically or cutaneously and varies in presentation based on the offending drug. Common systemic features include arthralgia and myalgia, while cutaneous lesions generally involving the lower extremity can include purpura or necrotizing vasculitis [1]. Leukocytoclastic vasculitis (LCV) is a histopathologic diagnosis with immune complex deposition into the vessel walls. Although LCV can be systemic, it most commonly is limited to cutaneous manifestations with palpable purpura in the lower extremities at 7–14 days after exposure to drug or infection [2]. DIL and LCV are not commonly described together nor commonly associated with apixaban.
2. Method
2.1. Case Report and Review of Literature
2.1.1. Case
An 86-year-old male presented with generalized weakness and dyspnea on exertion, additionally noted to have a new petechial rash on both of his feet without pruritus. The patient recently underwent placement of WATCHMAN left atrial appendage occlusion device and was converted from rivaroxaban to apixaban and aspirin, as well as from flecainide to amiodarone. Past medical history was significant for diverticulosis with partial bowel resection, paroxysmal atrial fibrillation complicated by multiple gastrointestinal bleeds, hypertension, type 2 diabetes mellitus, chronic kidney disease stage IIIb, major depressive disorder, and obstructive sleep apnea. Other medications include trazodone, citalopram, sitagliptin, metoprolol, pravastatin, oxybutynin, and tamsulosin. The patient denied chemical exposure, insect bites, or prior allergic reactions. On day 15 after starting apixaban, the patient noted nonpruritic petechial rash on his feet, followed by weakness and dyspnea on exertion leading to hospital admission (Figure 1). On physical exam, the patient had stable vitals on room air with an irregularly irregular rhythm, as well as a nonpruritic nonpainful nonblanching petechial rash beginning on the feet and later spread to his thighs and arms with associated diffuse myalgias. Laboratory data showed a white blood cell count of 11.3 with 0.3% eosinophil (0.3–5.0%), platelet count of 289, hemoglobin 12.1, creatinine 2.14 (baseline 1.5), erythrocyte sedimentation rate 63, C-reactive protein 11.7, borderline antinuclear antibody 1 : 40, strongly positive antihistone antibodies 4.4, positive hepatitis B core antibody, and C3 of 147 (75–152 mg/dL) with C4 of 72 (14–48 mg/dL). Further workup included negative double-stranded DNA, antineutrophil cytoplasmic antibodies, glomerular basement membrane antibodies, COVID-19, Rocky Mountain spotted fever, syphilis, coxsackie, and ehrlichia. A skin biopsy was performed. Apixaban was stopped, and the patient was started on prednisone 30 mg twice daily while waiting for skin biopsy results.
Skin biopsy showed superficial and deep perivascular neutrophilic infiltration consistent with LCV (Figure 2). During the hospitalization, the patient was bridged onto warfarin with heparin and discharged with a prednisone taper. The rash and associated symptoms were resolved when seen at 2-week outpatient follow-up.
3. Discussion
Drug-induced lupus (DIL) is an iatrogenic-induced autoimmune disease that is typically suspected when the patient presents with systemic or cutaneous lupus-like symptoms in the context of a known DIL offender. None of the patient's existing or new medications are common offenders of DIL [3]. Combining the patient's cutaneous manifestations and recent change of medication, our initial clinical diagnosis was of apixaban-related leukocytoclastic vasculitis (LCV), of which there are four preceding case reports [4–7].
LCV is a small-vessel vasculitis with immune complex deposition into vessel walls with neutrophil activation, small vessel vasculature destruction, and red blood cell extravasation, resulting in palpable purpura preferentially seen in dependent areas, typically 7–14 days after initiation of the offending drug. When small vessel vasculitis is suspected, skin biopsy of fresh lesions within 24–48 hours should be obtained for histopathologic evaluation, looking for evidence of neutrophilic infiltrate of small vessels with evidence of granulocytic debris and nuclear dust, endothelial swelling, fibrinoid necrosis of vessel walls, and extravasation of red blood cells. Although skin biopsy is required for the diagnosis of LCV, positive findings do not rule out the possibility of extracutaneous involvement, and additional testing to exclude systemic involvement should be pursued. Management of LCV involves discontinuing the offending agent, with or without the addition of systemic immunosuppression. For severe cases involving widespread, ulcerative, or necrotic lesions, corticosteroids with a 4–8 week taper is appropriate [8].
As part of the workup to exclude systemic involvement, the rheumatologic panel revealed a strongly positive antihistone antibody titer [9]. After apixaban was discontinued and prednisone initiated, the symptoms dramatically improved without another likely causative agent. This supports that the patient had apixaban-related DIL. DIL typically presents with mild lupus-like symptoms including arthralgia, myalgia, fever, and cutaneous manifestations, with additional symptoms varying based on the offending drug. Skin lesions of note include photodistributed erythema and annular plaques, purpura, urticarial lesions, and necrotizing vasculitis. The management of DIL is similar to LCV, with discontinuing the offending drug, and initiation of corticosteroids for patients with end organ damage.
It is our impression that this patient had apixaban-related DIL with cutaneous manifestation consistent with LCV. To our knowledge, this is the first case report of DIL associated with a direct oral anticoagulant. This is the fifth case report of LCV associated with apixaban. There is one other case report of DIL with LCV, and it is documented in association with adalimumab [10].
4. Conclusion
Apixaban is a potential precipitant of drug-induced lupus that was not previously described in the literature. While leukocytoclastic vasculitis may have a similar cutaneous presentation, it is important to remember that it is a diagnosis of exclusion and to keep a wide differential. Fortunately, the general treatment direction for both diagnoses is similar, and in most cases, symptoms should improve and resolve after stopping the offending medication.
Data Availability
The data used to support the findings of this study are available from the corresponding author upon request.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Rash of the left lower extremity.
Figure 2 Excisional biopsy demonstrating superficial and deep perivascular neutrophil infiltration consistent with leukocytoclastic vasculitis. | Oral | DrugAdministrationRoute | CC BY | 33628568 | 19,001,114 | 2021 |
What was the outcome of reaction 'Hypersensitivity vasculitis'? | Drug-Induced Lupus with Leukocytoclastic Vasculitis Associated with Apixaban.
Drug-induced lupus is an iatrogenic-induced autoimmune disease with common offending agents well documented in the literature. To our knowledge, there are no prior case reports of drug-induced lupus associated with apixaban or any other direct oral anticoagulant. We describe a case of drug-induced lupus with leukocytoclastic vasculitis associated with apixaban started 15 days prior, after a WATCHMAN procedure for atrial fibrillation in an 86-year-old male previously anticoagulated on rivaroxaban.
1. Introduction
Drug-induced lupus (DIL) is an iatrogenic-induced autoimmune disease that can present systemically or cutaneously and varies in presentation based on the offending drug. Common systemic features include arthralgia and myalgia, while cutaneous lesions generally involving the lower extremity can include purpura or necrotizing vasculitis [1]. Leukocytoclastic vasculitis (LCV) is a histopathologic diagnosis with immune complex deposition into the vessel walls. Although LCV can be systemic, it most commonly is limited to cutaneous manifestations with palpable purpura in the lower extremities at 7–14 days after exposure to drug or infection [2]. DIL and LCV are not commonly described together nor commonly associated with apixaban.
2. Method
2.1. Case Report and Review of Literature
2.1.1. Case
An 86-year-old male presented with generalized weakness and dyspnea on exertion, additionally noted to have a new petechial rash on both of his feet without pruritus. The patient recently underwent placement of WATCHMAN left atrial appendage occlusion device and was converted from rivaroxaban to apixaban and aspirin, as well as from flecainide to amiodarone. Past medical history was significant for diverticulosis with partial bowel resection, paroxysmal atrial fibrillation complicated by multiple gastrointestinal bleeds, hypertension, type 2 diabetes mellitus, chronic kidney disease stage IIIb, major depressive disorder, and obstructive sleep apnea. Other medications include trazodone, citalopram, sitagliptin, metoprolol, pravastatin, oxybutynin, and tamsulosin. The patient denied chemical exposure, insect bites, or prior allergic reactions. On day 15 after starting apixaban, the patient noted nonpruritic petechial rash on his feet, followed by weakness and dyspnea on exertion leading to hospital admission (Figure 1). On physical exam, the patient had stable vitals on room air with an irregularly irregular rhythm, as well as a nonpruritic nonpainful nonblanching petechial rash beginning on the feet and later spread to his thighs and arms with associated diffuse myalgias. Laboratory data showed a white blood cell count of 11.3 with 0.3% eosinophil (0.3–5.0%), platelet count of 289, hemoglobin 12.1, creatinine 2.14 (baseline 1.5), erythrocyte sedimentation rate 63, C-reactive protein 11.7, borderline antinuclear antibody 1 : 40, strongly positive antihistone antibodies 4.4, positive hepatitis B core antibody, and C3 of 147 (75–152 mg/dL) with C4 of 72 (14–48 mg/dL). Further workup included negative double-stranded DNA, antineutrophil cytoplasmic antibodies, glomerular basement membrane antibodies, COVID-19, Rocky Mountain spotted fever, syphilis, coxsackie, and ehrlichia. A skin biopsy was performed. Apixaban was stopped, and the patient was started on prednisone 30 mg twice daily while waiting for skin biopsy results.
Skin biopsy showed superficial and deep perivascular neutrophilic infiltration consistent with LCV (Figure 2). During the hospitalization, the patient was bridged onto warfarin with heparin and discharged with a prednisone taper. The rash and associated symptoms were resolved when seen at 2-week outpatient follow-up.
3. Discussion
Drug-induced lupus (DIL) is an iatrogenic-induced autoimmune disease that is typically suspected when the patient presents with systemic or cutaneous lupus-like symptoms in the context of a known DIL offender. None of the patient's existing or new medications are common offenders of DIL [3]. Combining the patient's cutaneous manifestations and recent change of medication, our initial clinical diagnosis was of apixaban-related leukocytoclastic vasculitis (LCV), of which there are four preceding case reports [4–7].
LCV is a small-vessel vasculitis with immune complex deposition into vessel walls with neutrophil activation, small vessel vasculature destruction, and red blood cell extravasation, resulting in palpable purpura preferentially seen in dependent areas, typically 7–14 days after initiation of the offending drug. When small vessel vasculitis is suspected, skin biopsy of fresh lesions within 24–48 hours should be obtained for histopathologic evaluation, looking for evidence of neutrophilic infiltrate of small vessels with evidence of granulocytic debris and nuclear dust, endothelial swelling, fibrinoid necrosis of vessel walls, and extravasation of red blood cells. Although skin biopsy is required for the diagnosis of LCV, positive findings do not rule out the possibility of extracutaneous involvement, and additional testing to exclude systemic involvement should be pursued. Management of LCV involves discontinuing the offending agent, with or without the addition of systemic immunosuppression. For severe cases involving widespread, ulcerative, or necrotic lesions, corticosteroids with a 4–8 week taper is appropriate [8].
As part of the workup to exclude systemic involvement, the rheumatologic panel revealed a strongly positive antihistone antibody titer [9]. After apixaban was discontinued and prednisone initiated, the symptoms dramatically improved without another likely causative agent. This supports that the patient had apixaban-related DIL. DIL typically presents with mild lupus-like symptoms including arthralgia, myalgia, fever, and cutaneous manifestations, with additional symptoms varying based on the offending drug. Skin lesions of note include photodistributed erythema and annular plaques, purpura, urticarial lesions, and necrotizing vasculitis. The management of DIL is similar to LCV, with discontinuing the offending drug, and initiation of corticosteroids for patients with end organ damage.
It is our impression that this patient had apixaban-related DIL with cutaneous manifestation consistent with LCV. To our knowledge, this is the first case report of DIL associated with a direct oral anticoagulant. This is the fifth case report of LCV associated with apixaban. There is one other case report of DIL with LCV, and it is documented in association with adalimumab [10].
4. Conclusion
Apixaban is a potential precipitant of drug-induced lupus that was not previously described in the literature. While leukocytoclastic vasculitis may have a similar cutaneous presentation, it is important to remember that it is a diagnosis of exclusion and to keep a wide differential. Fortunately, the general treatment direction for both diagnoses is similar, and in most cases, symptoms should improve and resolve after stopping the offending medication.
Data Availability
The data used to support the findings of this study are available from the corresponding author upon request.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Rash of the left lower extremity.
Figure 2 Excisional biopsy demonstrating superficial and deep perivascular neutrophil infiltration consistent with leukocytoclastic vasculitis. | Recovered | ReactionOutcome | CC BY | 33628568 | 19,001,114 | 2021 |
What was the outcome of reaction 'Lupus-like syndrome'? | Drug-Induced Lupus with Leukocytoclastic Vasculitis Associated with Apixaban.
Drug-induced lupus is an iatrogenic-induced autoimmune disease with common offending agents well documented in the literature. To our knowledge, there are no prior case reports of drug-induced lupus associated with apixaban or any other direct oral anticoagulant. We describe a case of drug-induced lupus with leukocytoclastic vasculitis associated with apixaban started 15 days prior, after a WATCHMAN procedure for atrial fibrillation in an 86-year-old male previously anticoagulated on rivaroxaban.
1. Introduction
Drug-induced lupus (DIL) is an iatrogenic-induced autoimmune disease that can present systemically or cutaneously and varies in presentation based on the offending drug. Common systemic features include arthralgia and myalgia, while cutaneous lesions generally involving the lower extremity can include purpura or necrotizing vasculitis [1]. Leukocytoclastic vasculitis (LCV) is a histopathologic diagnosis with immune complex deposition into the vessel walls. Although LCV can be systemic, it most commonly is limited to cutaneous manifestations with palpable purpura in the lower extremities at 7–14 days after exposure to drug or infection [2]. DIL and LCV are not commonly described together nor commonly associated with apixaban.
2. Method
2.1. Case Report and Review of Literature
2.1.1. Case
An 86-year-old male presented with generalized weakness and dyspnea on exertion, additionally noted to have a new petechial rash on both of his feet without pruritus. The patient recently underwent placement of WATCHMAN left atrial appendage occlusion device and was converted from rivaroxaban to apixaban and aspirin, as well as from flecainide to amiodarone. Past medical history was significant for diverticulosis with partial bowel resection, paroxysmal atrial fibrillation complicated by multiple gastrointestinal bleeds, hypertension, type 2 diabetes mellitus, chronic kidney disease stage IIIb, major depressive disorder, and obstructive sleep apnea. Other medications include trazodone, citalopram, sitagliptin, metoprolol, pravastatin, oxybutynin, and tamsulosin. The patient denied chemical exposure, insect bites, or prior allergic reactions. On day 15 after starting apixaban, the patient noted nonpruritic petechial rash on his feet, followed by weakness and dyspnea on exertion leading to hospital admission (Figure 1). On physical exam, the patient had stable vitals on room air with an irregularly irregular rhythm, as well as a nonpruritic nonpainful nonblanching petechial rash beginning on the feet and later spread to his thighs and arms with associated diffuse myalgias. Laboratory data showed a white blood cell count of 11.3 with 0.3% eosinophil (0.3–5.0%), platelet count of 289, hemoglobin 12.1, creatinine 2.14 (baseline 1.5), erythrocyte sedimentation rate 63, C-reactive protein 11.7, borderline antinuclear antibody 1 : 40, strongly positive antihistone antibodies 4.4, positive hepatitis B core antibody, and C3 of 147 (75–152 mg/dL) with C4 of 72 (14–48 mg/dL). Further workup included negative double-stranded DNA, antineutrophil cytoplasmic antibodies, glomerular basement membrane antibodies, COVID-19, Rocky Mountain spotted fever, syphilis, coxsackie, and ehrlichia. A skin biopsy was performed. Apixaban was stopped, and the patient was started on prednisone 30 mg twice daily while waiting for skin biopsy results.
Skin biopsy showed superficial and deep perivascular neutrophilic infiltration consistent with LCV (Figure 2). During the hospitalization, the patient was bridged onto warfarin with heparin and discharged with a prednisone taper. The rash and associated symptoms were resolved when seen at 2-week outpatient follow-up.
3. Discussion
Drug-induced lupus (DIL) is an iatrogenic-induced autoimmune disease that is typically suspected when the patient presents with systemic or cutaneous lupus-like symptoms in the context of a known DIL offender. None of the patient's existing or new medications are common offenders of DIL [3]. Combining the patient's cutaneous manifestations and recent change of medication, our initial clinical diagnosis was of apixaban-related leukocytoclastic vasculitis (LCV), of which there are four preceding case reports [4–7].
LCV is a small-vessel vasculitis with immune complex deposition into vessel walls with neutrophil activation, small vessel vasculature destruction, and red blood cell extravasation, resulting in palpable purpura preferentially seen in dependent areas, typically 7–14 days after initiation of the offending drug. When small vessel vasculitis is suspected, skin biopsy of fresh lesions within 24–48 hours should be obtained for histopathologic evaluation, looking for evidence of neutrophilic infiltrate of small vessels with evidence of granulocytic debris and nuclear dust, endothelial swelling, fibrinoid necrosis of vessel walls, and extravasation of red blood cells. Although skin biopsy is required for the diagnosis of LCV, positive findings do not rule out the possibility of extracutaneous involvement, and additional testing to exclude systemic involvement should be pursued. Management of LCV involves discontinuing the offending agent, with or without the addition of systemic immunosuppression. For severe cases involving widespread, ulcerative, or necrotic lesions, corticosteroids with a 4–8 week taper is appropriate [8].
As part of the workup to exclude systemic involvement, the rheumatologic panel revealed a strongly positive antihistone antibody titer [9]. After apixaban was discontinued and prednisone initiated, the symptoms dramatically improved without another likely causative agent. This supports that the patient had apixaban-related DIL. DIL typically presents with mild lupus-like symptoms including arthralgia, myalgia, fever, and cutaneous manifestations, with additional symptoms varying based on the offending drug. Skin lesions of note include photodistributed erythema and annular plaques, purpura, urticarial lesions, and necrotizing vasculitis. The management of DIL is similar to LCV, with discontinuing the offending drug, and initiation of corticosteroids for patients with end organ damage.
It is our impression that this patient had apixaban-related DIL with cutaneous manifestation consistent with LCV. To our knowledge, this is the first case report of DIL associated with a direct oral anticoagulant. This is the fifth case report of LCV associated with apixaban. There is one other case report of DIL with LCV, and it is documented in association with adalimumab [10].
4. Conclusion
Apixaban is a potential precipitant of drug-induced lupus that was not previously described in the literature. While leukocytoclastic vasculitis may have a similar cutaneous presentation, it is important to remember that it is a diagnosis of exclusion and to keep a wide differential. Fortunately, the general treatment direction for both diagnoses is similar, and in most cases, symptoms should improve and resolve after stopping the offending medication.
Data Availability
The data used to support the findings of this study are available from the corresponding author upon request.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Rash of the left lower extremity.
Figure 2 Excisional biopsy demonstrating superficial and deep perivascular neutrophil infiltration consistent with leukocytoclastic vasculitis. | Recovered | ReactionOutcome | CC BY | 33628568 | 19,001,114 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cholestatic liver injury'. | Nafcillin-Induced Hepatic Injury: A Case Report and Literature Review.
BACKGROUND
Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the Western world. While it requires a diagnosis of exclusion, it is exceedingly prevalent in patients taking multiple hepatotoxic agents, the foremost of which are antibiotics, followed by herbal and dietary supplements. Below we will discuss a case of nafcillin-induced liver injury suggested by a thorough work-up and rule-out of other hepatic and biliary pathologies.
METHODS
We report the case of a 66-year-old white male who presented with painless jaundice. Clinical, laboratory and radiographic features demonstrated a cholestatic pattern of liver injury without significant abnormalities in the biliary tract. All workup for viral hepatitis and autoimmune diseases with liver involvement was negative. Liver biopsy showed acute necro-inflammatory changes suggestive of drug-induced liver injury. The patient had received 18 days of IV nafcillin for blood culture positive methicillin-susceptible Staphylococcus aureus (MSSA) four weeks prior to his presentation. He showed clinical and laboratory improvement of his liver functions with supportive care only.
CONCLUSIONS
Nafcillin is a safe and effective antibiotic for the treatment of methicillin-susceptible Staphylococcal infections. However, physicians and prescribing healthcare professionals should be aware of the rare, but serious side effects, especially one of drug-induced liver injury with emphasis on the need for early cessation of nafcillin if liver function abnormalities develop.
Introduction
Drug-induced liver injury is a serious side effect of several drugs; studies have shown that antibiotics are the most common drugs associated with drug-induced hepatotoxicity, with amoxicillin-clavulanic acid being the main one. The other two groups that are also known to cause the majority of drug-induced liver injury are nonsteroidal anti-inflammatory drugs (NSAIDS) and isoniazid [1].
Nafcillin is a beta-lactam antibiotic most commonly used for methicillin-susceptible Staphylococcus aureus (MSSA) skin infections. It is also used for the treatment of subacute staphylococcal endocarditis in patients without artificial heart valves [2]. Nafcillin is often prescribed and generally well-tolerated. Drug adverse effects include Clostridioides colitis, oral thrush, and, although uncommon, allergic anaphylaxis [3]. Reports of nafcillin-induced liver injury are rare but serious.
Case presentation
The patient is a 66-year-old white male with a past medical history of a traumatic brain injury with left-sided hemiplegia since childhood, hypertension, leukemia in remission since 2005, and bilateral renal artery stenosis.
The first time the patient presented to the hospital on day one complaining of generalized weakness and malaise of one week duration. Physical exam was significant for right second toe ulcer with mild erythema and purulence. He had tachycardia on presentation. Laboratory values were significant for white blood cells (WBCs) count of 24.0 and C-reactive protein (CRP) of 13.4. The patient was admitted for infected right second toe with concerns of sepsis. He was treated empirically with intravenous vancomycin and piperacillin-tazobactam. Blood cultures from day two grew methicillin-susceptible Staphylococcus aureus (MSSA) and the patient was switched to intravenous nafcillin 2 g every four hours (12g/day) on day three. Repeat blood cultures on day three grew methicillin-susceptible Staphylococcus aureus (MSSA) and cultures on day seven had no growth. Nafcillin was continued for two weeks following the first negative blood culture. He was discharged to a nursing facility on day 12. He completed 18 days of IV nafcillin on day 21 of his illness.
The patient was re-admitted from the nursing facility on day 20 for a large bloody bowel movement and completed IV nafcillin in the first two days of his second admission. He was worked up appropriately for lower GI bleeding with colonoscopy findings of diverticulosis and recovered with minimal intervention. A liver panel on day 21 was unremarkable: total bilirubin 0.7 mg/dl, alkaline phosphatase (ALK) 60 IU/L, aspartate aminotransferase (AST) 21 U/L, alanine aminotransferase (ALT) 25 U/L.
He was re-admitted for the third time on day 30 of his illness from the nursing home (27 days after IV nafcillin was started and nine days after completion of IV nafcillin) for painless jaundice. Upon re-admission, his labs were remarkable for a cholestasis pattern of liver injury with total bilirubin 6.3 mg/dl (5.6 direct, 0.7 indirect), ALK 506 IU/L, AST 206 U/L, ALT 415 U/L (Figures 1, 2, 3).
Figure 1 Bilirubin level according to hospital day
Figure 2 Alkaline Phosphatase according to hospital day
Figure 3 AST and ALT according to hospital day
AST: aspartate aminotransferase, ALT: alanine aminotransferase
At that time his home medications with potential hepatotoxicity including atorvastatin and doxazosin were held. An ultrasound of the liver and biliary tract showed hepatomegaly with normal liver echogenicity, no mass or fluid collection, patent portal and hepatic veins. It also showed cholelithiasis without sonographic signs of cholecystitis, no intrahepatic or extrahepatic biliary ductal dilation. Further workup for infectious causes of liver injury including viral hepatitis panel for hepatitis A, B, C was negative (hepatitis A IgM antibody, hepatitis C antibody, hepatitis B surface antigen, hepatitis B surface and core antibodies all were non-reactive). A serology panel for autoimmune disorders associated with possible liver injury revealed the patient to be negative for anti-nuclear, anti-mitochondrial, anti-smooth muscle, and anti-centromere antibodies. The patient was coronavirus disease 2019 (COVID-19) negative. He does not drink alcohol, smoke cigarettes, or use any recreational drugs. The remainder of the workup was done to exclude alternative liver pathologies. Serum copper and ceruloplasmin, Epstein-Barr virus (EBV) serology, alpha-1-antitripsin all were negative or unremarkable. Magnetic resonance cholangiopancreatography (MRCP) demonstrated cholelithiasis without choledocholithiasis or bile duct dilation. A percutaneous liver biopsy was obtained on day 30 which demonstrated acute necro-inflammatory liver disease suspicious for drug-induced liver injury (Figures 4, 5, 6).
Figure 4 Liver biopsy histopathological examination
Sections show lobular necrosis and severe portal tract inflammation with a mixed inflammatory infiltrate of neutrophils, eosinophils, lymphocytes and histiocytes. There is mild bile stasis within hepatocytes. There is no steatosis. PAS and PAS-D are negative for cytoplasmic inclusions. Trichrome stain highlights mild periportal fibrosis. Prussian blue stain is negative for iron granules .Reticulin stain shows preserved liver architecture.
Figure 5 Liver biopsy histopathological examination
Figure 6 Liver biopsy histopathological examination
Endoscopic retrograde cholangiopancreatography (ERCP) done on day 33 showed a small amount of biliary sludge that was evacuated after a stent placed in the common bile duct - there was no obstruction or inflammatory changes. A review of prior labs from his previous admission was significant for elevated eosinophil percent on day 25 with 11.7% (normal 1-8%), absolute eosinophil count of 1100 (upper limit of normal is 700) (Figure 7).
Figure 7 Eosinophil percent according to hospital day
After admission, his liver enzymes continued to worsen, with total bilirubin peaked on day 34 with 8.2 mg/dl (7.0 direct, 1.2 indirect), ALK peaked on day 40 with 865 IU/L, AST and ALT both peaked on day 30 with 206 U/L, 415 U/L, respectively (Figures 1, 2, 3). After ERCP, his liver function tests continued to worsen; the first day total bilirubin started to drop (day 37) was four days after ERCP was done. Throughout his hospital stay, the patient was monitored for signs of encephalopathy including asterixis and mental status changes, which he showed none. In addition to that, international normalized ratio (INR)/prothrombin time test (PT) was monitored daily for coagulopathy but his INR/PT remained within normal limits during his hospitalization. His liver panel steadily declined while he remained in the hospital with supportive treatment only. At time of discharge on day 42, liver lab values were total bilirubin 3.0 mg/dl, ALK 710 IU/L, AST 56 U/L, ALT 164 U/L (Figures 1, 2, 3). See Table 1 for normal laboratory reference ranges.
Table 1 Normal laboratory reference ranges in healthy adult.
Lab test Normal Lab value range
Aspartate aminotransferase (AST) (15-41 U/L)
Alanine aminotransferase (ALT) (7-35 U/L)
Alkaline Phosphatase (40-129 IU/L)
Total Bilirubin (0.3-1.2 mg/dl)
Direct Bilirubin (0.1-0.5 mg/dl)
Indirect Bilirubin (0-0.7 mg/dl)
Eosinophil percent (1-8%)
White blood cells count (WBCs) (4.3-10.8 10^3/cmm)
C-reactive protein (CRP) (0-1 mg/dl)
Discussion
Nafcillin is a penicillin antibiotic that is used currently for sensitive staphylococcal infections coverage. Unique about this drug that it is liver excreted through the bile system compared to other antibiotics in the same family (oxacillin and dicloxacillin) [4]. Several cases of nafcillin-induced liver injury have been reported in the literature; some are listed in Table 2 below.
Table 2 Comparison between several case reports of nafcillin-induced hepatotoxicity
Study number/ face of comparison Baseline Liver function tests (LFTs) Reason for Nafcillin use Onset of liver injury Dose Outcome Liver Biopsy Treatment used Day of Peak Pattern of liver injury Eosinophilia Reference
1 Normal Methicillin-susceptible Staphylococcus aureus (MSSA) + blood culture Day 27 Nafcillin 12 g/day Complete resolution Acute necro-inflammatory liver disease Supportive 33 Cholestatic Yes (11.7%) This case
2 Normal Lumbar Osteomyelitis with methicillin-susceptible Staphylococcus aureus (MSSA) Day 28 Nafcillin 12 g/day Complete resolution Findings consistent with cholestatic hepatitis Lactulose and empiric IV N-Acetyl Cystine 27 Cholestatic Yes (20.7%) [5]
3 Normal Great toe osteomyelitis with methicillin-susceptible Staphylococcus aureus (MSSA) Day 15 Nafcillin 12 g/day Patient died Picture of cholestatic liver injury Ursodiol 40 Cholestatic No [2]
4 Normal Culture negative cellulitis Day 5 Nafcillin 12 g/day Complete resolution Findings consistent with cholestatic inflammatory drug reaction Supportive 45 Cholestatic No [6]
5 Not reported Methicillin-susceptible Staphylococcus aureus (MSSA) septic arthritis Week 6 Nafcillin, dose not reported Complete resolution Findings consistent with cholestatic hepatitis Supportive 49-55 Cholestatic Yes (20%) [4]
Nearly all of the listed cases had cholestatic pattern of drug-induced liver injury. In our case as well, the ALK and bilirubin remained elevated out of proportion to the ALT/AST. The patient in our case showed evidence of immune-mediated idiosyncratic liver injury supported by the finding of eosinophilia (Figure 4); other case reports [4,5] also showed evidence of peripheral eosinophilia (Table 2). This also fit the timeline of weeks to months as opposed to the non-immune pattern which usually takes more than six weeks until onset. [7]
The use of prednisone in drug-induced liver injury is poorly supported due to the lack of sufficient evidence supporting severity reduction and the side effects of long-term use outweighing the potential benefits [8]. Recovery of liver injury in most cases of nafcillin-induced idiosyncratic liver injury occurs between four and twelve weeks. All cases listed in Table 2 including our patient showed complete resolution of liver injury with basically supportive treatment except one case ended with the death of the affected patient secondary to fulminant liver failure [2]. Due to the unusual presentation of nafcillin-induced liver injury, liver biopsy was done in all listed cases in Table 2. The findings were similar with evidence of necrosis, infiltration of several inflammatory cells, and changes consistent of fibrosis. These findings are not specific for drug-induced hepatic injury. However, they keep this diagnosis as one of the most likely differential diagnosis.
In this patient, nafcillin use was terminated prior to onset of elevated liver enzymes. A thorough pharmacy evaluation revealed nafcillin to be the biggest recent change to the patient's medication list. Although atorvastatin and doxazosin were also listed on the patient’s medication reconciliation, they were less likely offenders in this scenario. Atorvastatin had been started many years ago with no recent dose changes. Furthermore, case reports of atorvastatin-induced liver injury favor the hepatocellular pattern [9,10], which includes markedly elevated ALT with lower increases in ALK, unlike our patient. Doxazosin-induced liver toxicity is not only exceedingly rare, but poorly supported by the medical literature, especially to the magnitude seen above [3].
Conclusions
Nafcillin is an effective and widely used antibiotic at treating staphylococcal infections that are susceptible to methicillin. However, drug-induced liver injury with nafcillin use should not be taken lightly. When prescribing nafcillin for infection, especially in higher doses, a renal and liver panel ought to be evaluated to gauge for idiosyncratic reactions. The best treatment for nafcillin-induced liver injury is to immediately stop the antibiotic, avoid hepatotoxic drugs, and trend the liver enzymes for recovery. In the future, these patients should not be given nafcillin and penicillinase-resistant penicillins, including dicloxacillin and oxacillin.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | ATORVASTATIN, DOXAZOSIN MESYLATE, NAFCILLIN SODIUM | DrugsGivenReaction | CC BY | 33628683 | 19,005,231 | 2021-01-20 |
What was the administration route of drug 'NAFCILLIN SODIUM'? | Nafcillin-Induced Hepatic Injury: A Case Report and Literature Review.
BACKGROUND
Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the Western world. While it requires a diagnosis of exclusion, it is exceedingly prevalent in patients taking multiple hepatotoxic agents, the foremost of which are antibiotics, followed by herbal and dietary supplements. Below we will discuss a case of nafcillin-induced liver injury suggested by a thorough work-up and rule-out of other hepatic and biliary pathologies.
METHODS
We report the case of a 66-year-old white male who presented with painless jaundice. Clinical, laboratory and radiographic features demonstrated a cholestatic pattern of liver injury without significant abnormalities in the biliary tract. All workup for viral hepatitis and autoimmune diseases with liver involvement was negative. Liver biopsy showed acute necro-inflammatory changes suggestive of drug-induced liver injury. The patient had received 18 days of IV nafcillin for blood culture positive methicillin-susceptible Staphylococcus aureus (MSSA) four weeks prior to his presentation. He showed clinical and laboratory improvement of his liver functions with supportive care only.
CONCLUSIONS
Nafcillin is a safe and effective antibiotic for the treatment of methicillin-susceptible Staphylococcal infections. However, physicians and prescribing healthcare professionals should be aware of the rare, but serious side effects, especially one of drug-induced liver injury with emphasis on the need for early cessation of nafcillin if liver function abnormalities develop.
Introduction
Drug-induced liver injury is a serious side effect of several drugs; studies have shown that antibiotics are the most common drugs associated with drug-induced hepatotoxicity, with amoxicillin-clavulanic acid being the main one. The other two groups that are also known to cause the majority of drug-induced liver injury are nonsteroidal anti-inflammatory drugs (NSAIDS) and isoniazid [1].
Nafcillin is a beta-lactam antibiotic most commonly used for methicillin-susceptible Staphylococcus aureus (MSSA) skin infections. It is also used for the treatment of subacute staphylococcal endocarditis in patients without artificial heart valves [2]. Nafcillin is often prescribed and generally well-tolerated. Drug adverse effects include Clostridioides colitis, oral thrush, and, although uncommon, allergic anaphylaxis [3]. Reports of nafcillin-induced liver injury are rare but serious.
Case presentation
The patient is a 66-year-old white male with a past medical history of a traumatic brain injury with left-sided hemiplegia since childhood, hypertension, leukemia in remission since 2005, and bilateral renal artery stenosis.
The first time the patient presented to the hospital on day one complaining of generalized weakness and malaise of one week duration. Physical exam was significant for right second toe ulcer with mild erythema and purulence. He had tachycardia on presentation. Laboratory values were significant for white blood cells (WBCs) count of 24.0 and C-reactive protein (CRP) of 13.4. The patient was admitted for infected right second toe with concerns of sepsis. He was treated empirically with intravenous vancomycin and piperacillin-tazobactam. Blood cultures from day two grew methicillin-susceptible Staphylococcus aureus (MSSA) and the patient was switched to intravenous nafcillin 2 g every four hours (12g/day) on day three. Repeat blood cultures on day three grew methicillin-susceptible Staphylococcus aureus (MSSA) and cultures on day seven had no growth. Nafcillin was continued for two weeks following the first negative blood culture. He was discharged to a nursing facility on day 12. He completed 18 days of IV nafcillin on day 21 of his illness.
The patient was re-admitted from the nursing facility on day 20 for a large bloody bowel movement and completed IV nafcillin in the first two days of his second admission. He was worked up appropriately for lower GI bleeding with colonoscopy findings of diverticulosis and recovered with minimal intervention. A liver panel on day 21 was unremarkable: total bilirubin 0.7 mg/dl, alkaline phosphatase (ALK) 60 IU/L, aspartate aminotransferase (AST) 21 U/L, alanine aminotransferase (ALT) 25 U/L.
He was re-admitted for the third time on day 30 of his illness from the nursing home (27 days after IV nafcillin was started and nine days after completion of IV nafcillin) for painless jaundice. Upon re-admission, his labs were remarkable for a cholestasis pattern of liver injury with total bilirubin 6.3 mg/dl (5.6 direct, 0.7 indirect), ALK 506 IU/L, AST 206 U/L, ALT 415 U/L (Figures 1, 2, 3).
Figure 1 Bilirubin level according to hospital day
Figure 2 Alkaline Phosphatase according to hospital day
Figure 3 AST and ALT according to hospital day
AST: aspartate aminotransferase, ALT: alanine aminotransferase
At that time his home medications with potential hepatotoxicity including atorvastatin and doxazosin were held. An ultrasound of the liver and biliary tract showed hepatomegaly with normal liver echogenicity, no mass or fluid collection, patent portal and hepatic veins. It also showed cholelithiasis without sonographic signs of cholecystitis, no intrahepatic or extrahepatic biliary ductal dilation. Further workup for infectious causes of liver injury including viral hepatitis panel for hepatitis A, B, C was negative (hepatitis A IgM antibody, hepatitis C antibody, hepatitis B surface antigen, hepatitis B surface and core antibodies all were non-reactive). A serology panel for autoimmune disorders associated with possible liver injury revealed the patient to be negative for anti-nuclear, anti-mitochondrial, anti-smooth muscle, and anti-centromere antibodies. The patient was coronavirus disease 2019 (COVID-19) negative. He does not drink alcohol, smoke cigarettes, or use any recreational drugs. The remainder of the workup was done to exclude alternative liver pathologies. Serum copper and ceruloplasmin, Epstein-Barr virus (EBV) serology, alpha-1-antitripsin all were negative or unremarkable. Magnetic resonance cholangiopancreatography (MRCP) demonstrated cholelithiasis without choledocholithiasis or bile duct dilation. A percutaneous liver biopsy was obtained on day 30 which demonstrated acute necro-inflammatory liver disease suspicious for drug-induced liver injury (Figures 4, 5, 6).
Figure 4 Liver biopsy histopathological examination
Sections show lobular necrosis and severe portal tract inflammation with a mixed inflammatory infiltrate of neutrophils, eosinophils, lymphocytes and histiocytes. There is mild bile stasis within hepatocytes. There is no steatosis. PAS and PAS-D are negative for cytoplasmic inclusions. Trichrome stain highlights mild periportal fibrosis. Prussian blue stain is negative for iron granules .Reticulin stain shows preserved liver architecture.
Figure 5 Liver biopsy histopathological examination
Figure 6 Liver biopsy histopathological examination
Endoscopic retrograde cholangiopancreatography (ERCP) done on day 33 showed a small amount of biliary sludge that was evacuated after a stent placed in the common bile duct - there was no obstruction or inflammatory changes. A review of prior labs from his previous admission was significant for elevated eosinophil percent on day 25 with 11.7% (normal 1-8%), absolute eosinophil count of 1100 (upper limit of normal is 700) (Figure 7).
Figure 7 Eosinophil percent according to hospital day
After admission, his liver enzymes continued to worsen, with total bilirubin peaked on day 34 with 8.2 mg/dl (7.0 direct, 1.2 indirect), ALK peaked on day 40 with 865 IU/L, AST and ALT both peaked on day 30 with 206 U/L, 415 U/L, respectively (Figures 1, 2, 3). After ERCP, his liver function tests continued to worsen; the first day total bilirubin started to drop (day 37) was four days after ERCP was done. Throughout his hospital stay, the patient was monitored for signs of encephalopathy including asterixis and mental status changes, which he showed none. In addition to that, international normalized ratio (INR)/prothrombin time test (PT) was monitored daily for coagulopathy but his INR/PT remained within normal limits during his hospitalization. His liver panel steadily declined while he remained in the hospital with supportive treatment only. At time of discharge on day 42, liver lab values were total bilirubin 3.0 mg/dl, ALK 710 IU/L, AST 56 U/L, ALT 164 U/L (Figures 1, 2, 3). See Table 1 for normal laboratory reference ranges.
Table 1 Normal laboratory reference ranges in healthy adult.
Lab test Normal Lab value range
Aspartate aminotransferase (AST) (15-41 U/L)
Alanine aminotransferase (ALT) (7-35 U/L)
Alkaline Phosphatase (40-129 IU/L)
Total Bilirubin (0.3-1.2 mg/dl)
Direct Bilirubin (0.1-0.5 mg/dl)
Indirect Bilirubin (0-0.7 mg/dl)
Eosinophil percent (1-8%)
White blood cells count (WBCs) (4.3-10.8 10^3/cmm)
C-reactive protein (CRP) (0-1 mg/dl)
Discussion
Nafcillin is a penicillin antibiotic that is used currently for sensitive staphylococcal infections coverage. Unique about this drug that it is liver excreted through the bile system compared to other antibiotics in the same family (oxacillin and dicloxacillin) [4]. Several cases of nafcillin-induced liver injury have been reported in the literature; some are listed in Table 2 below.
Table 2 Comparison between several case reports of nafcillin-induced hepatotoxicity
Study number/ face of comparison Baseline Liver function tests (LFTs) Reason for Nafcillin use Onset of liver injury Dose Outcome Liver Biopsy Treatment used Day of Peak Pattern of liver injury Eosinophilia Reference
1 Normal Methicillin-susceptible Staphylococcus aureus (MSSA) + blood culture Day 27 Nafcillin 12 g/day Complete resolution Acute necro-inflammatory liver disease Supportive 33 Cholestatic Yes (11.7%) This case
2 Normal Lumbar Osteomyelitis with methicillin-susceptible Staphylococcus aureus (MSSA) Day 28 Nafcillin 12 g/day Complete resolution Findings consistent with cholestatic hepatitis Lactulose and empiric IV N-Acetyl Cystine 27 Cholestatic Yes (20.7%) [5]
3 Normal Great toe osteomyelitis with methicillin-susceptible Staphylococcus aureus (MSSA) Day 15 Nafcillin 12 g/day Patient died Picture of cholestatic liver injury Ursodiol 40 Cholestatic No [2]
4 Normal Culture negative cellulitis Day 5 Nafcillin 12 g/day Complete resolution Findings consistent with cholestatic inflammatory drug reaction Supportive 45 Cholestatic No [6]
5 Not reported Methicillin-susceptible Staphylococcus aureus (MSSA) septic arthritis Week 6 Nafcillin, dose not reported Complete resolution Findings consistent with cholestatic hepatitis Supportive 49-55 Cholestatic Yes (20%) [4]
Nearly all of the listed cases had cholestatic pattern of drug-induced liver injury. In our case as well, the ALK and bilirubin remained elevated out of proportion to the ALT/AST. The patient in our case showed evidence of immune-mediated idiosyncratic liver injury supported by the finding of eosinophilia (Figure 4); other case reports [4,5] also showed evidence of peripheral eosinophilia (Table 2). This also fit the timeline of weeks to months as opposed to the non-immune pattern which usually takes more than six weeks until onset. [7]
The use of prednisone in drug-induced liver injury is poorly supported due to the lack of sufficient evidence supporting severity reduction and the side effects of long-term use outweighing the potential benefits [8]. Recovery of liver injury in most cases of nafcillin-induced idiosyncratic liver injury occurs between four and twelve weeks. All cases listed in Table 2 including our patient showed complete resolution of liver injury with basically supportive treatment except one case ended with the death of the affected patient secondary to fulminant liver failure [2]. Due to the unusual presentation of nafcillin-induced liver injury, liver biopsy was done in all listed cases in Table 2. The findings were similar with evidence of necrosis, infiltration of several inflammatory cells, and changes consistent of fibrosis. These findings are not specific for drug-induced hepatic injury. However, they keep this diagnosis as one of the most likely differential diagnosis.
In this patient, nafcillin use was terminated prior to onset of elevated liver enzymes. A thorough pharmacy evaluation revealed nafcillin to be the biggest recent change to the patient's medication list. Although atorvastatin and doxazosin were also listed on the patient’s medication reconciliation, they were less likely offenders in this scenario. Atorvastatin had been started many years ago with no recent dose changes. Furthermore, case reports of atorvastatin-induced liver injury favor the hepatocellular pattern [9,10], which includes markedly elevated ALT with lower increases in ALK, unlike our patient. Doxazosin-induced liver toxicity is not only exceedingly rare, but poorly supported by the medical literature, especially to the magnitude seen above [3].
Conclusions
Nafcillin is an effective and widely used antibiotic at treating staphylococcal infections that are susceptible to methicillin. However, drug-induced liver injury with nafcillin use should not be taken lightly. When prescribing nafcillin for infection, especially in higher doses, a renal and liver panel ought to be evaluated to gauge for idiosyncratic reactions. The best treatment for nafcillin-induced liver injury is to immediately stop the antibiotic, avoid hepatotoxic drugs, and trend the liver enzymes for recovery. In the future, these patients should not be given nafcillin and penicillinase-resistant penicillins, including dicloxacillin and oxacillin.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33628683 | 19,005,231 | 2021-01-20 |
What was the outcome of reaction 'Cholestatic liver injury'? | Nafcillin-Induced Hepatic Injury: A Case Report and Literature Review.
BACKGROUND
Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the Western world. While it requires a diagnosis of exclusion, it is exceedingly prevalent in patients taking multiple hepatotoxic agents, the foremost of which are antibiotics, followed by herbal and dietary supplements. Below we will discuss a case of nafcillin-induced liver injury suggested by a thorough work-up and rule-out of other hepatic and biliary pathologies.
METHODS
We report the case of a 66-year-old white male who presented with painless jaundice. Clinical, laboratory and radiographic features demonstrated a cholestatic pattern of liver injury without significant abnormalities in the biliary tract. All workup for viral hepatitis and autoimmune diseases with liver involvement was negative. Liver biopsy showed acute necro-inflammatory changes suggestive of drug-induced liver injury. The patient had received 18 days of IV nafcillin for blood culture positive methicillin-susceptible Staphylococcus aureus (MSSA) four weeks prior to his presentation. He showed clinical and laboratory improvement of his liver functions with supportive care only.
CONCLUSIONS
Nafcillin is a safe and effective antibiotic for the treatment of methicillin-susceptible Staphylococcal infections. However, physicians and prescribing healthcare professionals should be aware of the rare, but serious side effects, especially one of drug-induced liver injury with emphasis on the need for early cessation of nafcillin if liver function abnormalities develop.
Introduction
Drug-induced liver injury is a serious side effect of several drugs; studies have shown that antibiotics are the most common drugs associated with drug-induced hepatotoxicity, with amoxicillin-clavulanic acid being the main one. The other two groups that are also known to cause the majority of drug-induced liver injury are nonsteroidal anti-inflammatory drugs (NSAIDS) and isoniazid [1].
Nafcillin is a beta-lactam antibiotic most commonly used for methicillin-susceptible Staphylococcus aureus (MSSA) skin infections. It is also used for the treatment of subacute staphylococcal endocarditis in patients without artificial heart valves [2]. Nafcillin is often prescribed and generally well-tolerated. Drug adverse effects include Clostridioides colitis, oral thrush, and, although uncommon, allergic anaphylaxis [3]. Reports of nafcillin-induced liver injury are rare but serious.
Case presentation
The patient is a 66-year-old white male with a past medical history of a traumatic brain injury with left-sided hemiplegia since childhood, hypertension, leukemia in remission since 2005, and bilateral renal artery stenosis.
The first time the patient presented to the hospital on day one complaining of generalized weakness and malaise of one week duration. Physical exam was significant for right second toe ulcer with mild erythema and purulence. He had tachycardia on presentation. Laboratory values were significant for white blood cells (WBCs) count of 24.0 and C-reactive protein (CRP) of 13.4. The patient was admitted for infected right second toe with concerns of sepsis. He was treated empirically with intravenous vancomycin and piperacillin-tazobactam. Blood cultures from day two grew methicillin-susceptible Staphylococcus aureus (MSSA) and the patient was switched to intravenous nafcillin 2 g every four hours (12g/day) on day three. Repeat blood cultures on day three grew methicillin-susceptible Staphylococcus aureus (MSSA) and cultures on day seven had no growth. Nafcillin was continued for two weeks following the first negative blood culture. He was discharged to a nursing facility on day 12. He completed 18 days of IV nafcillin on day 21 of his illness.
The patient was re-admitted from the nursing facility on day 20 for a large bloody bowel movement and completed IV nafcillin in the first two days of his second admission. He was worked up appropriately for lower GI bleeding with colonoscopy findings of diverticulosis and recovered with minimal intervention. A liver panel on day 21 was unremarkable: total bilirubin 0.7 mg/dl, alkaline phosphatase (ALK) 60 IU/L, aspartate aminotransferase (AST) 21 U/L, alanine aminotransferase (ALT) 25 U/L.
He was re-admitted for the third time on day 30 of his illness from the nursing home (27 days after IV nafcillin was started and nine days after completion of IV nafcillin) for painless jaundice. Upon re-admission, his labs were remarkable for a cholestasis pattern of liver injury with total bilirubin 6.3 mg/dl (5.6 direct, 0.7 indirect), ALK 506 IU/L, AST 206 U/L, ALT 415 U/L (Figures 1, 2, 3).
Figure 1 Bilirubin level according to hospital day
Figure 2 Alkaline Phosphatase according to hospital day
Figure 3 AST and ALT according to hospital day
AST: aspartate aminotransferase, ALT: alanine aminotransferase
At that time his home medications with potential hepatotoxicity including atorvastatin and doxazosin were held. An ultrasound of the liver and biliary tract showed hepatomegaly with normal liver echogenicity, no mass or fluid collection, patent portal and hepatic veins. It also showed cholelithiasis without sonographic signs of cholecystitis, no intrahepatic or extrahepatic biliary ductal dilation. Further workup for infectious causes of liver injury including viral hepatitis panel for hepatitis A, B, C was negative (hepatitis A IgM antibody, hepatitis C antibody, hepatitis B surface antigen, hepatitis B surface and core antibodies all were non-reactive). A serology panel for autoimmune disorders associated with possible liver injury revealed the patient to be negative for anti-nuclear, anti-mitochondrial, anti-smooth muscle, and anti-centromere antibodies. The patient was coronavirus disease 2019 (COVID-19) negative. He does not drink alcohol, smoke cigarettes, or use any recreational drugs. The remainder of the workup was done to exclude alternative liver pathologies. Serum copper and ceruloplasmin, Epstein-Barr virus (EBV) serology, alpha-1-antitripsin all were negative or unremarkable. Magnetic resonance cholangiopancreatography (MRCP) demonstrated cholelithiasis without choledocholithiasis or bile duct dilation. A percutaneous liver biopsy was obtained on day 30 which demonstrated acute necro-inflammatory liver disease suspicious for drug-induced liver injury (Figures 4, 5, 6).
Figure 4 Liver biopsy histopathological examination
Sections show lobular necrosis and severe portal tract inflammation with a mixed inflammatory infiltrate of neutrophils, eosinophils, lymphocytes and histiocytes. There is mild bile stasis within hepatocytes. There is no steatosis. PAS and PAS-D are negative for cytoplasmic inclusions. Trichrome stain highlights mild periportal fibrosis. Prussian blue stain is negative for iron granules .Reticulin stain shows preserved liver architecture.
Figure 5 Liver biopsy histopathological examination
Figure 6 Liver biopsy histopathological examination
Endoscopic retrograde cholangiopancreatography (ERCP) done on day 33 showed a small amount of biliary sludge that was evacuated after a stent placed in the common bile duct - there was no obstruction or inflammatory changes. A review of prior labs from his previous admission was significant for elevated eosinophil percent on day 25 with 11.7% (normal 1-8%), absolute eosinophil count of 1100 (upper limit of normal is 700) (Figure 7).
Figure 7 Eosinophil percent according to hospital day
After admission, his liver enzymes continued to worsen, with total bilirubin peaked on day 34 with 8.2 mg/dl (7.0 direct, 1.2 indirect), ALK peaked on day 40 with 865 IU/L, AST and ALT both peaked on day 30 with 206 U/L, 415 U/L, respectively (Figures 1, 2, 3). After ERCP, his liver function tests continued to worsen; the first day total bilirubin started to drop (day 37) was four days after ERCP was done. Throughout his hospital stay, the patient was monitored for signs of encephalopathy including asterixis and mental status changes, which he showed none. In addition to that, international normalized ratio (INR)/prothrombin time test (PT) was monitored daily for coagulopathy but his INR/PT remained within normal limits during his hospitalization. His liver panel steadily declined while he remained in the hospital with supportive treatment only. At time of discharge on day 42, liver lab values were total bilirubin 3.0 mg/dl, ALK 710 IU/L, AST 56 U/L, ALT 164 U/L (Figures 1, 2, 3). See Table 1 for normal laboratory reference ranges.
Table 1 Normal laboratory reference ranges in healthy adult.
Lab test Normal Lab value range
Aspartate aminotransferase (AST) (15-41 U/L)
Alanine aminotransferase (ALT) (7-35 U/L)
Alkaline Phosphatase (40-129 IU/L)
Total Bilirubin (0.3-1.2 mg/dl)
Direct Bilirubin (0.1-0.5 mg/dl)
Indirect Bilirubin (0-0.7 mg/dl)
Eosinophil percent (1-8%)
White blood cells count (WBCs) (4.3-10.8 10^3/cmm)
C-reactive protein (CRP) (0-1 mg/dl)
Discussion
Nafcillin is a penicillin antibiotic that is used currently for sensitive staphylococcal infections coverage. Unique about this drug that it is liver excreted through the bile system compared to other antibiotics in the same family (oxacillin and dicloxacillin) [4]. Several cases of nafcillin-induced liver injury have been reported in the literature; some are listed in Table 2 below.
Table 2 Comparison between several case reports of nafcillin-induced hepatotoxicity
Study number/ face of comparison Baseline Liver function tests (LFTs) Reason for Nafcillin use Onset of liver injury Dose Outcome Liver Biopsy Treatment used Day of Peak Pattern of liver injury Eosinophilia Reference
1 Normal Methicillin-susceptible Staphylococcus aureus (MSSA) + blood culture Day 27 Nafcillin 12 g/day Complete resolution Acute necro-inflammatory liver disease Supportive 33 Cholestatic Yes (11.7%) This case
2 Normal Lumbar Osteomyelitis with methicillin-susceptible Staphylococcus aureus (MSSA) Day 28 Nafcillin 12 g/day Complete resolution Findings consistent with cholestatic hepatitis Lactulose and empiric IV N-Acetyl Cystine 27 Cholestatic Yes (20.7%) [5]
3 Normal Great toe osteomyelitis with methicillin-susceptible Staphylococcus aureus (MSSA) Day 15 Nafcillin 12 g/day Patient died Picture of cholestatic liver injury Ursodiol 40 Cholestatic No [2]
4 Normal Culture negative cellulitis Day 5 Nafcillin 12 g/day Complete resolution Findings consistent with cholestatic inflammatory drug reaction Supportive 45 Cholestatic No [6]
5 Not reported Methicillin-susceptible Staphylococcus aureus (MSSA) septic arthritis Week 6 Nafcillin, dose not reported Complete resolution Findings consistent with cholestatic hepatitis Supportive 49-55 Cholestatic Yes (20%) [4]
Nearly all of the listed cases had cholestatic pattern of drug-induced liver injury. In our case as well, the ALK and bilirubin remained elevated out of proportion to the ALT/AST. The patient in our case showed evidence of immune-mediated idiosyncratic liver injury supported by the finding of eosinophilia (Figure 4); other case reports [4,5] also showed evidence of peripheral eosinophilia (Table 2). This also fit the timeline of weeks to months as opposed to the non-immune pattern which usually takes more than six weeks until onset. [7]
The use of prednisone in drug-induced liver injury is poorly supported due to the lack of sufficient evidence supporting severity reduction and the side effects of long-term use outweighing the potential benefits [8]. Recovery of liver injury in most cases of nafcillin-induced idiosyncratic liver injury occurs between four and twelve weeks. All cases listed in Table 2 including our patient showed complete resolution of liver injury with basically supportive treatment except one case ended with the death of the affected patient secondary to fulminant liver failure [2]. Due to the unusual presentation of nafcillin-induced liver injury, liver biopsy was done in all listed cases in Table 2. The findings were similar with evidence of necrosis, infiltration of several inflammatory cells, and changes consistent of fibrosis. These findings are not specific for drug-induced hepatic injury. However, they keep this diagnosis as one of the most likely differential diagnosis.
In this patient, nafcillin use was terminated prior to onset of elevated liver enzymes. A thorough pharmacy evaluation revealed nafcillin to be the biggest recent change to the patient's medication list. Although atorvastatin and doxazosin were also listed on the patient’s medication reconciliation, they were less likely offenders in this scenario. Atorvastatin had been started many years ago with no recent dose changes. Furthermore, case reports of atorvastatin-induced liver injury favor the hepatocellular pattern [9,10], which includes markedly elevated ALT with lower increases in ALK, unlike our patient. Doxazosin-induced liver toxicity is not only exceedingly rare, but poorly supported by the medical literature, especially to the magnitude seen above [3].
Conclusions
Nafcillin is an effective and widely used antibiotic at treating staphylococcal infections that are susceptible to methicillin. However, drug-induced liver injury with nafcillin use should not be taken lightly. When prescribing nafcillin for infection, especially in higher doses, a renal and liver panel ought to be evaluated to gauge for idiosyncratic reactions. The best treatment for nafcillin-induced liver injury is to immediately stop the antibiotic, avoid hepatotoxic drugs, and trend the liver enzymes for recovery. In the future, these patients should not be given nafcillin and penicillinase-resistant penicillins, including dicloxacillin and oxacillin.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | Recovering | ReactionOutcome | CC BY | 33628683 | 19,005,231 | 2021-01-20 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastrointestinal perforation'. | Gastrointestinal Perforation With an Intraluminal Stent and Bevacizumab use in Advanced Metastatic Colorectal Cancer.
Intestinal obstruction is a common acute presentation of advanced rectal cancer, which could be managed with surgical or non-surgical techniques including metallic stenting. Bevacizumab has been gaining popularity in the treatment of advanced colorectal cancer (CRC) in combination with different chemotherapeutic agents, to improve the overall survival rate; however, data regarding the adverse effects of bevacizumab in combination with other treatment modalities have been insufficient. Herein, we present a case of a 37-year-old man diagnosed with advanced rectal cancer with concurrent liver and lung metastases. He was started on Xelox (capecitabine plus oxaliplatin) chemotherapy in combination with bevacizumab for palliative care. He developed an episode of bowel obstruction, which was managed with emergent placement of a metallic stent. Soon after that, the patient presented emergently with signs and symptoms of intestinal perforation. He underwent emergent surgical intervention with stoma creation and a complicated hospital course. Despite the oncological benefits of bevacizumab for treating metastatic CRC, complications can occur resulting in a devastating outcome, with intestinal perforation being the most serious rare complication.
Introduction
Colorectal cancer (CRC) is considered the third most common malignancy worldwide, affecting 1.4 million humans each year. Its wide distribution and natural history make it the fourth leading cause of cancer deaths globally [1].
Rectal cancer represents 35% of the total incidence of CRC in the European Union [2]. Presentations range from asymptomatic, incidental findings to locally advanced and metastatic disease, where complications have already occurred. Studies found that 25% of patients present late in stage 4, 85% of whom initially present with intestinal obstruction that manifests as vomiting, obstipation, or abdominal distention. Management of advanced cases includes a variety of surgical and non-surgical options, which may either be curative or palliative. However, poor overall survival and a survival deficit persist for up to one year after surgical intervention as candidates are usually older and have other comorbidities [3].
One of the acceptable surgical therapeutic options to relieve symptoms of obstruction related to advanced CRC in emergency situations is the Hartmann procedure with colostomy creation. Although this approach has been the gold standard for managing emergency situations over the past two decades, its complications are devastating [4]. Self-expanding metallic stents (SEMS) have gained popularity in the management of distal malignant obstruction, either for palliation or as a bridge to surgery for resectable tumors, allowing relief of the obstruction without stoma formation [5]. Although SEMS have success rates exceeding 90% and mortality rates as low as 1%, the possibility of developing [6] a life-threatening perforation raises the mortality rates to approximately 20%-30% [7], despite an overall perforation incidence of 4% [6].
Bevacizumab (Avastin®), a monoclonal antibody that blocks vascular endothelial growth factor, is an important mediator of tumor angiogenesis [8]. Studies have demonstrated that bevacizumab significantly improves the overall survival in patients with advanced metastatic CRC [9].
A study of patients with advanced CRC who were treated with bevacizumab in combination with chemotherapy and surgical interventions with a total of three years surveillance found that, for all patients who were treated with bevacizumab, most adverse effects were hematological (neutropenia and leukopenia). No severe bevacizumab-related toxicities were noted in this study, including bleeding, gastric-intestinal perforation, and thromboembolism. Despite its oncological benefits, bevacizumab can result in rare complications such as bowel perforation, a life-threatening condition with poor survival and devastating outcomes [10].
Case presentation
A 37-year-old man was diagnosed with advanced rectosigmoid adenocarcinoma with concurrent lung and liver metastasis and received palliative Xelox (capecitabine plus oxaliplatin) chemotherapy in combination with bevacizumab. He presented to the emergency department at King Abdelaziz Hospital in the Kingdom of Saudi Arabia, with symptoms suggestive of intestinal obstruction. He was managed with placement of a metal stent and discharged in a good condition. Three weeks later, a few days after he finished his 7th and last cycle of chemotherapy, he presented to the emergency department again complaining of a two-day history of abdominal pain. Physical examination found a rigid peritonitic abdomen, tachycardia of 110, and blood pressure of 110/60. His lab results were unremarkable, and initial erect and supine abdominal radiographs showed bowel loops distended within normal limits, no air-fluid level, and no free air. His abdominal and pelvic CT scans with intravenous and oral contrast revealed a stent in its proper position with the superior anterior part indenting the anterior rectal wall, which led us to suspect perforation (Figures 1-3). Free fluid with free air was also noted in the sub-hepatic and right pelvic regions.
Figure 1 CT scan of the abdomen demonstrating the rectal stent in its place but intending the anterior rectal wall; note the free air in the abdomen (sagittal view)
Figure 2 CT scan of the abdomen demonstrating the rectal stent in its place but intending the anterior rectal wall; note the free air in the abdomen (axial view)
Figure 3 CT scan of the abdomen demonstrating the rectal stent in its place but intending the anterior rectal wall; note the free air in the abdomen (coronal view)
The patient underwent exploratory laparotomy, which revealed fecal material in the peritoneal cavity. Abdominal exploration showed a perforation at the rectosigmoid junction with the stent exposed (Figure 4). After peritoneal lavage, a loop colostomy was created and a pelvic drain was inserted. The post-operative course was complicated by a pelvic abscess and partial wound dehiscence. Moreover, he developed multiple attacks of rectal bleeding that were controlled through palliative radiotherapy. The total length of hospital stay was two months after which the patient was discharged in a satisfactory condition. Following this admission, he was lost to follow up.
Figure 4 Intraoperative picture of the perforated anterior rectal wall
Discussion
One might expect that combining chemotherapy, bevacizumab, and a self-expanding metal stent would increase the perforation rates. However, the paucity of the literature on this special circumstance limits judgment.
The oncological benefits of bevacizumab in combination with chemotherapy were demonstrated in a phase III trial by Chen et al. [11]. They reported that the addition of bevacizumab to irinotecan/5-fluorouracil/leucovorin as a first-line therapy for metastatic CRC was associated with a significantly increased response rate, progression-free survival, and survival rates.
Multiple studies have demonstrated the risk of perforation in similar conditions, i.e., advanced obstructed rectal cancer combined with metal stent placement, neoadjuvant chemotherapy, and bevacizumab therapy. One study that enrolled all of the patients with advanced CRC who were treated in their institute over an 11-year period, found no significant difference in the incidence of gastrointestinal perforation between the groups that underwent chemotherapy alone and chemotherapy plus bevacizumab, chemotherapy and chemotherapy plus bevacizumab, or chemotherapy alone and no chemotherapy (p = 0.21, p = 0.63, and p = 0.42, respectively) [12].
The predisposing factors that are most commonly suggested for bevacizumab-related perforation are peptic ulcer disease, diverticulitis, chemotherapy-induced colitis, a history of abdominal radiation, and abdominal carcinomatosis have been discussed in many articles as independent risk factors; however, there are no associations that have been sufficiently established [13]. Saif et al. [14] reported that the incidence of bowel perforation tends to be higher in candidates with a recent history of colonoscopy or sigmoidoscopy. None of these factors were present in our case except for the patient having a history of bowel obstruction that was treated with a metal stent three weeks prior to the perforation, which may have posed an additional risk of perforation. However, there have been cases reported of bevacizumab-induced bowel perforation in patients that were treated for non-small cell lung cancer despite the absence of evidence of metastatic spread to the abdomen or other predisposing risks for perforation [15].
As in our case, stenting could be an additional risk for patients on bevacizumab. The European Society of Gastrointestinal Endoscopy (ESGE) clinical guidelines provides strong recommendations for the use of self-expanding metal stents as palliative care for advanced obstructed colon cancer, except for in patients using bevacizumab; however, the evidence to substantiate this recommendation is of low quality [16].
The timing of systemic chemotherapy administration in relation to stent insertion and the number of cycles may influence the risk of perforation; however, this idea has not yet been well established. A study reported that receiving chemotherapy after stent insertion, regardless of bevacizumab use, raises the incidence of perforation to 11% compared to only 6% in patients who received systemic therapy before the procedure, regardless of bevacizumab use [12]. One reasonable explanation for this is that, the different tumor responses to therapies result in a weakened intestinal wall and subsequent erosion of the applied stent; however, despite its occurrence, this concept could not be applied to therapies after stenting and it requires more justifiable explanations [17].
Conclusions
There are multiple modalities that can be used to manage obstructed CRC. For patients treated with bevacizumab, the risk of perforation increases, which should be taken into consideration despite it being a rare complication. Stenting on the other hand carries an additional risk of perforation, not to mention that many possible factors could augment or diminish bevacizumab’s perforation risk. This includes interpersonal differences such as demographics, disease onset and course, histological type, and location. In addition, the different treatment modalities, types of chemotherapeutic agents, timing of administration, and the period separating the last dose from the surgical procedure should be considered; however, the scarcity of these conditions has not yet been made clear. Further studies are required to investigate the different associated factors and their possible contributions to similar conditions.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | BEVACIZUMAB, CAPECITABINE, OXALIPLATIN | DrugsGivenReaction | CC BY | 33628692 | 18,997,006 | 2021-01-21 |
What was the administration route of drug 'CAPECITABINE'? | Gastrointestinal Perforation With an Intraluminal Stent and Bevacizumab use in Advanced Metastatic Colorectal Cancer.
Intestinal obstruction is a common acute presentation of advanced rectal cancer, which could be managed with surgical or non-surgical techniques including metallic stenting. Bevacizumab has been gaining popularity in the treatment of advanced colorectal cancer (CRC) in combination with different chemotherapeutic agents, to improve the overall survival rate; however, data regarding the adverse effects of bevacizumab in combination with other treatment modalities have been insufficient. Herein, we present a case of a 37-year-old man diagnosed with advanced rectal cancer with concurrent liver and lung metastases. He was started on Xelox (capecitabine plus oxaliplatin) chemotherapy in combination with bevacizumab for palliative care. He developed an episode of bowel obstruction, which was managed with emergent placement of a metallic stent. Soon after that, the patient presented emergently with signs and symptoms of intestinal perforation. He underwent emergent surgical intervention with stoma creation and a complicated hospital course. Despite the oncological benefits of bevacizumab for treating metastatic CRC, complications can occur resulting in a devastating outcome, with intestinal perforation being the most serious rare complication.
Introduction
Colorectal cancer (CRC) is considered the third most common malignancy worldwide, affecting 1.4 million humans each year. Its wide distribution and natural history make it the fourth leading cause of cancer deaths globally [1].
Rectal cancer represents 35% of the total incidence of CRC in the European Union [2]. Presentations range from asymptomatic, incidental findings to locally advanced and metastatic disease, where complications have already occurred. Studies found that 25% of patients present late in stage 4, 85% of whom initially present with intestinal obstruction that manifests as vomiting, obstipation, or abdominal distention. Management of advanced cases includes a variety of surgical and non-surgical options, which may either be curative or palliative. However, poor overall survival and a survival deficit persist for up to one year after surgical intervention as candidates are usually older and have other comorbidities [3].
One of the acceptable surgical therapeutic options to relieve symptoms of obstruction related to advanced CRC in emergency situations is the Hartmann procedure with colostomy creation. Although this approach has been the gold standard for managing emergency situations over the past two decades, its complications are devastating [4]. Self-expanding metallic stents (SEMS) have gained popularity in the management of distal malignant obstruction, either for palliation or as a bridge to surgery for resectable tumors, allowing relief of the obstruction without stoma formation [5]. Although SEMS have success rates exceeding 90% and mortality rates as low as 1%, the possibility of developing [6] a life-threatening perforation raises the mortality rates to approximately 20%-30% [7], despite an overall perforation incidence of 4% [6].
Bevacizumab (Avastin®), a monoclonal antibody that blocks vascular endothelial growth factor, is an important mediator of tumor angiogenesis [8]. Studies have demonstrated that bevacizumab significantly improves the overall survival in patients with advanced metastatic CRC [9].
A study of patients with advanced CRC who were treated with bevacizumab in combination with chemotherapy and surgical interventions with a total of three years surveillance found that, for all patients who were treated with bevacizumab, most adverse effects were hematological (neutropenia and leukopenia). No severe bevacizumab-related toxicities were noted in this study, including bleeding, gastric-intestinal perforation, and thromboembolism. Despite its oncological benefits, bevacizumab can result in rare complications such as bowel perforation, a life-threatening condition with poor survival and devastating outcomes [10].
Case presentation
A 37-year-old man was diagnosed with advanced rectosigmoid adenocarcinoma with concurrent lung and liver metastasis and received palliative Xelox (capecitabine plus oxaliplatin) chemotherapy in combination with bevacizumab. He presented to the emergency department at King Abdelaziz Hospital in the Kingdom of Saudi Arabia, with symptoms suggestive of intestinal obstruction. He was managed with placement of a metal stent and discharged in a good condition. Three weeks later, a few days after he finished his 7th and last cycle of chemotherapy, he presented to the emergency department again complaining of a two-day history of abdominal pain. Physical examination found a rigid peritonitic abdomen, tachycardia of 110, and blood pressure of 110/60. His lab results were unremarkable, and initial erect and supine abdominal radiographs showed bowel loops distended within normal limits, no air-fluid level, and no free air. His abdominal and pelvic CT scans with intravenous and oral contrast revealed a stent in its proper position with the superior anterior part indenting the anterior rectal wall, which led us to suspect perforation (Figures 1-3). Free fluid with free air was also noted in the sub-hepatic and right pelvic regions.
Figure 1 CT scan of the abdomen demonstrating the rectal stent in its place but intending the anterior rectal wall; note the free air in the abdomen (sagittal view)
Figure 2 CT scan of the abdomen demonstrating the rectal stent in its place but intending the anterior rectal wall; note the free air in the abdomen (axial view)
Figure 3 CT scan of the abdomen demonstrating the rectal stent in its place but intending the anterior rectal wall; note the free air in the abdomen (coronal view)
The patient underwent exploratory laparotomy, which revealed fecal material in the peritoneal cavity. Abdominal exploration showed a perforation at the rectosigmoid junction with the stent exposed (Figure 4). After peritoneal lavage, a loop colostomy was created and a pelvic drain was inserted. The post-operative course was complicated by a pelvic abscess and partial wound dehiscence. Moreover, he developed multiple attacks of rectal bleeding that were controlled through palliative radiotherapy. The total length of hospital stay was two months after which the patient was discharged in a satisfactory condition. Following this admission, he was lost to follow up.
Figure 4 Intraoperative picture of the perforated anterior rectal wall
Discussion
One might expect that combining chemotherapy, bevacizumab, and a self-expanding metal stent would increase the perforation rates. However, the paucity of the literature on this special circumstance limits judgment.
The oncological benefits of bevacizumab in combination with chemotherapy were demonstrated in a phase III trial by Chen et al. [11]. They reported that the addition of bevacizumab to irinotecan/5-fluorouracil/leucovorin as a first-line therapy for metastatic CRC was associated with a significantly increased response rate, progression-free survival, and survival rates.
Multiple studies have demonstrated the risk of perforation in similar conditions, i.e., advanced obstructed rectal cancer combined with metal stent placement, neoadjuvant chemotherapy, and bevacizumab therapy. One study that enrolled all of the patients with advanced CRC who were treated in their institute over an 11-year period, found no significant difference in the incidence of gastrointestinal perforation between the groups that underwent chemotherapy alone and chemotherapy plus bevacizumab, chemotherapy and chemotherapy plus bevacizumab, or chemotherapy alone and no chemotherapy (p = 0.21, p = 0.63, and p = 0.42, respectively) [12].
The predisposing factors that are most commonly suggested for bevacizumab-related perforation are peptic ulcer disease, diverticulitis, chemotherapy-induced colitis, a history of abdominal radiation, and abdominal carcinomatosis have been discussed in many articles as independent risk factors; however, there are no associations that have been sufficiently established [13]. Saif et al. [14] reported that the incidence of bowel perforation tends to be higher in candidates with a recent history of colonoscopy or sigmoidoscopy. None of these factors were present in our case except for the patient having a history of bowel obstruction that was treated with a metal stent three weeks prior to the perforation, which may have posed an additional risk of perforation. However, there have been cases reported of bevacizumab-induced bowel perforation in patients that were treated for non-small cell lung cancer despite the absence of evidence of metastatic spread to the abdomen or other predisposing risks for perforation [15].
As in our case, stenting could be an additional risk for patients on bevacizumab. The European Society of Gastrointestinal Endoscopy (ESGE) clinical guidelines provides strong recommendations for the use of self-expanding metal stents as palliative care for advanced obstructed colon cancer, except for in patients using bevacizumab; however, the evidence to substantiate this recommendation is of low quality [16].
The timing of systemic chemotherapy administration in relation to stent insertion and the number of cycles may influence the risk of perforation; however, this idea has not yet been well established. A study reported that receiving chemotherapy after stent insertion, regardless of bevacizumab use, raises the incidence of perforation to 11% compared to only 6% in patients who received systemic therapy before the procedure, regardless of bevacizumab use [12]. One reasonable explanation for this is that, the different tumor responses to therapies result in a weakened intestinal wall and subsequent erosion of the applied stent; however, despite its occurrence, this concept could not be applied to therapies after stenting and it requires more justifiable explanations [17].
Conclusions
There are multiple modalities that can be used to manage obstructed CRC. For patients treated with bevacizumab, the risk of perforation increases, which should be taken into consideration despite it being a rare complication. Stenting on the other hand carries an additional risk of perforation, not to mention that many possible factors could augment or diminish bevacizumab’s perforation risk. This includes interpersonal differences such as demographics, disease onset and course, histological type, and location. In addition, the different treatment modalities, types of chemotherapeutic agents, timing of administration, and the period separating the last dose from the surgical procedure should be considered; however, the scarcity of these conditions has not yet been made clear. Further studies are required to investigate the different associated factors and their possible contributions to similar conditions.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | Oral | DrugAdministrationRoute | CC BY | 33628692 | 18,997,006 | 2021-01-21 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diarrhoea'. | Preliminary, Real-world, Multicenter Experience With Omadacycline for Mycobacterium abscessus Infections.
Twelve patients were treated with omadacycline (OMC) as part of a multidrug regimen for Mycobacterium abscessus. The majority of infections were of pulmonary origin (7/12; 58.3%). The median (interquartile range) duration of OMC was 6.2 (4.2-11.0) months. Clinical success occurred in 9/12 (75.0%) patients. Three patients experienced a possible adverse effect while on therapy.
Nontuberculous mycobacteria (NTM) are opportunistic pathogens that are intrinsically resistant to many antimicrobials and lead to significant health care costs, morbidity, and mortality [1]. Specifically, Mycobacterium abscessus complex (composed of the subspecies M. abscessus, M. bolletii, and M. massiliense) is the most drug-resistant and pathogenic of the rapidly growing mycobacteria (RGM) and is very challenging to treat, partly owing to the varying resistance mechanisms between these subspecies (including to macrolides, an important therapeutic for NTM treatment, if susceptible, and also available in an oral formulation) and prolonged treatment durations that are typically expensive [2]. Furthermore, a lack of clinical trials and minimally effective oral therapies lead to variations in how patients are treated and further compromise patient satisfaction, respectively [3]. It is crucial that novel antibiotics with optimal oral bioavailability, minimal adverse effects (AEs), and effectiveness against all subspecies of M. abscessus complex be discovered, developed, and clinically evaluated.
Omadacycline (OMC), a semisynthetic aminomethylcycline within the tetracycline (TCN) class, is available both in intravenous and oral formulations and is Food and Drug Administration (FDA) approved for community-acquired pneumonia and acute bacterial skin and skin structure infections [4]. Recent investigations have shown potent in vitro activity of OMC against drug-resistant M. abscessus complex clinical isolates, with observed minimum inhibitory concentration (MIC)90 values similar to tigecycline (TGC) and eravacycline (ERV; intravenous-only glycylcycline and fluorocycline, respectively, within the TCN class) [5, 6]. However, limited studies have reported patient outcomes of those treated with OMC for M. abscessus infections [7]. The objective of this case series was to describe preliminary real-world experience of OMC for the treatment of M. abscessus infections.
METHODS
This was a multicenter, retrospective, observational case series at 6 geographically distinct medical centers in the United States in which OMC was initiated between January and August 2020. We included individuals aged ≥18 years with ≥1 M. abscessus–positive culture, in the setting of clinical suspicion for either pulmonary or extrapulmonary infection, who received OMC for ≥3 months with ≥3 months of documented NTM follow-up after OMC initiation. Patients were still included if negative circumstances (eg, OMC discontinued due to AE, death) precluded insufficient exposure or duration (<3 months) of OMC continuation and/or follow-up.
Early clinical success was defined as a composite of survival, lack of clinical/radiographic worsening, lack of alteration of OMC therapy due to concerns for treatment failure, lack of microbiologic relapse (if patient has achieved culture conversion or microbiologic clearance and cultures were drawn), and lack of culture persistence for 3 consecutive positive cultures following OMC initiation (if patient has not had at least 2 negative cultures and cultures were drawn), which was evaluated throughout the required follow-up. We also reported intentions for OMC utilization and incidence of AE.
Microbiologic relapse was defined as 2 consecutive cultures positive for the same pathogen isolated from index culture following sputum culture conversion (respiratory) or microbiologic clearance (nonrespiratory). Sputum culture conversion was defined as having at least 3 consecutive negative sputum NTM cultures over 12 months. Microbiologic clearance was defined as having any negative culture following positive index culture (nonrespiratory). The Clinical and Laboratory Standards Institute (CLSI) susceptibility breakpoints were applied, when applicable, for interpretation of MIC values, while the FDA antibacterial susceptibility interpretive criteria were used when information was not available via CLSI [8, 9]. Combination therapy was defined as any antibiotic used in tandem with OMC for ≥28 days. All adverse effects while on OMC were reported, although they could not be fully attributed to OMC due to combination regimens. Descriptive statistics were utilized for analysis using IBM SPSS software, version 26.0 (SPSS, Inc., Chicago, IL, USA).
RESULTS
Overall, 12 patients met inclusion criteria. Four individuals were excluded due to insufficient exposure to OMC (3/4) and/or insufficient duration of follow-up (4/4). Included individuals had a median age (interquartile range [IQR]) of 58 (54–63) years, they had a median body mass index (IQR) of 23.6 (21.1–28.9) kg/m2, 50.0% were female, and 91.7% were Caucasian. Common comorbidities in those with nontuberculous mycobacterial pulmonary disease (NTM-PD) included interstitial lung disease (5/7; 71.4%), chronic obstructive pulmonary disease (2/7; 28.6%), asthma (2/7; 28.6%), and solid organ malignancy and/or acute myeloid leukemia (2/7; 28.6%), while no patients had cystic fibrosis or autoimmune disease. The majority of patients had insurance coverage through private entities (6/12; 50.0%), followed by Medicare (3/12; 25.0%; evaluated due to insurance coverage associated with selection of medications), and were treated with OMC strictly in the outpatient setting (10/12; 83.3%). Of patients included in this analysis, 5/12 (41.7%) had surgical interventions (debridement and/or incision and drainage).
The source of infection was primarily NTM-PD (7/12; 58.3%), followed by bone/joint (2/12; 16.7%). Three other extrapulmonary sites of infection involved an intra-abdominal infection, a skin and soft tissue infection, and an infected intravenous catheter. Of those with NTM-PD, the radiographic pattern was 57.1% (4/7) nodular bronchiectatic and 42.9% (3/7) fibrocavitary. Disseminated infection occurred in 2/12 (16.7%) of patients. The initial M. abscessus isolates were most commonly isolated from expectorated sputum (4/12; 33.3%), wound/tissue (4/12; 33.3%), or induced sputum (1/12; 8.3%). Of all included cases, 7/12 (58.3%) of isolates underwent subspeciation (6/7; 85.7% subspecies M. abscessus, 1/7; 14.3% subspecies M. massiliense). Erm gene genotyping (genes that can express inducible macrolide resistance) was conducted in 9/12 (75.0%) isolates, with functional erm gene detected in 6/9 (66.7%) [2].
Before OMC initiation, antibiotic therapy was administered in 10/12 (83.3%) cases, for a median (IQR) of 4.7 (3.4–12.7) months (these data were calculated based on 11 patients, as data were not available for 1 patient). Mycobacterial cultures were positive at the time of OMC initiation in 6/9 (66.7%) patients for whom this information was known. Only a single isolate underwent MIC determination for OMC, which was 0.5 mcg/mL. However, TIG MICs were reported for 11/12 (91.7%) isolates (range, 0.06–1 mcg/mL; MIC90, 1 mcg/mL). MIC values for other antibiotics are reported in Supplementary Table 1.
The total median duration of OMC (IQR) was 6.2 (4.2–11.0) months, with the median duration of follow-up post-OMC initiation (IQR) being 5.1 (3.4–7.2) months. All patients received ≥2 companion antibiotics, with the most common being amikacin (8/12; 66.7%), imipenem (5/12; 41.7%), linezolid/tedizolid (5/12; 41.7%), azithromycin (4/12; 33.3%), and/or clofazimine (4/12; 33.3%). Interestingly, 2 patients received TIG concomitantly with OMC. Oral therapy was strictly utilized in all cases, with a loading dose of 450 mg once daily on days 1 and 2 used for initiation of therapy in 2/12 (16.7%) patients, while most patients did not receive a loading dose on initiation and received a maintenance dose of 300 mg once daily (10/12; 83.3%).
Clinical success occurred in 9/12 (75.0%) cases. Failures involved 3 cases with radiographic fibrocavitary and nodular bronchiectatic (plus dissemination) sources and skin and soft tissue sources. Other clinical and composite end point characteristics can be found in Table 1. The primary reasons for OMC utilization were related to antimicrobial resistance to previous antibiotic(s) (8/12; 66.7%), previous antibiotic failure (6/12; 50.0%), ease of administration (6/12; 50.0%), and oral bioavailability of OMC (6/12; 50.0%).
Table 1. Clinical Characteristics of Patients Treated With Omadacycline for Various Mycobacterium abscessus Infections
Subject ID Age/Sex/Subspecies/Erm Gene Presence Infection Source (Dissemination) TIG MIC, mg/L Positive Culture When Switched to OMC? Duration of OMC, mo Duration of Follow-up After OMC Initiation, mo Companion Drugs With OMC Number of Negative Cultures After Initiation Were Cultures Actually Drawn to Verify if They Were Negative? Clinical Success Death Persistently Positive Culture Microbiologic Relapse Alteration of OMC Therapy due to Concerns of Failure Clinical/Radiographic Worsening While on OMC
1 59/M/-/yes IAI-multiple abscesses (no) 0.5 Unknown 11.7 11.3 Clofazimine, tedizolid 3 N/A Yes No No No No No
2 57/M/massiliense/- Hip bone/joint + indwelling medical device (no) 1 Unknown 6.3 3.5 Azithromycin, clofazimine 1 N/A Yes No No No No No
3 68/F/-/- Fibrocavitary (no) 0.5 No 8.8 5.5 Azithromycin, tedizolid 0 No Yes No - - No No
4 49/F/abscessus/yes Fibrocavitary (no) 0.12 Yes 20.6 16.2 Amikacin, imipenem 1 N/A Yes No No No No No
5 80/M/abscessus/no Nodular bronchiectatic (no) 0.25 Yes 7.2 6.0 Amikacin, imipenem, linezolid 3 N/A Yes No No No No No
6 57/F/abscessus/yes Fibrocavitary (no) 0.25 Yes 5.4 3.3 Amikacin, clofazimine 0 Yes No No Yes N/A No No
7 63/F/abscessus/no Nodular bronchiectatic (no) 0.12 No 6.0 4.9 Amikacin, azithromycin, imipenem 2 N/A Yes No No No No No
8 53/M/abscessus/yes Nodular bronchiectatic (yes-skin) No Yes 12.0 7.6 Amikacin, imipenem, tigecycline 4 N/A Yes No No No No No
9 26/M/abscessus/yes Foot osteomyelitis (no) 1 Yes 3.3 3.3 Amikacin, meropenem, tigecycline 0 No Yes No - - No No
10 59/F/-/yes SSTI (no) 0.25 Yes 5.4 5.2 Clofazimine, imipenem 3 N/A No No No No No Yes
11 55/F/-/- CLABSI (no) 0.06 No 3.8 3.7 Amikacin, tedizolid 1 N/A Yes No No No No No
12 62/M/-/no Nodular bronchiectatic (yes-skin, liver) 0.06 Unknown 0.6 0.6 (died) Amikacin, azithromycin, linezolid 0 No No Yes - - No Yes
Abbreviations: -, information not available; CLABSI, central line bloodstream infection; IAI, intra-abdominal infection; OMC, omadacycline; SSTI, skin and soft tissue infection; TIG, tigecycline.
Three patients experienced an AE while on therapy. One patient experienced a gastrointestinal AE (nausea/vomiting/diarrhea), and the OMC dose was reduced from 300 mg daily to 150 mg twice daily, with improvement in symptoms. Another patient experienced serum creatinine increase ≥0.5 mg/dL; OMC was temporarily discontinued, and this AE resolved. The third patient experienced AST/ALT elevations >3× the upper limit of normal; OMC was continued, despite these laboratory abnormalities, and the abnormalities resolved.
DISCUSSION
We report the largest real-world, observational, multicenter description of early treatment outcomes for patients treated with OMC for pulmonary and extrapulmonary M. abscessus infections with promising results. Due to the in vitro activity of OMC against M. abscessus and the available oral formulation, it is expected that the medical community would have elevated curiosity about the use of OMC for patients with M. abscessus. Our results show similar (or slightly higher) preliminary results congruent with smaller reports of OMC and with other agent(s) used for M. abscessus infections, both in index and refractory disease [7, 10, 11]. Although the OMC treatment in its entirety was not included (as treatment is still ongoing for the majority of cases), no NTM-treating clinician discontinued OMC due to concerns of failure, with a current median OMC duration of 6.2 months. Furthermore, incidence rates of possible AEs due to OMC were relatively similar to those in the phase 3 trials for OMC and other real-world analyses of novel tetracyclines, despite much longer durations of exposure in this case series [12, 13].
An important therapeutic for NTM infections is macrolides (if susceptible), which are subject to inducible resistance via the erm gene and prolongation of the QTc interval [14]. Importantly, OMC is not impacted by functional erm gene expression and has not been shown to cause clinically significant QTc prolongation. Given the lack of some clinical laboratories performing subspeciation or erm gene detection (highlighted in this analysis with conduction in 58.3% and 75.0%, respectively), OMC could provide a viable oral alternative option for those clinicians and sites without the complete microbiological picture.
Tigecycline and ERV have demonstrated similar in vitro activity against isolates of M. abscessus; however, both antibiotics are only available in intravenous formulations and are dosed twice daily, which is not ideal for prolonged treatment courses, and are associated with significant gastrointestinal AEs. OMC is dosed once daily and has shown fewer gastrointestinal AEs than TIG or ERV (8.3% in this analysis). Importantly, reported MIC90 values of ERV against M. abscessus (1 mcg/mL) are higher than the current FDA breakpoint for Enterobacterales, while reported MIC90 values for OMC against M. abscessus have been reported to be 2-fold lower than their current FDA breakpoint [5, 9].
This report has obvious limitations. First, this was a retrospective, observational case series with a small number of patients and the possibility of selection bias. Inclusion criteria for our analysis required relatively short durations of OMC exposure and follow-up (≥3 months) relative to traditional treatment durations associated with M. abscessus; therefore, although the median duration of OMC was 6.2 months, the duration of OMC exposure as it relates to outcomes may have been inadequate to detect a more (or less) favorable response. We included both pulmonary and extrapulmonary cases of NTM infection, the outcomes of which may be difficult to compare directly based on potential differences in nonpharmacological management (eg, removal of device in extrapulmonary cases). Also, subspeciation and functional erm gene detection were not available in all cases. However, given the rarity of this disease, these data reflect pragmatic outcomes that can be useful for clinicians with limited to no options for M. abscessus treatment, even without the full microbiologic picture. Next, all patients were on ≥2 additional antimicrobials; therefore, analysis of the direct response of OMC is difficult. However, this is also the case with any antimicrobial used within a combination regimen. Given the multicenter analysis of our study and the complexities of performing in vitro susceptibility with novel antimicrobials, we were unable to perform MIC testing for OMC on the majority of the clinical M. abscessus isolates to determine initial susceptibility, and the possibility of development of OMC resistance while on therapy remains.
Despite these limitations, this is the largest real-world observational description reporting the experience of early treatment with OMC for M. abscessus within multiple infectious sites. A ≥3-month follow-up evaluating OMC therapy by NTM-treating clinicians was required for inclusion in this analysis, which is a strength compared with other retrospective observational studies. Also, OMC was studied in some patients who had been treated with numerous antibiotics without success over long intervals of time. Finally, although MICs for OMC were only reported in 8.3% of isolates, MICs for TIG were reported in 91.7% of isolates, and previous reports have shown a high correlation between the 2 antibiotics for M. abscessus [5, 6]. While these early experiences with OMC for M. abscessus are important to document, prospective studies and larger real-world analyses are urgently needed for these difficult-to-treat infections.
Supplementary Data
Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
ofab002_suppl_Supplementary_Table_1 Click here for additional data file.
Acknowledgments
Financial support. This work was supported by an investigator-initiated grant from Paratek Pharmaceuticals.
Potential conflicts of interest. T.M., S.A., C.S., C.H., A.J.W., M.L.B., J.B., T.W.G., A.M.L., I.A., and C.M.-C. have no conflicts of interest to disclose. J.V.P. has been on advisory boards for Insmed, A2N, Paratek Pharmaceuticals, and Cipla Technologies and has spoken for Insmed. M.P.V. has received research funding from Paratek Pharmaceuticals and Cumberland Pharmaceuticals. K.A.C. has received consulting fees from Insmed, Hillrom, Merck, and Microbion, unrelated to the current investigation, and is supported by National Heart, Lung, and Blood Institute K08 HL1139994 and the Burroughs Wellcome Fund Career Award for Medical Scientists. M.J.R. has received funds for research and consulting or participated in speaking bureaus for Allergan, Contrafect, Melinta, Merck, Paratek Pharmaceuticals, Shionogi, Sunovian, and Tetraphase and is partially supported by National Institute of Allergy and Infectious Diseases R01 AI121400. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Author contributions. 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.
Patient consent. This study does not include factors necessitating patient consent. Furthermore, the design of the work has been approved by local ethical committees. | AMIKACIN SULFATE, AZITHROMYCIN ANHYDROUS, LINEZOLID, OMADACYCLINE | DrugsGivenReaction | CC BY-NC-ND | 33628856 | 19,736,721 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hyperkalaemia'. | Preliminary, Real-world, Multicenter Experience With Omadacycline for Mycobacterium abscessus Infections.
Twelve patients were treated with omadacycline (OMC) as part of a multidrug regimen for Mycobacterium abscessus. The majority of infections were of pulmonary origin (7/12; 58.3%). The median (interquartile range) duration of OMC was 6.2 (4.2-11.0) months. Clinical success occurred in 9/12 (75.0%) patients. Three patients experienced a possible adverse effect while on therapy.
Nontuberculous mycobacteria (NTM) are opportunistic pathogens that are intrinsically resistant to many antimicrobials and lead to significant health care costs, morbidity, and mortality [1]. Specifically, Mycobacterium abscessus complex (composed of the subspecies M. abscessus, M. bolletii, and M. massiliense) is the most drug-resistant and pathogenic of the rapidly growing mycobacteria (RGM) and is very challenging to treat, partly owing to the varying resistance mechanisms between these subspecies (including to macrolides, an important therapeutic for NTM treatment, if susceptible, and also available in an oral formulation) and prolonged treatment durations that are typically expensive [2]. Furthermore, a lack of clinical trials and minimally effective oral therapies lead to variations in how patients are treated and further compromise patient satisfaction, respectively [3]. It is crucial that novel antibiotics with optimal oral bioavailability, minimal adverse effects (AEs), and effectiveness against all subspecies of M. abscessus complex be discovered, developed, and clinically evaluated.
Omadacycline (OMC), a semisynthetic aminomethylcycline within the tetracycline (TCN) class, is available both in intravenous and oral formulations and is Food and Drug Administration (FDA) approved for community-acquired pneumonia and acute bacterial skin and skin structure infections [4]. Recent investigations have shown potent in vitro activity of OMC against drug-resistant M. abscessus complex clinical isolates, with observed minimum inhibitory concentration (MIC)90 values similar to tigecycline (TGC) and eravacycline (ERV; intravenous-only glycylcycline and fluorocycline, respectively, within the TCN class) [5, 6]. However, limited studies have reported patient outcomes of those treated with OMC for M. abscessus infections [7]. The objective of this case series was to describe preliminary real-world experience of OMC for the treatment of M. abscessus infections.
METHODS
This was a multicenter, retrospective, observational case series at 6 geographically distinct medical centers in the United States in which OMC was initiated between January and August 2020. We included individuals aged ≥18 years with ≥1 M. abscessus–positive culture, in the setting of clinical suspicion for either pulmonary or extrapulmonary infection, who received OMC for ≥3 months with ≥3 months of documented NTM follow-up after OMC initiation. Patients were still included if negative circumstances (eg, OMC discontinued due to AE, death) precluded insufficient exposure or duration (<3 months) of OMC continuation and/or follow-up.
Early clinical success was defined as a composite of survival, lack of clinical/radiographic worsening, lack of alteration of OMC therapy due to concerns for treatment failure, lack of microbiologic relapse (if patient has achieved culture conversion or microbiologic clearance and cultures were drawn), and lack of culture persistence for 3 consecutive positive cultures following OMC initiation (if patient has not had at least 2 negative cultures and cultures were drawn), which was evaluated throughout the required follow-up. We also reported intentions for OMC utilization and incidence of AE.
Microbiologic relapse was defined as 2 consecutive cultures positive for the same pathogen isolated from index culture following sputum culture conversion (respiratory) or microbiologic clearance (nonrespiratory). Sputum culture conversion was defined as having at least 3 consecutive negative sputum NTM cultures over 12 months. Microbiologic clearance was defined as having any negative culture following positive index culture (nonrespiratory). The Clinical and Laboratory Standards Institute (CLSI) susceptibility breakpoints were applied, when applicable, for interpretation of MIC values, while the FDA antibacterial susceptibility interpretive criteria were used when information was not available via CLSI [8, 9]. Combination therapy was defined as any antibiotic used in tandem with OMC for ≥28 days. All adverse effects while on OMC were reported, although they could not be fully attributed to OMC due to combination regimens. Descriptive statistics were utilized for analysis using IBM SPSS software, version 26.0 (SPSS, Inc., Chicago, IL, USA).
RESULTS
Overall, 12 patients met inclusion criteria. Four individuals were excluded due to insufficient exposure to OMC (3/4) and/or insufficient duration of follow-up (4/4). Included individuals had a median age (interquartile range [IQR]) of 58 (54–63) years, they had a median body mass index (IQR) of 23.6 (21.1–28.9) kg/m2, 50.0% were female, and 91.7% were Caucasian. Common comorbidities in those with nontuberculous mycobacterial pulmonary disease (NTM-PD) included interstitial lung disease (5/7; 71.4%), chronic obstructive pulmonary disease (2/7; 28.6%), asthma (2/7; 28.6%), and solid organ malignancy and/or acute myeloid leukemia (2/7; 28.6%), while no patients had cystic fibrosis or autoimmune disease. The majority of patients had insurance coverage through private entities (6/12; 50.0%), followed by Medicare (3/12; 25.0%; evaluated due to insurance coverage associated with selection of medications), and were treated with OMC strictly in the outpatient setting (10/12; 83.3%). Of patients included in this analysis, 5/12 (41.7%) had surgical interventions (debridement and/or incision and drainage).
The source of infection was primarily NTM-PD (7/12; 58.3%), followed by bone/joint (2/12; 16.7%). Three other extrapulmonary sites of infection involved an intra-abdominal infection, a skin and soft tissue infection, and an infected intravenous catheter. Of those with NTM-PD, the radiographic pattern was 57.1% (4/7) nodular bronchiectatic and 42.9% (3/7) fibrocavitary. Disseminated infection occurred in 2/12 (16.7%) of patients. The initial M. abscessus isolates were most commonly isolated from expectorated sputum (4/12; 33.3%), wound/tissue (4/12; 33.3%), or induced sputum (1/12; 8.3%). Of all included cases, 7/12 (58.3%) of isolates underwent subspeciation (6/7; 85.7% subspecies M. abscessus, 1/7; 14.3% subspecies M. massiliense). Erm gene genotyping (genes that can express inducible macrolide resistance) was conducted in 9/12 (75.0%) isolates, with functional erm gene detected in 6/9 (66.7%) [2].
Before OMC initiation, antibiotic therapy was administered in 10/12 (83.3%) cases, for a median (IQR) of 4.7 (3.4–12.7) months (these data were calculated based on 11 patients, as data were not available for 1 patient). Mycobacterial cultures were positive at the time of OMC initiation in 6/9 (66.7%) patients for whom this information was known. Only a single isolate underwent MIC determination for OMC, which was 0.5 mcg/mL. However, TIG MICs were reported for 11/12 (91.7%) isolates (range, 0.06–1 mcg/mL; MIC90, 1 mcg/mL). MIC values for other antibiotics are reported in Supplementary Table 1.
The total median duration of OMC (IQR) was 6.2 (4.2–11.0) months, with the median duration of follow-up post-OMC initiation (IQR) being 5.1 (3.4–7.2) months. All patients received ≥2 companion antibiotics, with the most common being amikacin (8/12; 66.7%), imipenem (5/12; 41.7%), linezolid/tedizolid (5/12; 41.7%), azithromycin (4/12; 33.3%), and/or clofazimine (4/12; 33.3%). Interestingly, 2 patients received TIG concomitantly with OMC. Oral therapy was strictly utilized in all cases, with a loading dose of 450 mg once daily on days 1 and 2 used for initiation of therapy in 2/12 (16.7%) patients, while most patients did not receive a loading dose on initiation and received a maintenance dose of 300 mg once daily (10/12; 83.3%).
Clinical success occurred in 9/12 (75.0%) cases. Failures involved 3 cases with radiographic fibrocavitary and nodular bronchiectatic (plus dissemination) sources and skin and soft tissue sources. Other clinical and composite end point characteristics can be found in Table 1. The primary reasons for OMC utilization were related to antimicrobial resistance to previous antibiotic(s) (8/12; 66.7%), previous antibiotic failure (6/12; 50.0%), ease of administration (6/12; 50.0%), and oral bioavailability of OMC (6/12; 50.0%).
Table 1. Clinical Characteristics of Patients Treated With Omadacycline for Various Mycobacterium abscessus Infections
Subject ID Age/Sex/Subspecies/Erm Gene Presence Infection Source (Dissemination) TIG MIC, mg/L Positive Culture When Switched to OMC? Duration of OMC, mo Duration of Follow-up After OMC Initiation, mo Companion Drugs With OMC Number of Negative Cultures After Initiation Were Cultures Actually Drawn to Verify if They Were Negative? Clinical Success Death Persistently Positive Culture Microbiologic Relapse Alteration of OMC Therapy due to Concerns of Failure Clinical/Radiographic Worsening While on OMC
1 59/M/-/yes IAI-multiple abscesses (no) 0.5 Unknown 11.7 11.3 Clofazimine, tedizolid 3 N/A Yes No No No No No
2 57/M/massiliense/- Hip bone/joint + indwelling medical device (no) 1 Unknown 6.3 3.5 Azithromycin, clofazimine 1 N/A Yes No No No No No
3 68/F/-/- Fibrocavitary (no) 0.5 No 8.8 5.5 Azithromycin, tedizolid 0 No Yes No - - No No
4 49/F/abscessus/yes Fibrocavitary (no) 0.12 Yes 20.6 16.2 Amikacin, imipenem 1 N/A Yes No No No No No
5 80/M/abscessus/no Nodular bronchiectatic (no) 0.25 Yes 7.2 6.0 Amikacin, imipenem, linezolid 3 N/A Yes No No No No No
6 57/F/abscessus/yes Fibrocavitary (no) 0.25 Yes 5.4 3.3 Amikacin, clofazimine 0 Yes No No Yes N/A No No
7 63/F/abscessus/no Nodular bronchiectatic (no) 0.12 No 6.0 4.9 Amikacin, azithromycin, imipenem 2 N/A Yes No No No No No
8 53/M/abscessus/yes Nodular bronchiectatic (yes-skin) No Yes 12.0 7.6 Amikacin, imipenem, tigecycline 4 N/A Yes No No No No No
9 26/M/abscessus/yes Foot osteomyelitis (no) 1 Yes 3.3 3.3 Amikacin, meropenem, tigecycline 0 No Yes No - - No No
10 59/F/-/yes SSTI (no) 0.25 Yes 5.4 5.2 Clofazimine, imipenem 3 N/A No No No No No Yes
11 55/F/-/- CLABSI (no) 0.06 No 3.8 3.7 Amikacin, tedizolid 1 N/A Yes No No No No No
12 62/M/-/no Nodular bronchiectatic (yes-skin, liver) 0.06 Unknown 0.6 0.6 (died) Amikacin, azithromycin, linezolid 0 No No Yes - - No Yes
Abbreviations: -, information not available; CLABSI, central line bloodstream infection; IAI, intra-abdominal infection; OMC, omadacycline; SSTI, skin and soft tissue infection; TIG, tigecycline.
Three patients experienced an AE while on therapy. One patient experienced a gastrointestinal AE (nausea/vomiting/diarrhea), and the OMC dose was reduced from 300 mg daily to 150 mg twice daily, with improvement in symptoms. Another patient experienced serum creatinine increase ≥0.5 mg/dL; OMC was temporarily discontinued, and this AE resolved. The third patient experienced AST/ALT elevations >3× the upper limit of normal; OMC was continued, despite these laboratory abnormalities, and the abnormalities resolved.
DISCUSSION
We report the largest real-world, observational, multicenter description of early treatment outcomes for patients treated with OMC for pulmonary and extrapulmonary M. abscessus infections with promising results. Due to the in vitro activity of OMC against M. abscessus and the available oral formulation, it is expected that the medical community would have elevated curiosity about the use of OMC for patients with M. abscessus. Our results show similar (or slightly higher) preliminary results congruent with smaller reports of OMC and with other agent(s) used for M. abscessus infections, both in index and refractory disease [7, 10, 11]. Although the OMC treatment in its entirety was not included (as treatment is still ongoing for the majority of cases), no NTM-treating clinician discontinued OMC due to concerns of failure, with a current median OMC duration of 6.2 months. Furthermore, incidence rates of possible AEs due to OMC were relatively similar to those in the phase 3 trials for OMC and other real-world analyses of novel tetracyclines, despite much longer durations of exposure in this case series [12, 13].
An important therapeutic for NTM infections is macrolides (if susceptible), which are subject to inducible resistance via the erm gene and prolongation of the QTc interval [14]. Importantly, OMC is not impacted by functional erm gene expression and has not been shown to cause clinically significant QTc prolongation. Given the lack of some clinical laboratories performing subspeciation or erm gene detection (highlighted in this analysis with conduction in 58.3% and 75.0%, respectively), OMC could provide a viable oral alternative option for those clinicians and sites without the complete microbiological picture.
Tigecycline and ERV have demonstrated similar in vitro activity against isolates of M. abscessus; however, both antibiotics are only available in intravenous formulations and are dosed twice daily, which is not ideal for prolonged treatment courses, and are associated with significant gastrointestinal AEs. OMC is dosed once daily and has shown fewer gastrointestinal AEs than TIG or ERV (8.3% in this analysis). Importantly, reported MIC90 values of ERV against M. abscessus (1 mcg/mL) are higher than the current FDA breakpoint for Enterobacterales, while reported MIC90 values for OMC against M. abscessus have been reported to be 2-fold lower than their current FDA breakpoint [5, 9].
This report has obvious limitations. First, this was a retrospective, observational case series with a small number of patients and the possibility of selection bias. Inclusion criteria for our analysis required relatively short durations of OMC exposure and follow-up (≥3 months) relative to traditional treatment durations associated with M. abscessus; therefore, although the median duration of OMC was 6.2 months, the duration of OMC exposure as it relates to outcomes may have been inadequate to detect a more (or less) favorable response. We included both pulmonary and extrapulmonary cases of NTM infection, the outcomes of which may be difficult to compare directly based on potential differences in nonpharmacological management (eg, removal of device in extrapulmonary cases). Also, subspeciation and functional erm gene detection were not available in all cases. However, given the rarity of this disease, these data reflect pragmatic outcomes that can be useful for clinicians with limited to no options for M. abscessus treatment, even without the full microbiologic picture. Next, all patients were on ≥2 additional antimicrobials; therefore, analysis of the direct response of OMC is difficult. However, this is also the case with any antimicrobial used within a combination regimen. Given the multicenter analysis of our study and the complexities of performing in vitro susceptibility with novel antimicrobials, we were unable to perform MIC testing for OMC on the majority of the clinical M. abscessus isolates to determine initial susceptibility, and the possibility of development of OMC resistance while on therapy remains.
Despite these limitations, this is the largest real-world observational description reporting the experience of early treatment with OMC for M. abscessus within multiple infectious sites. A ≥3-month follow-up evaluating OMC therapy by NTM-treating clinicians was required for inclusion in this analysis, which is a strength compared with other retrospective observational studies. Also, OMC was studied in some patients who had been treated with numerous antibiotics without success over long intervals of time. Finally, although MICs for OMC were only reported in 8.3% of isolates, MICs for TIG were reported in 91.7% of isolates, and previous reports have shown a high correlation between the 2 antibiotics for M. abscessus [5, 6]. While these early experiences with OMC for M. abscessus are important to document, prospective studies and larger real-world analyses are urgently needed for these difficult-to-treat infections.
Supplementary Data
Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
ofab002_suppl_Supplementary_Table_1 Click here for additional data file.
Acknowledgments
Financial support. This work was supported by an investigator-initiated grant from Paratek Pharmaceuticals.
Potential conflicts of interest. T.M., S.A., C.S., C.H., A.J.W., M.L.B., J.B., T.W.G., A.M.L., I.A., and C.M.-C. have no conflicts of interest to disclose. J.V.P. has been on advisory boards for Insmed, A2N, Paratek Pharmaceuticals, and Cipla Technologies and has spoken for Insmed. M.P.V. has received research funding from Paratek Pharmaceuticals and Cumberland Pharmaceuticals. K.A.C. has received consulting fees from Insmed, Hillrom, Merck, and Microbion, unrelated to the current investigation, and is supported by National Heart, Lung, and Blood Institute K08 HL1139994 and the Burroughs Wellcome Fund Career Award for Medical Scientists. M.J.R. has received funds for research and consulting or participated in speaking bureaus for Allergan, Contrafect, Melinta, Merck, Paratek Pharmaceuticals, Shionogi, Sunovian, and Tetraphase and is partially supported by National Institute of Allergy and Infectious Diseases R01 AI121400. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Author contributions. 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.
Patient consent. This study does not include factors necessitating patient consent. Furthermore, the design of the work has been approved by local ethical committees. | AMIKACIN SULFATE, AZITHROMYCIN ANHYDROUS, LINEZOLID, OMADACYCLINE | DrugsGivenReaction | CC BY-NC-ND | 33628856 | 19,736,721 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nausea'. | Preliminary, Real-world, Multicenter Experience With Omadacycline for Mycobacterium abscessus Infections.
Twelve patients were treated with omadacycline (OMC) as part of a multidrug regimen for Mycobacterium abscessus. The majority of infections were of pulmonary origin (7/12; 58.3%). The median (interquartile range) duration of OMC was 6.2 (4.2-11.0) months. Clinical success occurred in 9/12 (75.0%) patients. Three patients experienced a possible adverse effect while on therapy.
Nontuberculous mycobacteria (NTM) are opportunistic pathogens that are intrinsically resistant to many antimicrobials and lead to significant health care costs, morbidity, and mortality [1]. Specifically, Mycobacterium abscessus complex (composed of the subspecies M. abscessus, M. bolletii, and M. massiliense) is the most drug-resistant and pathogenic of the rapidly growing mycobacteria (RGM) and is very challenging to treat, partly owing to the varying resistance mechanisms between these subspecies (including to macrolides, an important therapeutic for NTM treatment, if susceptible, and also available in an oral formulation) and prolonged treatment durations that are typically expensive [2]. Furthermore, a lack of clinical trials and minimally effective oral therapies lead to variations in how patients are treated and further compromise patient satisfaction, respectively [3]. It is crucial that novel antibiotics with optimal oral bioavailability, minimal adverse effects (AEs), and effectiveness against all subspecies of M. abscessus complex be discovered, developed, and clinically evaluated.
Omadacycline (OMC), a semisynthetic aminomethylcycline within the tetracycline (TCN) class, is available both in intravenous and oral formulations and is Food and Drug Administration (FDA) approved for community-acquired pneumonia and acute bacterial skin and skin structure infections [4]. Recent investigations have shown potent in vitro activity of OMC against drug-resistant M. abscessus complex clinical isolates, with observed minimum inhibitory concentration (MIC)90 values similar to tigecycline (TGC) and eravacycline (ERV; intravenous-only glycylcycline and fluorocycline, respectively, within the TCN class) [5, 6]. However, limited studies have reported patient outcomes of those treated with OMC for M. abscessus infections [7]. The objective of this case series was to describe preliminary real-world experience of OMC for the treatment of M. abscessus infections.
METHODS
This was a multicenter, retrospective, observational case series at 6 geographically distinct medical centers in the United States in which OMC was initiated between January and August 2020. We included individuals aged ≥18 years with ≥1 M. abscessus–positive culture, in the setting of clinical suspicion for either pulmonary or extrapulmonary infection, who received OMC for ≥3 months with ≥3 months of documented NTM follow-up after OMC initiation. Patients were still included if negative circumstances (eg, OMC discontinued due to AE, death) precluded insufficient exposure or duration (<3 months) of OMC continuation and/or follow-up.
Early clinical success was defined as a composite of survival, lack of clinical/radiographic worsening, lack of alteration of OMC therapy due to concerns for treatment failure, lack of microbiologic relapse (if patient has achieved culture conversion or microbiologic clearance and cultures were drawn), and lack of culture persistence for 3 consecutive positive cultures following OMC initiation (if patient has not had at least 2 negative cultures and cultures were drawn), which was evaluated throughout the required follow-up. We also reported intentions for OMC utilization and incidence of AE.
Microbiologic relapse was defined as 2 consecutive cultures positive for the same pathogen isolated from index culture following sputum culture conversion (respiratory) or microbiologic clearance (nonrespiratory). Sputum culture conversion was defined as having at least 3 consecutive negative sputum NTM cultures over 12 months. Microbiologic clearance was defined as having any negative culture following positive index culture (nonrespiratory). The Clinical and Laboratory Standards Institute (CLSI) susceptibility breakpoints were applied, when applicable, for interpretation of MIC values, while the FDA antibacterial susceptibility interpretive criteria were used when information was not available via CLSI [8, 9]. Combination therapy was defined as any antibiotic used in tandem with OMC for ≥28 days. All adverse effects while on OMC were reported, although they could not be fully attributed to OMC due to combination regimens. Descriptive statistics were utilized for analysis using IBM SPSS software, version 26.0 (SPSS, Inc., Chicago, IL, USA).
RESULTS
Overall, 12 patients met inclusion criteria. Four individuals were excluded due to insufficient exposure to OMC (3/4) and/or insufficient duration of follow-up (4/4). Included individuals had a median age (interquartile range [IQR]) of 58 (54–63) years, they had a median body mass index (IQR) of 23.6 (21.1–28.9) kg/m2, 50.0% were female, and 91.7% were Caucasian. Common comorbidities in those with nontuberculous mycobacterial pulmonary disease (NTM-PD) included interstitial lung disease (5/7; 71.4%), chronic obstructive pulmonary disease (2/7; 28.6%), asthma (2/7; 28.6%), and solid organ malignancy and/or acute myeloid leukemia (2/7; 28.6%), while no patients had cystic fibrosis or autoimmune disease. The majority of patients had insurance coverage through private entities (6/12; 50.0%), followed by Medicare (3/12; 25.0%; evaluated due to insurance coverage associated with selection of medications), and were treated with OMC strictly in the outpatient setting (10/12; 83.3%). Of patients included in this analysis, 5/12 (41.7%) had surgical interventions (debridement and/or incision and drainage).
The source of infection was primarily NTM-PD (7/12; 58.3%), followed by bone/joint (2/12; 16.7%). Three other extrapulmonary sites of infection involved an intra-abdominal infection, a skin and soft tissue infection, and an infected intravenous catheter. Of those with NTM-PD, the radiographic pattern was 57.1% (4/7) nodular bronchiectatic and 42.9% (3/7) fibrocavitary. Disseminated infection occurred in 2/12 (16.7%) of patients. The initial M. abscessus isolates were most commonly isolated from expectorated sputum (4/12; 33.3%), wound/tissue (4/12; 33.3%), or induced sputum (1/12; 8.3%). Of all included cases, 7/12 (58.3%) of isolates underwent subspeciation (6/7; 85.7% subspecies M. abscessus, 1/7; 14.3% subspecies M. massiliense). Erm gene genotyping (genes that can express inducible macrolide resistance) was conducted in 9/12 (75.0%) isolates, with functional erm gene detected in 6/9 (66.7%) [2].
Before OMC initiation, antibiotic therapy was administered in 10/12 (83.3%) cases, for a median (IQR) of 4.7 (3.4–12.7) months (these data were calculated based on 11 patients, as data were not available for 1 patient). Mycobacterial cultures were positive at the time of OMC initiation in 6/9 (66.7%) patients for whom this information was known. Only a single isolate underwent MIC determination for OMC, which was 0.5 mcg/mL. However, TIG MICs were reported for 11/12 (91.7%) isolates (range, 0.06–1 mcg/mL; MIC90, 1 mcg/mL). MIC values for other antibiotics are reported in Supplementary Table 1.
The total median duration of OMC (IQR) was 6.2 (4.2–11.0) months, with the median duration of follow-up post-OMC initiation (IQR) being 5.1 (3.4–7.2) months. All patients received ≥2 companion antibiotics, with the most common being amikacin (8/12; 66.7%), imipenem (5/12; 41.7%), linezolid/tedizolid (5/12; 41.7%), azithromycin (4/12; 33.3%), and/or clofazimine (4/12; 33.3%). Interestingly, 2 patients received TIG concomitantly with OMC. Oral therapy was strictly utilized in all cases, with a loading dose of 450 mg once daily on days 1 and 2 used for initiation of therapy in 2/12 (16.7%) patients, while most patients did not receive a loading dose on initiation and received a maintenance dose of 300 mg once daily (10/12; 83.3%).
Clinical success occurred in 9/12 (75.0%) cases. Failures involved 3 cases with radiographic fibrocavitary and nodular bronchiectatic (plus dissemination) sources and skin and soft tissue sources. Other clinical and composite end point characteristics can be found in Table 1. The primary reasons for OMC utilization were related to antimicrobial resistance to previous antibiotic(s) (8/12; 66.7%), previous antibiotic failure (6/12; 50.0%), ease of administration (6/12; 50.0%), and oral bioavailability of OMC (6/12; 50.0%).
Table 1. Clinical Characteristics of Patients Treated With Omadacycline for Various Mycobacterium abscessus Infections
Subject ID Age/Sex/Subspecies/Erm Gene Presence Infection Source (Dissemination) TIG MIC, mg/L Positive Culture When Switched to OMC? Duration of OMC, mo Duration of Follow-up After OMC Initiation, mo Companion Drugs With OMC Number of Negative Cultures After Initiation Were Cultures Actually Drawn to Verify if They Were Negative? Clinical Success Death Persistently Positive Culture Microbiologic Relapse Alteration of OMC Therapy due to Concerns of Failure Clinical/Radiographic Worsening While on OMC
1 59/M/-/yes IAI-multiple abscesses (no) 0.5 Unknown 11.7 11.3 Clofazimine, tedizolid 3 N/A Yes No No No No No
2 57/M/massiliense/- Hip bone/joint + indwelling medical device (no) 1 Unknown 6.3 3.5 Azithromycin, clofazimine 1 N/A Yes No No No No No
3 68/F/-/- Fibrocavitary (no) 0.5 No 8.8 5.5 Azithromycin, tedizolid 0 No Yes No - - No No
4 49/F/abscessus/yes Fibrocavitary (no) 0.12 Yes 20.6 16.2 Amikacin, imipenem 1 N/A Yes No No No No No
5 80/M/abscessus/no Nodular bronchiectatic (no) 0.25 Yes 7.2 6.0 Amikacin, imipenem, linezolid 3 N/A Yes No No No No No
6 57/F/abscessus/yes Fibrocavitary (no) 0.25 Yes 5.4 3.3 Amikacin, clofazimine 0 Yes No No Yes N/A No No
7 63/F/abscessus/no Nodular bronchiectatic (no) 0.12 No 6.0 4.9 Amikacin, azithromycin, imipenem 2 N/A Yes No No No No No
8 53/M/abscessus/yes Nodular bronchiectatic (yes-skin) No Yes 12.0 7.6 Amikacin, imipenem, tigecycline 4 N/A Yes No No No No No
9 26/M/abscessus/yes Foot osteomyelitis (no) 1 Yes 3.3 3.3 Amikacin, meropenem, tigecycline 0 No Yes No - - No No
10 59/F/-/yes SSTI (no) 0.25 Yes 5.4 5.2 Clofazimine, imipenem 3 N/A No No No No No Yes
11 55/F/-/- CLABSI (no) 0.06 No 3.8 3.7 Amikacin, tedizolid 1 N/A Yes No No No No No
12 62/M/-/no Nodular bronchiectatic (yes-skin, liver) 0.06 Unknown 0.6 0.6 (died) Amikacin, azithromycin, linezolid 0 No No Yes - - No Yes
Abbreviations: -, information not available; CLABSI, central line bloodstream infection; IAI, intra-abdominal infection; OMC, omadacycline; SSTI, skin and soft tissue infection; TIG, tigecycline.
Three patients experienced an AE while on therapy. One patient experienced a gastrointestinal AE (nausea/vomiting/diarrhea), and the OMC dose was reduced from 300 mg daily to 150 mg twice daily, with improvement in symptoms. Another patient experienced serum creatinine increase ≥0.5 mg/dL; OMC was temporarily discontinued, and this AE resolved. The third patient experienced AST/ALT elevations >3× the upper limit of normal; OMC was continued, despite these laboratory abnormalities, and the abnormalities resolved.
DISCUSSION
We report the largest real-world, observational, multicenter description of early treatment outcomes for patients treated with OMC for pulmonary and extrapulmonary M. abscessus infections with promising results. Due to the in vitro activity of OMC against M. abscessus and the available oral formulation, it is expected that the medical community would have elevated curiosity about the use of OMC for patients with M. abscessus. Our results show similar (or slightly higher) preliminary results congruent with smaller reports of OMC and with other agent(s) used for M. abscessus infections, both in index and refractory disease [7, 10, 11]. Although the OMC treatment in its entirety was not included (as treatment is still ongoing for the majority of cases), no NTM-treating clinician discontinued OMC due to concerns of failure, with a current median OMC duration of 6.2 months. Furthermore, incidence rates of possible AEs due to OMC were relatively similar to those in the phase 3 trials for OMC and other real-world analyses of novel tetracyclines, despite much longer durations of exposure in this case series [12, 13].
An important therapeutic for NTM infections is macrolides (if susceptible), which are subject to inducible resistance via the erm gene and prolongation of the QTc interval [14]. Importantly, OMC is not impacted by functional erm gene expression and has not been shown to cause clinically significant QTc prolongation. Given the lack of some clinical laboratories performing subspeciation or erm gene detection (highlighted in this analysis with conduction in 58.3% and 75.0%, respectively), OMC could provide a viable oral alternative option for those clinicians and sites without the complete microbiological picture.
Tigecycline and ERV have demonstrated similar in vitro activity against isolates of M. abscessus; however, both antibiotics are only available in intravenous formulations and are dosed twice daily, which is not ideal for prolonged treatment courses, and are associated with significant gastrointestinal AEs. OMC is dosed once daily and has shown fewer gastrointestinal AEs than TIG or ERV (8.3% in this analysis). Importantly, reported MIC90 values of ERV against M. abscessus (1 mcg/mL) are higher than the current FDA breakpoint for Enterobacterales, while reported MIC90 values for OMC against M. abscessus have been reported to be 2-fold lower than their current FDA breakpoint [5, 9].
This report has obvious limitations. First, this was a retrospective, observational case series with a small number of patients and the possibility of selection bias. Inclusion criteria for our analysis required relatively short durations of OMC exposure and follow-up (≥3 months) relative to traditional treatment durations associated with M. abscessus; therefore, although the median duration of OMC was 6.2 months, the duration of OMC exposure as it relates to outcomes may have been inadequate to detect a more (or less) favorable response. We included both pulmonary and extrapulmonary cases of NTM infection, the outcomes of which may be difficult to compare directly based on potential differences in nonpharmacological management (eg, removal of device in extrapulmonary cases). Also, subspeciation and functional erm gene detection were not available in all cases. However, given the rarity of this disease, these data reflect pragmatic outcomes that can be useful for clinicians with limited to no options for M. abscessus treatment, even without the full microbiologic picture. Next, all patients were on ≥2 additional antimicrobials; therefore, analysis of the direct response of OMC is difficult. However, this is also the case with any antimicrobial used within a combination regimen. Given the multicenter analysis of our study and the complexities of performing in vitro susceptibility with novel antimicrobials, we were unable to perform MIC testing for OMC on the majority of the clinical M. abscessus isolates to determine initial susceptibility, and the possibility of development of OMC resistance while on therapy remains.
Despite these limitations, this is the largest real-world observational description reporting the experience of early treatment with OMC for M. abscessus within multiple infectious sites. A ≥3-month follow-up evaluating OMC therapy by NTM-treating clinicians was required for inclusion in this analysis, which is a strength compared with other retrospective observational studies. Also, OMC was studied in some patients who had been treated with numerous antibiotics without success over long intervals of time. Finally, although MICs for OMC were only reported in 8.3% of isolates, MICs for TIG were reported in 91.7% of isolates, and previous reports have shown a high correlation between the 2 antibiotics for M. abscessus [5, 6]. While these early experiences with OMC for M. abscessus are important to document, prospective studies and larger real-world analyses are urgently needed for these difficult-to-treat infections.
Supplementary Data
Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
ofab002_suppl_Supplementary_Table_1 Click here for additional data file.
Acknowledgments
Financial support. This work was supported by an investigator-initiated grant from Paratek Pharmaceuticals.
Potential conflicts of interest. T.M., S.A., C.S., C.H., A.J.W., M.L.B., J.B., T.W.G., A.M.L., I.A., and C.M.-C. have no conflicts of interest to disclose. J.V.P. has been on advisory boards for Insmed, A2N, Paratek Pharmaceuticals, and Cipla Technologies and has spoken for Insmed. M.P.V. has received research funding from Paratek Pharmaceuticals and Cumberland Pharmaceuticals. K.A.C. has received consulting fees from Insmed, Hillrom, Merck, and Microbion, unrelated to the current investigation, and is supported by National Heart, Lung, and Blood Institute K08 HL1139994 and the Burroughs Wellcome Fund Career Award for Medical Scientists. M.J.R. has received funds for research and consulting or participated in speaking bureaus for Allergan, Contrafect, Melinta, Merck, Paratek Pharmaceuticals, Shionogi, Sunovian, and Tetraphase and is partially supported by National Institute of Allergy and Infectious Diseases R01 AI121400. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Author contributions. 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.
Patient consent. This study does not include factors necessitating patient consent. Furthermore, the design of the work has been approved by local ethical committees. | AMIKACIN SULFATE, AZITHROMYCIN ANHYDROUS, LINEZOLID, OMADACYCLINE | DrugsGivenReaction | CC BY-NC-ND | 33628856 | 19,736,721 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Preliminary, Real-world, Multicenter Experience With Omadacycline for Mycobacterium abscessus Infections.
Twelve patients were treated with omadacycline (OMC) as part of a multidrug regimen for Mycobacterium abscessus. The majority of infections were of pulmonary origin (7/12; 58.3%). The median (interquartile range) duration of OMC was 6.2 (4.2-11.0) months. Clinical success occurred in 9/12 (75.0%) patients. Three patients experienced a possible adverse effect while on therapy.
Nontuberculous mycobacteria (NTM) are opportunistic pathogens that are intrinsically resistant to many antimicrobials and lead to significant health care costs, morbidity, and mortality [1]. Specifically, Mycobacterium abscessus complex (composed of the subspecies M. abscessus, M. bolletii, and M. massiliense) is the most drug-resistant and pathogenic of the rapidly growing mycobacteria (RGM) and is very challenging to treat, partly owing to the varying resistance mechanisms between these subspecies (including to macrolides, an important therapeutic for NTM treatment, if susceptible, and also available in an oral formulation) and prolonged treatment durations that are typically expensive [2]. Furthermore, a lack of clinical trials and minimally effective oral therapies lead to variations in how patients are treated and further compromise patient satisfaction, respectively [3]. It is crucial that novel antibiotics with optimal oral bioavailability, minimal adverse effects (AEs), and effectiveness against all subspecies of M. abscessus complex be discovered, developed, and clinically evaluated.
Omadacycline (OMC), a semisynthetic aminomethylcycline within the tetracycline (TCN) class, is available both in intravenous and oral formulations and is Food and Drug Administration (FDA) approved for community-acquired pneumonia and acute bacterial skin and skin structure infections [4]. Recent investigations have shown potent in vitro activity of OMC against drug-resistant M. abscessus complex clinical isolates, with observed minimum inhibitory concentration (MIC)90 values similar to tigecycline (TGC) and eravacycline (ERV; intravenous-only glycylcycline and fluorocycline, respectively, within the TCN class) [5, 6]. However, limited studies have reported patient outcomes of those treated with OMC for M. abscessus infections [7]. The objective of this case series was to describe preliminary real-world experience of OMC for the treatment of M. abscessus infections.
METHODS
This was a multicenter, retrospective, observational case series at 6 geographically distinct medical centers in the United States in which OMC was initiated between January and August 2020. We included individuals aged ≥18 years with ≥1 M. abscessus–positive culture, in the setting of clinical suspicion for either pulmonary or extrapulmonary infection, who received OMC for ≥3 months with ≥3 months of documented NTM follow-up after OMC initiation. Patients were still included if negative circumstances (eg, OMC discontinued due to AE, death) precluded insufficient exposure or duration (<3 months) of OMC continuation and/or follow-up.
Early clinical success was defined as a composite of survival, lack of clinical/radiographic worsening, lack of alteration of OMC therapy due to concerns for treatment failure, lack of microbiologic relapse (if patient has achieved culture conversion or microbiologic clearance and cultures were drawn), and lack of culture persistence for 3 consecutive positive cultures following OMC initiation (if patient has not had at least 2 negative cultures and cultures were drawn), which was evaluated throughout the required follow-up. We also reported intentions for OMC utilization and incidence of AE.
Microbiologic relapse was defined as 2 consecutive cultures positive for the same pathogen isolated from index culture following sputum culture conversion (respiratory) or microbiologic clearance (nonrespiratory). Sputum culture conversion was defined as having at least 3 consecutive negative sputum NTM cultures over 12 months. Microbiologic clearance was defined as having any negative culture following positive index culture (nonrespiratory). The Clinical and Laboratory Standards Institute (CLSI) susceptibility breakpoints were applied, when applicable, for interpretation of MIC values, while the FDA antibacterial susceptibility interpretive criteria were used when information was not available via CLSI [8, 9]. Combination therapy was defined as any antibiotic used in tandem with OMC for ≥28 days. All adverse effects while on OMC were reported, although they could not be fully attributed to OMC due to combination regimens. Descriptive statistics were utilized for analysis using IBM SPSS software, version 26.0 (SPSS, Inc., Chicago, IL, USA).
RESULTS
Overall, 12 patients met inclusion criteria. Four individuals were excluded due to insufficient exposure to OMC (3/4) and/or insufficient duration of follow-up (4/4). Included individuals had a median age (interquartile range [IQR]) of 58 (54–63) years, they had a median body mass index (IQR) of 23.6 (21.1–28.9) kg/m2, 50.0% were female, and 91.7% were Caucasian. Common comorbidities in those with nontuberculous mycobacterial pulmonary disease (NTM-PD) included interstitial lung disease (5/7; 71.4%), chronic obstructive pulmonary disease (2/7; 28.6%), asthma (2/7; 28.6%), and solid organ malignancy and/or acute myeloid leukemia (2/7; 28.6%), while no patients had cystic fibrosis or autoimmune disease. The majority of patients had insurance coverage through private entities (6/12; 50.0%), followed by Medicare (3/12; 25.0%; evaluated due to insurance coverage associated with selection of medications), and were treated with OMC strictly in the outpatient setting (10/12; 83.3%). Of patients included in this analysis, 5/12 (41.7%) had surgical interventions (debridement and/or incision and drainage).
The source of infection was primarily NTM-PD (7/12; 58.3%), followed by bone/joint (2/12; 16.7%). Three other extrapulmonary sites of infection involved an intra-abdominal infection, a skin and soft tissue infection, and an infected intravenous catheter. Of those with NTM-PD, the radiographic pattern was 57.1% (4/7) nodular bronchiectatic and 42.9% (3/7) fibrocavitary. Disseminated infection occurred in 2/12 (16.7%) of patients. The initial M. abscessus isolates were most commonly isolated from expectorated sputum (4/12; 33.3%), wound/tissue (4/12; 33.3%), or induced sputum (1/12; 8.3%). Of all included cases, 7/12 (58.3%) of isolates underwent subspeciation (6/7; 85.7% subspecies M. abscessus, 1/7; 14.3% subspecies M. massiliense). Erm gene genotyping (genes that can express inducible macrolide resistance) was conducted in 9/12 (75.0%) isolates, with functional erm gene detected in 6/9 (66.7%) [2].
Before OMC initiation, antibiotic therapy was administered in 10/12 (83.3%) cases, for a median (IQR) of 4.7 (3.4–12.7) months (these data were calculated based on 11 patients, as data were not available for 1 patient). Mycobacterial cultures were positive at the time of OMC initiation in 6/9 (66.7%) patients for whom this information was known. Only a single isolate underwent MIC determination for OMC, which was 0.5 mcg/mL. However, TIG MICs were reported for 11/12 (91.7%) isolates (range, 0.06–1 mcg/mL; MIC90, 1 mcg/mL). MIC values for other antibiotics are reported in Supplementary Table 1.
The total median duration of OMC (IQR) was 6.2 (4.2–11.0) months, with the median duration of follow-up post-OMC initiation (IQR) being 5.1 (3.4–7.2) months. All patients received ≥2 companion antibiotics, with the most common being amikacin (8/12; 66.7%), imipenem (5/12; 41.7%), linezolid/tedizolid (5/12; 41.7%), azithromycin (4/12; 33.3%), and/or clofazimine (4/12; 33.3%). Interestingly, 2 patients received TIG concomitantly with OMC. Oral therapy was strictly utilized in all cases, with a loading dose of 450 mg once daily on days 1 and 2 used for initiation of therapy in 2/12 (16.7%) patients, while most patients did not receive a loading dose on initiation and received a maintenance dose of 300 mg once daily (10/12; 83.3%).
Clinical success occurred in 9/12 (75.0%) cases. Failures involved 3 cases with radiographic fibrocavitary and nodular bronchiectatic (plus dissemination) sources and skin and soft tissue sources. Other clinical and composite end point characteristics can be found in Table 1. The primary reasons for OMC utilization were related to antimicrobial resistance to previous antibiotic(s) (8/12; 66.7%), previous antibiotic failure (6/12; 50.0%), ease of administration (6/12; 50.0%), and oral bioavailability of OMC (6/12; 50.0%).
Table 1. Clinical Characteristics of Patients Treated With Omadacycline for Various Mycobacterium abscessus Infections
Subject ID Age/Sex/Subspecies/Erm Gene Presence Infection Source (Dissemination) TIG MIC, mg/L Positive Culture When Switched to OMC? Duration of OMC, mo Duration of Follow-up After OMC Initiation, mo Companion Drugs With OMC Number of Negative Cultures After Initiation Were Cultures Actually Drawn to Verify if They Were Negative? Clinical Success Death Persistently Positive Culture Microbiologic Relapse Alteration of OMC Therapy due to Concerns of Failure Clinical/Radiographic Worsening While on OMC
1 59/M/-/yes IAI-multiple abscesses (no) 0.5 Unknown 11.7 11.3 Clofazimine, tedizolid 3 N/A Yes No No No No No
2 57/M/massiliense/- Hip bone/joint + indwelling medical device (no) 1 Unknown 6.3 3.5 Azithromycin, clofazimine 1 N/A Yes No No No No No
3 68/F/-/- Fibrocavitary (no) 0.5 No 8.8 5.5 Azithromycin, tedizolid 0 No Yes No - - No No
4 49/F/abscessus/yes Fibrocavitary (no) 0.12 Yes 20.6 16.2 Amikacin, imipenem 1 N/A Yes No No No No No
5 80/M/abscessus/no Nodular bronchiectatic (no) 0.25 Yes 7.2 6.0 Amikacin, imipenem, linezolid 3 N/A Yes No No No No No
6 57/F/abscessus/yes Fibrocavitary (no) 0.25 Yes 5.4 3.3 Amikacin, clofazimine 0 Yes No No Yes N/A No No
7 63/F/abscessus/no Nodular bronchiectatic (no) 0.12 No 6.0 4.9 Amikacin, azithromycin, imipenem 2 N/A Yes No No No No No
8 53/M/abscessus/yes Nodular bronchiectatic (yes-skin) No Yes 12.0 7.6 Amikacin, imipenem, tigecycline 4 N/A Yes No No No No No
9 26/M/abscessus/yes Foot osteomyelitis (no) 1 Yes 3.3 3.3 Amikacin, meropenem, tigecycline 0 No Yes No - - No No
10 59/F/-/yes SSTI (no) 0.25 Yes 5.4 5.2 Clofazimine, imipenem 3 N/A No No No No No Yes
11 55/F/-/- CLABSI (no) 0.06 No 3.8 3.7 Amikacin, tedizolid 1 N/A Yes No No No No No
12 62/M/-/no Nodular bronchiectatic (yes-skin, liver) 0.06 Unknown 0.6 0.6 (died) Amikacin, azithromycin, linezolid 0 No No Yes - - No Yes
Abbreviations: -, information not available; CLABSI, central line bloodstream infection; IAI, intra-abdominal infection; OMC, omadacycline; SSTI, skin and soft tissue infection; TIG, tigecycline.
Three patients experienced an AE while on therapy. One patient experienced a gastrointestinal AE (nausea/vomiting/diarrhea), and the OMC dose was reduced from 300 mg daily to 150 mg twice daily, with improvement in symptoms. Another patient experienced serum creatinine increase ≥0.5 mg/dL; OMC was temporarily discontinued, and this AE resolved. The third patient experienced AST/ALT elevations >3× the upper limit of normal; OMC was continued, despite these laboratory abnormalities, and the abnormalities resolved.
DISCUSSION
We report the largest real-world, observational, multicenter description of early treatment outcomes for patients treated with OMC for pulmonary and extrapulmonary M. abscessus infections with promising results. Due to the in vitro activity of OMC against M. abscessus and the available oral formulation, it is expected that the medical community would have elevated curiosity about the use of OMC for patients with M. abscessus. Our results show similar (or slightly higher) preliminary results congruent with smaller reports of OMC and with other agent(s) used for M. abscessus infections, both in index and refractory disease [7, 10, 11]. Although the OMC treatment in its entirety was not included (as treatment is still ongoing for the majority of cases), no NTM-treating clinician discontinued OMC due to concerns of failure, with a current median OMC duration of 6.2 months. Furthermore, incidence rates of possible AEs due to OMC were relatively similar to those in the phase 3 trials for OMC and other real-world analyses of novel tetracyclines, despite much longer durations of exposure in this case series [12, 13].
An important therapeutic for NTM infections is macrolides (if susceptible), which are subject to inducible resistance via the erm gene and prolongation of the QTc interval [14]. Importantly, OMC is not impacted by functional erm gene expression and has not been shown to cause clinically significant QTc prolongation. Given the lack of some clinical laboratories performing subspeciation or erm gene detection (highlighted in this analysis with conduction in 58.3% and 75.0%, respectively), OMC could provide a viable oral alternative option for those clinicians and sites without the complete microbiological picture.
Tigecycline and ERV have demonstrated similar in vitro activity against isolates of M. abscessus; however, both antibiotics are only available in intravenous formulations and are dosed twice daily, which is not ideal for prolonged treatment courses, and are associated with significant gastrointestinal AEs. OMC is dosed once daily and has shown fewer gastrointestinal AEs than TIG or ERV (8.3% in this analysis). Importantly, reported MIC90 values of ERV against M. abscessus (1 mcg/mL) are higher than the current FDA breakpoint for Enterobacterales, while reported MIC90 values for OMC against M. abscessus have been reported to be 2-fold lower than their current FDA breakpoint [5, 9].
This report has obvious limitations. First, this was a retrospective, observational case series with a small number of patients and the possibility of selection bias. Inclusion criteria for our analysis required relatively short durations of OMC exposure and follow-up (≥3 months) relative to traditional treatment durations associated with M. abscessus; therefore, although the median duration of OMC was 6.2 months, the duration of OMC exposure as it relates to outcomes may have been inadequate to detect a more (or less) favorable response. We included both pulmonary and extrapulmonary cases of NTM infection, the outcomes of which may be difficult to compare directly based on potential differences in nonpharmacological management (eg, removal of device in extrapulmonary cases). Also, subspeciation and functional erm gene detection were not available in all cases. However, given the rarity of this disease, these data reflect pragmatic outcomes that can be useful for clinicians with limited to no options for M. abscessus treatment, even without the full microbiologic picture. Next, all patients were on ≥2 additional antimicrobials; therefore, analysis of the direct response of OMC is difficult. However, this is also the case with any antimicrobial used within a combination regimen. Given the multicenter analysis of our study and the complexities of performing in vitro susceptibility with novel antimicrobials, we were unable to perform MIC testing for OMC on the majority of the clinical M. abscessus isolates to determine initial susceptibility, and the possibility of development of OMC resistance while on therapy remains.
Despite these limitations, this is the largest real-world observational description reporting the experience of early treatment with OMC for M. abscessus within multiple infectious sites. A ≥3-month follow-up evaluating OMC therapy by NTM-treating clinicians was required for inclusion in this analysis, which is a strength compared with other retrospective observational studies. Also, OMC was studied in some patients who had been treated with numerous antibiotics without success over long intervals of time. Finally, although MICs for OMC were only reported in 8.3% of isolates, MICs for TIG were reported in 91.7% of isolates, and previous reports have shown a high correlation between the 2 antibiotics for M. abscessus [5, 6]. While these early experiences with OMC for M. abscessus are important to document, prospective studies and larger real-world analyses are urgently needed for these difficult-to-treat infections.
Supplementary Data
Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
ofab002_suppl_Supplementary_Table_1 Click here for additional data file.
Acknowledgments
Financial support. This work was supported by an investigator-initiated grant from Paratek Pharmaceuticals.
Potential conflicts of interest. T.M., S.A., C.S., C.H., A.J.W., M.L.B., J.B., T.W.G., A.M.L., I.A., and C.M.-C. have no conflicts of interest to disclose. J.V.P. has been on advisory boards for Insmed, A2N, Paratek Pharmaceuticals, and Cipla Technologies and has spoken for Insmed. M.P.V. has received research funding from Paratek Pharmaceuticals and Cumberland Pharmaceuticals. K.A.C. has received consulting fees from Insmed, Hillrom, Merck, and Microbion, unrelated to the current investigation, and is supported by National Heart, Lung, and Blood Institute K08 HL1139994 and the Burroughs Wellcome Fund Career Award for Medical Scientists. M.J.R. has received funds for research and consulting or participated in speaking bureaus for Allergan, Contrafect, Melinta, Merck, Paratek Pharmaceuticals, Shionogi, Sunovian, and Tetraphase and is partially supported by National Institute of Allergy and Infectious Diseases R01 AI121400. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Author contributions. 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.
Patient consent. This study does not include factors necessitating patient consent. Furthermore, the design of the work has been approved by local ethical committees. | AMIKACIN SULFATE, AZITHROMYCIN ANHYDROUS, LINEZOLID, OMADACYCLINE | DrugsGivenReaction | CC BY-NC-ND | 33628856 | 19,736,721 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Treatment failure'. | Preliminary, Real-world, Multicenter Experience With Omadacycline for Mycobacterium abscessus Infections.
Twelve patients were treated with omadacycline (OMC) as part of a multidrug regimen for Mycobacterium abscessus. The majority of infections were of pulmonary origin (7/12; 58.3%). The median (interquartile range) duration of OMC was 6.2 (4.2-11.0) months. Clinical success occurred in 9/12 (75.0%) patients. Three patients experienced a possible adverse effect while on therapy.
Nontuberculous mycobacteria (NTM) are opportunistic pathogens that are intrinsically resistant to many antimicrobials and lead to significant health care costs, morbidity, and mortality [1]. Specifically, Mycobacterium abscessus complex (composed of the subspecies M. abscessus, M. bolletii, and M. massiliense) is the most drug-resistant and pathogenic of the rapidly growing mycobacteria (RGM) and is very challenging to treat, partly owing to the varying resistance mechanisms between these subspecies (including to macrolides, an important therapeutic for NTM treatment, if susceptible, and also available in an oral formulation) and prolonged treatment durations that are typically expensive [2]. Furthermore, a lack of clinical trials and minimally effective oral therapies lead to variations in how patients are treated and further compromise patient satisfaction, respectively [3]. It is crucial that novel antibiotics with optimal oral bioavailability, minimal adverse effects (AEs), and effectiveness against all subspecies of M. abscessus complex be discovered, developed, and clinically evaluated.
Omadacycline (OMC), a semisynthetic aminomethylcycline within the tetracycline (TCN) class, is available both in intravenous and oral formulations and is Food and Drug Administration (FDA) approved for community-acquired pneumonia and acute bacterial skin and skin structure infections [4]. Recent investigations have shown potent in vitro activity of OMC against drug-resistant M. abscessus complex clinical isolates, with observed minimum inhibitory concentration (MIC)90 values similar to tigecycline (TGC) and eravacycline (ERV; intravenous-only glycylcycline and fluorocycline, respectively, within the TCN class) [5, 6]. However, limited studies have reported patient outcomes of those treated with OMC for M. abscessus infections [7]. The objective of this case series was to describe preliminary real-world experience of OMC for the treatment of M. abscessus infections.
METHODS
This was a multicenter, retrospective, observational case series at 6 geographically distinct medical centers in the United States in which OMC was initiated between January and August 2020. We included individuals aged ≥18 years with ≥1 M. abscessus–positive culture, in the setting of clinical suspicion for either pulmonary or extrapulmonary infection, who received OMC for ≥3 months with ≥3 months of documented NTM follow-up after OMC initiation. Patients were still included if negative circumstances (eg, OMC discontinued due to AE, death) precluded insufficient exposure or duration (<3 months) of OMC continuation and/or follow-up.
Early clinical success was defined as a composite of survival, lack of clinical/radiographic worsening, lack of alteration of OMC therapy due to concerns for treatment failure, lack of microbiologic relapse (if patient has achieved culture conversion or microbiologic clearance and cultures were drawn), and lack of culture persistence for 3 consecutive positive cultures following OMC initiation (if patient has not had at least 2 negative cultures and cultures were drawn), which was evaluated throughout the required follow-up. We also reported intentions for OMC utilization and incidence of AE.
Microbiologic relapse was defined as 2 consecutive cultures positive for the same pathogen isolated from index culture following sputum culture conversion (respiratory) or microbiologic clearance (nonrespiratory). Sputum culture conversion was defined as having at least 3 consecutive negative sputum NTM cultures over 12 months. Microbiologic clearance was defined as having any negative culture following positive index culture (nonrespiratory). The Clinical and Laboratory Standards Institute (CLSI) susceptibility breakpoints were applied, when applicable, for interpretation of MIC values, while the FDA antibacterial susceptibility interpretive criteria were used when information was not available via CLSI [8, 9]. Combination therapy was defined as any antibiotic used in tandem with OMC for ≥28 days. All adverse effects while on OMC were reported, although they could not be fully attributed to OMC due to combination regimens. Descriptive statistics were utilized for analysis using IBM SPSS software, version 26.0 (SPSS, Inc., Chicago, IL, USA).
RESULTS
Overall, 12 patients met inclusion criteria. Four individuals were excluded due to insufficient exposure to OMC (3/4) and/or insufficient duration of follow-up (4/4). Included individuals had a median age (interquartile range [IQR]) of 58 (54–63) years, they had a median body mass index (IQR) of 23.6 (21.1–28.9) kg/m2, 50.0% were female, and 91.7% were Caucasian. Common comorbidities in those with nontuberculous mycobacterial pulmonary disease (NTM-PD) included interstitial lung disease (5/7; 71.4%), chronic obstructive pulmonary disease (2/7; 28.6%), asthma (2/7; 28.6%), and solid organ malignancy and/or acute myeloid leukemia (2/7; 28.6%), while no patients had cystic fibrosis or autoimmune disease. The majority of patients had insurance coverage through private entities (6/12; 50.0%), followed by Medicare (3/12; 25.0%; evaluated due to insurance coverage associated with selection of medications), and were treated with OMC strictly in the outpatient setting (10/12; 83.3%). Of patients included in this analysis, 5/12 (41.7%) had surgical interventions (debridement and/or incision and drainage).
The source of infection was primarily NTM-PD (7/12; 58.3%), followed by bone/joint (2/12; 16.7%). Three other extrapulmonary sites of infection involved an intra-abdominal infection, a skin and soft tissue infection, and an infected intravenous catheter. Of those with NTM-PD, the radiographic pattern was 57.1% (4/7) nodular bronchiectatic and 42.9% (3/7) fibrocavitary. Disseminated infection occurred in 2/12 (16.7%) of patients. The initial M. abscessus isolates were most commonly isolated from expectorated sputum (4/12; 33.3%), wound/tissue (4/12; 33.3%), or induced sputum (1/12; 8.3%). Of all included cases, 7/12 (58.3%) of isolates underwent subspeciation (6/7; 85.7% subspecies M. abscessus, 1/7; 14.3% subspecies M. massiliense). Erm gene genotyping (genes that can express inducible macrolide resistance) was conducted in 9/12 (75.0%) isolates, with functional erm gene detected in 6/9 (66.7%) [2].
Before OMC initiation, antibiotic therapy was administered in 10/12 (83.3%) cases, for a median (IQR) of 4.7 (3.4–12.7) months (these data were calculated based on 11 patients, as data were not available for 1 patient). Mycobacterial cultures were positive at the time of OMC initiation in 6/9 (66.7%) patients for whom this information was known. Only a single isolate underwent MIC determination for OMC, which was 0.5 mcg/mL. However, TIG MICs were reported for 11/12 (91.7%) isolates (range, 0.06–1 mcg/mL; MIC90, 1 mcg/mL). MIC values for other antibiotics are reported in Supplementary Table 1.
The total median duration of OMC (IQR) was 6.2 (4.2–11.0) months, with the median duration of follow-up post-OMC initiation (IQR) being 5.1 (3.4–7.2) months. All patients received ≥2 companion antibiotics, with the most common being amikacin (8/12; 66.7%), imipenem (5/12; 41.7%), linezolid/tedizolid (5/12; 41.7%), azithromycin (4/12; 33.3%), and/or clofazimine (4/12; 33.3%). Interestingly, 2 patients received TIG concomitantly with OMC. Oral therapy was strictly utilized in all cases, with a loading dose of 450 mg once daily on days 1 and 2 used for initiation of therapy in 2/12 (16.7%) patients, while most patients did not receive a loading dose on initiation and received a maintenance dose of 300 mg once daily (10/12; 83.3%).
Clinical success occurred in 9/12 (75.0%) cases. Failures involved 3 cases with radiographic fibrocavitary and nodular bronchiectatic (plus dissemination) sources and skin and soft tissue sources. Other clinical and composite end point characteristics can be found in Table 1. The primary reasons for OMC utilization were related to antimicrobial resistance to previous antibiotic(s) (8/12; 66.7%), previous antibiotic failure (6/12; 50.0%), ease of administration (6/12; 50.0%), and oral bioavailability of OMC (6/12; 50.0%).
Table 1. Clinical Characteristics of Patients Treated With Omadacycline for Various Mycobacterium abscessus Infections
Subject ID Age/Sex/Subspecies/Erm Gene Presence Infection Source (Dissemination) TIG MIC, mg/L Positive Culture When Switched to OMC? Duration of OMC, mo Duration of Follow-up After OMC Initiation, mo Companion Drugs With OMC Number of Negative Cultures After Initiation Were Cultures Actually Drawn to Verify if They Were Negative? Clinical Success Death Persistently Positive Culture Microbiologic Relapse Alteration of OMC Therapy due to Concerns of Failure Clinical/Radiographic Worsening While on OMC
1 59/M/-/yes IAI-multiple abscesses (no) 0.5 Unknown 11.7 11.3 Clofazimine, tedizolid 3 N/A Yes No No No No No
2 57/M/massiliense/- Hip bone/joint + indwelling medical device (no) 1 Unknown 6.3 3.5 Azithromycin, clofazimine 1 N/A Yes No No No No No
3 68/F/-/- Fibrocavitary (no) 0.5 No 8.8 5.5 Azithromycin, tedizolid 0 No Yes No - - No No
4 49/F/abscessus/yes Fibrocavitary (no) 0.12 Yes 20.6 16.2 Amikacin, imipenem 1 N/A Yes No No No No No
5 80/M/abscessus/no Nodular bronchiectatic (no) 0.25 Yes 7.2 6.0 Amikacin, imipenem, linezolid 3 N/A Yes No No No No No
6 57/F/abscessus/yes Fibrocavitary (no) 0.25 Yes 5.4 3.3 Amikacin, clofazimine 0 Yes No No Yes N/A No No
7 63/F/abscessus/no Nodular bronchiectatic (no) 0.12 No 6.0 4.9 Amikacin, azithromycin, imipenem 2 N/A Yes No No No No No
8 53/M/abscessus/yes Nodular bronchiectatic (yes-skin) No Yes 12.0 7.6 Amikacin, imipenem, tigecycline 4 N/A Yes No No No No No
9 26/M/abscessus/yes Foot osteomyelitis (no) 1 Yes 3.3 3.3 Amikacin, meropenem, tigecycline 0 No Yes No - - No No
10 59/F/-/yes SSTI (no) 0.25 Yes 5.4 5.2 Clofazimine, imipenem 3 N/A No No No No No Yes
11 55/F/-/- CLABSI (no) 0.06 No 3.8 3.7 Amikacin, tedizolid 1 N/A Yes No No No No No
12 62/M/-/no Nodular bronchiectatic (yes-skin, liver) 0.06 Unknown 0.6 0.6 (died) Amikacin, azithromycin, linezolid 0 No No Yes - - No Yes
Abbreviations: -, information not available; CLABSI, central line bloodstream infection; IAI, intra-abdominal infection; OMC, omadacycline; SSTI, skin and soft tissue infection; TIG, tigecycline.
Three patients experienced an AE while on therapy. One patient experienced a gastrointestinal AE (nausea/vomiting/diarrhea), and the OMC dose was reduced from 300 mg daily to 150 mg twice daily, with improvement in symptoms. Another patient experienced serum creatinine increase ≥0.5 mg/dL; OMC was temporarily discontinued, and this AE resolved. The third patient experienced AST/ALT elevations >3× the upper limit of normal; OMC was continued, despite these laboratory abnormalities, and the abnormalities resolved.
DISCUSSION
We report the largest real-world, observational, multicenter description of early treatment outcomes for patients treated with OMC for pulmonary and extrapulmonary M. abscessus infections with promising results. Due to the in vitro activity of OMC against M. abscessus and the available oral formulation, it is expected that the medical community would have elevated curiosity about the use of OMC for patients with M. abscessus. Our results show similar (or slightly higher) preliminary results congruent with smaller reports of OMC and with other agent(s) used for M. abscessus infections, both in index and refractory disease [7, 10, 11]. Although the OMC treatment in its entirety was not included (as treatment is still ongoing for the majority of cases), no NTM-treating clinician discontinued OMC due to concerns of failure, with a current median OMC duration of 6.2 months. Furthermore, incidence rates of possible AEs due to OMC were relatively similar to those in the phase 3 trials for OMC and other real-world analyses of novel tetracyclines, despite much longer durations of exposure in this case series [12, 13].
An important therapeutic for NTM infections is macrolides (if susceptible), which are subject to inducible resistance via the erm gene and prolongation of the QTc interval [14]. Importantly, OMC is not impacted by functional erm gene expression and has not been shown to cause clinically significant QTc prolongation. Given the lack of some clinical laboratories performing subspeciation or erm gene detection (highlighted in this analysis with conduction in 58.3% and 75.0%, respectively), OMC could provide a viable oral alternative option for those clinicians and sites without the complete microbiological picture.
Tigecycline and ERV have demonstrated similar in vitro activity against isolates of M. abscessus; however, both antibiotics are only available in intravenous formulations and are dosed twice daily, which is not ideal for prolonged treatment courses, and are associated with significant gastrointestinal AEs. OMC is dosed once daily and has shown fewer gastrointestinal AEs than TIG or ERV (8.3% in this analysis). Importantly, reported MIC90 values of ERV against M. abscessus (1 mcg/mL) are higher than the current FDA breakpoint for Enterobacterales, while reported MIC90 values for OMC against M. abscessus have been reported to be 2-fold lower than their current FDA breakpoint [5, 9].
This report has obvious limitations. First, this was a retrospective, observational case series with a small number of patients and the possibility of selection bias. Inclusion criteria for our analysis required relatively short durations of OMC exposure and follow-up (≥3 months) relative to traditional treatment durations associated with M. abscessus; therefore, although the median duration of OMC was 6.2 months, the duration of OMC exposure as it relates to outcomes may have been inadequate to detect a more (or less) favorable response. We included both pulmonary and extrapulmonary cases of NTM infection, the outcomes of which may be difficult to compare directly based on potential differences in nonpharmacological management (eg, removal of device in extrapulmonary cases). Also, subspeciation and functional erm gene detection were not available in all cases. However, given the rarity of this disease, these data reflect pragmatic outcomes that can be useful for clinicians with limited to no options for M. abscessus treatment, even without the full microbiologic picture. Next, all patients were on ≥2 additional antimicrobials; therefore, analysis of the direct response of OMC is difficult. However, this is also the case with any antimicrobial used within a combination regimen. Given the multicenter analysis of our study and the complexities of performing in vitro susceptibility with novel antimicrobials, we were unable to perform MIC testing for OMC on the majority of the clinical M. abscessus isolates to determine initial susceptibility, and the possibility of development of OMC resistance while on therapy remains.
Despite these limitations, this is the largest real-world observational description reporting the experience of early treatment with OMC for M. abscessus within multiple infectious sites. A ≥3-month follow-up evaluating OMC therapy by NTM-treating clinicians was required for inclusion in this analysis, which is a strength compared with other retrospective observational studies. Also, OMC was studied in some patients who had been treated with numerous antibiotics without success over long intervals of time. Finally, although MICs for OMC were only reported in 8.3% of isolates, MICs for TIG were reported in 91.7% of isolates, and previous reports have shown a high correlation between the 2 antibiotics for M. abscessus [5, 6]. While these early experiences with OMC for M. abscessus are important to document, prospective studies and larger real-world analyses are urgently needed for these difficult-to-treat infections.
Supplementary Data
Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
ofab002_suppl_Supplementary_Table_1 Click here for additional data file.
Acknowledgments
Financial support. This work was supported by an investigator-initiated grant from Paratek Pharmaceuticals.
Potential conflicts of interest. T.M., S.A., C.S., C.H., A.J.W., M.L.B., J.B., T.W.G., A.M.L., I.A., and C.M.-C. have no conflicts of interest to disclose. J.V.P. has been on advisory boards for Insmed, A2N, Paratek Pharmaceuticals, and Cipla Technologies and has spoken for Insmed. M.P.V. has received research funding from Paratek Pharmaceuticals and Cumberland Pharmaceuticals. K.A.C. has received consulting fees from Insmed, Hillrom, Merck, and Microbion, unrelated to the current investigation, and is supported by National Heart, Lung, and Blood Institute K08 HL1139994 and the Burroughs Wellcome Fund Career Award for Medical Scientists. M.J.R. has received funds for research and consulting or participated in speaking bureaus for Allergan, Contrafect, Melinta, Merck, Paratek Pharmaceuticals, Shionogi, Sunovian, and Tetraphase and is partially supported by National Institute of Allergy and Infectious Diseases R01 AI121400. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Author contributions. 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.
Patient consent. This study does not include factors necessitating patient consent. Furthermore, the design of the work has been approved by local ethical committees. | AMIKACIN, AZITHROMYCIN ANHYDROUS, LINEZOLID, OMADACYCLINE | DrugsGivenReaction | CC BY-NC-ND | 33628856 | 19,628,349 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vomiting'. | Preliminary, Real-world, Multicenter Experience With Omadacycline for Mycobacterium abscessus Infections.
Twelve patients were treated with omadacycline (OMC) as part of a multidrug regimen for Mycobacterium abscessus. The majority of infections were of pulmonary origin (7/12; 58.3%). The median (interquartile range) duration of OMC was 6.2 (4.2-11.0) months. Clinical success occurred in 9/12 (75.0%) patients. Three patients experienced a possible adverse effect while on therapy.
Nontuberculous mycobacteria (NTM) are opportunistic pathogens that are intrinsically resistant to many antimicrobials and lead to significant health care costs, morbidity, and mortality [1]. Specifically, Mycobacterium abscessus complex (composed of the subspecies M. abscessus, M. bolletii, and M. massiliense) is the most drug-resistant and pathogenic of the rapidly growing mycobacteria (RGM) and is very challenging to treat, partly owing to the varying resistance mechanisms between these subspecies (including to macrolides, an important therapeutic for NTM treatment, if susceptible, and also available in an oral formulation) and prolonged treatment durations that are typically expensive [2]. Furthermore, a lack of clinical trials and minimally effective oral therapies lead to variations in how patients are treated and further compromise patient satisfaction, respectively [3]. It is crucial that novel antibiotics with optimal oral bioavailability, minimal adverse effects (AEs), and effectiveness against all subspecies of M. abscessus complex be discovered, developed, and clinically evaluated.
Omadacycline (OMC), a semisynthetic aminomethylcycline within the tetracycline (TCN) class, is available both in intravenous and oral formulations and is Food and Drug Administration (FDA) approved for community-acquired pneumonia and acute bacterial skin and skin structure infections [4]. Recent investigations have shown potent in vitro activity of OMC against drug-resistant M. abscessus complex clinical isolates, with observed minimum inhibitory concentration (MIC)90 values similar to tigecycline (TGC) and eravacycline (ERV; intravenous-only glycylcycline and fluorocycline, respectively, within the TCN class) [5, 6]. However, limited studies have reported patient outcomes of those treated with OMC for M. abscessus infections [7]. The objective of this case series was to describe preliminary real-world experience of OMC for the treatment of M. abscessus infections.
METHODS
This was a multicenter, retrospective, observational case series at 6 geographically distinct medical centers in the United States in which OMC was initiated between January and August 2020. We included individuals aged ≥18 years with ≥1 M. abscessus–positive culture, in the setting of clinical suspicion for either pulmonary or extrapulmonary infection, who received OMC for ≥3 months with ≥3 months of documented NTM follow-up after OMC initiation. Patients were still included if negative circumstances (eg, OMC discontinued due to AE, death) precluded insufficient exposure or duration (<3 months) of OMC continuation and/or follow-up.
Early clinical success was defined as a composite of survival, lack of clinical/radiographic worsening, lack of alteration of OMC therapy due to concerns for treatment failure, lack of microbiologic relapse (if patient has achieved culture conversion or microbiologic clearance and cultures were drawn), and lack of culture persistence for 3 consecutive positive cultures following OMC initiation (if patient has not had at least 2 negative cultures and cultures were drawn), which was evaluated throughout the required follow-up. We also reported intentions for OMC utilization and incidence of AE.
Microbiologic relapse was defined as 2 consecutive cultures positive for the same pathogen isolated from index culture following sputum culture conversion (respiratory) or microbiologic clearance (nonrespiratory). Sputum culture conversion was defined as having at least 3 consecutive negative sputum NTM cultures over 12 months. Microbiologic clearance was defined as having any negative culture following positive index culture (nonrespiratory). The Clinical and Laboratory Standards Institute (CLSI) susceptibility breakpoints were applied, when applicable, for interpretation of MIC values, while the FDA antibacterial susceptibility interpretive criteria were used when information was not available via CLSI [8, 9]. Combination therapy was defined as any antibiotic used in tandem with OMC for ≥28 days. All adverse effects while on OMC were reported, although they could not be fully attributed to OMC due to combination regimens. Descriptive statistics were utilized for analysis using IBM SPSS software, version 26.0 (SPSS, Inc., Chicago, IL, USA).
RESULTS
Overall, 12 patients met inclusion criteria. Four individuals were excluded due to insufficient exposure to OMC (3/4) and/or insufficient duration of follow-up (4/4). Included individuals had a median age (interquartile range [IQR]) of 58 (54–63) years, they had a median body mass index (IQR) of 23.6 (21.1–28.9) kg/m2, 50.0% were female, and 91.7% were Caucasian. Common comorbidities in those with nontuberculous mycobacterial pulmonary disease (NTM-PD) included interstitial lung disease (5/7; 71.4%), chronic obstructive pulmonary disease (2/7; 28.6%), asthma (2/7; 28.6%), and solid organ malignancy and/or acute myeloid leukemia (2/7; 28.6%), while no patients had cystic fibrosis or autoimmune disease. The majority of patients had insurance coverage through private entities (6/12; 50.0%), followed by Medicare (3/12; 25.0%; evaluated due to insurance coverage associated with selection of medications), and were treated with OMC strictly in the outpatient setting (10/12; 83.3%). Of patients included in this analysis, 5/12 (41.7%) had surgical interventions (debridement and/or incision and drainage).
The source of infection was primarily NTM-PD (7/12; 58.3%), followed by bone/joint (2/12; 16.7%). Three other extrapulmonary sites of infection involved an intra-abdominal infection, a skin and soft tissue infection, and an infected intravenous catheter. Of those with NTM-PD, the radiographic pattern was 57.1% (4/7) nodular bronchiectatic and 42.9% (3/7) fibrocavitary. Disseminated infection occurred in 2/12 (16.7%) of patients. The initial M. abscessus isolates were most commonly isolated from expectorated sputum (4/12; 33.3%), wound/tissue (4/12; 33.3%), or induced sputum (1/12; 8.3%). Of all included cases, 7/12 (58.3%) of isolates underwent subspeciation (6/7; 85.7% subspecies M. abscessus, 1/7; 14.3% subspecies M. massiliense). Erm gene genotyping (genes that can express inducible macrolide resistance) was conducted in 9/12 (75.0%) isolates, with functional erm gene detected in 6/9 (66.7%) [2].
Before OMC initiation, antibiotic therapy was administered in 10/12 (83.3%) cases, for a median (IQR) of 4.7 (3.4–12.7) months (these data were calculated based on 11 patients, as data were not available for 1 patient). Mycobacterial cultures were positive at the time of OMC initiation in 6/9 (66.7%) patients for whom this information was known. Only a single isolate underwent MIC determination for OMC, which was 0.5 mcg/mL. However, TIG MICs were reported for 11/12 (91.7%) isolates (range, 0.06–1 mcg/mL; MIC90, 1 mcg/mL). MIC values for other antibiotics are reported in Supplementary Table 1.
The total median duration of OMC (IQR) was 6.2 (4.2–11.0) months, with the median duration of follow-up post-OMC initiation (IQR) being 5.1 (3.4–7.2) months. All patients received ≥2 companion antibiotics, with the most common being amikacin (8/12; 66.7%), imipenem (5/12; 41.7%), linezolid/tedizolid (5/12; 41.7%), azithromycin (4/12; 33.3%), and/or clofazimine (4/12; 33.3%). Interestingly, 2 patients received TIG concomitantly with OMC. Oral therapy was strictly utilized in all cases, with a loading dose of 450 mg once daily on days 1 and 2 used for initiation of therapy in 2/12 (16.7%) patients, while most patients did not receive a loading dose on initiation and received a maintenance dose of 300 mg once daily (10/12; 83.3%).
Clinical success occurred in 9/12 (75.0%) cases. Failures involved 3 cases with radiographic fibrocavitary and nodular bronchiectatic (plus dissemination) sources and skin and soft tissue sources. Other clinical and composite end point characteristics can be found in Table 1. The primary reasons for OMC utilization were related to antimicrobial resistance to previous antibiotic(s) (8/12; 66.7%), previous antibiotic failure (6/12; 50.0%), ease of administration (6/12; 50.0%), and oral bioavailability of OMC (6/12; 50.0%).
Table 1. Clinical Characteristics of Patients Treated With Omadacycline for Various Mycobacterium abscessus Infections
Subject ID Age/Sex/Subspecies/Erm Gene Presence Infection Source (Dissemination) TIG MIC, mg/L Positive Culture When Switched to OMC? Duration of OMC, mo Duration of Follow-up After OMC Initiation, mo Companion Drugs With OMC Number of Negative Cultures After Initiation Were Cultures Actually Drawn to Verify if They Were Negative? Clinical Success Death Persistently Positive Culture Microbiologic Relapse Alteration of OMC Therapy due to Concerns of Failure Clinical/Radiographic Worsening While on OMC
1 59/M/-/yes IAI-multiple abscesses (no) 0.5 Unknown 11.7 11.3 Clofazimine, tedizolid 3 N/A Yes No No No No No
2 57/M/massiliense/- Hip bone/joint + indwelling medical device (no) 1 Unknown 6.3 3.5 Azithromycin, clofazimine 1 N/A Yes No No No No No
3 68/F/-/- Fibrocavitary (no) 0.5 No 8.8 5.5 Azithromycin, tedizolid 0 No Yes No - - No No
4 49/F/abscessus/yes Fibrocavitary (no) 0.12 Yes 20.6 16.2 Amikacin, imipenem 1 N/A Yes No No No No No
5 80/M/abscessus/no Nodular bronchiectatic (no) 0.25 Yes 7.2 6.0 Amikacin, imipenem, linezolid 3 N/A Yes No No No No No
6 57/F/abscessus/yes Fibrocavitary (no) 0.25 Yes 5.4 3.3 Amikacin, clofazimine 0 Yes No No Yes N/A No No
7 63/F/abscessus/no Nodular bronchiectatic (no) 0.12 No 6.0 4.9 Amikacin, azithromycin, imipenem 2 N/A Yes No No No No No
8 53/M/abscessus/yes Nodular bronchiectatic (yes-skin) No Yes 12.0 7.6 Amikacin, imipenem, tigecycline 4 N/A Yes No No No No No
9 26/M/abscessus/yes Foot osteomyelitis (no) 1 Yes 3.3 3.3 Amikacin, meropenem, tigecycline 0 No Yes No - - No No
10 59/F/-/yes SSTI (no) 0.25 Yes 5.4 5.2 Clofazimine, imipenem 3 N/A No No No No No Yes
11 55/F/-/- CLABSI (no) 0.06 No 3.8 3.7 Amikacin, tedizolid 1 N/A Yes No No No No No
12 62/M/-/no Nodular bronchiectatic (yes-skin, liver) 0.06 Unknown 0.6 0.6 (died) Amikacin, azithromycin, linezolid 0 No No Yes - - No Yes
Abbreviations: -, information not available; CLABSI, central line bloodstream infection; IAI, intra-abdominal infection; OMC, omadacycline; SSTI, skin and soft tissue infection; TIG, tigecycline.
Three patients experienced an AE while on therapy. One patient experienced a gastrointestinal AE (nausea/vomiting/diarrhea), and the OMC dose was reduced from 300 mg daily to 150 mg twice daily, with improvement in symptoms. Another patient experienced serum creatinine increase ≥0.5 mg/dL; OMC was temporarily discontinued, and this AE resolved. The third patient experienced AST/ALT elevations >3× the upper limit of normal; OMC was continued, despite these laboratory abnormalities, and the abnormalities resolved.
DISCUSSION
We report the largest real-world, observational, multicenter description of early treatment outcomes for patients treated with OMC for pulmonary and extrapulmonary M. abscessus infections with promising results. Due to the in vitro activity of OMC against M. abscessus and the available oral formulation, it is expected that the medical community would have elevated curiosity about the use of OMC for patients with M. abscessus. Our results show similar (or slightly higher) preliminary results congruent with smaller reports of OMC and with other agent(s) used for M. abscessus infections, both in index and refractory disease [7, 10, 11]. Although the OMC treatment in its entirety was not included (as treatment is still ongoing for the majority of cases), no NTM-treating clinician discontinued OMC due to concerns of failure, with a current median OMC duration of 6.2 months. Furthermore, incidence rates of possible AEs due to OMC were relatively similar to those in the phase 3 trials for OMC and other real-world analyses of novel tetracyclines, despite much longer durations of exposure in this case series [12, 13].
An important therapeutic for NTM infections is macrolides (if susceptible), which are subject to inducible resistance via the erm gene and prolongation of the QTc interval [14]. Importantly, OMC is not impacted by functional erm gene expression and has not been shown to cause clinically significant QTc prolongation. Given the lack of some clinical laboratories performing subspeciation or erm gene detection (highlighted in this analysis with conduction in 58.3% and 75.0%, respectively), OMC could provide a viable oral alternative option for those clinicians and sites without the complete microbiological picture.
Tigecycline and ERV have demonstrated similar in vitro activity against isolates of M. abscessus; however, both antibiotics are only available in intravenous formulations and are dosed twice daily, which is not ideal for prolonged treatment courses, and are associated with significant gastrointestinal AEs. OMC is dosed once daily and has shown fewer gastrointestinal AEs than TIG or ERV (8.3% in this analysis). Importantly, reported MIC90 values of ERV against M. abscessus (1 mcg/mL) are higher than the current FDA breakpoint for Enterobacterales, while reported MIC90 values for OMC against M. abscessus have been reported to be 2-fold lower than their current FDA breakpoint [5, 9].
This report has obvious limitations. First, this was a retrospective, observational case series with a small number of patients and the possibility of selection bias. Inclusion criteria for our analysis required relatively short durations of OMC exposure and follow-up (≥3 months) relative to traditional treatment durations associated with M. abscessus; therefore, although the median duration of OMC was 6.2 months, the duration of OMC exposure as it relates to outcomes may have been inadequate to detect a more (or less) favorable response. We included both pulmonary and extrapulmonary cases of NTM infection, the outcomes of which may be difficult to compare directly based on potential differences in nonpharmacological management (eg, removal of device in extrapulmonary cases). Also, subspeciation and functional erm gene detection were not available in all cases. However, given the rarity of this disease, these data reflect pragmatic outcomes that can be useful for clinicians with limited to no options for M. abscessus treatment, even without the full microbiologic picture. Next, all patients were on ≥2 additional antimicrobials; therefore, analysis of the direct response of OMC is difficult. However, this is also the case with any antimicrobial used within a combination regimen. Given the multicenter analysis of our study and the complexities of performing in vitro susceptibility with novel antimicrobials, we were unable to perform MIC testing for OMC on the majority of the clinical M. abscessus isolates to determine initial susceptibility, and the possibility of development of OMC resistance while on therapy remains.
Despite these limitations, this is the largest real-world observational description reporting the experience of early treatment with OMC for M. abscessus within multiple infectious sites. A ≥3-month follow-up evaluating OMC therapy by NTM-treating clinicians was required for inclusion in this analysis, which is a strength compared with other retrospective observational studies. Also, OMC was studied in some patients who had been treated with numerous antibiotics without success over long intervals of time. Finally, although MICs for OMC were only reported in 8.3% of isolates, MICs for TIG were reported in 91.7% of isolates, and previous reports have shown a high correlation between the 2 antibiotics for M. abscessus [5, 6]. While these early experiences with OMC for M. abscessus are important to document, prospective studies and larger real-world analyses are urgently needed for these difficult-to-treat infections.
Supplementary Data
Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
ofab002_suppl_Supplementary_Table_1 Click here for additional data file.
Acknowledgments
Financial support. This work was supported by an investigator-initiated grant from Paratek Pharmaceuticals.
Potential conflicts of interest. T.M., S.A., C.S., C.H., A.J.W., M.L.B., J.B., T.W.G., A.M.L., I.A., and C.M.-C. have no conflicts of interest to disclose. J.V.P. has been on advisory boards for Insmed, A2N, Paratek Pharmaceuticals, and Cipla Technologies and has spoken for Insmed. M.P.V. has received research funding from Paratek Pharmaceuticals and Cumberland Pharmaceuticals. K.A.C. has received consulting fees from Insmed, Hillrom, Merck, and Microbion, unrelated to the current investigation, and is supported by National Heart, Lung, and Blood Institute K08 HL1139994 and the Burroughs Wellcome Fund Career Award for Medical Scientists. M.J.R. has received funds for research and consulting or participated in speaking bureaus for Allergan, Contrafect, Melinta, Merck, Paratek Pharmaceuticals, Shionogi, Sunovian, and Tetraphase and is partially supported by National Institute of Allergy and Infectious Diseases R01 AI121400. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Author contributions. 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.
Patient consent. This study does not include factors necessitating patient consent. Furthermore, the design of the work has been approved by local ethical committees. | AMIKACIN SULFATE, AZITHROMYCIN ANHYDROUS, LINEZOLID, OMADACYCLINE | DrugsGivenReaction | CC BY-NC-ND | 33628856 | 19,736,721 | 2021-02 |
What was the administration route of drug 'OMADACYCLINE'? | Preliminary, Real-world, Multicenter Experience With Omadacycline for Mycobacterium abscessus Infections.
Twelve patients were treated with omadacycline (OMC) as part of a multidrug regimen for Mycobacterium abscessus. The majority of infections were of pulmonary origin (7/12; 58.3%). The median (interquartile range) duration of OMC was 6.2 (4.2-11.0) months. Clinical success occurred in 9/12 (75.0%) patients. Three patients experienced a possible adverse effect while on therapy.
Nontuberculous mycobacteria (NTM) are opportunistic pathogens that are intrinsically resistant to many antimicrobials and lead to significant health care costs, morbidity, and mortality [1]. Specifically, Mycobacterium abscessus complex (composed of the subspecies M. abscessus, M. bolletii, and M. massiliense) is the most drug-resistant and pathogenic of the rapidly growing mycobacteria (RGM) and is very challenging to treat, partly owing to the varying resistance mechanisms between these subspecies (including to macrolides, an important therapeutic for NTM treatment, if susceptible, and also available in an oral formulation) and prolonged treatment durations that are typically expensive [2]. Furthermore, a lack of clinical trials and minimally effective oral therapies lead to variations in how patients are treated and further compromise patient satisfaction, respectively [3]. It is crucial that novel antibiotics with optimal oral bioavailability, minimal adverse effects (AEs), and effectiveness against all subspecies of M. abscessus complex be discovered, developed, and clinically evaluated.
Omadacycline (OMC), a semisynthetic aminomethylcycline within the tetracycline (TCN) class, is available both in intravenous and oral formulations and is Food and Drug Administration (FDA) approved for community-acquired pneumonia and acute bacterial skin and skin structure infections [4]. Recent investigations have shown potent in vitro activity of OMC against drug-resistant M. abscessus complex clinical isolates, with observed minimum inhibitory concentration (MIC)90 values similar to tigecycline (TGC) and eravacycline (ERV; intravenous-only glycylcycline and fluorocycline, respectively, within the TCN class) [5, 6]. However, limited studies have reported patient outcomes of those treated with OMC for M. abscessus infections [7]. The objective of this case series was to describe preliminary real-world experience of OMC for the treatment of M. abscessus infections.
METHODS
This was a multicenter, retrospective, observational case series at 6 geographically distinct medical centers in the United States in which OMC was initiated between January and August 2020. We included individuals aged ≥18 years with ≥1 M. abscessus–positive culture, in the setting of clinical suspicion for either pulmonary or extrapulmonary infection, who received OMC for ≥3 months with ≥3 months of documented NTM follow-up after OMC initiation. Patients were still included if negative circumstances (eg, OMC discontinued due to AE, death) precluded insufficient exposure or duration (<3 months) of OMC continuation and/or follow-up.
Early clinical success was defined as a composite of survival, lack of clinical/radiographic worsening, lack of alteration of OMC therapy due to concerns for treatment failure, lack of microbiologic relapse (if patient has achieved culture conversion or microbiologic clearance and cultures were drawn), and lack of culture persistence for 3 consecutive positive cultures following OMC initiation (if patient has not had at least 2 negative cultures and cultures were drawn), which was evaluated throughout the required follow-up. We also reported intentions for OMC utilization and incidence of AE.
Microbiologic relapse was defined as 2 consecutive cultures positive for the same pathogen isolated from index culture following sputum culture conversion (respiratory) or microbiologic clearance (nonrespiratory). Sputum culture conversion was defined as having at least 3 consecutive negative sputum NTM cultures over 12 months. Microbiologic clearance was defined as having any negative culture following positive index culture (nonrespiratory). The Clinical and Laboratory Standards Institute (CLSI) susceptibility breakpoints were applied, when applicable, for interpretation of MIC values, while the FDA antibacterial susceptibility interpretive criteria were used when information was not available via CLSI [8, 9]. Combination therapy was defined as any antibiotic used in tandem with OMC for ≥28 days. All adverse effects while on OMC were reported, although they could not be fully attributed to OMC due to combination regimens. Descriptive statistics were utilized for analysis using IBM SPSS software, version 26.0 (SPSS, Inc., Chicago, IL, USA).
RESULTS
Overall, 12 patients met inclusion criteria. Four individuals were excluded due to insufficient exposure to OMC (3/4) and/or insufficient duration of follow-up (4/4). Included individuals had a median age (interquartile range [IQR]) of 58 (54–63) years, they had a median body mass index (IQR) of 23.6 (21.1–28.9) kg/m2, 50.0% were female, and 91.7% were Caucasian. Common comorbidities in those with nontuberculous mycobacterial pulmonary disease (NTM-PD) included interstitial lung disease (5/7; 71.4%), chronic obstructive pulmonary disease (2/7; 28.6%), asthma (2/7; 28.6%), and solid organ malignancy and/or acute myeloid leukemia (2/7; 28.6%), while no patients had cystic fibrosis or autoimmune disease. The majority of patients had insurance coverage through private entities (6/12; 50.0%), followed by Medicare (3/12; 25.0%; evaluated due to insurance coverage associated with selection of medications), and were treated with OMC strictly in the outpatient setting (10/12; 83.3%). Of patients included in this analysis, 5/12 (41.7%) had surgical interventions (debridement and/or incision and drainage).
The source of infection was primarily NTM-PD (7/12; 58.3%), followed by bone/joint (2/12; 16.7%). Three other extrapulmonary sites of infection involved an intra-abdominal infection, a skin and soft tissue infection, and an infected intravenous catheter. Of those with NTM-PD, the radiographic pattern was 57.1% (4/7) nodular bronchiectatic and 42.9% (3/7) fibrocavitary. Disseminated infection occurred in 2/12 (16.7%) of patients. The initial M. abscessus isolates were most commonly isolated from expectorated sputum (4/12; 33.3%), wound/tissue (4/12; 33.3%), or induced sputum (1/12; 8.3%). Of all included cases, 7/12 (58.3%) of isolates underwent subspeciation (6/7; 85.7% subspecies M. abscessus, 1/7; 14.3% subspecies M. massiliense). Erm gene genotyping (genes that can express inducible macrolide resistance) was conducted in 9/12 (75.0%) isolates, with functional erm gene detected in 6/9 (66.7%) [2].
Before OMC initiation, antibiotic therapy was administered in 10/12 (83.3%) cases, for a median (IQR) of 4.7 (3.4–12.7) months (these data were calculated based on 11 patients, as data were not available for 1 patient). Mycobacterial cultures were positive at the time of OMC initiation in 6/9 (66.7%) patients for whom this information was known. Only a single isolate underwent MIC determination for OMC, which was 0.5 mcg/mL. However, TIG MICs were reported for 11/12 (91.7%) isolates (range, 0.06–1 mcg/mL; MIC90, 1 mcg/mL). MIC values for other antibiotics are reported in Supplementary Table 1.
The total median duration of OMC (IQR) was 6.2 (4.2–11.0) months, with the median duration of follow-up post-OMC initiation (IQR) being 5.1 (3.4–7.2) months. All patients received ≥2 companion antibiotics, with the most common being amikacin (8/12; 66.7%), imipenem (5/12; 41.7%), linezolid/tedizolid (5/12; 41.7%), azithromycin (4/12; 33.3%), and/or clofazimine (4/12; 33.3%). Interestingly, 2 patients received TIG concomitantly with OMC. Oral therapy was strictly utilized in all cases, with a loading dose of 450 mg once daily on days 1 and 2 used for initiation of therapy in 2/12 (16.7%) patients, while most patients did not receive a loading dose on initiation and received a maintenance dose of 300 mg once daily (10/12; 83.3%).
Clinical success occurred in 9/12 (75.0%) cases. Failures involved 3 cases with radiographic fibrocavitary and nodular bronchiectatic (plus dissemination) sources and skin and soft tissue sources. Other clinical and composite end point characteristics can be found in Table 1. The primary reasons for OMC utilization were related to antimicrobial resistance to previous antibiotic(s) (8/12; 66.7%), previous antibiotic failure (6/12; 50.0%), ease of administration (6/12; 50.0%), and oral bioavailability of OMC (6/12; 50.0%).
Table 1. Clinical Characteristics of Patients Treated With Omadacycline for Various Mycobacterium abscessus Infections
Subject ID Age/Sex/Subspecies/Erm Gene Presence Infection Source (Dissemination) TIG MIC, mg/L Positive Culture When Switched to OMC? Duration of OMC, mo Duration of Follow-up After OMC Initiation, mo Companion Drugs With OMC Number of Negative Cultures After Initiation Were Cultures Actually Drawn to Verify if They Were Negative? Clinical Success Death Persistently Positive Culture Microbiologic Relapse Alteration of OMC Therapy due to Concerns of Failure Clinical/Radiographic Worsening While on OMC
1 59/M/-/yes IAI-multiple abscesses (no) 0.5 Unknown 11.7 11.3 Clofazimine, tedizolid 3 N/A Yes No No No No No
2 57/M/massiliense/- Hip bone/joint + indwelling medical device (no) 1 Unknown 6.3 3.5 Azithromycin, clofazimine 1 N/A Yes No No No No No
3 68/F/-/- Fibrocavitary (no) 0.5 No 8.8 5.5 Azithromycin, tedizolid 0 No Yes No - - No No
4 49/F/abscessus/yes Fibrocavitary (no) 0.12 Yes 20.6 16.2 Amikacin, imipenem 1 N/A Yes No No No No No
5 80/M/abscessus/no Nodular bronchiectatic (no) 0.25 Yes 7.2 6.0 Amikacin, imipenem, linezolid 3 N/A Yes No No No No No
6 57/F/abscessus/yes Fibrocavitary (no) 0.25 Yes 5.4 3.3 Amikacin, clofazimine 0 Yes No No Yes N/A No No
7 63/F/abscessus/no Nodular bronchiectatic (no) 0.12 No 6.0 4.9 Amikacin, azithromycin, imipenem 2 N/A Yes No No No No No
8 53/M/abscessus/yes Nodular bronchiectatic (yes-skin) No Yes 12.0 7.6 Amikacin, imipenem, tigecycline 4 N/A Yes No No No No No
9 26/M/abscessus/yes Foot osteomyelitis (no) 1 Yes 3.3 3.3 Amikacin, meropenem, tigecycline 0 No Yes No - - No No
10 59/F/-/yes SSTI (no) 0.25 Yes 5.4 5.2 Clofazimine, imipenem 3 N/A No No No No No Yes
11 55/F/-/- CLABSI (no) 0.06 No 3.8 3.7 Amikacin, tedizolid 1 N/A Yes No No No No No
12 62/M/-/no Nodular bronchiectatic (yes-skin, liver) 0.06 Unknown 0.6 0.6 (died) Amikacin, azithromycin, linezolid 0 No No Yes - - No Yes
Abbreviations: -, information not available; CLABSI, central line bloodstream infection; IAI, intra-abdominal infection; OMC, omadacycline; SSTI, skin and soft tissue infection; TIG, tigecycline.
Three patients experienced an AE while on therapy. One patient experienced a gastrointestinal AE (nausea/vomiting/diarrhea), and the OMC dose was reduced from 300 mg daily to 150 mg twice daily, with improvement in symptoms. Another patient experienced serum creatinine increase ≥0.5 mg/dL; OMC was temporarily discontinued, and this AE resolved. The third patient experienced AST/ALT elevations >3× the upper limit of normal; OMC was continued, despite these laboratory abnormalities, and the abnormalities resolved.
DISCUSSION
We report the largest real-world, observational, multicenter description of early treatment outcomes for patients treated with OMC for pulmonary and extrapulmonary M. abscessus infections with promising results. Due to the in vitro activity of OMC against M. abscessus and the available oral formulation, it is expected that the medical community would have elevated curiosity about the use of OMC for patients with M. abscessus. Our results show similar (or slightly higher) preliminary results congruent with smaller reports of OMC and with other agent(s) used for M. abscessus infections, both in index and refractory disease [7, 10, 11]. Although the OMC treatment in its entirety was not included (as treatment is still ongoing for the majority of cases), no NTM-treating clinician discontinued OMC due to concerns of failure, with a current median OMC duration of 6.2 months. Furthermore, incidence rates of possible AEs due to OMC were relatively similar to those in the phase 3 trials for OMC and other real-world analyses of novel tetracyclines, despite much longer durations of exposure in this case series [12, 13].
An important therapeutic for NTM infections is macrolides (if susceptible), which are subject to inducible resistance via the erm gene and prolongation of the QTc interval [14]. Importantly, OMC is not impacted by functional erm gene expression and has not been shown to cause clinically significant QTc prolongation. Given the lack of some clinical laboratories performing subspeciation or erm gene detection (highlighted in this analysis with conduction in 58.3% and 75.0%, respectively), OMC could provide a viable oral alternative option for those clinicians and sites without the complete microbiological picture.
Tigecycline and ERV have demonstrated similar in vitro activity against isolates of M. abscessus; however, both antibiotics are only available in intravenous formulations and are dosed twice daily, which is not ideal for prolonged treatment courses, and are associated with significant gastrointestinal AEs. OMC is dosed once daily and has shown fewer gastrointestinal AEs than TIG or ERV (8.3% in this analysis). Importantly, reported MIC90 values of ERV against M. abscessus (1 mcg/mL) are higher than the current FDA breakpoint for Enterobacterales, while reported MIC90 values for OMC against M. abscessus have been reported to be 2-fold lower than their current FDA breakpoint [5, 9].
This report has obvious limitations. First, this was a retrospective, observational case series with a small number of patients and the possibility of selection bias. Inclusion criteria for our analysis required relatively short durations of OMC exposure and follow-up (≥3 months) relative to traditional treatment durations associated with M. abscessus; therefore, although the median duration of OMC was 6.2 months, the duration of OMC exposure as it relates to outcomes may have been inadequate to detect a more (or less) favorable response. We included both pulmonary and extrapulmonary cases of NTM infection, the outcomes of which may be difficult to compare directly based on potential differences in nonpharmacological management (eg, removal of device in extrapulmonary cases). Also, subspeciation and functional erm gene detection were not available in all cases. However, given the rarity of this disease, these data reflect pragmatic outcomes that can be useful for clinicians with limited to no options for M. abscessus treatment, even without the full microbiologic picture. Next, all patients were on ≥2 additional antimicrobials; therefore, analysis of the direct response of OMC is difficult. However, this is also the case with any antimicrobial used within a combination regimen. Given the multicenter analysis of our study and the complexities of performing in vitro susceptibility with novel antimicrobials, we were unable to perform MIC testing for OMC on the majority of the clinical M. abscessus isolates to determine initial susceptibility, and the possibility of development of OMC resistance while on therapy remains.
Despite these limitations, this is the largest real-world observational description reporting the experience of early treatment with OMC for M. abscessus within multiple infectious sites. A ≥3-month follow-up evaluating OMC therapy by NTM-treating clinicians was required for inclusion in this analysis, which is a strength compared with other retrospective observational studies. Also, OMC was studied in some patients who had been treated with numerous antibiotics without success over long intervals of time. Finally, although MICs for OMC were only reported in 8.3% of isolates, MICs for TIG were reported in 91.7% of isolates, and previous reports have shown a high correlation between the 2 antibiotics for M. abscessus [5, 6]. While these early experiences with OMC for M. abscessus are important to document, prospective studies and larger real-world analyses are urgently needed for these difficult-to-treat infections.
Supplementary Data
Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
ofab002_suppl_Supplementary_Table_1 Click here for additional data file.
Acknowledgments
Financial support. This work was supported by an investigator-initiated grant from Paratek Pharmaceuticals.
Potential conflicts of interest. T.M., S.A., C.S., C.H., A.J.W., M.L.B., J.B., T.W.G., A.M.L., I.A., and C.M.-C. have no conflicts of interest to disclose. J.V.P. has been on advisory boards for Insmed, A2N, Paratek Pharmaceuticals, and Cipla Technologies and has spoken for Insmed. M.P.V. has received research funding from Paratek Pharmaceuticals and Cumberland Pharmaceuticals. K.A.C. has received consulting fees from Insmed, Hillrom, Merck, and Microbion, unrelated to the current investigation, and is supported by National Heart, Lung, and Blood Institute K08 HL1139994 and the Burroughs Wellcome Fund Career Award for Medical Scientists. M.J.R. has received funds for research and consulting or participated in speaking bureaus for Allergan, Contrafect, Melinta, Merck, Paratek Pharmaceuticals, Shionogi, Sunovian, and Tetraphase and is partially supported by National Institute of Allergy and Infectious Diseases R01 AI121400. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Author contributions. 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.
Patient consent. This study does not include factors necessitating patient consent. Furthermore, the design of the work has been approved by local ethical committees. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33628856 | 19,628,349 | 2021-02 |
What was the outcome of reaction 'Treatment failure'? | Preliminary, Real-world, Multicenter Experience With Omadacycline for Mycobacterium abscessus Infections.
Twelve patients were treated with omadacycline (OMC) as part of a multidrug regimen for Mycobacterium abscessus. The majority of infections were of pulmonary origin (7/12; 58.3%). The median (interquartile range) duration of OMC was 6.2 (4.2-11.0) months. Clinical success occurred in 9/12 (75.0%) patients. Three patients experienced a possible adverse effect while on therapy.
Nontuberculous mycobacteria (NTM) are opportunistic pathogens that are intrinsically resistant to many antimicrobials and lead to significant health care costs, morbidity, and mortality [1]. Specifically, Mycobacterium abscessus complex (composed of the subspecies M. abscessus, M. bolletii, and M. massiliense) is the most drug-resistant and pathogenic of the rapidly growing mycobacteria (RGM) and is very challenging to treat, partly owing to the varying resistance mechanisms between these subspecies (including to macrolides, an important therapeutic for NTM treatment, if susceptible, and also available in an oral formulation) and prolonged treatment durations that are typically expensive [2]. Furthermore, a lack of clinical trials and minimally effective oral therapies lead to variations in how patients are treated and further compromise patient satisfaction, respectively [3]. It is crucial that novel antibiotics with optimal oral bioavailability, minimal adverse effects (AEs), and effectiveness against all subspecies of M. abscessus complex be discovered, developed, and clinically evaluated.
Omadacycline (OMC), a semisynthetic aminomethylcycline within the tetracycline (TCN) class, is available both in intravenous and oral formulations and is Food and Drug Administration (FDA) approved for community-acquired pneumonia and acute bacterial skin and skin structure infections [4]. Recent investigations have shown potent in vitro activity of OMC against drug-resistant M. abscessus complex clinical isolates, with observed minimum inhibitory concentration (MIC)90 values similar to tigecycline (TGC) and eravacycline (ERV; intravenous-only glycylcycline and fluorocycline, respectively, within the TCN class) [5, 6]. However, limited studies have reported patient outcomes of those treated with OMC for M. abscessus infections [7]. The objective of this case series was to describe preliminary real-world experience of OMC for the treatment of M. abscessus infections.
METHODS
This was a multicenter, retrospective, observational case series at 6 geographically distinct medical centers in the United States in which OMC was initiated between January and August 2020. We included individuals aged ≥18 years with ≥1 M. abscessus–positive culture, in the setting of clinical suspicion for either pulmonary or extrapulmonary infection, who received OMC for ≥3 months with ≥3 months of documented NTM follow-up after OMC initiation. Patients were still included if negative circumstances (eg, OMC discontinued due to AE, death) precluded insufficient exposure or duration (<3 months) of OMC continuation and/or follow-up.
Early clinical success was defined as a composite of survival, lack of clinical/radiographic worsening, lack of alteration of OMC therapy due to concerns for treatment failure, lack of microbiologic relapse (if patient has achieved culture conversion or microbiologic clearance and cultures were drawn), and lack of culture persistence for 3 consecutive positive cultures following OMC initiation (if patient has not had at least 2 negative cultures and cultures were drawn), which was evaluated throughout the required follow-up. We also reported intentions for OMC utilization and incidence of AE.
Microbiologic relapse was defined as 2 consecutive cultures positive for the same pathogen isolated from index culture following sputum culture conversion (respiratory) or microbiologic clearance (nonrespiratory). Sputum culture conversion was defined as having at least 3 consecutive negative sputum NTM cultures over 12 months. Microbiologic clearance was defined as having any negative culture following positive index culture (nonrespiratory). The Clinical and Laboratory Standards Institute (CLSI) susceptibility breakpoints were applied, when applicable, for interpretation of MIC values, while the FDA antibacterial susceptibility interpretive criteria were used when information was not available via CLSI [8, 9]. Combination therapy was defined as any antibiotic used in tandem with OMC for ≥28 days. All adverse effects while on OMC were reported, although they could not be fully attributed to OMC due to combination regimens. Descriptive statistics were utilized for analysis using IBM SPSS software, version 26.0 (SPSS, Inc., Chicago, IL, USA).
RESULTS
Overall, 12 patients met inclusion criteria. Four individuals were excluded due to insufficient exposure to OMC (3/4) and/or insufficient duration of follow-up (4/4). Included individuals had a median age (interquartile range [IQR]) of 58 (54–63) years, they had a median body mass index (IQR) of 23.6 (21.1–28.9) kg/m2, 50.0% were female, and 91.7% were Caucasian. Common comorbidities in those with nontuberculous mycobacterial pulmonary disease (NTM-PD) included interstitial lung disease (5/7; 71.4%), chronic obstructive pulmonary disease (2/7; 28.6%), asthma (2/7; 28.6%), and solid organ malignancy and/or acute myeloid leukemia (2/7; 28.6%), while no patients had cystic fibrosis or autoimmune disease. The majority of patients had insurance coverage through private entities (6/12; 50.0%), followed by Medicare (3/12; 25.0%; evaluated due to insurance coverage associated with selection of medications), and were treated with OMC strictly in the outpatient setting (10/12; 83.3%). Of patients included in this analysis, 5/12 (41.7%) had surgical interventions (debridement and/or incision and drainage).
The source of infection was primarily NTM-PD (7/12; 58.3%), followed by bone/joint (2/12; 16.7%). Three other extrapulmonary sites of infection involved an intra-abdominal infection, a skin and soft tissue infection, and an infected intravenous catheter. Of those with NTM-PD, the radiographic pattern was 57.1% (4/7) nodular bronchiectatic and 42.9% (3/7) fibrocavitary. Disseminated infection occurred in 2/12 (16.7%) of patients. The initial M. abscessus isolates were most commonly isolated from expectorated sputum (4/12; 33.3%), wound/tissue (4/12; 33.3%), or induced sputum (1/12; 8.3%). Of all included cases, 7/12 (58.3%) of isolates underwent subspeciation (6/7; 85.7% subspecies M. abscessus, 1/7; 14.3% subspecies M. massiliense). Erm gene genotyping (genes that can express inducible macrolide resistance) was conducted in 9/12 (75.0%) isolates, with functional erm gene detected in 6/9 (66.7%) [2].
Before OMC initiation, antibiotic therapy was administered in 10/12 (83.3%) cases, for a median (IQR) of 4.7 (3.4–12.7) months (these data were calculated based on 11 patients, as data were not available for 1 patient). Mycobacterial cultures were positive at the time of OMC initiation in 6/9 (66.7%) patients for whom this information was known. Only a single isolate underwent MIC determination for OMC, which was 0.5 mcg/mL. However, TIG MICs were reported for 11/12 (91.7%) isolates (range, 0.06–1 mcg/mL; MIC90, 1 mcg/mL). MIC values for other antibiotics are reported in Supplementary Table 1.
The total median duration of OMC (IQR) was 6.2 (4.2–11.0) months, with the median duration of follow-up post-OMC initiation (IQR) being 5.1 (3.4–7.2) months. All patients received ≥2 companion antibiotics, with the most common being amikacin (8/12; 66.7%), imipenem (5/12; 41.7%), linezolid/tedizolid (5/12; 41.7%), azithromycin (4/12; 33.3%), and/or clofazimine (4/12; 33.3%). Interestingly, 2 patients received TIG concomitantly with OMC. Oral therapy was strictly utilized in all cases, with a loading dose of 450 mg once daily on days 1 and 2 used for initiation of therapy in 2/12 (16.7%) patients, while most patients did not receive a loading dose on initiation and received a maintenance dose of 300 mg once daily (10/12; 83.3%).
Clinical success occurred in 9/12 (75.0%) cases. Failures involved 3 cases with radiographic fibrocavitary and nodular bronchiectatic (plus dissemination) sources and skin and soft tissue sources. Other clinical and composite end point characteristics can be found in Table 1. The primary reasons for OMC utilization were related to antimicrobial resistance to previous antibiotic(s) (8/12; 66.7%), previous antibiotic failure (6/12; 50.0%), ease of administration (6/12; 50.0%), and oral bioavailability of OMC (6/12; 50.0%).
Table 1. Clinical Characteristics of Patients Treated With Omadacycline for Various Mycobacterium abscessus Infections
Subject ID Age/Sex/Subspecies/Erm Gene Presence Infection Source (Dissemination) TIG MIC, mg/L Positive Culture When Switched to OMC? Duration of OMC, mo Duration of Follow-up After OMC Initiation, mo Companion Drugs With OMC Number of Negative Cultures After Initiation Were Cultures Actually Drawn to Verify if They Were Negative? Clinical Success Death Persistently Positive Culture Microbiologic Relapse Alteration of OMC Therapy due to Concerns of Failure Clinical/Radiographic Worsening While on OMC
1 59/M/-/yes IAI-multiple abscesses (no) 0.5 Unknown 11.7 11.3 Clofazimine, tedizolid 3 N/A Yes No No No No No
2 57/M/massiliense/- Hip bone/joint + indwelling medical device (no) 1 Unknown 6.3 3.5 Azithromycin, clofazimine 1 N/A Yes No No No No No
3 68/F/-/- Fibrocavitary (no) 0.5 No 8.8 5.5 Azithromycin, tedizolid 0 No Yes No - - No No
4 49/F/abscessus/yes Fibrocavitary (no) 0.12 Yes 20.6 16.2 Amikacin, imipenem 1 N/A Yes No No No No No
5 80/M/abscessus/no Nodular bronchiectatic (no) 0.25 Yes 7.2 6.0 Amikacin, imipenem, linezolid 3 N/A Yes No No No No No
6 57/F/abscessus/yes Fibrocavitary (no) 0.25 Yes 5.4 3.3 Amikacin, clofazimine 0 Yes No No Yes N/A No No
7 63/F/abscessus/no Nodular bronchiectatic (no) 0.12 No 6.0 4.9 Amikacin, azithromycin, imipenem 2 N/A Yes No No No No No
8 53/M/abscessus/yes Nodular bronchiectatic (yes-skin) No Yes 12.0 7.6 Amikacin, imipenem, tigecycline 4 N/A Yes No No No No No
9 26/M/abscessus/yes Foot osteomyelitis (no) 1 Yes 3.3 3.3 Amikacin, meropenem, tigecycline 0 No Yes No - - No No
10 59/F/-/yes SSTI (no) 0.25 Yes 5.4 5.2 Clofazimine, imipenem 3 N/A No No No No No Yes
11 55/F/-/- CLABSI (no) 0.06 No 3.8 3.7 Amikacin, tedizolid 1 N/A Yes No No No No No
12 62/M/-/no Nodular bronchiectatic (yes-skin, liver) 0.06 Unknown 0.6 0.6 (died) Amikacin, azithromycin, linezolid 0 No No Yes - - No Yes
Abbreviations: -, information not available; CLABSI, central line bloodstream infection; IAI, intra-abdominal infection; OMC, omadacycline; SSTI, skin and soft tissue infection; TIG, tigecycline.
Three patients experienced an AE while on therapy. One patient experienced a gastrointestinal AE (nausea/vomiting/diarrhea), and the OMC dose was reduced from 300 mg daily to 150 mg twice daily, with improvement in symptoms. Another patient experienced serum creatinine increase ≥0.5 mg/dL; OMC was temporarily discontinued, and this AE resolved. The third patient experienced AST/ALT elevations >3× the upper limit of normal; OMC was continued, despite these laboratory abnormalities, and the abnormalities resolved.
DISCUSSION
We report the largest real-world, observational, multicenter description of early treatment outcomes for patients treated with OMC for pulmonary and extrapulmonary M. abscessus infections with promising results. Due to the in vitro activity of OMC against M. abscessus and the available oral formulation, it is expected that the medical community would have elevated curiosity about the use of OMC for patients with M. abscessus. Our results show similar (or slightly higher) preliminary results congruent with smaller reports of OMC and with other agent(s) used for M. abscessus infections, both in index and refractory disease [7, 10, 11]. Although the OMC treatment in its entirety was not included (as treatment is still ongoing for the majority of cases), no NTM-treating clinician discontinued OMC due to concerns of failure, with a current median OMC duration of 6.2 months. Furthermore, incidence rates of possible AEs due to OMC were relatively similar to those in the phase 3 trials for OMC and other real-world analyses of novel tetracyclines, despite much longer durations of exposure in this case series [12, 13].
An important therapeutic for NTM infections is macrolides (if susceptible), which are subject to inducible resistance via the erm gene and prolongation of the QTc interval [14]. Importantly, OMC is not impacted by functional erm gene expression and has not been shown to cause clinically significant QTc prolongation. Given the lack of some clinical laboratories performing subspeciation or erm gene detection (highlighted in this analysis with conduction in 58.3% and 75.0%, respectively), OMC could provide a viable oral alternative option for those clinicians and sites without the complete microbiological picture.
Tigecycline and ERV have demonstrated similar in vitro activity against isolates of M. abscessus; however, both antibiotics are only available in intravenous formulations and are dosed twice daily, which is not ideal for prolonged treatment courses, and are associated with significant gastrointestinal AEs. OMC is dosed once daily and has shown fewer gastrointestinal AEs than TIG or ERV (8.3% in this analysis). Importantly, reported MIC90 values of ERV against M. abscessus (1 mcg/mL) are higher than the current FDA breakpoint for Enterobacterales, while reported MIC90 values for OMC against M. abscessus have been reported to be 2-fold lower than their current FDA breakpoint [5, 9].
This report has obvious limitations. First, this was a retrospective, observational case series with a small number of patients and the possibility of selection bias. Inclusion criteria for our analysis required relatively short durations of OMC exposure and follow-up (≥3 months) relative to traditional treatment durations associated with M. abscessus; therefore, although the median duration of OMC was 6.2 months, the duration of OMC exposure as it relates to outcomes may have been inadequate to detect a more (or less) favorable response. We included both pulmonary and extrapulmonary cases of NTM infection, the outcomes of which may be difficult to compare directly based on potential differences in nonpharmacological management (eg, removal of device in extrapulmonary cases). Also, subspeciation and functional erm gene detection were not available in all cases. However, given the rarity of this disease, these data reflect pragmatic outcomes that can be useful for clinicians with limited to no options for M. abscessus treatment, even without the full microbiologic picture. Next, all patients were on ≥2 additional antimicrobials; therefore, analysis of the direct response of OMC is difficult. However, this is also the case with any antimicrobial used within a combination regimen. Given the multicenter analysis of our study and the complexities of performing in vitro susceptibility with novel antimicrobials, we were unable to perform MIC testing for OMC on the majority of the clinical M. abscessus isolates to determine initial susceptibility, and the possibility of development of OMC resistance while on therapy remains.
Despite these limitations, this is the largest real-world observational description reporting the experience of early treatment with OMC for M. abscessus within multiple infectious sites. A ≥3-month follow-up evaluating OMC therapy by NTM-treating clinicians was required for inclusion in this analysis, which is a strength compared with other retrospective observational studies. Also, OMC was studied in some patients who had been treated with numerous antibiotics without success over long intervals of time. Finally, although MICs for OMC were only reported in 8.3% of isolates, MICs for TIG were reported in 91.7% of isolates, and previous reports have shown a high correlation between the 2 antibiotics for M. abscessus [5, 6]. While these early experiences with OMC for M. abscessus are important to document, prospective studies and larger real-world analyses are urgently needed for these difficult-to-treat infections.
Supplementary Data
Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
ofab002_suppl_Supplementary_Table_1 Click here for additional data file.
Acknowledgments
Financial support. This work was supported by an investigator-initiated grant from Paratek Pharmaceuticals.
Potential conflicts of interest. T.M., S.A., C.S., C.H., A.J.W., M.L.B., J.B., T.W.G., A.M.L., I.A., and C.M.-C. have no conflicts of interest to disclose. J.V.P. has been on advisory boards for Insmed, A2N, Paratek Pharmaceuticals, and Cipla Technologies and has spoken for Insmed. M.P.V. has received research funding from Paratek Pharmaceuticals and Cumberland Pharmaceuticals. K.A.C. has received consulting fees from Insmed, Hillrom, Merck, and Microbion, unrelated to the current investigation, and is supported by National Heart, Lung, and Blood Institute K08 HL1139994 and the Burroughs Wellcome Fund Career Award for Medical Scientists. M.J.R. has received funds for research and consulting or participated in speaking bureaus for Allergan, Contrafect, Melinta, Merck, Paratek Pharmaceuticals, Shionogi, Sunovian, and Tetraphase and is partially supported by National Institute of Allergy and Infectious Diseases R01 AI121400. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Author contributions. 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.
Patient consent. This study does not include factors necessitating patient consent. Furthermore, the design of the work has been approved by local ethical committees. | Fatal | ReactionOutcome | CC BY-NC-ND | 33628856 | 19,628,349 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abdominal discomfort'. | An Uncommon Presentation of DRESS Syndrome Secondary to Leflunomide Use: A Case Report.
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a constellation of symptoms that manifest as a result of certain medications. Several antipsychotics, antibiotics, and sulfa-containing drugs are known to be implicated in the etiology of DRESS syndrome. The clinical presentation of this disorder consists of a diffuse rash, lymphadenopathy, and systemic organ damage. Our patient presented with symptoms consistent with DRESS syndrome after being started on leflunomide, which is not commonly associated with DRESS. The diagnostic workup comprised of monitoring inflammatory markers on laboratory work, an excisional lymph node biopsy (to rule out malignancy), and a skin biopsy (to assess the etiology of the rash). Our patient received systemic steroids, dose-adjusted based on expert opinion. Further research is required to explore the association between leflunomide and DRESS and address guidelines for the management of DRESS.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe reaction that presents itself after the initiation of a drug or offending agent.1 Its presentation varies with patient and drug; however, common symptoms are a diffuse blanching rash, multiple end-organ involvement, and lymphadenopathy.2 Immediate diagnosis and appropriate management is necessary in order to avoid progression to severe DRESS symptoms requiring critical care management.3
There have been several antiepileptics, antibiotics, and sulfa drugs that have been heavily associated with DRESS syndrome. However, leflunomide has not been commonly associated with DRESS, as there have only been a few cases, to our knowledge, that have been documented thus far. Our patient was recently started on leflunomide and came in with a diffuse rash, diarrhea, and fever. After a thorough diagnostic approach, he was diagnosed with DRESS. Due to the lack of randomized controlled trials guiding the management of DRESS syndrome, our patient was started on a steroid dose deemed appropriate by expert opinion, which led to the resolution of his symptoms.
Case Presentation
We present the case of a 52-year-old male with past medical history of rheumatoid arthritis, essential hypertension and gastroesophageal reflux disease, who presented to our hospital with chief complaints of fever, diarrhea, and a rash that had been going on for a week prior to admission. He noticed a pruritic skin rash that started at his legs and then rapidly progressed to the rest of his body. He had multiple episodes of diarrhea and 3 episodes of emesis. Review of systems was negative for any possible sick contacts, pulmonary, or other abdominal symptoms.
Four months prior to admission, our patient was worked up for polyarthralgia and was diagnosed with seropositive rheumatoid arthritis. He was started on methotrexate without avail. He was switched to leflunomide, which he started taking 2 weeks prior to admission. His only medications were leflunomide, omeprazole, and ibuprofen.
Physical examination was remarkable for a middle-aged man who appeared his age and was is acute distress. He had a generalized maculopapular blanchable rash present diffusely across the surface of his body. Inguinal lymphadenopathy was noted, with the largest lymph node at 40 mm.
In the emergency department, he was noted to be tachypneic at a rate of 26 and tachycardic at a rate of 104. His laboratory work was significant for a white blood cell count of 18.7 × 103/µL, elevated eosinophil count at 2.19 × 103/µL, neutrophilia at 14.48 × 103/µL, C-reactive protein of 82 mg/L, erythrocyte sedimentation rate of 20 mm/h, ferritin of 246 ng/mL, and a low complement C4. Rapid strep test, monospot antibody test, and Lyme antibody testing were all negative. He was resuscitated with fluids and started on antibiotics. Computed tomography scan of the thorax, abdomen, and pelvis was done (Figure 1), which showed mediastinal, upper abdominal, axillary, and paraesophageal lymphadenopathy. Rheumatology, hematology/oncology, and dermatology services were consulted.
Figure 1. Diffuse inguinal lymphadenopathy seen on computed tomography scan of the abdomen/pelvis (marked by blue arrow).
Further studies showed an elevated rheumatoid factor of 241 IU/mL, an anti-CCP of >300 units, speckled pattern antibodies elevated at 160 (/dil), and quantitative immunoglobulin (Ig) E elevated at 20 184 IU/mL. Steroid therapy was deferred until an excisional lymph node biopsy could be obtained. His eosinophil count continued to increase to a peak of 21.34 × 103/µL.
After the excisional left inguinal lymph node biopsy was performed, our patient was started on intravenous (IV) methylprednisolone 40 mg twice daily, which was subsequently increased to 60 mg twice daily. His eosinophil count trended down to 10.70 × 103/µL.
Results of the excisional biopsy showed reactive lymphoid hyperplasia with increased polyclonal IgG4+ plasma cells, immunoblasts, Langerhans cells, and histiocytes, nonspecific findings that could be seen in drug-induced lymphadenopathy (Figure 2). There was no evidence of lymphoma, infection, or IgG4 disease. CD4:CD8 ratio was 8.2, which made the possibility of neoplasm less likely.
Figure 2. Lymph node biopsy showing partial effacement of normal lymph node architecture with expansion of the paracortical areas (indicated by blue arrow) by mixed cellular proliferation (hematoxylin and eosin, 4× magnification).
Eventually a skin biopsy was done which showed focal granular perivascular C3 and fibrinogen deposition. There was no specific deposition of immunoglobulin or complement in the epidermis or dermal-epidermal junction (Figure 3).
Figure 3. Skin biopsy showing superficial perivascular inflammation (blue arrow) and mild spongiosis (red arrow). There is no interface change or overt vascular damage (hematoxylin and eosin, 4× magnification).
After receiving 7 days of IV methylprednisolone 60 mg twice daily, our patient felt a significant resolution of his rash. He was discharged on a steroid taper.
Discussion
DRESS syndrome is a rare phenomenon that has an estimated incidence of 0.9 out of every 100 000 people.4 There are certain medications that are strongly linked to this syndrome. Antiepileptic drugs such as phenytoin, carbamazepine, and lamotrigine are noted to cause DRESS syndrome. Sulfa-containing medications, minocycline, and vancomycin are antibiotics that are linked to this syndrome as well. Other drugs such as allopurinol and mexiletine are associated.3,5
Leflunomide is not usually associated with DRESS syndrome. To our knowledge, there have been very few cases that have been presented similarly.6-8 We believe that further investigation is required to explore the association between leflunomide and DRESS, so as to allow safe prescription and education of patients who require leflunomide.
Although the pathogenesis of this disease is still being studied, there are 2 competing hypotheses that aim to explain the syndrome. One hypothesis is that DRESS syndrome occurs through a delayed hypersensitivity reaction whereby CD4 and CD8 T cells are specifically activated by the offending drug to overproduce cytokines and acute phase reactants.9 Another theory is that the offending agent leads to the activation of underlying HHV6/HHV7/Epstein–Barr virus or cytomegalovirus, and the ensuing symptoms are secondary to the body’s immune system attacking the virus.10 Our patient was tested for HHV6 and Epstein–Barr virus serologies, which came back negative.
Perhaps the most prominent clinical feature of DRESS syndrome is the diffuse, pruritic rash that emerges, as was the case in our patient. The rash can start out as maculopapular and can progress to being erythematous. In severe cases, pustule formation, exfoliation, or mucosal involvement can occur. Fever and lymphadenopathy are common presenting features of the disease as well.11
The following factors are considered as part of the diagnostic criteria in the workup of DRESS syndrome: a measured fever >101.3 °F, lymphadenopathy in 2 different anatomic areas, eosinophilia and atypical lymphocytes on blood work, and skin involvement, with the inclusion of a skin biopsy. Skin biopsy would show nonspecific changes, including vascular wall damage and lymphocytic infiltrate.12 Our patient met this criteria; however, the difficulty comes in the overlap of the clinical presentation of DRESS syndrome with multiple other medical conditions. Our patient necessitated an excisional lymph node biopsy in order to rule out lymphoma. Viral infections were excluded through the viral serologies that were obtained on admission. Hyper-eosinophilic syndrome was excluded due to lack of multiorgan involvement and nonspecific findings on skin biopsy.
There is a lack of evidence-based guideline directed therapy with regard to the management of DRESS syndrome. Initially, termination of the offending agent in addition to fluid resuscitation and symptom management are crucial. For mild disease without any overt organ involvement, oral prednisone is recommended. For patients with severe DRESS syndrome, with one or more end-organ involvement, systemic steroids, IV methylprednisolone dosed at 1 mg/kg is recommended with a taper of 2 to 3 months or oral steroids after symptoms subside. Other modes of therapy include cyclosporine and intravenous immunoglobulins.13 Our patient required the initiation of IV methylprednisolone 60 mg twice daily to alleviate his symptoms of rash, and this regimen helped decrease his eosinophil count as well.
Conclusion
DRESS syndrome is an incredibly rare disease that results due to an adverse medication reaction. Our case details the necessity of physicians to be aware of the difficulty in appropriately diagnosing DRESS syndrome, given its overlap to several other rheumatological and hematological conditions, including malignancy. We aim to shed light on the association of leflunomide and DRESS syndrome, calling for further research to assess the strength of association between the two. Further research is required to develop guideline directed therapy for the management of DRESS syndrome.
We acknowledge the pathology department for their help in procuring the biopsy slides.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.
ORCID iD: Suman Rao https://orcid.org/0000-0003-1746-1025 | IBUPROFEN, LEFLUNOMIDE, OMEPRAZOLE | DrugsGivenReaction | CC BY-NC | 33629602 | 19,046,277 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diarrhoea'. | An Uncommon Presentation of DRESS Syndrome Secondary to Leflunomide Use: A Case Report.
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a constellation of symptoms that manifest as a result of certain medications. Several antipsychotics, antibiotics, and sulfa-containing drugs are known to be implicated in the etiology of DRESS syndrome. The clinical presentation of this disorder consists of a diffuse rash, lymphadenopathy, and systemic organ damage. Our patient presented with symptoms consistent with DRESS syndrome after being started on leflunomide, which is not commonly associated with DRESS. The diagnostic workup comprised of monitoring inflammatory markers on laboratory work, an excisional lymph node biopsy (to rule out malignancy), and a skin biopsy (to assess the etiology of the rash). Our patient received systemic steroids, dose-adjusted based on expert opinion. Further research is required to explore the association between leflunomide and DRESS and address guidelines for the management of DRESS.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe reaction that presents itself after the initiation of a drug or offending agent.1 Its presentation varies with patient and drug; however, common symptoms are a diffuse blanching rash, multiple end-organ involvement, and lymphadenopathy.2 Immediate diagnosis and appropriate management is necessary in order to avoid progression to severe DRESS symptoms requiring critical care management.3
There have been several antiepileptics, antibiotics, and sulfa drugs that have been heavily associated with DRESS syndrome. However, leflunomide has not been commonly associated with DRESS, as there have only been a few cases, to our knowledge, that have been documented thus far. Our patient was recently started on leflunomide and came in with a diffuse rash, diarrhea, and fever. After a thorough diagnostic approach, he was diagnosed with DRESS. Due to the lack of randomized controlled trials guiding the management of DRESS syndrome, our patient was started on a steroid dose deemed appropriate by expert opinion, which led to the resolution of his symptoms.
Case Presentation
We present the case of a 52-year-old male with past medical history of rheumatoid arthritis, essential hypertension and gastroesophageal reflux disease, who presented to our hospital with chief complaints of fever, diarrhea, and a rash that had been going on for a week prior to admission. He noticed a pruritic skin rash that started at his legs and then rapidly progressed to the rest of his body. He had multiple episodes of diarrhea and 3 episodes of emesis. Review of systems was negative for any possible sick contacts, pulmonary, or other abdominal symptoms.
Four months prior to admission, our patient was worked up for polyarthralgia and was diagnosed with seropositive rheumatoid arthritis. He was started on methotrexate without avail. He was switched to leflunomide, which he started taking 2 weeks prior to admission. His only medications were leflunomide, omeprazole, and ibuprofen.
Physical examination was remarkable for a middle-aged man who appeared his age and was is acute distress. He had a generalized maculopapular blanchable rash present diffusely across the surface of his body. Inguinal lymphadenopathy was noted, with the largest lymph node at 40 mm.
In the emergency department, he was noted to be tachypneic at a rate of 26 and tachycardic at a rate of 104. His laboratory work was significant for a white blood cell count of 18.7 × 103/µL, elevated eosinophil count at 2.19 × 103/µL, neutrophilia at 14.48 × 103/µL, C-reactive protein of 82 mg/L, erythrocyte sedimentation rate of 20 mm/h, ferritin of 246 ng/mL, and a low complement C4. Rapid strep test, monospot antibody test, and Lyme antibody testing were all negative. He was resuscitated with fluids and started on antibiotics. Computed tomography scan of the thorax, abdomen, and pelvis was done (Figure 1), which showed mediastinal, upper abdominal, axillary, and paraesophageal lymphadenopathy. Rheumatology, hematology/oncology, and dermatology services were consulted.
Figure 1. Diffuse inguinal lymphadenopathy seen on computed tomography scan of the abdomen/pelvis (marked by blue arrow).
Further studies showed an elevated rheumatoid factor of 241 IU/mL, an anti-CCP of >300 units, speckled pattern antibodies elevated at 160 (/dil), and quantitative immunoglobulin (Ig) E elevated at 20 184 IU/mL. Steroid therapy was deferred until an excisional lymph node biopsy could be obtained. His eosinophil count continued to increase to a peak of 21.34 × 103/µL.
After the excisional left inguinal lymph node biopsy was performed, our patient was started on intravenous (IV) methylprednisolone 40 mg twice daily, which was subsequently increased to 60 mg twice daily. His eosinophil count trended down to 10.70 × 103/µL.
Results of the excisional biopsy showed reactive lymphoid hyperplasia with increased polyclonal IgG4+ plasma cells, immunoblasts, Langerhans cells, and histiocytes, nonspecific findings that could be seen in drug-induced lymphadenopathy (Figure 2). There was no evidence of lymphoma, infection, or IgG4 disease. CD4:CD8 ratio was 8.2, which made the possibility of neoplasm less likely.
Figure 2. Lymph node biopsy showing partial effacement of normal lymph node architecture with expansion of the paracortical areas (indicated by blue arrow) by mixed cellular proliferation (hematoxylin and eosin, 4× magnification).
Eventually a skin biopsy was done which showed focal granular perivascular C3 and fibrinogen deposition. There was no specific deposition of immunoglobulin or complement in the epidermis or dermal-epidermal junction (Figure 3).
Figure 3. Skin biopsy showing superficial perivascular inflammation (blue arrow) and mild spongiosis (red arrow). There is no interface change or overt vascular damage (hematoxylin and eosin, 4× magnification).
After receiving 7 days of IV methylprednisolone 60 mg twice daily, our patient felt a significant resolution of his rash. He was discharged on a steroid taper.
Discussion
DRESS syndrome is a rare phenomenon that has an estimated incidence of 0.9 out of every 100 000 people.4 There are certain medications that are strongly linked to this syndrome. Antiepileptic drugs such as phenytoin, carbamazepine, and lamotrigine are noted to cause DRESS syndrome. Sulfa-containing medications, minocycline, and vancomycin are antibiotics that are linked to this syndrome as well. Other drugs such as allopurinol and mexiletine are associated.3,5
Leflunomide is not usually associated with DRESS syndrome. To our knowledge, there have been very few cases that have been presented similarly.6-8 We believe that further investigation is required to explore the association between leflunomide and DRESS, so as to allow safe prescription and education of patients who require leflunomide.
Although the pathogenesis of this disease is still being studied, there are 2 competing hypotheses that aim to explain the syndrome. One hypothesis is that DRESS syndrome occurs through a delayed hypersensitivity reaction whereby CD4 and CD8 T cells are specifically activated by the offending drug to overproduce cytokines and acute phase reactants.9 Another theory is that the offending agent leads to the activation of underlying HHV6/HHV7/Epstein–Barr virus or cytomegalovirus, and the ensuing symptoms are secondary to the body’s immune system attacking the virus.10 Our patient was tested for HHV6 and Epstein–Barr virus serologies, which came back negative.
Perhaps the most prominent clinical feature of DRESS syndrome is the diffuse, pruritic rash that emerges, as was the case in our patient. The rash can start out as maculopapular and can progress to being erythematous. In severe cases, pustule formation, exfoliation, or mucosal involvement can occur. Fever and lymphadenopathy are common presenting features of the disease as well.11
The following factors are considered as part of the diagnostic criteria in the workup of DRESS syndrome: a measured fever >101.3 °F, lymphadenopathy in 2 different anatomic areas, eosinophilia and atypical lymphocytes on blood work, and skin involvement, with the inclusion of a skin biopsy. Skin biopsy would show nonspecific changes, including vascular wall damage and lymphocytic infiltrate.12 Our patient met this criteria; however, the difficulty comes in the overlap of the clinical presentation of DRESS syndrome with multiple other medical conditions. Our patient necessitated an excisional lymph node biopsy in order to rule out lymphoma. Viral infections were excluded through the viral serologies that were obtained on admission. Hyper-eosinophilic syndrome was excluded due to lack of multiorgan involvement and nonspecific findings on skin biopsy.
There is a lack of evidence-based guideline directed therapy with regard to the management of DRESS syndrome. Initially, termination of the offending agent in addition to fluid resuscitation and symptom management are crucial. For mild disease without any overt organ involvement, oral prednisone is recommended. For patients with severe DRESS syndrome, with one or more end-organ involvement, systemic steroids, IV methylprednisolone dosed at 1 mg/kg is recommended with a taper of 2 to 3 months or oral steroids after symptoms subside. Other modes of therapy include cyclosporine and intravenous immunoglobulins.13 Our patient required the initiation of IV methylprednisolone 60 mg twice daily to alleviate his symptoms of rash, and this regimen helped decrease his eosinophil count as well.
Conclusion
DRESS syndrome is an incredibly rare disease that results due to an adverse medication reaction. Our case details the necessity of physicians to be aware of the difficulty in appropriately diagnosing DRESS syndrome, given its overlap to several other rheumatological and hematological conditions, including malignancy. We aim to shed light on the association of leflunomide and DRESS syndrome, calling for further research to assess the strength of association between the two. Further research is required to develop guideline directed therapy for the management of DRESS syndrome.
We acknowledge the pathology department for their help in procuring the biopsy slides.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.
ORCID iD: Suman Rao https://orcid.org/0000-0003-1746-1025 | IBUPROFEN, LEFLUNOMIDE, OMEPRAZOLE | DrugsGivenReaction | CC BY-NC | 33629602 | 19,046,277 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lymphadenopathy'. | An Uncommon Presentation of DRESS Syndrome Secondary to Leflunomide Use: A Case Report.
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a constellation of symptoms that manifest as a result of certain medications. Several antipsychotics, antibiotics, and sulfa-containing drugs are known to be implicated in the etiology of DRESS syndrome. The clinical presentation of this disorder consists of a diffuse rash, lymphadenopathy, and systemic organ damage. Our patient presented with symptoms consistent with DRESS syndrome after being started on leflunomide, which is not commonly associated with DRESS. The diagnostic workup comprised of monitoring inflammatory markers on laboratory work, an excisional lymph node biopsy (to rule out malignancy), and a skin biopsy (to assess the etiology of the rash). Our patient received systemic steroids, dose-adjusted based on expert opinion. Further research is required to explore the association between leflunomide and DRESS and address guidelines for the management of DRESS.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe reaction that presents itself after the initiation of a drug or offending agent.1 Its presentation varies with patient and drug; however, common symptoms are a diffuse blanching rash, multiple end-organ involvement, and lymphadenopathy.2 Immediate diagnosis and appropriate management is necessary in order to avoid progression to severe DRESS symptoms requiring critical care management.3
There have been several antiepileptics, antibiotics, and sulfa drugs that have been heavily associated with DRESS syndrome. However, leflunomide has not been commonly associated with DRESS, as there have only been a few cases, to our knowledge, that have been documented thus far. Our patient was recently started on leflunomide and came in with a diffuse rash, diarrhea, and fever. After a thorough diagnostic approach, he was diagnosed with DRESS. Due to the lack of randomized controlled trials guiding the management of DRESS syndrome, our patient was started on a steroid dose deemed appropriate by expert opinion, which led to the resolution of his symptoms.
Case Presentation
We present the case of a 52-year-old male with past medical history of rheumatoid arthritis, essential hypertension and gastroesophageal reflux disease, who presented to our hospital with chief complaints of fever, diarrhea, and a rash that had been going on for a week prior to admission. He noticed a pruritic skin rash that started at his legs and then rapidly progressed to the rest of his body. He had multiple episodes of diarrhea and 3 episodes of emesis. Review of systems was negative for any possible sick contacts, pulmonary, or other abdominal symptoms.
Four months prior to admission, our patient was worked up for polyarthralgia and was diagnosed with seropositive rheumatoid arthritis. He was started on methotrexate without avail. He was switched to leflunomide, which he started taking 2 weeks prior to admission. His only medications were leflunomide, omeprazole, and ibuprofen.
Physical examination was remarkable for a middle-aged man who appeared his age and was is acute distress. He had a generalized maculopapular blanchable rash present diffusely across the surface of his body. Inguinal lymphadenopathy was noted, with the largest lymph node at 40 mm.
In the emergency department, he was noted to be tachypneic at a rate of 26 and tachycardic at a rate of 104. His laboratory work was significant for a white blood cell count of 18.7 × 103/µL, elevated eosinophil count at 2.19 × 103/µL, neutrophilia at 14.48 × 103/µL, C-reactive protein of 82 mg/L, erythrocyte sedimentation rate of 20 mm/h, ferritin of 246 ng/mL, and a low complement C4. Rapid strep test, monospot antibody test, and Lyme antibody testing were all negative. He was resuscitated with fluids and started on antibiotics. Computed tomography scan of the thorax, abdomen, and pelvis was done (Figure 1), which showed mediastinal, upper abdominal, axillary, and paraesophageal lymphadenopathy. Rheumatology, hematology/oncology, and dermatology services were consulted.
Figure 1. Diffuse inguinal lymphadenopathy seen on computed tomography scan of the abdomen/pelvis (marked by blue arrow).
Further studies showed an elevated rheumatoid factor of 241 IU/mL, an anti-CCP of >300 units, speckled pattern antibodies elevated at 160 (/dil), and quantitative immunoglobulin (Ig) E elevated at 20 184 IU/mL. Steroid therapy was deferred until an excisional lymph node biopsy could be obtained. His eosinophil count continued to increase to a peak of 21.34 × 103/µL.
After the excisional left inguinal lymph node biopsy was performed, our patient was started on intravenous (IV) methylprednisolone 40 mg twice daily, which was subsequently increased to 60 mg twice daily. His eosinophil count trended down to 10.70 × 103/µL.
Results of the excisional biopsy showed reactive lymphoid hyperplasia with increased polyclonal IgG4+ plasma cells, immunoblasts, Langerhans cells, and histiocytes, nonspecific findings that could be seen in drug-induced lymphadenopathy (Figure 2). There was no evidence of lymphoma, infection, or IgG4 disease. CD4:CD8 ratio was 8.2, which made the possibility of neoplasm less likely.
Figure 2. Lymph node biopsy showing partial effacement of normal lymph node architecture with expansion of the paracortical areas (indicated by blue arrow) by mixed cellular proliferation (hematoxylin and eosin, 4× magnification).
Eventually a skin biopsy was done which showed focal granular perivascular C3 and fibrinogen deposition. There was no specific deposition of immunoglobulin or complement in the epidermis or dermal-epidermal junction (Figure 3).
Figure 3. Skin biopsy showing superficial perivascular inflammation (blue arrow) and mild spongiosis (red arrow). There is no interface change or overt vascular damage (hematoxylin and eosin, 4× magnification).
After receiving 7 days of IV methylprednisolone 60 mg twice daily, our patient felt a significant resolution of his rash. He was discharged on a steroid taper.
Discussion
DRESS syndrome is a rare phenomenon that has an estimated incidence of 0.9 out of every 100 000 people.4 There are certain medications that are strongly linked to this syndrome. Antiepileptic drugs such as phenytoin, carbamazepine, and lamotrigine are noted to cause DRESS syndrome. Sulfa-containing medications, minocycline, and vancomycin are antibiotics that are linked to this syndrome as well. Other drugs such as allopurinol and mexiletine are associated.3,5
Leflunomide is not usually associated with DRESS syndrome. To our knowledge, there have been very few cases that have been presented similarly.6-8 We believe that further investigation is required to explore the association between leflunomide and DRESS, so as to allow safe prescription and education of patients who require leflunomide.
Although the pathogenesis of this disease is still being studied, there are 2 competing hypotheses that aim to explain the syndrome. One hypothesis is that DRESS syndrome occurs through a delayed hypersensitivity reaction whereby CD4 and CD8 T cells are specifically activated by the offending drug to overproduce cytokines and acute phase reactants.9 Another theory is that the offending agent leads to the activation of underlying HHV6/HHV7/Epstein–Barr virus or cytomegalovirus, and the ensuing symptoms are secondary to the body’s immune system attacking the virus.10 Our patient was tested for HHV6 and Epstein–Barr virus serologies, which came back negative.
Perhaps the most prominent clinical feature of DRESS syndrome is the diffuse, pruritic rash that emerges, as was the case in our patient. The rash can start out as maculopapular and can progress to being erythematous. In severe cases, pustule formation, exfoliation, or mucosal involvement can occur. Fever and lymphadenopathy are common presenting features of the disease as well.11
The following factors are considered as part of the diagnostic criteria in the workup of DRESS syndrome: a measured fever >101.3 °F, lymphadenopathy in 2 different anatomic areas, eosinophilia and atypical lymphocytes on blood work, and skin involvement, with the inclusion of a skin biopsy. Skin biopsy would show nonspecific changes, including vascular wall damage and lymphocytic infiltrate.12 Our patient met this criteria; however, the difficulty comes in the overlap of the clinical presentation of DRESS syndrome with multiple other medical conditions. Our patient necessitated an excisional lymph node biopsy in order to rule out lymphoma. Viral infections were excluded through the viral serologies that were obtained on admission. Hyper-eosinophilic syndrome was excluded due to lack of multiorgan involvement and nonspecific findings on skin biopsy.
There is a lack of evidence-based guideline directed therapy with regard to the management of DRESS syndrome. Initially, termination of the offending agent in addition to fluid resuscitation and symptom management are crucial. For mild disease without any overt organ involvement, oral prednisone is recommended. For patients with severe DRESS syndrome, with one or more end-organ involvement, systemic steroids, IV methylprednisolone dosed at 1 mg/kg is recommended with a taper of 2 to 3 months or oral steroids after symptoms subside. Other modes of therapy include cyclosporine and intravenous immunoglobulins.13 Our patient required the initiation of IV methylprednisolone 60 mg twice daily to alleviate his symptoms of rash, and this regimen helped decrease his eosinophil count as well.
Conclusion
DRESS syndrome is an incredibly rare disease that results due to an adverse medication reaction. Our case details the necessity of physicians to be aware of the difficulty in appropriately diagnosing DRESS syndrome, given its overlap to several other rheumatological and hematological conditions, including malignancy. We aim to shed light on the association of leflunomide and DRESS syndrome, calling for further research to assess the strength of association between the two. Further research is required to develop guideline directed therapy for the management of DRESS syndrome.
We acknowledge the pathology department for their help in procuring the biopsy slides.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.
ORCID iD: Suman Rao https://orcid.org/0000-0003-1746-1025 | IBUPROFEN, LEFLUNOMIDE, OMEPRAZOLE | DrugsGivenReaction | CC BY-NC | 33629602 | 19,046,277 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lymphoid hyperplasia of intestine'. | An Uncommon Presentation of DRESS Syndrome Secondary to Leflunomide Use: A Case Report.
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a constellation of symptoms that manifest as a result of certain medications. Several antipsychotics, antibiotics, and sulfa-containing drugs are known to be implicated in the etiology of DRESS syndrome. The clinical presentation of this disorder consists of a diffuse rash, lymphadenopathy, and systemic organ damage. Our patient presented with symptoms consistent with DRESS syndrome after being started on leflunomide, which is not commonly associated with DRESS. The diagnostic workup comprised of monitoring inflammatory markers on laboratory work, an excisional lymph node biopsy (to rule out malignancy), and a skin biopsy (to assess the etiology of the rash). Our patient received systemic steroids, dose-adjusted based on expert opinion. Further research is required to explore the association between leflunomide and DRESS and address guidelines for the management of DRESS.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe reaction that presents itself after the initiation of a drug or offending agent.1 Its presentation varies with patient and drug; however, common symptoms are a diffuse blanching rash, multiple end-organ involvement, and lymphadenopathy.2 Immediate diagnosis and appropriate management is necessary in order to avoid progression to severe DRESS symptoms requiring critical care management.3
There have been several antiepileptics, antibiotics, and sulfa drugs that have been heavily associated with DRESS syndrome. However, leflunomide has not been commonly associated with DRESS, as there have only been a few cases, to our knowledge, that have been documented thus far. Our patient was recently started on leflunomide and came in with a diffuse rash, diarrhea, and fever. After a thorough diagnostic approach, he was diagnosed with DRESS. Due to the lack of randomized controlled trials guiding the management of DRESS syndrome, our patient was started on a steroid dose deemed appropriate by expert opinion, which led to the resolution of his symptoms.
Case Presentation
We present the case of a 52-year-old male with past medical history of rheumatoid arthritis, essential hypertension and gastroesophageal reflux disease, who presented to our hospital with chief complaints of fever, diarrhea, and a rash that had been going on for a week prior to admission. He noticed a pruritic skin rash that started at his legs and then rapidly progressed to the rest of his body. He had multiple episodes of diarrhea and 3 episodes of emesis. Review of systems was negative for any possible sick contacts, pulmonary, or other abdominal symptoms.
Four months prior to admission, our patient was worked up for polyarthralgia and was diagnosed with seropositive rheumatoid arthritis. He was started on methotrexate without avail. He was switched to leflunomide, which he started taking 2 weeks prior to admission. His only medications were leflunomide, omeprazole, and ibuprofen.
Physical examination was remarkable for a middle-aged man who appeared his age and was is acute distress. He had a generalized maculopapular blanchable rash present diffusely across the surface of his body. Inguinal lymphadenopathy was noted, with the largest lymph node at 40 mm.
In the emergency department, he was noted to be tachypneic at a rate of 26 and tachycardic at a rate of 104. His laboratory work was significant for a white blood cell count of 18.7 × 103/µL, elevated eosinophil count at 2.19 × 103/µL, neutrophilia at 14.48 × 103/µL, C-reactive protein of 82 mg/L, erythrocyte sedimentation rate of 20 mm/h, ferritin of 246 ng/mL, and a low complement C4. Rapid strep test, monospot antibody test, and Lyme antibody testing were all negative. He was resuscitated with fluids and started on antibiotics. Computed tomography scan of the thorax, abdomen, and pelvis was done (Figure 1), which showed mediastinal, upper abdominal, axillary, and paraesophageal lymphadenopathy. Rheumatology, hematology/oncology, and dermatology services were consulted.
Figure 1. Diffuse inguinal lymphadenopathy seen on computed tomography scan of the abdomen/pelvis (marked by blue arrow).
Further studies showed an elevated rheumatoid factor of 241 IU/mL, an anti-CCP of >300 units, speckled pattern antibodies elevated at 160 (/dil), and quantitative immunoglobulin (Ig) E elevated at 20 184 IU/mL. Steroid therapy was deferred until an excisional lymph node biopsy could be obtained. His eosinophil count continued to increase to a peak of 21.34 × 103/µL.
After the excisional left inguinal lymph node biopsy was performed, our patient was started on intravenous (IV) methylprednisolone 40 mg twice daily, which was subsequently increased to 60 mg twice daily. His eosinophil count trended down to 10.70 × 103/µL.
Results of the excisional biopsy showed reactive lymphoid hyperplasia with increased polyclonal IgG4+ plasma cells, immunoblasts, Langerhans cells, and histiocytes, nonspecific findings that could be seen in drug-induced lymphadenopathy (Figure 2). There was no evidence of lymphoma, infection, or IgG4 disease. CD4:CD8 ratio was 8.2, which made the possibility of neoplasm less likely.
Figure 2. Lymph node biopsy showing partial effacement of normal lymph node architecture with expansion of the paracortical areas (indicated by blue arrow) by mixed cellular proliferation (hematoxylin and eosin, 4× magnification).
Eventually a skin biopsy was done which showed focal granular perivascular C3 and fibrinogen deposition. There was no specific deposition of immunoglobulin or complement in the epidermis or dermal-epidermal junction (Figure 3).
Figure 3. Skin biopsy showing superficial perivascular inflammation (blue arrow) and mild spongiosis (red arrow). There is no interface change or overt vascular damage (hematoxylin and eosin, 4× magnification).
After receiving 7 days of IV methylprednisolone 60 mg twice daily, our patient felt a significant resolution of his rash. He was discharged on a steroid taper.
Discussion
DRESS syndrome is a rare phenomenon that has an estimated incidence of 0.9 out of every 100 000 people.4 There are certain medications that are strongly linked to this syndrome. Antiepileptic drugs such as phenytoin, carbamazepine, and lamotrigine are noted to cause DRESS syndrome. Sulfa-containing medications, minocycline, and vancomycin are antibiotics that are linked to this syndrome as well. Other drugs such as allopurinol and mexiletine are associated.3,5
Leflunomide is not usually associated with DRESS syndrome. To our knowledge, there have been very few cases that have been presented similarly.6-8 We believe that further investigation is required to explore the association between leflunomide and DRESS, so as to allow safe prescription and education of patients who require leflunomide.
Although the pathogenesis of this disease is still being studied, there are 2 competing hypotheses that aim to explain the syndrome. One hypothesis is that DRESS syndrome occurs through a delayed hypersensitivity reaction whereby CD4 and CD8 T cells are specifically activated by the offending drug to overproduce cytokines and acute phase reactants.9 Another theory is that the offending agent leads to the activation of underlying HHV6/HHV7/Epstein–Barr virus or cytomegalovirus, and the ensuing symptoms are secondary to the body’s immune system attacking the virus.10 Our patient was tested for HHV6 and Epstein–Barr virus serologies, which came back negative.
Perhaps the most prominent clinical feature of DRESS syndrome is the diffuse, pruritic rash that emerges, as was the case in our patient. The rash can start out as maculopapular and can progress to being erythematous. In severe cases, pustule formation, exfoliation, or mucosal involvement can occur. Fever and lymphadenopathy are common presenting features of the disease as well.11
The following factors are considered as part of the diagnostic criteria in the workup of DRESS syndrome: a measured fever >101.3 °F, lymphadenopathy in 2 different anatomic areas, eosinophilia and atypical lymphocytes on blood work, and skin involvement, with the inclusion of a skin biopsy. Skin biopsy would show nonspecific changes, including vascular wall damage and lymphocytic infiltrate.12 Our patient met this criteria; however, the difficulty comes in the overlap of the clinical presentation of DRESS syndrome with multiple other medical conditions. Our patient necessitated an excisional lymph node biopsy in order to rule out lymphoma. Viral infections were excluded through the viral serologies that were obtained on admission. Hyper-eosinophilic syndrome was excluded due to lack of multiorgan involvement and nonspecific findings on skin biopsy.
There is a lack of evidence-based guideline directed therapy with regard to the management of DRESS syndrome. Initially, termination of the offending agent in addition to fluid resuscitation and symptom management are crucial. For mild disease without any overt organ involvement, oral prednisone is recommended. For patients with severe DRESS syndrome, with one or more end-organ involvement, systemic steroids, IV methylprednisolone dosed at 1 mg/kg is recommended with a taper of 2 to 3 months or oral steroids after symptoms subside. Other modes of therapy include cyclosporine and intravenous immunoglobulins.13 Our patient required the initiation of IV methylprednisolone 60 mg twice daily to alleviate his symptoms of rash, and this regimen helped decrease his eosinophil count as well.
Conclusion
DRESS syndrome is an incredibly rare disease that results due to an adverse medication reaction. Our case details the necessity of physicians to be aware of the difficulty in appropriately diagnosing DRESS syndrome, given its overlap to several other rheumatological and hematological conditions, including malignancy. We aim to shed light on the association of leflunomide and DRESS syndrome, calling for further research to assess the strength of association between the two. Further research is required to develop guideline directed therapy for the management of DRESS syndrome.
We acknowledge the pathology department for their help in procuring the biopsy slides.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.
ORCID iD: Suman Rao https://orcid.org/0000-0003-1746-1025 | IBUPROFEN, LEFLUNOMIDE, OMEPRAZOLE | DrugsGivenReaction | CC BY-NC | 33629602 | 19,046,277 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pyrexia'. | An Uncommon Presentation of DRESS Syndrome Secondary to Leflunomide Use: A Case Report.
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a constellation of symptoms that manifest as a result of certain medications. Several antipsychotics, antibiotics, and sulfa-containing drugs are known to be implicated in the etiology of DRESS syndrome. The clinical presentation of this disorder consists of a diffuse rash, lymphadenopathy, and systemic organ damage. Our patient presented with symptoms consistent with DRESS syndrome after being started on leflunomide, which is not commonly associated with DRESS. The diagnostic workup comprised of monitoring inflammatory markers on laboratory work, an excisional lymph node biopsy (to rule out malignancy), and a skin biopsy (to assess the etiology of the rash). Our patient received systemic steroids, dose-adjusted based on expert opinion. Further research is required to explore the association between leflunomide and DRESS and address guidelines for the management of DRESS.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe reaction that presents itself after the initiation of a drug or offending agent.1 Its presentation varies with patient and drug; however, common symptoms are a diffuse blanching rash, multiple end-organ involvement, and lymphadenopathy.2 Immediate diagnosis and appropriate management is necessary in order to avoid progression to severe DRESS symptoms requiring critical care management.3
There have been several antiepileptics, antibiotics, and sulfa drugs that have been heavily associated with DRESS syndrome. However, leflunomide has not been commonly associated with DRESS, as there have only been a few cases, to our knowledge, that have been documented thus far. Our patient was recently started on leflunomide and came in with a diffuse rash, diarrhea, and fever. After a thorough diagnostic approach, he was diagnosed with DRESS. Due to the lack of randomized controlled trials guiding the management of DRESS syndrome, our patient was started on a steroid dose deemed appropriate by expert opinion, which led to the resolution of his symptoms.
Case Presentation
We present the case of a 52-year-old male with past medical history of rheumatoid arthritis, essential hypertension and gastroesophageal reflux disease, who presented to our hospital with chief complaints of fever, diarrhea, and a rash that had been going on for a week prior to admission. He noticed a pruritic skin rash that started at his legs and then rapidly progressed to the rest of his body. He had multiple episodes of diarrhea and 3 episodes of emesis. Review of systems was negative for any possible sick contacts, pulmonary, or other abdominal symptoms.
Four months prior to admission, our patient was worked up for polyarthralgia and was diagnosed with seropositive rheumatoid arthritis. He was started on methotrexate without avail. He was switched to leflunomide, which he started taking 2 weeks prior to admission. His only medications were leflunomide, omeprazole, and ibuprofen.
Physical examination was remarkable for a middle-aged man who appeared his age and was is acute distress. He had a generalized maculopapular blanchable rash present diffusely across the surface of his body. Inguinal lymphadenopathy was noted, with the largest lymph node at 40 mm.
In the emergency department, he was noted to be tachypneic at a rate of 26 and tachycardic at a rate of 104. His laboratory work was significant for a white blood cell count of 18.7 × 103/µL, elevated eosinophil count at 2.19 × 103/µL, neutrophilia at 14.48 × 103/µL, C-reactive protein of 82 mg/L, erythrocyte sedimentation rate of 20 mm/h, ferritin of 246 ng/mL, and a low complement C4. Rapid strep test, monospot antibody test, and Lyme antibody testing were all negative. He was resuscitated with fluids and started on antibiotics. Computed tomography scan of the thorax, abdomen, and pelvis was done (Figure 1), which showed mediastinal, upper abdominal, axillary, and paraesophageal lymphadenopathy. Rheumatology, hematology/oncology, and dermatology services were consulted.
Figure 1. Diffuse inguinal lymphadenopathy seen on computed tomography scan of the abdomen/pelvis (marked by blue arrow).
Further studies showed an elevated rheumatoid factor of 241 IU/mL, an anti-CCP of >300 units, speckled pattern antibodies elevated at 160 (/dil), and quantitative immunoglobulin (Ig) E elevated at 20 184 IU/mL. Steroid therapy was deferred until an excisional lymph node biopsy could be obtained. His eosinophil count continued to increase to a peak of 21.34 × 103/µL.
After the excisional left inguinal lymph node biopsy was performed, our patient was started on intravenous (IV) methylprednisolone 40 mg twice daily, which was subsequently increased to 60 mg twice daily. His eosinophil count trended down to 10.70 × 103/µL.
Results of the excisional biopsy showed reactive lymphoid hyperplasia with increased polyclonal IgG4+ plasma cells, immunoblasts, Langerhans cells, and histiocytes, nonspecific findings that could be seen in drug-induced lymphadenopathy (Figure 2). There was no evidence of lymphoma, infection, or IgG4 disease. CD4:CD8 ratio was 8.2, which made the possibility of neoplasm less likely.
Figure 2. Lymph node biopsy showing partial effacement of normal lymph node architecture with expansion of the paracortical areas (indicated by blue arrow) by mixed cellular proliferation (hematoxylin and eosin, 4× magnification).
Eventually a skin biopsy was done which showed focal granular perivascular C3 and fibrinogen deposition. There was no specific deposition of immunoglobulin or complement in the epidermis or dermal-epidermal junction (Figure 3).
Figure 3. Skin biopsy showing superficial perivascular inflammation (blue arrow) and mild spongiosis (red arrow). There is no interface change or overt vascular damage (hematoxylin and eosin, 4× magnification).
After receiving 7 days of IV methylprednisolone 60 mg twice daily, our patient felt a significant resolution of his rash. He was discharged on a steroid taper.
Discussion
DRESS syndrome is a rare phenomenon that has an estimated incidence of 0.9 out of every 100 000 people.4 There are certain medications that are strongly linked to this syndrome. Antiepileptic drugs such as phenytoin, carbamazepine, and lamotrigine are noted to cause DRESS syndrome. Sulfa-containing medications, minocycline, and vancomycin are antibiotics that are linked to this syndrome as well. Other drugs such as allopurinol and mexiletine are associated.3,5
Leflunomide is not usually associated with DRESS syndrome. To our knowledge, there have been very few cases that have been presented similarly.6-8 We believe that further investigation is required to explore the association between leflunomide and DRESS, so as to allow safe prescription and education of patients who require leflunomide.
Although the pathogenesis of this disease is still being studied, there are 2 competing hypotheses that aim to explain the syndrome. One hypothesis is that DRESS syndrome occurs through a delayed hypersensitivity reaction whereby CD4 and CD8 T cells are specifically activated by the offending drug to overproduce cytokines and acute phase reactants.9 Another theory is that the offending agent leads to the activation of underlying HHV6/HHV7/Epstein–Barr virus or cytomegalovirus, and the ensuing symptoms are secondary to the body’s immune system attacking the virus.10 Our patient was tested for HHV6 and Epstein–Barr virus serologies, which came back negative.
Perhaps the most prominent clinical feature of DRESS syndrome is the diffuse, pruritic rash that emerges, as was the case in our patient. The rash can start out as maculopapular and can progress to being erythematous. In severe cases, pustule formation, exfoliation, or mucosal involvement can occur. Fever and lymphadenopathy are common presenting features of the disease as well.11
The following factors are considered as part of the diagnostic criteria in the workup of DRESS syndrome: a measured fever >101.3 °F, lymphadenopathy in 2 different anatomic areas, eosinophilia and atypical lymphocytes on blood work, and skin involvement, with the inclusion of a skin biopsy. Skin biopsy would show nonspecific changes, including vascular wall damage and lymphocytic infiltrate.12 Our patient met this criteria; however, the difficulty comes in the overlap of the clinical presentation of DRESS syndrome with multiple other medical conditions. Our patient necessitated an excisional lymph node biopsy in order to rule out lymphoma. Viral infections were excluded through the viral serologies that were obtained on admission. Hyper-eosinophilic syndrome was excluded due to lack of multiorgan involvement and nonspecific findings on skin biopsy.
There is a lack of evidence-based guideline directed therapy with regard to the management of DRESS syndrome. Initially, termination of the offending agent in addition to fluid resuscitation and symptom management are crucial. For mild disease without any overt organ involvement, oral prednisone is recommended. For patients with severe DRESS syndrome, with one or more end-organ involvement, systemic steroids, IV methylprednisolone dosed at 1 mg/kg is recommended with a taper of 2 to 3 months or oral steroids after symptoms subside. Other modes of therapy include cyclosporine and intravenous immunoglobulins.13 Our patient required the initiation of IV methylprednisolone 60 mg twice daily to alleviate his symptoms of rash, and this regimen helped decrease his eosinophil count as well.
Conclusion
DRESS syndrome is an incredibly rare disease that results due to an adverse medication reaction. Our case details the necessity of physicians to be aware of the difficulty in appropriately diagnosing DRESS syndrome, given its overlap to several other rheumatological and hematological conditions, including malignancy. We aim to shed light on the association of leflunomide and DRESS syndrome, calling for further research to assess the strength of association between the two. Further research is required to develop guideline directed therapy for the management of DRESS syndrome.
We acknowledge the pathology department for their help in procuring the biopsy slides.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.
ORCID iD: Suman Rao https://orcid.org/0000-0003-1746-1025 | IBUPROFEN, LEFLUNOMIDE, OMEPRAZOLE | DrugsGivenReaction | CC BY-NC | 33629602 | 19,046,277 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rash maculo-papular'. | An Uncommon Presentation of DRESS Syndrome Secondary to Leflunomide Use: A Case Report.
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a constellation of symptoms that manifest as a result of certain medications. Several antipsychotics, antibiotics, and sulfa-containing drugs are known to be implicated in the etiology of DRESS syndrome. The clinical presentation of this disorder consists of a diffuse rash, lymphadenopathy, and systemic organ damage. Our patient presented with symptoms consistent with DRESS syndrome after being started on leflunomide, which is not commonly associated with DRESS. The diagnostic workup comprised of monitoring inflammatory markers on laboratory work, an excisional lymph node biopsy (to rule out malignancy), and a skin biopsy (to assess the etiology of the rash). Our patient received systemic steroids, dose-adjusted based on expert opinion. Further research is required to explore the association between leflunomide and DRESS and address guidelines for the management of DRESS.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe reaction that presents itself after the initiation of a drug or offending agent.1 Its presentation varies with patient and drug; however, common symptoms are a diffuse blanching rash, multiple end-organ involvement, and lymphadenopathy.2 Immediate diagnosis and appropriate management is necessary in order to avoid progression to severe DRESS symptoms requiring critical care management.3
There have been several antiepileptics, antibiotics, and sulfa drugs that have been heavily associated with DRESS syndrome. However, leflunomide has not been commonly associated with DRESS, as there have only been a few cases, to our knowledge, that have been documented thus far. Our patient was recently started on leflunomide and came in with a diffuse rash, diarrhea, and fever. After a thorough diagnostic approach, he was diagnosed with DRESS. Due to the lack of randomized controlled trials guiding the management of DRESS syndrome, our patient was started on a steroid dose deemed appropriate by expert opinion, which led to the resolution of his symptoms.
Case Presentation
We present the case of a 52-year-old male with past medical history of rheumatoid arthritis, essential hypertension and gastroesophageal reflux disease, who presented to our hospital with chief complaints of fever, diarrhea, and a rash that had been going on for a week prior to admission. He noticed a pruritic skin rash that started at his legs and then rapidly progressed to the rest of his body. He had multiple episodes of diarrhea and 3 episodes of emesis. Review of systems was negative for any possible sick contacts, pulmonary, or other abdominal symptoms.
Four months prior to admission, our patient was worked up for polyarthralgia and was diagnosed with seropositive rheumatoid arthritis. He was started on methotrexate without avail. He was switched to leflunomide, which he started taking 2 weeks prior to admission. His only medications were leflunomide, omeprazole, and ibuprofen.
Physical examination was remarkable for a middle-aged man who appeared his age and was is acute distress. He had a generalized maculopapular blanchable rash present diffusely across the surface of his body. Inguinal lymphadenopathy was noted, with the largest lymph node at 40 mm.
In the emergency department, he was noted to be tachypneic at a rate of 26 and tachycardic at a rate of 104. His laboratory work was significant for a white blood cell count of 18.7 × 103/µL, elevated eosinophil count at 2.19 × 103/µL, neutrophilia at 14.48 × 103/µL, C-reactive protein of 82 mg/L, erythrocyte sedimentation rate of 20 mm/h, ferritin of 246 ng/mL, and a low complement C4. Rapid strep test, monospot antibody test, and Lyme antibody testing were all negative. He was resuscitated with fluids and started on antibiotics. Computed tomography scan of the thorax, abdomen, and pelvis was done (Figure 1), which showed mediastinal, upper abdominal, axillary, and paraesophageal lymphadenopathy. Rheumatology, hematology/oncology, and dermatology services were consulted.
Figure 1. Diffuse inguinal lymphadenopathy seen on computed tomography scan of the abdomen/pelvis (marked by blue arrow).
Further studies showed an elevated rheumatoid factor of 241 IU/mL, an anti-CCP of >300 units, speckled pattern antibodies elevated at 160 (/dil), and quantitative immunoglobulin (Ig) E elevated at 20 184 IU/mL. Steroid therapy was deferred until an excisional lymph node biopsy could be obtained. His eosinophil count continued to increase to a peak of 21.34 × 103/µL.
After the excisional left inguinal lymph node biopsy was performed, our patient was started on intravenous (IV) methylprednisolone 40 mg twice daily, which was subsequently increased to 60 mg twice daily. His eosinophil count trended down to 10.70 × 103/µL.
Results of the excisional biopsy showed reactive lymphoid hyperplasia with increased polyclonal IgG4+ plasma cells, immunoblasts, Langerhans cells, and histiocytes, nonspecific findings that could be seen in drug-induced lymphadenopathy (Figure 2). There was no evidence of lymphoma, infection, or IgG4 disease. CD4:CD8 ratio was 8.2, which made the possibility of neoplasm less likely.
Figure 2. Lymph node biopsy showing partial effacement of normal lymph node architecture with expansion of the paracortical areas (indicated by blue arrow) by mixed cellular proliferation (hematoxylin and eosin, 4× magnification).
Eventually a skin biopsy was done which showed focal granular perivascular C3 and fibrinogen deposition. There was no specific deposition of immunoglobulin or complement in the epidermis or dermal-epidermal junction (Figure 3).
Figure 3. Skin biopsy showing superficial perivascular inflammation (blue arrow) and mild spongiosis (red arrow). There is no interface change or overt vascular damage (hematoxylin and eosin, 4× magnification).
After receiving 7 days of IV methylprednisolone 60 mg twice daily, our patient felt a significant resolution of his rash. He was discharged on a steroid taper.
Discussion
DRESS syndrome is a rare phenomenon that has an estimated incidence of 0.9 out of every 100 000 people.4 There are certain medications that are strongly linked to this syndrome. Antiepileptic drugs such as phenytoin, carbamazepine, and lamotrigine are noted to cause DRESS syndrome. Sulfa-containing medications, minocycline, and vancomycin are antibiotics that are linked to this syndrome as well. Other drugs such as allopurinol and mexiletine are associated.3,5
Leflunomide is not usually associated with DRESS syndrome. To our knowledge, there have been very few cases that have been presented similarly.6-8 We believe that further investigation is required to explore the association between leflunomide and DRESS, so as to allow safe prescription and education of patients who require leflunomide.
Although the pathogenesis of this disease is still being studied, there are 2 competing hypotheses that aim to explain the syndrome. One hypothesis is that DRESS syndrome occurs through a delayed hypersensitivity reaction whereby CD4 and CD8 T cells are specifically activated by the offending drug to overproduce cytokines and acute phase reactants.9 Another theory is that the offending agent leads to the activation of underlying HHV6/HHV7/Epstein–Barr virus or cytomegalovirus, and the ensuing symptoms are secondary to the body’s immune system attacking the virus.10 Our patient was tested for HHV6 and Epstein–Barr virus serologies, which came back negative.
Perhaps the most prominent clinical feature of DRESS syndrome is the diffuse, pruritic rash that emerges, as was the case in our patient. The rash can start out as maculopapular and can progress to being erythematous. In severe cases, pustule formation, exfoliation, or mucosal involvement can occur. Fever and lymphadenopathy are common presenting features of the disease as well.11
The following factors are considered as part of the diagnostic criteria in the workup of DRESS syndrome: a measured fever >101.3 °F, lymphadenopathy in 2 different anatomic areas, eosinophilia and atypical lymphocytes on blood work, and skin involvement, with the inclusion of a skin biopsy. Skin biopsy would show nonspecific changes, including vascular wall damage and lymphocytic infiltrate.12 Our patient met this criteria; however, the difficulty comes in the overlap of the clinical presentation of DRESS syndrome with multiple other medical conditions. Our patient necessitated an excisional lymph node biopsy in order to rule out lymphoma. Viral infections were excluded through the viral serologies that were obtained on admission. Hyper-eosinophilic syndrome was excluded due to lack of multiorgan involvement and nonspecific findings on skin biopsy.
There is a lack of evidence-based guideline directed therapy with regard to the management of DRESS syndrome. Initially, termination of the offending agent in addition to fluid resuscitation and symptom management are crucial. For mild disease without any overt organ involvement, oral prednisone is recommended. For patients with severe DRESS syndrome, with one or more end-organ involvement, systemic steroids, IV methylprednisolone dosed at 1 mg/kg is recommended with a taper of 2 to 3 months or oral steroids after symptoms subside. Other modes of therapy include cyclosporine and intravenous immunoglobulins.13 Our patient required the initiation of IV methylprednisolone 60 mg twice daily to alleviate his symptoms of rash, and this regimen helped decrease his eosinophil count as well.
Conclusion
DRESS syndrome is an incredibly rare disease that results due to an adverse medication reaction. Our case details the necessity of physicians to be aware of the difficulty in appropriately diagnosing DRESS syndrome, given its overlap to several other rheumatological and hematological conditions, including malignancy. We aim to shed light on the association of leflunomide and DRESS syndrome, calling for further research to assess the strength of association between the two. Further research is required to develop guideline directed therapy for the management of DRESS syndrome.
We acknowledge the pathology department for their help in procuring the biopsy slides.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.
ORCID iD: Suman Rao https://orcid.org/0000-0003-1746-1025 | IBUPROFEN, LEFLUNOMIDE, OMEPRAZOLE | DrugsGivenReaction | CC BY-NC | 33629602 | 19,046,277 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rash pruritic'. | An Uncommon Presentation of DRESS Syndrome Secondary to Leflunomide Use: A Case Report.
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a constellation of symptoms that manifest as a result of certain medications. Several antipsychotics, antibiotics, and sulfa-containing drugs are known to be implicated in the etiology of DRESS syndrome. The clinical presentation of this disorder consists of a diffuse rash, lymphadenopathy, and systemic organ damage. Our patient presented with symptoms consistent with DRESS syndrome after being started on leflunomide, which is not commonly associated with DRESS. The diagnostic workup comprised of monitoring inflammatory markers on laboratory work, an excisional lymph node biopsy (to rule out malignancy), and a skin biopsy (to assess the etiology of the rash). Our patient received systemic steroids, dose-adjusted based on expert opinion. Further research is required to explore the association between leflunomide and DRESS and address guidelines for the management of DRESS.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe reaction that presents itself after the initiation of a drug or offending agent.1 Its presentation varies with patient and drug; however, common symptoms are a diffuse blanching rash, multiple end-organ involvement, and lymphadenopathy.2 Immediate diagnosis and appropriate management is necessary in order to avoid progression to severe DRESS symptoms requiring critical care management.3
There have been several antiepileptics, antibiotics, and sulfa drugs that have been heavily associated with DRESS syndrome. However, leflunomide has not been commonly associated with DRESS, as there have only been a few cases, to our knowledge, that have been documented thus far. Our patient was recently started on leflunomide and came in with a diffuse rash, diarrhea, and fever. After a thorough diagnostic approach, he was diagnosed with DRESS. Due to the lack of randomized controlled trials guiding the management of DRESS syndrome, our patient was started on a steroid dose deemed appropriate by expert opinion, which led to the resolution of his symptoms.
Case Presentation
We present the case of a 52-year-old male with past medical history of rheumatoid arthritis, essential hypertension and gastroesophageal reflux disease, who presented to our hospital with chief complaints of fever, diarrhea, and a rash that had been going on for a week prior to admission. He noticed a pruritic skin rash that started at his legs and then rapidly progressed to the rest of his body. He had multiple episodes of diarrhea and 3 episodes of emesis. Review of systems was negative for any possible sick contacts, pulmonary, or other abdominal symptoms.
Four months prior to admission, our patient was worked up for polyarthralgia and was diagnosed with seropositive rheumatoid arthritis. He was started on methotrexate without avail. He was switched to leflunomide, which he started taking 2 weeks prior to admission. His only medications were leflunomide, omeprazole, and ibuprofen.
Physical examination was remarkable for a middle-aged man who appeared his age and was is acute distress. He had a generalized maculopapular blanchable rash present diffusely across the surface of his body. Inguinal lymphadenopathy was noted, with the largest lymph node at 40 mm.
In the emergency department, he was noted to be tachypneic at a rate of 26 and tachycardic at a rate of 104. His laboratory work was significant for a white blood cell count of 18.7 × 103/µL, elevated eosinophil count at 2.19 × 103/µL, neutrophilia at 14.48 × 103/µL, C-reactive protein of 82 mg/L, erythrocyte sedimentation rate of 20 mm/h, ferritin of 246 ng/mL, and a low complement C4. Rapid strep test, monospot antibody test, and Lyme antibody testing were all negative. He was resuscitated with fluids and started on antibiotics. Computed tomography scan of the thorax, abdomen, and pelvis was done (Figure 1), which showed mediastinal, upper abdominal, axillary, and paraesophageal lymphadenopathy. Rheumatology, hematology/oncology, and dermatology services were consulted.
Figure 1. Diffuse inguinal lymphadenopathy seen on computed tomography scan of the abdomen/pelvis (marked by blue arrow).
Further studies showed an elevated rheumatoid factor of 241 IU/mL, an anti-CCP of >300 units, speckled pattern antibodies elevated at 160 (/dil), and quantitative immunoglobulin (Ig) E elevated at 20 184 IU/mL. Steroid therapy was deferred until an excisional lymph node biopsy could be obtained. His eosinophil count continued to increase to a peak of 21.34 × 103/µL.
After the excisional left inguinal lymph node biopsy was performed, our patient was started on intravenous (IV) methylprednisolone 40 mg twice daily, which was subsequently increased to 60 mg twice daily. His eosinophil count trended down to 10.70 × 103/µL.
Results of the excisional biopsy showed reactive lymphoid hyperplasia with increased polyclonal IgG4+ plasma cells, immunoblasts, Langerhans cells, and histiocytes, nonspecific findings that could be seen in drug-induced lymphadenopathy (Figure 2). There was no evidence of lymphoma, infection, or IgG4 disease. CD4:CD8 ratio was 8.2, which made the possibility of neoplasm less likely.
Figure 2. Lymph node biopsy showing partial effacement of normal lymph node architecture with expansion of the paracortical areas (indicated by blue arrow) by mixed cellular proliferation (hematoxylin and eosin, 4× magnification).
Eventually a skin biopsy was done which showed focal granular perivascular C3 and fibrinogen deposition. There was no specific deposition of immunoglobulin or complement in the epidermis or dermal-epidermal junction (Figure 3).
Figure 3. Skin biopsy showing superficial perivascular inflammation (blue arrow) and mild spongiosis (red arrow). There is no interface change or overt vascular damage (hematoxylin and eosin, 4× magnification).
After receiving 7 days of IV methylprednisolone 60 mg twice daily, our patient felt a significant resolution of his rash. He was discharged on a steroid taper.
Discussion
DRESS syndrome is a rare phenomenon that has an estimated incidence of 0.9 out of every 100 000 people.4 There are certain medications that are strongly linked to this syndrome. Antiepileptic drugs such as phenytoin, carbamazepine, and lamotrigine are noted to cause DRESS syndrome. Sulfa-containing medications, minocycline, and vancomycin are antibiotics that are linked to this syndrome as well. Other drugs such as allopurinol and mexiletine are associated.3,5
Leflunomide is not usually associated with DRESS syndrome. To our knowledge, there have been very few cases that have been presented similarly.6-8 We believe that further investigation is required to explore the association between leflunomide and DRESS, so as to allow safe prescription and education of patients who require leflunomide.
Although the pathogenesis of this disease is still being studied, there are 2 competing hypotheses that aim to explain the syndrome. One hypothesis is that DRESS syndrome occurs through a delayed hypersensitivity reaction whereby CD4 and CD8 T cells are specifically activated by the offending drug to overproduce cytokines and acute phase reactants.9 Another theory is that the offending agent leads to the activation of underlying HHV6/HHV7/Epstein–Barr virus or cytomegalovirus, and the ensuing symptoms are secondary to the body’s immune system attacking the virus.10 Our patient was tested for HHV6 and Epstein–Barr virus serologies, which came back negative.
Perhaps the most prominent clinical feature of DRESS syndrome is the diffuse, pruritic rash that emerges, as was the case in our patient. The rash can start out as maculopapular and can progress to being erythematous. In severe cases, pustule formation, exfoliation, or mucosal involvement can occur. Fever and lymphadenopathy are common presenting features of the disease as well.11
The following factors are considered as part of the diagnostic criteria in the workup of DRESS syndrome: a measured fever >101.3 °F, lymphadenopathy in 2 different anatomic areas, eosinophilia and atypical lymphocytes on blood work, and skin involvement, with the inclusion of a skin biopsy. Skin biopsy would show nonspecific changes, including vascular wall damage and lymphocytic infiltrate.12 Our patient met this criteria; however, the difficulty comes in the overlap of the clinical presentation of DRESS syndrome with multiple other medical conditions. Our patient necessitated an excisional lymph node biopsy in order to rule out lymphoma. Viral infections were excluded through the viral serologies that were obtained on admission. Hyper-eosinophilic syndrome was excluded due to lack of multiorgan involvement and nonspecific findings on skin biopsy.
There is a lack of evidence-based guideline directed therapy with regard to the management of DRESS syndrome. Initially, termination of the offending agent in addition to fluid resuscitation and symptom management are crucial. For mild disease without any overt organ involvement, oral prednisone is recommended. For patients with severe DRESS syndrome, with one or more end-organ involvement, systemic steroids, IV methylprednisolone dosed at 1 mg/kg is recommended with a taper of 2 to 3 months or oral steroids after symptoms subside. Other modes of therapy include cyclosporine and intravenous immunoglobulins.13 Our patient required the initiation of IV methylprednisolone 60 mg twice daily to alleviate his symptoms of rash, and this regimen helped decrease his eosinophil count as well.
Conclusion
DRESS syndrome is an incredibly rare disease that results due to an adverse medication reaction. Our case details the necessity of physicians to be aware of the difficulty in appropriately diagnosing DRESS syndrome, given its overlap to several other rheumatological and hematological conditions, including malignancy. We aim to shed light on the association of leflunomide and DRESS syndrome, calling for further research to assess the strength of association between the two. Further research is required to develop guideline directed therapy for the management of DRESS syndrome.
We acknowledge the pathology department for their help in procuring the biopsy slides.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.
ORCID iD: Suman Rao https://orcid.org/0000-0003-1746-1025 | IBUPROFEN, LEFLUNOMIDE, OMEPRAZOLE | DrugsGivenReaction | CC BY-NC | 33629602 | 19,046,277 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rash'. | An Uncommon Presentation of DRESS Syndrome Secondary to Leflunomide Use: A Case Report.
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a constellation of symptoms that manifest as a result of certain medications. Several antipsychotics, antibiotics, and sulfa-containing drugs are known to be implicated in the etiology of DRESS syndrome. The clinical presentation of this disorder consists of a diffuse rash, lymphadenopathy, and systemic organ damage. Our patient presented with symptoms consistent with DRESS syndrome after being started on leflunomide, which is not commonly associated with DRESS. The diagnostic workup comprised of monitoring inflammatory markers on laboratory work, an excisional lymph node biopsy (to rule out malignancy), and a skin biopsy (to assess the etiology of the rash). Our patient received systemic steroids, dose-adjusted based on expert opinion. Further research is required to explore the association between leflunomide and DRESS and address guidelines for the management of DRESS.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe reaction that presents itself after the initiation of a drug or offending agent.1 Its presentation varies with patient and drug; however, common symptoms are a diffuse blanching rash, multiple end-organ involvement, and lymphadenopathy.2 Immediate diagnosis and appropriate management is necessary in order to avoid progression to severe DRESS symptoms requiring critical care management.3
There have been several antiepileptics, antibiotics, and sulfa drugs that have been heavily associated with DRESS syndrome. However, leflunomide has not been commonly associated with DRESS, as there have only been a few cases, to our knowledge, that have been documented thus far. Our patient was recently started on leflunomide and came in with a diffuse rash, diarrhea, and fever. After a thorough diagnostic approach, he was diagnosed with DRESS. Due to the lack of randomized controlled trials guiding the management of DRESS syndrome, our patient was started on a steroid dose deemed appropriate by expert opinion, which led to the resolution of his symptoms.
Case Presentation
We present the case of a 52-year-old male with past medical history of rheumatoid arthritis, essential hypertension and gastroesophageal reflux disease, who presented to our hospital with chief complaints of fever, diarrhea, and a rash that had been going on for a week prior to admission. He noticed a pruritic skin rash that started at his legs and then rapidly progressed to the rest of his body. He had multiple episodes of diarrhea and 3 episodes of emesis. Review of systems was negative for any possible sick contacts, pulmonary, or other abdominal symptoms.
Four months prior to admission, our patient was worked up for polyarthralgia and was diagnosed with seropositive rheumatoid arthritis. He was started on methotrexate without avail. He was switched to leflunomide, which he started taking 2 weeks prior to admission. His only medications were leflunomide, omeprazole, and ibuprofen.
Physical examination was remarkable for a middle-aged man who appeared his age and was is acute distress. He had a generalized maculopapular blanchable rash present diffusely across the surface of his body. Inguinal lymphadenopathy was noted, with the largest lymph node at 40 mm.
In the emergency department, he was noted to be tachypneic at a rate of 26 and tachycardic at a rate of 104. His laboratory work was significant for a white blood cell count of 18.7 × 103/µL, elevated eosinophil count at 2.19 × 103/µL, neutrophilia at 14.48 × 103/µL, C-reactive protein of 82 mg/L, erythrocyte sedimentation rate of 20 mm/h, ferritin of 246 ng/mL, and a low complement C4. Rapid strep test, monospot antibody test, and Lyme antibody testing were all negative. He was resuscitated with fluids and started on antibiotics. Computed tomography scan of the thorax, abdomen, and pelvis was done (Figure 1), which showed mediastinal, upper abdominal, axillary, and paraesophageal lymphadenopathy. Rheumatology, hematology/oncology, and dermatology services were consulted.
Figure 1. Diffuse inguinal lymphadenopathy seen on computed tomography scan of the abdomen/pelvis (marked by blue arrow).
Further studies showed an elevated rheumatoid factor of 241 IU/mL, an anti-CCP of >300 units, speckled pattern antibodies elevated at 160 (/dil), and quantitative immunoglobulin (Ig) E elevated at 20 184 IU/mL. Steroid therapy was deferred until an excisional lymph node biopsy could be obtained. His eosinophil count continued to increase to a peak of 21.34 × 103/µL.
After the excisional left inguinal lymph node biopsy was performed, our patient was started on intravenous (IV) methylprednisolone 40 mg twice daily, which was subsequently increased to 60 mg twice daily. His eosinophil count trended down to 10.70 × 103/µL.
Results of the excisional biopsy showed reactive lymphoid hyperplasia with increased polyclonal IgG4+ plasma cells, immunoblasts, Langerhans cells, and histiocytes, nonspecific findings that could be seen in drug-induced lymphadenopathy (Figure 2). There was no evidence of lymphoma, infection, or IgG4 disease. CD4:CD8 ratio was 8.2, which made the possibility of neoplasm less likely.
Figure 2. Lymph node biopsy showing partial effacement of normal lymph node architecture with expansion of the paracortical areas (indicated by blue arrow) by mixed cellular proliferation (hematoxylin and eosin, 4× magnification).
Eventually a skin biopsy was done which showed focal granular perivascular C3 and fibrinogen deposition. There was no specific deposition of immunoglobulin or complement in the epidermis or dermal-epidermal junction (Figure 3).
Figure 3. Skin biopsy showing superficial perivascular inflammation (blue arrow) and mild spongiosis (red arrow). There is no interface change or overt vascular damage (hematoxylin and eosin, 4× magnification).
After receiving 7 days of IV methylprednisolone 60 mg twice daily, our patient felt a significant resolution of his rash. He was discharged on a steroid taper.
Discussion
DRESS syndrome is a rare phenomenon that has an estimated incidence of 0.9 out of every 100 000 people.4 There are certain medications that are strongly linked to this syndrome. Antiepileptic drugs such as phenytoin, carbamazepine, and lamotrigine are noted to cause DRESS syndrome. Sulfa-containing medications, minocycline, and vancomycin are antibiotics that are linked to this syndrome as well. Other drugs such as allopurinol and mexiletine are associated.3,5
Leflunomide is not usually associated with DRESS syndrome. To our knowledge, there have been very few cases that have been presented similarly.6-8 We believe that further investigation is required to explore the association between leflunomide and DRESS, so as to allow safe prescription and education of patients who require leflunomide.
Although the pathogenesis of this disease is still being studied, there are 2 competing hypotheses that aim to explain the syndrome. One hypothesis is that DRESS syndrome occurs through a delayed hypersensitivity reaction whereby CD4 and CD8 T cells are specifically activated by the offending drug to overproduce cytokines and acute phase reactants.9 Another theory is that the offending agent leads to the activation of underlying HHV6/HHV7/Epstein–Barr virus or cytomegalovirus, and the ensuing symptoms are secondary to the body’s immune system attacking the virus.10 Our patient was tested for HHV6 and Epstein–Barr virus serologies, which came back negative.
Perhaps the most prominent clinical feature of DRESS syndrome is the diffuse, pruritic rash that emerges, as was the case in our patient. The rash can start out as maculopapular and can progress to being erythematous. In severe cases, pustule formation, exfoliation, or mucosal involvement can occur. Fever and lymphadenopathy are common presenting features of the disease as well.11
The following factors are considered as part of the diagnostic criteria in the workup of DRESS syndrome: a measured fever >101.3 °F, lymphadenopathy in 2 different anatomic areas, eosinophilia and atypical lymphocytes on blood work, and skin involvement, with the inclusion of a skin biopsy. Skin biopsy would show nonspecific changes, including vascular wall damage and lymphocytic infiltrate.12 Our patient met this criteria; however, the difficulty comes in the overlap of the clinical presentation of DRESS syndrome with multiple other medical conditions. Our patient necessitated an excisional lymph node biopsy in order to rule out lymphoma. Viral infections were excluded through the viral serologies that were obtained on admission. Hyper-eosinophilic syndrome was excluded due to lack of multiorgan involvement and nonspecific findings on skin biopsy.
There is a lack of evidence-based guideline directed therapy with regard to the management of DRESS syndrome. Initially, termination of the offending agent in addition to fluid resuscitation and symptom management are crucial. For mild disease without any overt organ involvement, oral prednisone is recommended. For patients with severe DRESS syndrome, with one or more end-organ involvement, systemic steroids, IV methylprednisolone dosed at 1 mg/kg is recommended with a taper of 2 to 3 months or oral steroids after symptoms subside. Other modes of therapy include cyclosporine and intravenous immunoglobulins.13 Our patient required the initiation of IV methylprednisolone 60 mg twice daily to alleviate his symptoms of rash, and this regimen helped decrease his eosinophil count as well.
Conclusion
DRESS syndrome is an incredibly rare disease that results due to an adverse medication reaction. Our case details the necessity of physicians to be aware of the difficulty in appropriately diagnosing DRESS syndrome, given its overlap to several other rheumatological and hematological conditions, including malignancy. We aim to shed light on the association of leflunomide and DRESS syndrome, calling for further research to assess the strength of association between the two. Further research is required to develop guideline directed therapy for the management of DRESS syndrome.
We acknowledge the pathology department for their help in procuring the biopsy slides.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.
ORCID iD: Suman Rao https://orcid.org/0000-0003-1746-1025 | IBUPROFEN, LEFLUNOMIDE, OMEPRAZOLE | DrugsGivenReaction | CC BY-NC | 33629602 | 19,046,277 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Tachypnoea'. | An Uncommon Presentation of DRESS Syndrome Secondary to Leflunomide Use: A Case Report.
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a constellation of symptoms that manifest as a result of certain medications. Several antipsychotics, antibiotics, and sulfa-containing drugs are known to be implicated in the etiology of DRESS syndrome. The clinical presentation of this disorder consists of a diffuse rash, lymphadenopathy, and systemic organ damage. Our patient presented with symptoms consistent with DRESS syndrome after being started on leflunomide, which is not commonly associated with DRESS. The diagnostic workup comprised of monitoring inflammatory markers on laboratory work, an excisional lymph node biopsy (to rule out malignancy), and a skin biopsy (to assess the etiology of the rash). Our patient received systemic steroids, dose-adjusted based on expert opinion. Further research is required to explore the association between leflunomide and DRESS and address guidelines for the management of DRESS.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe reaction that presents itself after the initiation of a drug or offending agent.1 Its presentation varies with patient and drug; however, common symptoms are a diffuse blanching rash, multiple end-organ involvement, and lymphadenopathy.2 Immediate diagnosis and appropriate management is necessary in order to avoid progression to severe DRESS symptoms requiring critical care management.3
There have been several antiepileptics, antibiotics, and sulfa drugs that have been heavily associated with DRESS syndrome. However, leflunomide has not been commonly associated with DRESS, as there have only been a few cases, to our knowledge, that have been documented thus far. Our patient was recently started on leflunomide and came in with a diffuse rash, diarrhea, and fever. After a thorough diagnostic approach, he was diagnosed with DRESS. Due to the lack of randomized controlled trials guiding the management of DRESS syndrome, our patient was started on a steroid dose deemed appropriate by expert opinion, which led to the resolution of his symptoms.
Case Presentation
We present the case of a 52-year-old male with past medical history of rheumatoid arthritis, essential hypertension and gastroesophageal reflux disease, who presented to our hospital with chief complaints of fever, diarrhea, and a rash that had been going on for a week prior to admission. He noticed a pruritic skin rash that started at his legs and then rapidly progressed to the rest of his body. He had multiple episodes of diarrhea and 3 episodes of emesis. Review of systems was negative for any possible sick contacts, pulmonary, or other abdominal symptoms.
Four months prior to admission, our patient was worked up for polyarthralgia and was diagnosed with seropositive rheumatoid arthritis. He was started on methotrexate without avail. He was switched to leflunomide, which he started taking 2 weeks prior to admission. His only medications were leflunomide, omeprazole, and ibuprofen.
Physical examination was remarkable for a middle-aged man who appeared his age and was is acute distress. He had a generalized maculopapular blanchable rash present diffusely across the surface of his body. Inguinal lymphadenopathy was noted, with the largest lymph node at 40 mm.
In the emergency department, he was noted to be tachypneic at a rate of 26 and tachycardic at a rate of 104. His laboratory work was significant for a white blood cell count of 18.7 × 103/µL, elevated eosinophil count at 2.19 × 103/µL, neutrophilia at 14.48 × 103/µL, C-reactive protein of 82 mg/L, erythrocyte sedimentation rate of 20 mm/h, ferritin of 246 ng/mL, and a low complement C4. Rapid strep test, monospot antibody test, and Lyme antibody testing were all negative. He was resuscitated with fluids and started on antibiotics. Computed tomography scan of the thorax, abdomen, and pelvis was done (Figure 1), which showed mediastinal, upper abdominal, axillary, and paraesophageal lymphadenopathy. Rheumatology, hematology/oncology, and dermatology services were consulted.
Figure 1. Diffuse inguinal lymphadenopathy seen on computed tomography scan of the abdomen/pelvis (marked by blue arrow).
Further studies showed an elevated rheumatoid factor of 241 IU/mL, an anti-CCP of >300 units, speckled pattern antibodies elevated at 160 (/dil), and quantitative immunoglobulin (Ig) E elevated at 20 184 IU/mL. Steroid therapy was deferred until an excisional lymph node biopsy could be obtained. His eosinophil count continued to increase to a peak of 21.34 × 103/µL.
After the excisional left inguinal lymph node biopsy was performed, our patient was started on intravenous (IV) methylprednisolone 40 mg twice daily, which was subsequently increased to 60 mg twice daily. His eosinophil count trended down to 10.70 × 103/µL.
Results of the excisional biopsy showed reactive lymphoid hyperplasia with increased polyclonal IgG4+ plasma cells, immunoblasts, Langerhans cells, and histiocytes, nonspecific findings that could be seen in drug-induced lymphadenopathy (Figure 2). There was no evidence of lymphoma, infection, or IgG4 disease. CD4:CD8 ratio was 8.2, which made the possibility of neoplasm less likely.
Figure 2. Lymph node biopsy showing partial effacement of normal lymph node architecture with expansion of the paracortical areas (indicated by blue arrow) by mixed cellular proliferation (hematoxylin and eosin, 4× magnification).
Eventually a skin biopsy was done which showed focal granular perivascular C3 and fibrinogen deposition. There was no specific deposition of immunoglobulin or complement in the epidermis or dermal-epidermal junction (Figure 3).
Figure 3. Skin biopsy showing superficial perivascular inflammation (blue arrow) and mild spongiosis (red arrow). There is no interface change or overt vascular damage (hematoxylin and eosin, 4× magnification).
After receiving 7 days of IV methylprednisolone 60 mg twice daily, our patient felt a significant resolution of his rash. He was discharged on a steroid taper.
Discussion
DRESS syndrome is a rare phenomenon that has an estimated incidence of 0.9 out of every 100 000 people.4 There are certain medications that are strongly linked to this syndrome. Antiepileptic drugs such as phenytoin, carbamazepine, and lamotrigine are noted to cause DRESS syndrome. Sulfa-containing medications, minocycline, and vancomycin are antibiotics that are linked to this syndrome as well. Other drugs such as allopurinol and mexiletine are associated.3,5
Leflunomide is not usually associated with DRESS syndrome. To our knowledge, there have been very few cases that have been presented similarly.6-8 We believe that further investigation is required to explore the association between leflunomide and DRESS, so as to allow safe prescription and education of patients who require leflunomide.
Although the pathogenesis of this disease is still being studied, there are 2 competing hypotheses that aim to explain the syndrome. One hypothesis is that DRESS syndrome occurs through a delayed hypersensitivity reaction whereby CD4 and CD8 T cells are specifically activated by the offending drug to overproduce cytokines and acute phase reactants.9 Another theory is that the offending agent leads to the activation of underlying HHV6/HHV7/Epstein–Barr virus or cytomegalovirus, and the ensuing symptoms are secondary to the body’s immune system attacking the virus.10 Our patient was tested for HHV6 and Epstein–Barr virus serologies, which came back negative.
Perhaps the most prominent clinical feature of DRESS syndrome is the diffuse, pruritic rash that emerges, as was the case in our patient. The rash can start out as maculopapular and can progress to being erythematous. In severe cases, pustule formation, exfoliation, or mucosal involvement can occur. Fever and lymphadenopathy are common presenting features of the disease as well.11
The following factors are considered as part of the diagnostic criteria in the workup of DRESS syndrome: a measured fever >101.3 °F, lymphadenopathy in 2 different anatomic areas, eosinophilia and atypical lymphocytes on blood work, and skin involvement, with the inclusion of a skin biopsy. Skin biopsy would show nonspecific changes, including vascular wall damage and lymphocytic infiltrate.12 Our patient met this criteria; however, the difficulty comes in the overlap of the clinical presentation of DRESS syndrome with multiple other medical conditions. Our patient necessitated an excisional lymph node biopsy in order to rule out lymphoma. Viral infections were excluded through the viral serologies that were obtained on admission. Hyper-eosinophilic syndrome was excluded due to lack of multiorgan involvement and nonspecific findings on skin biopsy.
There is a lack of evidence-based guideline directed therapy with regard to the management of DRESS syndrome. Initially, termination of the offending agent in addition to fluid resuscitation and symptom management are crucial. For mild disease without any overt organ involvement, oral prednisone is recommended. For patients with severe DRESS syndrome, with one or more end-organ involvement, systemic steroids, IV methylprednisolone dosed at 1 mg/kg is recommended with a taper of 2 to 3 months or oral steroids after symptoms subside. Other modes of therapy include cyclosporine and intravenous immunoglobulins.13 Our patient required the initiation of IV methylprednisolone 60 mg twice daily to alleviate his symptoms of rash, and this regimen helped decrease his eosinophil count as well.
Conclusion
DRESS syndrome is an incredibly rare disease that results due to an adverse medication reaction. Our case details the necessity of physicians to be aware of the difficulty in appropriately diagnosing DRESS syndrome, given its overlap to several other rheumatological and hematological conditions, including malignancy. We aim to shed light on the association of leflunomide and DRESS syndrome, calling for further research to assess the strength of association between the two. Further research is required to develop guideline directed therapy for the management of DRESS syndrome.
We acknowledge the pathology department for their help in procuring the biopsy slides.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.
ORCID iD: Suman Rao https://orcid.org/0000-0003-1746-1025 | IBUPROFEN, LEFLUNOMIDE, OMEPRAZOLE | DrugsGivenReaction | CC BY-NC | 33629602 | 19,046,277 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vomiting'. | An Uncommon Presentation of DRESS Syndrome Secondary to Leflunomide Use: A Case Report.
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a constellation of symptoms that manifest as a result of certain medications. Several antipsychotics, antibiotics, and sulfa-containing drugs are known to be implicated in the etiology of DRESS syndrome. The clinical presentation of this disorder consists of a diffuse rash, lymphadenopathy, and systemic organ damage. Our patient presented with symptoms consistent with DRESS syndrome after being started on leflunomide, which is not commonly associated with DRESS. The diagnostic workup comprised of monitoring inflammatory markers on laboratory work, an excisional lymph node biopsy (to rule out malignancy), and a skin biopsy (to assess the etiology of the rash). Our patient received systemic steroids, dose-adjusted based on expert opinion. Further research is required to explore the association between leflunomide and DRESS and address guidelines for the management of DRESS.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe reaction that presents itself after the initiation of a drug or offending agent.1 Its presentation varies with patient and drug; however, common symptoms are a diffuse blanching rash, multiple end-organ involvement, and lymphadenopathy.2 Immediate diagnosis and appropriate management is necessary in order to avoid progression to severe DRESS symptoms requiring critical care management.3
There have been several antiepileptics, antibiotics, and sulfa drugs that have been heavily associated with DRESS syndrome. However, leflunomide has not been commonly associated with DRESS, as there have only been a few cases, to our knowledge, that have been documented thus far. Our patient was recently started on leflunomide and came in with a diffuse rash, diarrhea, and fever. After a thorough diagnostic approach, he was diagnosed with DRESS. Due to the lack of randomized controlled trials guiding the management of DRESS syndrome, our patient was started on a steroid dose deemed appropriate by expert opinion, which led to the resolution of his symptoms.
Case Presentation
We present the case of a 52-year-old male with past medical history of rheumatoid arthritis, essential hypertension and gastroesophageal reflux disease, who presented to our hospital with chief complaints of fever, diarrhea, and a rash that had been going on for a week prior to admission. He noticed a pruritic skin rash that started at his legs and then rapidly progressed to the rest of his body. He had multiple episodes of diarrhea and 3 episodes of emesis. Review of systems was negative for any possible sick contacts, pulmonary, or other abdominal symptoms.
Four months prior to admission, our patient was worked up for polyarthralgia and was diagnosed with seropositive rheumatoid arthritis. He was started on methotrexate without avail. He was switched to leflunomide, which he started taking 2 weeks prior to admission. His only medications were leflunomide, omeprazole, and ibuprofen.
Physical examination was remarkable for a middle-aged man who appeared his age and was is acute distress. He had a generalized maculopapular blanchable rash present diffusely across the surface of his body. Inguinal lymphadenopathy was noted, with the largest lymph node at 40 mm.
In the emergency department, he was noted to be tachypneic at a rate of 26 and tachycardic at a rate of 104. His laboratory work was significant for a white blood cell count of 18.7 × 103/µL, elevated eosinophil count at 2.19 × 103/µL, neutrophilia at 14.48 × 103/µL, C-reactive protein of 82 mg/L, erythrocyte sedimentation rate of 20 mm/h, ferritin of 246 ng/mL, and a low complement C4. Rapid strep test, monospot antibody test, and Lyme antibody testing were all negative. He was resuscitated with fluids and started on antibiotics. Computed tomography scan of the thorax, abdomen, and pelvis was done (Figure 1), which showed mediastinal, upper abdominal, axillary, and paraesophageal lymphadenopathy. Rheumatology, hematology/oncology, and dermatology services were consulted.
Figure 1. Diffuse inguinal lymphadenopathy seen on computed tomography scan of the abdomen/pelvis (marked by blue arrow).
Further studies showed an elevated rheumatoid factor of 241 IU/mL, an anti-CCP of >300 units, speckled pattern antibodies elevated at 160 (/dil), and quantitative immunoglobulin (Ig) E elevated at 20 184 IU/mL. Steroid therapy was deferred until an excisional lymph node biopsy could be obtained. His eosinophil count continued to increase to a peak of 21.34 × 103/µL.
After the excisional left inguinal lymph node biopsy was performed, our patient was started on intravenous (IV) methylprednisolone 40 mg twice daily, which was subsequently increased to 60 mg twice daily. His eosinophil count trended down to 10.70 × 103/µL.
Results of the excisional biopsy showed reactive lymphoid hyperplasia with increased polyclonal IgG4+ plasma cells, immunoblasts, Langerhans cells, and histiocytes, nonspecific findings that could be seen in drug-induced lymphadenopathy (Figure 2). There was no evidence of lymphoma, infection, or IgG4 disease. CD4:CD8 ratio was 8.2, which made the possibility of neoplasm less likely.
Figure 2. Lymph node biopsy showing partial effacement of normal lymph node architecture with expansion of the paracortical areas (indicated by blue arrow) by mixed cellular proliferation (hematoxylin and eosin, 4× magnification).
Eventually a skin biopsy was done which showed focal granular perivascular C3 and fibrinogen deposition. There was no specific deposition of immunoglobulin or complement in the epidermis or dermal-epidermal junction (Figure 3).
Figure 3. Skin biopsy showing superficial perivascular inflammation (blue arrow) and mild spongiosis (red arrow). There is no interface change or overt vascular damage (hematoxylin and eosin, 4× magnification).
After receiving 7 days of IV methylprednisolone 60 mg twice daily, our patient felt a significant resolution of his rash. He was discharged on a steroid taper.
Discussion
DRESS syndrome is a rare phenomenon that has an estimated incidence of 0.9 out of every 100 000 people.4 There are certain medications that are strongly linked to this syndrome. Antiepileptic drugs such as phenytoin, carbamazepine, and lamotrigine are noted to cause DRESS syndrome. Sulfa-containing medications, minocycline, and vancomycin are antibiotics that are linked to this syndrome as well. Other drugs such as allopurinol and mexiletine are associated.3,5
Leflunomide is not usually associated with DRESS syndrome. To our knowledge, there have been very few cases that have been presented similarly.6-8 We believe that further investigation is required to explore the association between leflunomide and DRESS, so as to allow safe prescription and education of patients who require leflunomide.
Although the pathogenesis of this disease is still being studied, there are 2 competing hypotheses that aim to explain the syndrome. One hypothesis is that DRESS syndrome occurs through a delayed hypersensitivity reaction whereby CD4 and CD8 T cells are specifically activated by the offending drug to overproduce cytokines and acute phase reactants.9 Another theory is that the offending agent leads to the activation of underlying HHV6/HHV7/Epstein–Barr virus or cytomegalovirus, and the ensuing symptoms are secondary to the body’s immune system attacking the virus.10 Our patient was tested for HHV6 and Epstein–Barr virus serologies, which came back negative.
Perhaps the most prominent clinical feature of DRESS syndrome is the diffuse, pruritic rash that emerges, as was the case in our patient. The rash can start out as maculopapular and can progress to being erythematous. In severe cases, pustule formation, exfoliation, or mucosal involvement can occur. Fever and lymphadenopathy are common presenting features of the disease as well.11
The following factors are considered as part of the diagnostic criteria in the workup of DRESS syndrome: a measured fever >101.3 °F, lymphadenopathy in 2 different anatomic areas, eosinophilia and atypical lymphocytes on blood work, and skin involvement, with the inclusion of a skin biopsy. Skin biopsy would show nonspecific changes, including vascular wall damage and lymphocytic infiltrate.12 Our patient met this criteria; however, the difficulty comes in the overlap of the clinical presentation of DRESS syndrome with multiple other medical conditions. Our patient necessitated an excisional lymph node biopsy in order to rule out lymphoma. Viral infections were excluded through the viral serologies that were obtained on admission. Hyper-eosinophilic syndrome was excluded due to lack of multiorgan involvement and nonspecific findings on skin biopsy.
There is a lack of evidence-based guideline directed therapy with regard to the management of DRESS syndrome. Initially, termination of the offending agent in addition to fluid resuscitation and symptom management are crucial. For mild disease without any overt organ involvement, oral prednisone is recommended. For patients with severe DRESS syndrome, with one or more end-organ involvement, systemic steroids, IV methylprednisolone dosed at 1 mg/kg is recommended with a taper of 2 to 3 months or oral steroids after symptoms subside. Other modes of therapy include cyclosporine and intravenous immunoglobulins.13 Our patient required the initiation of IV methylprednisolone 60 mg twice daily to alleviate his symptoms of rash, and this regimen helped decrease his eosinophil count as well.
Conclusion
DRESS syndrome is an incredibly rare disease that results due to an adverse medication reaction. Our case details the necessity of physicians to be aware of the difficulty in appropriately diagnosing DRESS syndrome, given its overlap to several other rheumatological and hematological conditions, including malignancy. We aim to shed light on the association of leflunomide and DRESS syndrome, calling for further research to assess the strength of association between the two. Further research is required to develop guideline directed therapy for the management of DRESS syndrome.
We acknowledge the pathology department for their help in procuring the biopsy slides.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.
ORCID iD: Suman Rao https://orcid.org/0000-0003-1746-1025 | IBUPROFEN, LEFLUNOMIDE, OMEPRAZOLE | DrugsGivenReaction | CC BY-NC | 33629602 | 19,046,277 | 2021 |
What was the outcome of reaction 'Abdominal discomfort'? | An Uncommon Presentation of DRESS Syndrome Secondary to Leflunomide Use: A Case Report.
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a constellation of symptoms that manifest as a result of certain medications. Several antipsychotics, antibiotics, and sulfa-containing drugs are known to be implicated in the etiology of DRESS syndrome. The clinical presentation of this disorder consists of a diffuse rash, lymphadenopathy, and systemic organ damage. Our patient presented with symptoms consistent with DRESS syndrome after being started on leflunomide, which is not commonly associated with DRESS. The diagnostic workup comprised of monitoring inflammatory markers on laboratory work, an excisional lymph node biopsy (to rule out malignancy), and a skin biopsy (to assess the etiology of the rash). Our patient received systemic steroids, dose-adjusted based on expert opinion. Further research is required to explore the association between leflunomide and DRESS and address guidelines for the management of DRESS.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe reaction that presents itself after the initiation of a drug or offending agent.1 Its presentation varies with patient and drug; however, common symptoms are a diffuse blanching rash, multiple end-organ involvement, and lymphadenopathy.2 Immediate diagnosis and appropriate management is necessary in order to avoid progression to severe DRESS symptoms requiring critical care management.3
There have been several antiepileptics, antibiotics, and sulfa drugs that have been heavily associated with DRESS syndrome. However, leflunomide has not been commonly associated with DRESS, as there have only been a few cases, to our knowledge, that have been documented thus far. Our patient was recently started on leflunomide and came in with a diffuse rash, diarrhea, and fever. After a thorough diagnostic approach, he was diagnosed with DRESS. Due to the lack of randomized controlled trials guiding the management of DRESS syndrome, our patient was started on a steroid dose deemed appropriate by expert opinion, which led to the resolution of his symptoms.
Case Presentation
We present the case of a 52-year-old male with past medical history of rheumatoid arthritis, essential hypertension and gastroesophageal reflux disease, who presented to our hospital with chief complaints of fever, diarrhea, and a rash that had been going on for a week prior to admission. He noticed a pruritic skin rash that started at his legs and then rapidly progressed to the rest of his body. He had multiple episodes of diarrhea and 3 episodes of emesis. Review of systems was negative for any possible sick contacts, pulmonary, or other abdominal symptoms.
Four months prior to admission, our patient was worked up for polyarthralgia and was diagnosed with seropositive rheumatoid arthritis. He was started on methotrexate without avail. He was switched to leflunomide, which he started taking 2 weeks prior to admission. His only medications were leflunomide, omeprazole, and ibuprofen.
Physical examination was remarkable for a middle-aged man who appeared his age and was is acute distress. He had a generalized maculopapular blanchable rash present diffusely across the surface of his body. Inguinal lymphadenopathy was noted, with the largest lymph node at 40 mm.
In the emergency department, he was noted to be tachypneic at a rate of 26 and tachycardic at a rate of 104. His laboratory work was significant for a white blood cell count of 18.7 × 103/µL, elevated eosinophil count at 2.19 × 103/µL, neutrophilia at 14.48 × 103/µL, C-reactive protein of 82 mg/L, erythrocyte sedimentation rate of 20 mm/h, ferritin of 246 ng/mL, and a low complement C4. Rapid strep test, monospot antibody test, and Lyme antibody testing were all negative. He was resuscitated with fluids and started on antibiotics. Computed tomography scan of the thorax, abdomen, and pelvis was done (Figure 1), which showed mediastinal, upper abdominal, axillary, and paraesophageal lymphadenopathy. Rheumatology, hematology/oncology, and dermatology services were consulted.
Figure 1. Diffuse inguinal lymphadenopathy seen on computed tomography scan of the abdomen/pelvis (marked by blue arrow).
Further studies showed an elevated rheumatoid factor of 241 IU/mL, an anti-CCP of >300 units, speckled pattern antibodies elevated at 160 (/dil), and quantitative immunoglobulin (Ig) E elevated at 20 184 IU/mL. Steroid therapy was deferred until an excisional lymph node biopsy could be obtained. His eosinophil count continued to increase to a peak of 21.34 × 103/µL.
After the excisional left inguinal lymph node biopsy was performed, our patient was started on intravenous (IV) methylprednisolone 40 mg twice daily, which was subsequently increased to 60 mg twice daily. His eosinophil count trended down to 10.70 × 103/µL.
Results of the excisional biopsy showed reactive lymphoid hyperplasia with increased polyclonal IgG4+ plasma cells, immunoblasts, Langerhans cells, and histiocytes, nonspecific findings that could be seen in drug-induced lymphadenopathy (Figure 2). There was no evidence of lymphoma, infection, or IgG4 disease. CD4:CD8 ratio was 8.2, which made the possibility of neoplasm less likely.
Figure 2. Lymph node biopsy showing partial effacement of normal lymph node architecture with expansion of the paracortical areas (indicated by blue arrow) by mixed cellular proliferation (hematoxylin and eosin, 4× magnification).
Eventually a skin biopsy was done which showed focal granular perivascular C3 and fibrinogen deposition. There was no specific deposition of immunoglobulin or complement in the epidermis or dermal-epidermal junction (Figure 3).
Figure 3. Skin biopsy showing superficial perivascular inflammation (blue arrow) and mild spongiosis (red arrow). There is no interface change or overt vascular damage (hematoxylin and eosin, 4× magnification).
After receiving 7 days of IV methylprednisolone 60 mg twice daily, our patient felt a significant resolution of his rash. He was discharged on a steroid taper.
Discussion
DRESS syndrome is a rare phenomenon that has an estimated incidence of 0.9 out of every 100 000 people.4 There are certain medications that are strongly linked to this syndrome. Antiepileptic drugs such as phenytoin, carbamazepine, and lamotrigine are noted to cause DRESS syndrome. Sulfa-containing medications, minocycline, and vancomycin are antibiotics that are linked to this syndrome as well. Other drugs such as allopurinol and mexiletine are associated.3,5
Leflunomide is not usually associated with DRESS syndrome. To our knowledge, there have been very few cases that have been presented similarly.6-8 We believe that further investigation is required to explore the association between leflunomide and DRESS, so as to allow safe prescription and education of patients who require leflunomide.
Although the pathogenesis of this disease is still being studied, there are 2 competing hypotheses that aim to explain the syndrome. One hypothesis is that DRESS syndrome occurs through a delayed hypersensitivity reaction whereby CD4 and CD8 T cells are specifically activated by the offending drug to overproduce cytokines and acute phase reactants.9 Another theory is that the offending agent leads to the activation of underlying HHV6/HHV7/Epstein–Barr virus or cytomegalovirus, and the ensuing symptoms are secondary to the body’s immune system attacking the virus.10 Our patient was tested for HHV6 and Epstein–Barr virus serologies, which came back negative.
Perhaps the most prominent clinical feature of DRESS syndrome is the diffuse, pruritic rash that emerges, as was the case in our patient. The rash can start out as maculopapular and can progress to being erythematous. In severe cases, pustule formation, exfoliation, or mucosal involvement can occur. Fever and lymphadenopathy are common presenting features of the disease as well.11
The following factors are considered as part of the diagnostic criteria in the workup of DRESS syndrome: a measured fever >101.3 °F, lymphadenopathy in 2 different anatomic areas, eosinophilia and atypical lymphocytes on blood work, and skin involvement, with the inclusion of a skin biopsy. Skin biopsy would show nonspecific changes, including vascular wall damage and lymphocytic infiltrate.12 Our patient met this criteria; however, the difficulty comes in the overlap of the clinical presentation of DRESS syndrome with multiple other medical conditions. Our patient necessitated an excisional lymph node biopsy in order to rule out lymphoma. Viral infections were excluded through the viral serologies that were obtained on admission. Hyper-eosinophilic syndrome was excluded due to lack of multiorgan involvement and nonspecific findings on skin biopsy.
There is a lack of evidence-based guideline directed therapy with regard to the management of DRESS syndrome. Initially, termination of the offending agent in addition to fluid resuscitation and symptom management are crucial. For mild disease without any overt organ involvement, oral prednisone is recommended. For patients with severe DRESS syndrome, with one or more end-organ involvement, systemic steroids, IV methylprednisolone dosed at 1 mg/kg is recommended with a taper of 2 to 3 months or oral steroids after symptoms subside. Other modes of therapy include cyclosporine and intravenous immunoglobulins.13 Our patient required the initiation of IV methylprednisolone 60 mg twice daily to alleviate his symptoms of rash, and this regimen helped decrease his eosinophil count as well.
Conclusion
DRESS syndrome is an incredibly rare disease that results due to an adverse medication reaction. Our case details the necessity of physicians to be aware of the difficulty in appropriately diagnosing DRESS syndrome, given its overlap to several other rheumatological and hematological conditions, including malignancy. We aim to shed light on the association of leflunomide and DRESS syndrome, calling for further research to assess the strength of association between the two. Further research is required to develop guideline directed therapy for the management of DRESS syndrome.
We acknowledge the pathology department for their help in procuring the biopsy slides.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.
ORCID iD: Suman Rao https://orcid.org/0000-0003-1746-1025 | Recovered | ReactionOutcome | CC BY-NC | 33629602 | 19,046,277 | 2021 |
What was the outcome of reaction 'Diarrhoea'? | An Uncommon Presentation of DRESS Syndrome Secondary to Leflunomide Use: A Case Report.
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a constellation of symptoms that manifest as a result of certain medications. Several antipsychotics, antibiotics, and sulfa-containing drugs are known to be implicated in the etiology of DRESS syndrome. The clinical presentation of this disorder consists of a diffuse rash, lymphadenopathy, and systemic organ damage. Our patient presented with symptoms consistent with DRESS syndrome after being started on leflunomide, which is not commonly associated with DRESS. The diagnostic workup comprised of monitoring inflammatory markers on laboratory work, an excisional lymph node biopsy (to rule out malignancy), and a skin biopsy (to assess the etiology of the rash). Our patient received systemic steroids, dose-adjusted based on expert opinion. Further research is required to explore the association between leflunomide and DRESS and address guidelines for the management of DRESS.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe reaction that presents itself after the initiation of a drug or offending agent.1 Its presentation varies with patient and drug; however, common symptoms are a diffuse blanching rash, multiple end-organ involvement, and lymphadenopathy.2 Immediate diagnosis and appropriate management is necessary in order to avoid progression to severe DRESS symptoms requiring critical care management.3
There have been several antiepileptics, antibiotics, and sulfa drugs that have been heavily associated with DRESS syndrome. However, leflunomide has not been commonly associated with DRESS, as there have only been a few cases, to our knowledge, that have been documented thus far. Our patient was recently started on leflunomide and came in with a diffuse rash, diarrhea, and fever. After a thorough diagnostic approach, he was diagnosed with DRESS. Due to the lack of randomized controlled trials guiding the management of DRESS syndrome, our patient was started on a steroid dose deemed appropriate by expert opinion, which led to the resolution of his symptoms.
Case Presentation
We present the case of a 52-year-old male with past medical history of rheumatoid arthritis, essential hypertension and gastroesophageal reflux disease, who presented to our hospital with chief complaints of fever, diarrhea, and a rash that had been going on for a week prior to admission. He noticed a pruritic skin rash that started at his legs and then rapidly progressed to the rest of his body. He had multiple episodes of diarrhea and 3 episodes of emesis. Review of systems was negative for any possible sick contacts, pulmonary, or other abdominal symptoms.
Four months prior to admission, our patient was worked up for polyarthralgia and was diagnosed with seropositive rheumatoid arthritis. He was started on methotrexate without avail. He was switched to leflunomide, which he started taking 2 weeks prior to admission. His only medications were leflunomide, omeprazole, and ibuprofen.
Physical examination was remarkable for a middle-aged man who appeared his age and was is acute distress. He had a generalized maculopapular blanchable rash present diffusely across the surface of his body. Inguinal lymphadenopathy was noted, with the largest lymph node at 40 mm.
In the emergency department, he was noted to be tachypneic at a rate of 26 and tachycardic at a rate of 104. His laboratory work was significant for a white blood cell count of 18.7 × 103/µL, elevated eosinophil count at 2.19 × 103/µL, neutrophilia at 14.48 × 103/µL, C-reactive protein of 82 mg/L, erythrocyte sedimentation rate of 20 mm/h, ferritin of 246 ng/mL, and a low complement C4. Rapid strep test, monospot antibody test, and Lyme antibody testing were all negative. He was resuscitated with fluids and started on antibiotics. Computed tomography scan of the thorax, abdomen, and pelvis was done (Figure 1), which showed mediastinal, upper abdominal, axillary, and paraesophageal lymphadenopathy. Rheumatology, hematology/oncology, and dermatology services were consulted.
Figure 1. Diffuse inguinal lymphadenopathy seen on computed tomography scan of the abdomen/pelvis (marked by blue arrow).
Further studies showed an elevated rheumatoid factor of 241 IU/mL, an anti-CCP of >300 units, speckled pattern antibodies elevated at 160 (/dil), and quantitative immunoglobulin (Ig) E elevated at 20 184 IU/mL. Steroid therapy was deferred until an excisional lymph node biopsy could be obtained. His eosinophil count continued to increase to a peak of 21.34 × 103/µL.
After the excisional left inguinal lymph node biopsy was performed, our patient was started on intravenous (IV) methylprednisolone 40 mg twice daily, which was subsequently increased to 60 mg twice daily. His eosinophil count trended down to 10.70 × 103/µL.
Results of the excisional biopsy showed reactive lymphoid hyperplasia with increased polyclonal IgG4+ plasma cells, immunoblasts, Langerhans cells, and histiocytes, nonspecific findings that could be seen in drug-induced lymphadenopathy (Figure 2). There was no evidence of lymphoma, infection, or IgG4 disease. CD4:CD8 ratio was 8.2, which made the possibility of neoplasm less likely.
Figure 2. Lymph node biopsy showing partial effacement of normal lymph node architecture with expansion of the paracortical areas (indicated by blue arrow) by mixed cellular proliferation (hematoxylin and eosin, 4× magnification).
Eventually a skin biopsy was done which showed focal granular perivascular C3 and fibrinogen deposition. There was no specific deposition of immunoglobulin or complement in the epidermis or dermal-epidermal junction (Figure 3).
Figure 3. Skin biopsy showing superficial perivascular inflammation (blue arrow) and mild spongiosis (red arrow). There is no interface change or overt vascular damage (hematoxylin and eosin, 4× magnification).
After receiving 7 days of IV methylprednisolone 60 mg twice daily, our patient felt a significant resolution of his rash. He was discharged on a steroid taper.
Discussion
DRESS syndrome is a rare phenomenon that has an estimated incidence of 0.9 out of every 100 000 people.4 There are certain medications that are strongly linked to this syndrome. Antiepileptic drugs such as phenytoin, carbamazepine, and lamotrigine are noted to cause DRESS syndrome. Sulfa-containing medications, minocycline, and vancomycin are antibiotics that are linked to this syndrome as well. Other drugs such as allopurinol and mexiletine are associated.3,5
Leflunomide is not usually associated with DRESS syndrome. To our knowledge, there have been very few cases that have been presented similarly.6-8 We believe that further investigation is required to explore the association between leflunomide and DRESS, so as to allow safe prescription and education of patients who require leflunomide.
Although the pathogenesis of this disease is still being studied, there are 2 competing hypotheses that aim to explain the syndrome. One hypothesis is that DRESS syndrome occurs through a delayed hypersensitivity reaction whereby CD4 and CD8 T cells are specifically activated by the offending drug to overproduce cytokines and acute phase reactants.9 Another theory is that the offending agent leads to the activation of underlying HHV6/HHV7/Epstein–Barr virus or cytomegalovirus, and the ensuing symptoms are secondary to the body’s immune system attacking the virus.10 Our patient was tested for HHV6 and Epstein–Barr virus serologies, which came back negative.
Perhaps the most prominent clinical feature of DRESS syndrome is the diffuse, pruritic rash that emerges, as was the case in our patient. The rash can start out as maculopapular and can progress to being erythematous. In severe cases, pustule formation, exfoliation, or mucosal involvement can occur. Fever and lymphadenopathy are common presenting features of the disease as well.11
The following factors are considered as part of the diagnostic criteria in the workup of DRESS syndrome: a measured fever >101.3 °F, lymphadenopathy in 2 different anatomic areas, eosinophilia and atypical lymphocytes on blood work, and skin involvement, with the inclusion of a skin biopsy. Skin biopsy would show nonspecific changes, including vascular wall damage and lymphocytic infiltrate.12 Our patient met this criteria; however, the difficulty comes in the overlap of the clinical presentation of DRESS syndrome with multiple other medical conditions. Our patient necessitated an excisional lymph node biopsy in order to rule out lymphoma. Viral infections were excluded through the viral serologies that were obtained on admission. Hyper-eosinophilic syndrome was excluded due to lack of multiorgan involvement and nonspecific findings on skin biopsy.
There is a lack of evidence-based guideline directed therapy with regard to the management of DRESS syndrome. Initially, termination of the offending agent in addition to fluid resuscitation and symptom management are crucial. For mild disease without any overt organ involvement, oral prednisone is recommended. For patients with severe DRESS syndrome, with one or more end-organ involvement, systemic steroids, IV methylprednisolone dosed at 1 mg/kg is recommended with a taper of 2 to 3 months or oral steroids after symptoms subside. Other modes of therapy include cyclosporine and intravenous immunoglobulins.13 Our patient required the initiation of IV methylprednisolone 60 mg twice daily to alleviate his symptoms of rash, and this regimen helped decrease his eosinophil count as well.
Conclusion
DRESS syndrome is an incredibly rare disease that results due to an adverse medication reaction. Our case details the necessity of physicians to be aware of the difficulty in appropriately diagnosing DRESS syndrome, given its overlap to several other rheumatological and hematological conditions, including malignancy. We aim to shed light on the association of leflunomide and DRESS syndrome, calling for further research to assess the strength of association between the two. Further research is required to develop guideline directed therapy for the management of DRESS syndrome.
We acknowledge the pathology department for their help in procuring the biopsy slides.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.
ORCID iD: Suman Rao https://orcid.org/0000-0003-1746-1025 | Recovered | ReactionOutcome | CC BY-NC | 33629602 | 19,046,277 | 2021 |
What was the outcome of reaction 'Lymphadenopathy'? | An Uncommon Presentation of DRESS Syndrome Secondary to Leflunomide Use: A Case Report.
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a constellation of symptoms that manifest as a result of certain medications. Several antipsychotics, antibiotics, and sulfa-containing drugs are known to be implicated in the etiology of DRESS syndrome. The clinical presentation of this disorder consists of a diffuse rash, lymphadenopathy, and systemic organ damage. Our patient presented with symptoms consistent with DRESS syndrome after being started on leflunomide, which is not commonly associated with DRESS. The diagnostic workup comprised of monitoring inflammatory markers on laboratory work, an excisional lymph node biopsy (to rule out malignancy), and a skin biopsy (to assess the etiology of the rash). Our patient received systemic steroids, dose-adjusted based on expert opinion. Further research is required to explore the association between leflunomide and DRESS and address guidelines for the management of DRESS.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe reaction that presents itself after the initiation of a drug or offending agent.1 Its presentation varies with patient and drug; however, common symptoms are a diffuse blanching rash, multiple end-organ involvement, and lymphadenopathy.2 Immediate diagnosis and appropriate management is necessary in order to avoid progression to severe DRESS symptoms requiring critical care management.3
There have been several antiepileptics, antibiotics, and sulfa drugs that have been heavily associated with DRESS syndrome. However, leflunomide has not been commonly associated with DRESS, as there have only been a few cases, to our knowledge, that have been documented thus far. Our patient was recently started on leflunomide and came in with a diffuse rash, diarrhea, and fever. After a thorough diagnostic approach, he was diagnosed with DRESS. Due to the lack of randomized controlled trials guiding the management of DRESS syndrome, our patient was started on a steroid dose deemed appropriate by expert opinion, which led to the resolution of his symptoms.
Case Presentation
We present the case of a 52-year-old male with past medical history of rheumatoid arthritis, essential hypertension and gastroesophageal reflux disease, who presented to our hospital with chief complaints of fever, diarrhea, and a rash that had been going on for a week prior to admission. He noticed a pruritic skin rash that started at his legs and then rapidly progressed to the rest of his body. He had multiple episodes of diarrhea and 3 episodes of emesis. Review of systems was negative for any possible sick contacts, pulmonary, or other abdominal symptoms.
Four months prior to admission, our patient was worked up for polyarthralgia and was diagnosed with seropositive rheumatoid arthritis. He was started on methotrexate without avail. He was switched to leflunomide, which he started taking 2 weeks prior to admission. His only medications were leflunomide, omeprazole, and ibuprofen.
Physical examination was remarkable for a middle-aged man who appeared his age and was is acute distress. He had a generalized maculopapular blanchable rash present diffusely across the surface of his body. Inguinal lymphadenopathy was noted, with the largest lymph node at 40 mm.
In the emergency department, he was noted to be tachypneic at a rate of 26 and tachycardic at a rate of 104. His laboratory work was significant for a white blood cell count of 18.7 × 103/µL, elevated eosinophil count at 2.19 × 103/µL, neutrophilia at 14.48 × 103/µL, C-reactive protein of 82 mg/L, erythrocyte sedimentation rate of 20 mm/h, ferritin of 246 ng/mL, and a low complement C4. Rapid strep test, monospot antibody test, and Lyme antibody testing were all negative. He was resuscitated with fluids and started on antibiotics. Computed tomography scan of the thorax, abdomen, and pelvis was done (Figure 1), which showed mediastinal, upper abdominal, axillary, and paraesophageal lymphadenopathy. Rheumatology, hematology/oncology, and dermatology services were consulted.
Figure 1. Diffuse inguinal lymphadenopathy seen on computed tomography scan of the abdomen/pelvis (marked by blue arrow).
Further studies showed an elevated rheumatoid factor of 241 IU/mL, an anti-CCP of >300 units, speckled pattern antibodies elevated at 160 (/dil), and quantitative immunoglobulin (Ig) E elevated at 20 184 IU/mL. Steroid therapy was deferred until an excisional lymph node biopsy could be obtained. His eosinophil count continued to increase to a peak of 21.34 × 103/µL.
After the excisional left inguinal lymph node biopsy was performed, our patient was started on intravenous (IV) methylprednisolone 40 mg twice daily, which was subsequently increased to 60 mg twice daily. His eosinophil count trended down to 10.70 × 103/µL.
Results of the excisional biopsy showed reactive lymphoid hyperplasia with increased polyclonal IgG4+ plasma cells, immunoblasts, Langerhans cells, and histiocytes, nonspecific findings that could be seen in drug-induced lymphadenopathy (Figure 2). There was no evidence of lymphoma, infection, or IgG4 disease. CD4:CD8 ratio was 8.2, which made the possibility of neoplasm less likely.
Figure 2. Lymph node biopsy showing partial effacement of normal lymph node architecture with expansion of the paracortical areas (indicated by blue arrow) by mixed cellular proliferation (hematoxylin and eosin, 4× magnification).
Eventually a skin biopsy was done which showed focal granular perivascular C3 and fibrinogen deposition. There was no specific deposition of immunoglobulin or complement in the epidermis or dermal-epidermal junction (Figure 3).
Figure 3. Skin biopsy showing superficial perivascular inflammation (blue arrow) and mild spongiosis (red arrow). There is no interface change or overt vascular damage (hematoxylin and eosin, 4× magnification).
After receiving 7 days of IV methylprednisolone 60 mg twice daily, our patient felt a significant resolution of his rash. He was discharged on a steroid taper.
Discussion
DRESS syndrome is a rare phenomenon that has an estimated incidence of 0.9 out of every 100 000 people.4 There are certain medications that are strongly linked to this syndrome. Antiepileptic drugs such as phenytoin, carbamazepine, and lamotrigine are noted to cause DRESS syndrome. Sulfa-containing medications, minocycline, and vancomycin are antibiotics that are linked to this syndrome as well. Other drugs such as allopurinol and mexiletine are associated.3,5
Leflunomide is not usually associated with DRESS syndrome. To our knowledge, there have been very few cases that have been presented similarly.6-8 We believe that further investigation is required to explore the association between leflunomide and DRESS, so as to allow safe prescription and education of patients who require leflunomide.
Although the pathogenesis of this disease is still being studied, there are 2 competing hypotheses that aim to explain the syndrome. One hypothesis is that DRESS syndrome occurs through a delayed hypersensitivity reaction whereby CD4 and CD8 T cells are specifically activated by the offending drug to overproduce cytokines and acute phase reactants.9 Another theory is that the offending agent leads to the activation of underlying HHV6/HHV7/Epstein–Barr virus or cytomegalovirus, and the ensuing symptoms are secondary to the body’s immune system attacking the virus.10 Our patient was tested for HHV6 and Epstein–Barr virus serologies, which came back negative.
Perhaps the most prominent clinical feature of DRESS syndrome is the diffuse, pruritic rash that emerges, as was the case in our patient. The rash can start out as maculopapular and can progress to being erythematous. In severe cases, pustule formation, exfoliation, or mucosal involvement can occur. Fever and lymphadenopathy are common presenting features of the disease as well.11
The following factors are considered as part of the diagnostic criteria in the workup of DRESS syndrome: a measured fever >101.3 °F, lymphadenopathy in 2 different anatomic areas, eosinophilia and atypical lymphocytes on blood work, and skin involvement, with the inclusion of a skin biopsy. Skin biopsy would show nonspecific changes, including vascular wall damage and lymphocytic infiltrate.12 Our patient met this criteria; however, the difficulty comes in the overlap of the clinical presentation of DRESS syndrome with multiple other medical conditions. Our patient necessitated an excisional lymph node biopsy in order to rule out lymphoma. Viral infections were excluded through the viral serologies that were obtained on admission. Hyper-eosinophilic syndrome was excluded due to lack of multiorgan involvement and nonspecific findings on skin biopsy.
There is a lack of evidence-based guideline directed therapy with regard to the management of DRESS syndrome. Initially, termination of the offending agent in addition to fluid resuscitation and symptom management are crucial. For mild disease without any overt organ involvement, oral prednisone is recommended. For patients with severe DRESS syndrome, with one or more end-organ involvement, systemic steroids, IV methylprednisolone dosed at 1 mg/kg is recommended with a taper of 2 to 3 months or oral steroids after symptoms subside. Other modes of therapy include cyclosporine and intravenous immunoglobulins.13 Our patient required the initiation of IV methylprednisolone 60 mg twice daily to alleviate his symptoms of rash, and this regimen helped decrease his eosinophil count as well.
Conclusion
DRESS syndrome is an incredibly rare disease that results due to an adverse medication reaction. Our case details the necessity of physicians to be aware of the difficulty in appropriately diagnosing DRESS syndrome, given its overlap to several other rheumatological and hematological conditions, including malignancy. We aim to shed light on the association of leflunomide and DRESS syndrome, calling for further research to assess the strength of association between the two. Further research is required to develop guideline directed therapy for the management of DRESS syndrome.
We acknowledge the pathology department for their help in procuring the biopsy slides.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.
ORCID iD: Suman Rao https://orcid.org/0000-0003-1746-1025 | Recovered | ReactionOutcome | CC BY-NC | 33629602 | 19,046,277 | 2021 |
What was the outcome of reaction 'Lymphoid hyperplasia of intestine'? | An Uncommon Presentation of DRESS Syndrome Secondary to Leflunomide Use: A Case Report.
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a constellation of symptoms that manifest as a result of certain medications. Several antipsychotics, antibiotics, and sulfa-containing drugs are known to be implicated in the etiology of DRESS syndrome. The clinical presentation of this disorder consists of a diffuse rash, lymphadenopathy, and systemic organ damage. Our patient presented with symptoms consistent with DRESS syndrome after being started on leflunomide, which is not commonly associated with DRESS. The diagnostic workup comprised of monitoring inflammatory markers on laboratory work, an excisional lymph node biopsy (to rule out malignancy), and a skin biopsy (to assess the etiology of the rash). Our patient received systemic steroids, dose-adjusted based on expert opinion. Further research is required to explore the association between leflunomide and DRESS and address guidelines for the management of DRESS.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe reaction that presents itself after the initiation of a drug or offending agent.1 Its presentation varies with patient and drug; however, common symptoms are a diffuse blanching rash, multiple end-organ involvement, and lymphadenopathy.2 Immediate diagnosis and appropriate management is necessary in order to avoid progression to severe DRESS symptoms requiring critical care management.3
There have been several antiepileptics, antibiotics, and sulfa drugs that have been heavily associated with DRESS syndrome. However, leflunomide has not been commonly associated with DRESS, as there have only been a few cases, to our knowledge, that have been documented thus far. Our patient was recently started on leflunomide and came in with a diffuse rash, diarrhea, and fever. After a thorough diagnostic approach, he was diagnosed with DRESS. Due to the lack of randomized controlled trials guiding the management of DRESS syndrome, our patient was started on a steroid dose deemed appropriate by expert opinion, which led to the resolution of his symptoms.
Case Presentation
We present the case of a 52-year-old male with past medical history of rheumatoid arthritis, essential hypertension and gastroesophageal reflux disease, who presented to our hospital with chief complaints of fever, diarrhea, and a rash that had been going on for a week prior to admission. He noticed a pruritic skin rash that started at his legs and then rapidly progressed to the rest of his body. He had multiple episodes of diarrhea and 3 episodes of emesis. Review of systems was negative for any possible sick contacts, pulmonary, or other abdominal symptoms.
Four months prior to admission, our patient was worked up for polyarthralgia and was diagnosed with seropositive rheumatoid arthritis. He was started on methotrexate without avail. He was switched to leflunomide, which he started taking 2 weeks prior to admission. His only medications were leflunomide, omeprazole, and ibuprofen.
Physical examination was remarkable for a middle-aged man who appeared his age and was is acute distress. He had a generalized maculopapular blanchable rash present diffusely across the surface of his body. Inguinal lymphadenopathy was noted, with the largest lymph node at 40 mm.
In the emergency department, he was noted to be tachypneic at a rate of 26 and tachycardic at a rate of 104. His laboratory work was significant for a white blood cell count of 18.7 × 103/µL, elevated eosinophil count at 2.19 × 103/µL, neutrophilia at 14.48 × 103/µL, C-reactive protein of 82 mg/L, erythrocyte sedimentation rate of 20 mm/h, ferritin of 246 ng/mL, and a low complement C4. Rapid strep test, monospot antibody test, and Lyme antibody testing were all negative. He was resuscitated with fluids and started on antibiotics. Computed tomography scan of the thorax, abdomen, and pelvis was done (Figure 1), which showed mediastinal, upper abdominal, axillary, and paraesophageal lymphadenopathy. Rheumatology, hematology/oncology, and dermatology services were consulted.
Figure 1. Diffuse inguinal lymphadenopathy seen on computed tomography scan of the abdomen/pelvis (marked by blue arrow).
Further studies showed an elevated rheumatoid factor of 241 IU/mL, an anti-CCP of >300 units, speckled pattern antibodies elevated at 160 (/dil), and quantitative immunoglobulin (Ig) E elevated at 20 184 IU/mL. Steroid therapy was deferred until an excisional lymph node biopsy could be obtained. His eosinophil count continued to increase to a peak of 21.34 × 103/µL.
After the excisional left inguinal lymph node biopsy was performed, our patient was started on intravenous (IV) methylprednisolone 40 mg twice daily, which was subsequently increased to 60 mg twice daily. His eosinophil count trended down to 10.70 × 103/µL.
Results of the excisional biopsy showed reactive lymphoid hyperplasia with increased polyclonal IgG4+ plasma cells, immunoblasts, Langerhans cells, and histiocytes, nonspecific findings that could be seen in drug-induced lymphadenopathy (Figure 2). There was no evidence of lymphoma, infection, or IgG4 disease. CD4:CD8 ratio was 8.2, which made the possibility of neoplasm less likely.
Figure 2. Lymph node biopsy showing partial effacement of normal lymph node architecture with expansion of the paracortical areas (indicated by blue arrow) by mixed cellular proliferation (hematoxylin and eosin, 4× magnification).
Eventually a skin biopsy was done which showed focal granular perivascular C3 and fibrinogen deposition. There was no specific deposition of immunoglobulin or complement in the epidermis or dermal-epidermal junction (Figure 3).
Figure 3. Skin biopsy showing superficial perivascular inflammation (blue arrow) and mild spongiosis (red arrow). There is no interface change or overt vascular damage (hematoxylin and eosin, 4× magnification).
After receiving 7 days of IV methylprednisolone 60 mg twice daily, our patient felt a significant resolution of his rash. He was discharged on a steroid taper.
Discussion
DRESS syndrome is a rare phenomenon that has an estimated incidence of 0.9 out of every 100 000 people.4 There are certain medications that are strongly linked to this syndrome. Antiepileptic drugs such as phenytoin, carbamazepine, and lamotrigine are noted to cause DRESS syndrome. Sulfa-containing medications, minocycline, and vancomycin are antibiotics that are linked to this syndrome as well. Other drugs such as allopurinol and mexiletine are associated.3,5
Leflunomide is not usually associated with DRESS syndrome. To our knowledge, there have been very few cases that have been presented similarly.6-8 We believe that further investigation is required to explore the association between leflunomide and DRESS, so as to allow safe prescription and education of patients who require leflunomide.
Although the pathogenesis of this disease is still being studied, there are 2 competing hypotheses that aim to explain the syndrome. One hypothesis is that DRESS syndrome occurs through a delayed hypersensitivity reaction whereby CD4 and CD8 T cells are specifically activated by the offending drug to overproduce cytokines and acute phase reactants.9 Another theory is that the offending agent leads to the activation of underlying HHV6/HHV7/Epstein–Barr virus or cytomegalovirus, and the ensuing symptoms are secondary to the body’s immune system attacking the virus.10 Our patient was tested for HHV6 and Epstein–Barr virus serologies, which came back negative.
Perhaps the most prominent clinical feature of DRESS syndrome is the diffuse, pruritic rash that emerges, as was the case in our patient. The rash can start out as maculopapular and can progress to being erythematous. In severe cases, pustule formation, exfoliation, or mucosal involvement can occur. Fever and lymphadenopathy are common presenting features of the disease as well.11
The following factors are considered as part of the diagnostic criteria in the workup of DRESS syndrome: a measured fever >101.3 °F, lymphadenopathy in 2 different anatomic areas, eosinophilia and atypical lymphocytes on blood work, and skin involvement, with the inclusion of a skin biopsy. Skin biopsy would show nonspecific changes, including vascular wall damage and lymphocytic infiltrate.12 Our patient met this criteria; however, the difficulty comes in the overlap of the clinical presentation of DRESS syndrome with multiple other medical conditions. Our patient necessitated an excisional lymph node biopsy in order to rule out lymphoma. Viral infections were excluded through the viral serologies that were obtained on admission. Hyper-eosinophilic syndrome was excluded due to lack of multiorgan involvement and nonspecific findings on skin biopsy.
There is a lack of evidence-based guideline directed therapy with regard to the management of DRESS syndrome. Initially, termination of the offending agent in addition to fluid resuscitation and symptom management are crucial. For mild disease without any overt organ involvement, oral prednisone is recommended. For patients with severe DRESS syndrome, with one or more end-organ involvement, systemic steroids, IV methylprednisolone dosed at 1 mg/kg is recommended with a taper of 2 to 3 months or oral steroids after symptoms subside. Other modes of therapy include cyclosporine and intravenous immunoglobulins.13 Our patient required the initiation of IV methylprednisolone 60 mg twice daily to alleviate his symptoms of rash, and this regimen helped decrease his eosinophil count as well.
Conclusion
DRESS syndrome is an incredibly rare disease that results due to an adverse medication reaction. Our case details the necessity of physicians to be aware of the difficulty in appropriately diagnosing DRESS syndrome, given its overlap to several other rheumatological and hematological conditions, including malignancy. We aim to shed light on the association of leflunomide and DRESS syndrome, calling for further research to assess the strength of association between the two. Further research is required to develop guideline directed therapy for the management of DRESS syndrome.
We acknowledge the pathology department for their help in procuring the biopsy slides.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.
ORCID iD: Suman Rao https://orcid.org/0000-0003-1746-1025 | Recovered | ReactionOutcome | CC BY-NC | 33629602 | 19,046,277 | 2021 |
What was the outcome of reaction 'Pyrexia'? | An Uncommon Presentation of DRESS Syndrome Secondary to Leflunomide Use: A Case Report.
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a constellation of symptoms that manifest as a result of certain medications. Several antipsychotics, antibiotics, and sulfa-containing drugs are known to be implicated in the etiology of DRESS syndrome. The clinical presentation of this disorder consists of a diffuse rash, lymphadenopathy, and systemic organ damage. Our patient presented with symptoms consistent with DRESS syndrome after being started on leflunomide, which is not commonly associated with DRESS. The diagnostic workup comprised of monitoring inflammatory markers on laboratory work, an excisional lymph node biopsy (to rule out malignancy), and a skin biopsy (to assess the etiology of the rash). Our patient received systemic steroids, dose-adjusted based on expert opinion. Further research is required to explore the association between leflunomide and DRESS and address guidelines for the management of DRESS.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe reaction that presents itself after the initiation of a drug or offending agent.1 Its presentation varies with patient and drug; however, common symptoms are a diffuse blanching rash, multiple end-organ involvement, and lymphadenopathy.2 Immediate diagnosis and appropriate management is necessary in order to avoid progression to severe DRESS symptoms requiring critical care management.3
There have been several antiepileptics, antibiotics, and sulfa drugs that have been heavily associated with DRESS syndrome. However, leflunomide has not been commonly associated with DRESS, as there have only been a few cases, to our knowledge, that have been documented thus far. Our patient was recently started on leflunomide and came in with a diffuse rash, diarrhea, and fever. After a thorough diagnostic approach, he was diagnosed with DRESS. Due to the lack of randomized controlled trials guiding the management of DRESS syndrome, our patient was started on a steroid dose deemed appropriate by expert opinion, which led to the resolution of his symptoms.
Case Presentation
We present the case of a 52-year-old male with past medical history of rheumatoid arthritis, essential hypertension and gastroesophageal reflux disease, who presented to our hospital with chief complaints of fever, diarrhea, and a rash that had been going on for a week prior to admission. He noticed a pruritic skin rash that started at his legs and then rapidly progressed to the rest of his body. He had multiple episodes of diarrhea and 3 episodes of emesis. Review of systems was negative for any possible sick contacts, pulmonary, or other abdominal symptoms.
Four months prior to admission, our patient was worked up for polyarthralgia and was diagnosed with seropositive rheumatoid arthritis. He was started on methotrexate without avail. He was switched to leflunomide, which he started taking 2 weeks prior to admission. His only medications were leflunomide, omeprazole, and ibuprofen.
Physical examination was remarkable for a middle-aged man who appeared his age and was is acute distress. He had a generalized maculopapular blanchable rash present diffusely across the surface of his body. Inguinal lymphadenopathy was noted, with the largest lymph node at 40 mm.
In the emergency department, he was noted to be tachypneic at a rate of 26 and tachycardic at a rate of 104. His laboratory work was significant for a white blood cell count of 18.7 × 103/µL, elevated eosinophil count at 2.19 × 103/µL, neutrophilia at 14.48 × 103/µL, C-reactive protein of 82 mg/L, erythrocyte sedimentation rate of 20 mm/h, ferritin of 246 ng/mL, and a low complement C4. Rapid strep test, monospot antibody test, and Lyme antibody testing were all negative. He was resuscitated with fluids and started on antibiotics. Computed tomography scan of the thorax, abdomen, and pelvis was done (Figure 1), which showed mediastinal, upper abdominal, axillary, and paraesophageal lymphadenopathy. Rheumatology, hematology/oncology, and dermatology services were consulted.
Figure 1. Diffuse inguinal lymphadenopathy seen on computed tomography scan of the abdomen/pelvis (marked by blue arrow).
Further studies showed an elevated rheumatoid factor of 241 IU/mL, an anti-CCP of >300 units, speckled pattern antibodies elevated at 160 (/dil), and quantitative immunoglobulin (Ig) E elevated at 20 184 IU/mL. Steroid therapy was deferred until an excisional lymph node biopsy could be obtained. His eosinophil count continued to increase to a peak of 21.34 × 103/µL.
After the excisional left inguinal lymph node biopsy was performed, our patient was started on intravenous (IV) methylprednisolone 40 mg twice daily, which was subsequently increased to 60 mg twice daily. His eosinophil count trended down to 10.70 × 103/µL.
Results of the excisional biopsy showed reactive lymphoid hyperplasia with increased polyclonal IgG4+ plasma cells, immunoblasts, Langerhans cells, and histiocytes, nonspecific findings that could be seen in drug-induced lymphadenopathy (Figure 2). There was no evidence of lymphoma, infection, or IgG4 disease. CD4:CD8 ratio was 8.2, which made the possibility of neoplasm less likely.
Figure 2. Lymph node biopsy showing partial effacement of normal lymph node architecture with expansion of the paracortical areas (indicated by blue arrow) by mixed cellular proliferation (hematoxylin and eosin, 4× magnification).
Eventually a skin biopsy was done which showed focal granular perivascular C3 and fibrinogen deposition. There was no specific deposition of immunoglobulin or complement in the epidermis or dermal-epidermal junction (Figure 3).
Figure 3. Skin biopsy showing superficial perivascular inflammation (blue arrow) and mild spongiosis (red arrow). There is no interface change or overt vascular damage (hematoxylin and eosin, 4× magnification).
After receiving 7 days of IV methylprednisolone 60 mg twice daily, our patient felt a significant resolution of his rash. He was discharged on a steroid taper.
Discussion
DRESS syndrome is a rare phenomenon that has an estimated incidence of 0.9 out of every 100 000 people.4 There are certain medications that are strongly linked to this syndrome. Antiepileptic drugs such as phenytoin, carbamazepine, and lamotrigine are noted to cause DRESS syndrome. Sulfa-containing medications, minocycline, and vancomycin are antibiotics that are linked to this syndrome as well. Other drugs such as allopurinol and mexiletine are associated.3,5
Leflunomide is not usually associated with DRESS syndrome. To our knowledge, there have been very few cases that have been presented similarly.6-8 We believe that further investigation is required to explore the association between leflunomide and DRESS, so as to allow safe prescription and education of patients who require leflunomide.
Although the pathogenesis of this disease is still being studied, there are 2 competing hypotheses that aim to explain the syndrome. One hypothesis is that DRESS syndrome occurs through a delayed hypersensitivity reaction whereby CD4 and CD8 T cells are specifically activated by the offending drug to overproduce cytokines and acute phase reactants.9 Another theory is that the offending agent leads to the activation of underlying HHV6/HHV7/Epstein–Barr virus or cytomegalovirus, and the ensuing symptoms are secondary to the body’s immune system attacking the virus.10 Our patient was tested for HHV6 and Epstein–Barr virus serologies, which came back negative.
Perhaps the most prominent clinical feature of DRESS syndrome is the diffuse, pruritic rash that emerges, as was the case in our patient. The rash can start out as maculopapular and can progress to being erythematous. In severe cases, pustule formation, exfoliation, or mucosal involvement can occur. Fever and lymphadenopathy are common presenting features of the disease as well.11
The following factors are considered as part of the diagnostic criteria in the workup of DRESS syndrome: a measured fever >101.3 °F, lymphadenopathy in 2 different anatomic areas, eosinophilia and atypical lymphocytes on blood work, and skin involvement, with the inclusion of a skin biopsy. Skin biopsy would show nonspecific changes, including vascular wall damage and lymphocytic infiltrate.12 Our patient met this criteria; however, the difficulty comes in the overlap of the clinical presentation of DRESS syndrome with multiple other medical conditions. Our patient necessitated an excisional lymph node biopsy in order to rule out lymphoma. Viral infections were excluded through the viral serologies that were obtained on admission. Hyper-eosinophilic syndrome was excluded due to lack of multiorgan involvement and nonspecific findings on skin biopsy.
There is a lack of evidence-based guideline directed therapy with regard to the management of DRESS syndrome. Initially, termination of the offending agent in addition to fluid resuscitation and symptom management are crucial. For mild disease without any overt organ involvement, oral prednisone is recommended. For patients with severe DRESS syndrome, with one or more end-organ involvement, systemic steroids, IV methylprednisolone dosed at 1 mg/kg is recommended with a taper of 2 to 3 months or oral steroids after symptoms subside. Other modes of therapy include cyclosporine and intravenous immunoglobulins.13 Our patient required the initiation of IV methylprednisolone 60 mg twice daily to alleviate his symptoms of rash, and this regimen helped decrease his eosinophil count as well.
Conclusion
DRESS syndrome is an incredibly rare disease that results due to an adverse medication reaction. Our case details the necessity of physicians to be aware of the difficulty in appropriately diagnosing DRESS syndrome, given its overlap to several other rheumatological and hematological conditions, including malignancy. We aim to shed light on the association of leflunomide and DRESS syndrome, calling for further research to assess the strength of association between the two. Further research is required to develop guideline directed therapy for the management of DRESS syndrome.
We acknowledge the pathology department for their help in procuring the biopsy slides.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.
ORCID iD: Suman Rao https://orcid.org/0000-0003-1746-1025 | Recovered | ReactionOutcome | CC BY-NC | 33629602 | 19,046,277 | 2021 |
What was the outcome of reaction 'Rash maculo-papular'? | An Uncommon Presentation of DRESS Syndrome Secondary to Leflunomide Use: A Case Report.
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a constellation of symptoms that manifest as a result of certain medications. Several antipsychotics, antibiotics, and sulfa-containing drugs are known to be implicated in the etiology of DRESS syndrome. The clinical presentation of this disorder consists of a diffuse rash, lymphadenopathy, and systemic organ damage. Our patient presented with symptoms consistent with DRESS syndrome after being started on leflunomide, which is not commonly associated with DRESS. The diagnostic workup comprised of monitoring inflammatory markers on laboratory work, an excisional lymph node biopsy (to rule out malignancy), and a skin biopsy (to assess the etiology of the rash). Our patient received systemic steroids, dose-adjusted based on expert opinion. Further research is required to explore the association between leflunomide and DRESS and address guidelines for the management of DRESS.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe reaction that presents itself after the initiation of a drug or offending agent.1 Its presentation varies with patient and drug; however, common symptoms are a diffuse blanching rash, multiple end-organ involvement, and lymphadenopathy.2 Immediate diagnosis and appropriate management is necessary in order to avoid progression to severe DRESS symptoms requiring critical care management.3
There have been several antiepileptics, antibiotics, and sulfa drugs that have been heavily associated with DRESS syndrome. However, leflunomide has not been commonly associated with DRESS, as there have only been a few cases, to our knowledge, that have been documented thus far. Our patient was recently started on leflunomide and came in with a diffuse rash, diarrhea, and fever. After a thorough diagnostic approach, he was diagnosed with DRESS. Due to the lack of randomized controlled trials guiding the management of DRESS syndrome, our patient was started on a steroid dose deemed appropriate by expert opinion, which led to the resolution of his symptoms.
Case Presentation
We present the case of a 52-year-old male with past medical history of rheumatoid arthritis, essential hypertension and gastroesophageal reflux disease, who presented to our hospital with chief complaints of fever, diarrhea, and a rash that had been going on for a week prior to admission. He noticed a pruritic skin rash that started at his legs and then rapidly progressed to the rest of his body. He had multiple episodes of diarrhea and 3 episodes of emesis. Review of systems was negative for any possible sick contacts, pulmonary, or other abdominal symptoms.
Four months prior to admission, our patient was worked up for polyarthralgia and was diagnosed with seropositive rheumatoid arthritis. He was started on methotrexate without avail. He was switched to leflunomide, which he started taking 2 weeks prior to admission. His only medications were leflunomide, omeprazole, and ibuprofen.
Physical examination was remarkable for a middle-aged man who appeared his age and was is acute distress. He had a generalized maculopapular blanchable rash present diffusely across the surface of his body. Inguinal lymphadenopathy was noted, with the largest lymph node at 40 mm.
In the emergency department, he was noted to be tachypneic at a rate of 26 and tachycardic at a rate of 104. His laboratory work was significant for a white blood cell count of 18.7 × 103/µL, elevated eosinophil count at 2.19 × 103/µL, neutrophilia at 14.48 × 103/µL, C-reactive protein of 82 mg/L, erythrocyte sedimentation rate of 20 mm/h, ferritin of 246 ng/mL, and a low complement C4. Rapid strep test, monospot antibody test, and Lyme antibody testing were all negative. He was resuscitated with fluids and started on antibiotics. Computed tomography scan of the thorax, abdomen, and pelvis was done (Figure 1), which showed mediastinal, upper abdominal, axillary, and paraesophageal lymphadenopathy. Rheumatology, hematology/oncology, and dermatology services were consulted.
Figure 1. Diffuse inguinal lymphadenopathy seen on computed tomography scan of the abdomen/pelvis (marked by blue arrow).
Further studies showed an elevated rheumatoid factor of 241 IU/mL, an anti-CCP of >300 units, speckled pattern antibodies elevated at 160 (/dil), and quantitative immunoglobulin (Ig) E elevated at 20 184 IU/mL. Steroid therapy was deferred until an excisional lymph node biopsy could be obtained. His eosinophil count continued to increase to a peak of 21.34 × 103/µL.
After the excisional left inguinal lymph node biopsy was performed, our patient was started on intravenous (IV) methylprednisolone 40 mg twice daily, which was subsequently increased to 60 mg twice daily. His eosinophil count trended down to 10.70 × 103/µL.
Results of the excisional biopsy showed reactive lymphoid hyperplasia with increased polyclonal IgG4+ plasma cells, immunoblasts, Langerhans cells, and histiocytes, nonspecific findings that could be seen in drug-induced lymphadenopathy (Figure 2). There was no evidence of lymphoma, infection, or IgG4 disease. CD4:CD8 ratio was 8.2, which made the possibility of neoplasm less likely.
Figure 2. Lymph node biopsy showing partial effacement of normal lymph node architecture with expansion of the paracortical areas (indicated by blue arrow) by mixed cellular proliferation (hematoxylin and eosin, 4× magnification).
Eventually a skin biopsy was done which showed focal granular perivascular C3 and fibrinogen deposition. There was no specific deposition of immunoglobulin or complement in the epidermis or dermal-epidermal junction (Figure 3).
Figure 3. Skin biopsy showing superficial perivascular inflammation (blue arrow) and mild spongiosis (red arrow). There is no interface change or overt vascular damage (hematoxylin and eosin, 4× magnification).
After receiving 7 days of IV methylprednisolone 60 mg twice daily, our patient felt a significant resolution of his rash. He was discharged on a steroid taper.
Discussion
DRESS syndrome is a rare phenomenon that has an estimated incidence of 0.9 out of every 100 000 people.4 There are certain medications that are strongly linked to this syndrome. Antiepileptic drugs such as phenytoin, carbamazepine, and lamotrigine are noted to cause DRESS syndrome. Sulfa-containing medications, minocycline, and vancomycin are antibiotics that are linked to this syndrome as well. Other drugs such as allopurinol and mexiletine are associated.3,5
Leflunomide is not usually associated with DRESS syndrome. To our knowledge, there have been very few cases that have been presented similarly.6-8 We believe that further investigation is required to explore the association between leflunomide and DRESS, so as to allow safe prescription and education of patients who require leflunomide.
Although the pathogenesis of this disease is still being studied, there are 2 competing hypotheses that aim to explain the syndrome. One hypothesis is that DRESS syndrome occurs through a delayed hypersensitivity reaction whereby CD4 and CD8 T cells are specifically activated by the offending drug to overproduce cytokines and acute phase reactants.9 Another theory is that the offending agent leads to the activation of underlying HHV6/HHV7/Epstein–Barr virus or cytomegalovirus, and the ensuing symptoms are secondary to the body’s immune system attacking the virus.10 Our patient was tested for HHV6 and Epstein–Barr virus serologies, which came back negative.
Perhaps the most prominent clinical feature of DRESS syndrome is the diffuse, pruritic rash that emerges, as was the case in our patient. The rash can start out as maculopapular and can progress to being erythematous. In severe cases, pustule formation, exfoliation, or mucosal involvement can occur. Fever and lymphadenopathy are common presenting features of the disease as well.11
The following factors are considered as part of the diagnostic criteria in the workup of DRESS syndrome: a measured fever >101.3 °F, lymphadenopathy in 2 different anatomic areas, eosinophilia and atypical lymphocytes on blood work, and skin involvement, with the inclusion of a skin biopsy. Skin biopsy would show nonspecific changes, including vascular wall damage and lymphocytic infiltrate.12 Our patient met this criteria; however, the difficulty comes in the overlap of the clinical presentation of DRESS syndrome with multiple other medical conditions. Our patient necessitated an excisional lymph node biopsy in order to rule out lymphoma. Viral infections were excluded through the viral serologies that were obtained on admission. Hyper-eosinophilic syndrome was excluded due to lack of multiorgan involvement and nonspecific findings on skin biopsy.
There is a lack of evidence-based guideline directed therapy with regard to the management of DRESS syndrome. Initially, termination of the offending agent in addition to fluid resuscitation and symptom management are crucial. For mild disease without any overt organ involvement, oral prednisone is recommended. For patients with severe DRESS syndrome, with one or more end-organ involvement, systemic steroids, IV methylprednisolone dosed at 1 mg/kg is recommended with a taper of 2 to 3 months or oral steroids after symptoms subside. Other modes of therapy include cyclosporine and intravenous immunoglobulins.13 Our patient required the initiation of IV methylprednisolone 60 mg twice daily to alleviate his symptoms of rash, and this regimen helped decrease his eosinophil count as well.
Conclusion
DRESS syndrome is an incredibly rare disease that results due to an adverse medication reaction. Our case details the necessity of physicians to be aware of the difficulty in appropriately diagnosing DRESS syndrome, given its overlap to several other rheumatological and hematological conditions, including malignancy. We aim to shed light on the association of leflunomide and DRESS syndrome, calling for further research to assess the strength of association between the two. Further research is required to develop guideline directed therapy for the management of DRESS syndrome.
We acknowledge the pathology department for their help in procuring the biopsy slides.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.
ORCID iD: Suman Rao https://orcid.org/0000-0003-1746-1025 | Recovered | ReactionOutcome | CC BY-NC | 33629602 | 19,046,277 | 2021 |
What was the outcome of reaction 'Rash pruritic'? | An Uncommon Presentation of DRESS Syndrome Secondary to Leflunomide Use: A Case Report.
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a constellation of symptoms that manifest as a result of certain medications. Several antipsychotics, antibiotics, and sulfa-containing drugs are known to be implicated in the etiology of DRESS syndrome. The clinical presentation of this disorder consists of a diffuse rash, lymphadenopathy, and systemic organ damage. Our patient presented with symptoms consistent with DRESS syndrome after being started on leflunomide, which is not commonly associated with DRESS. The diagnostic workup comprised of monitoring inflammatory markers on laboratory work, an excisional lymph node biopsy (to rule out malignancy), and a skin biopsy (to assess the etiology of the rash). Our patient received systemic steroids, dose-adjusted based on expert opinion. Further research is required to explore the association between leflunomide and DRESS and address guidelines for the management of DRESS.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe reaction that presents itself after the initiation of a drug or offending agent.1 Its presentation varies with patient and drug; however, common symptoms are a diffuse blanching rash, multiple end-organ involvement, and lymphadenopathy.2 Immediate diagnosis and appropriate management is necessary in order to avoid progression to severe DRESS symptoms requiring critical care management.3
There have been several antiepileptics, antibiotics, and sulfa drugs that have been heavily associated with DRESS syndrome. However, leflunomide has not been commonly associated with DRESS, as there have only been a few cases, to our knowledge, that have been documented thus far. Our patient was recently started on leflunomide and came in with a diffuse rash, diarrhea, and fever. After a thorough diagnostic approach, he was diagnosed with DRESS. Due to the lack of randomized controlled trials guiding the management of DRESS syndrome, our patient was started on a steroid dose deemed appropriate by expert opinion, which led to the resolution of his symptoms.
Case Presentation
We present the case of a 52-year-old male with past medical history of rheumatoid arthritis, essential hypertension and gastroesophageal reflux disease, who presented to our hospital with chief complaints of fever, diarrhea, and a rash that had been going on for a week prior to admission. He noticed a pruritic skin rash that started at his legs and then rapidly progressed to the rest of his body. He had multiple episodes of diarrhea and 3 episodes of emesis. Review of systems was negative for any possible sick contacts, pulmonary, or other abdominal symptoms.
Four months prior to admission, our patient was worked up for polyarthralgia and was diagnosed with seropositive rheumatoid arthritis. He was started on methotrexate without avail. He was switched to leflunomide, which he started taking 2 weeks prior to admission. His only medications were leflunomide, omeprazole, and ibuprofen.
Physical examination was remarkable for a middle-aged man who appeared his age and was is acute distress. He had a generalized maculopapular blanchable rash present diffusely across the surface of his body. Inguinal lymphadenopathy was noted, with the largest lymph node at 40 mm.
In the emergency department, he was noted to be tachypneic at a rate of 26 and tachycardic at a rate of 104. His laboratory work was significant for a white blood cell count of 18.7 × 103/µL, elevated eosinophil count at 2.19 × 103/µL, neutrophilia at 14.48 × 103/µL, C-reactive protein of 82 mg/L, erythrocyte sedimentation rate of 20 mm/h, ferritin of 246 ng/mL, and a low complement C4. Rapid strep test, monospot antibody test, and Lyme antibody testing were all negative. He was resuscitated with fluids and started on antibiotics. Computed tomography scan of the thorax, abdomen, and pelvis was done (Figure 1), which showed mediastinal, upper abdominal, axillary, and paraesophageal lymphadenopathy. Rheumatology, hematology/oncology, and dermatology services were consulted.
Figure 1. Diffuse inguinal lymphadenopathy seen on computed tomography scan of the abdomen/pelvis (marked by blue arrow).
Further studies showed an elevated rheumatoid factor of 241 IU/mL, an anti-CCP of >300 units, speckled pattern antibodies elevated at 160 (/dil), and quantitative immunoglobulin (Ig) E elevated at 20 184 IU/mL. Steroid therapy was deferred until an excisional lymph node biopsy could be obtained. His eosinophil count continued to increase to a peak of 21.34 × 103/µL.
After the excisional left inguinal lymph node biopsy was performed, our patient was started on intravenous (IV) methylprednisolone 40 mg twice daily, which was subsequently increased to 60 mg twice daily. His eosinophil count trended down to 10.70 × 103/µL.
Results of the excisional biopsy showed reactive lymphoid hyperplasia with increased polyclonal IgG4+ plasma cells, immunoblasts, Langerhans cells, and histiocytes, nonspecific findings that could be seen in drug-induced lymphadenopathy (Figure 2). There was no evidence of lymphoma, infection, or IgG4 disease. CD4:CD8 ratio was 8.2, which made the possibility of neoplasm less likely.
Figure 2. Lymph node biopsy showing partial effacement of normal lymph node architecture with expansion of the paracortical areas (indicated by blue arrow) by mixed cellular proliferation (hematoxylin and eosin, 4× magnification).
Eventually a skin biopsy was done which showed focal granular perivascular C3 and fibrinogen deposition. There was no specific deposition of immunoglobulin or complement in the epidermis or dermal-epidermal junction (Figure 3).
Figure 3. Skin biopsy showing superficial perivascular inflammation (blue arrow) and mild spongiosis (red arrow). There is no interface change or overt vascular damage (hematoxylin and eosin, 4× magnification).
After receiving 7 days of IV methylprednisolone 60 mg twice daily, our patient felt a significant resolution of his rash. He was discharged on a steroid taper.
Discussion
DRESS syndrome is a rare phenomenon that has an estimated incidence of 0.9 out of every 100 000 people.4 There are certain medications that are strongly linked to this syndrome. Antiepileptic drugs such as phenytoin, carbamazepine, and lamotrigine are noted to cause DRESS syndrome. Sulfa-containing medications, minocycline, and vancomycin are antibiotics that are linked to this syndrome as well. Other drugs such as allopurinol and mexiletine are associated.3,5
Leflunomide is not usually associated with DRESS syndrome. To our knowledge, there have been very few cases that have been presented similarly.6-8 We believe that further investigation is required to explore the association between leflunomide and DRESS, so as to allow safe prescription and education of patients who require leflunomide.
Although the pathogenesis of this disease is still being studied, there are 2 competing hypotheses that aim to explain the syndrome. One hypothesis is that DRESS syndrome occurs through a delayed hypersensitivity reaction whereby CD4 and CD8 T cells are specifically activated by the offending drug to overproduce cytokines and acute phase reactants.9 Another theory is that the offending agent leads to the activation of underlying HHV6/HHV7/Epstein–Barr virus or cytomegalovirus, and the ensuing symptoms are secondary to the body’s immune system attacking the virus.10 Our patient was tested for HHV6 and Epstein–Barr virus serologies, which came back negative.
Perhaps the most prominent clinical feature of DRESS syndrome is the diffuse, pruritic rash that emerges, as was the case in our patient. The rash can start out as maculopapular and can progress to being erythematous. In severe cases, pustule formation, exfoliation, or mucosal involvement can occur. Fever and lymphadenopathy are common presenting features of the disease as well.11
The following factors are considered as part of the diagnostic criteria in the workup of DRESS syndrome: a measured fever >101.3 °F, lymphadenopathy in 2 different anatomic areas, eosinophilia and atypical lymphocytes on blood work, and skin involvement, with the inclusion of a skin biopsy. Skin biopsy would show nonspecific changes, including vascular wall damage and lymphocytic infiltrate.12 Our patient met this criteria; however, the difficulty comes in the overlap of the clinical presentation of DRESS syndrome with multiple other medical conditions. Our patient necessitated an excisional lymph node biopsy in order to rule out lymphoma. Viral infections were excluded through the viral serologies that were obtained on admission. Hyper-eosinophilic syndrome was excluded due to lack of multiorgan involvement and nonspecific findings on skin biopsy.
There is a lack of evidence-based guideline directed therapy with regard to the management of DRESS syndrome. Initially, termination of the offending agent in addition to fluid resuscitation and symptom management are crucial. For mild disease without any overt organ involvement, oral prednisone is recommended. For patients with severe DRESS syndrome, with one or more end-organ involvement, systemic steroids, IV methylprednisolone dosed at 1 mg/kg is recommended with a taper of 2 to 3 months or oral steroids after symptoms subside. Other modes of therapy include cyclosporine and intravenous immunoglobulins.13 Our patient required the initiation of IV methylprednisolone 60 mg twice daily to alleviate his symptoms of rash, and this regimen helped decrease his eosinophil count as well.
Conclusion
DRESS syndrome is an incredibly rare disease that results due to an adverse medication reaction. Our case details the necessity of physicians to be aware of the difficulty in appropriately diagnosing DRESS syndrome, given its overlap to several other rheumatological and hematological conditions, including malignancy. We aim to shed light on the association of leflunomide and DRESS syndrome, calling for further research to assess the strength of association between the two. Further research is required to develop guideline directed therapy for the management of DRESS syndrome.
We acknowledge the pathology department for their help in procuring the biopsy slides.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.
ORCID iD: Suman Rao https://orcid.org/0000-0003-1746-1025 | Recovered | ReactionOutcome | CC BY-NC | 33629602 | 19,046,277 | 2021 |
What was the outcome of reaction 'Rash'? | An Uncommon Presentation of DRESS Syndrome Secondary to Leflunomide Use: A Case Report.
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a constellation of symptoms that manifest as a result of certain medications. Several antipsychotics, antibiotics, and sulfa-containing drugs are known to be implicated in the etiology of DRESS syndrome. The clinical presentation of this disorder consists of a diffuse rash, lymphadenopathy, and systemic organ damage. Our patient presented with symptoms consistent with DRESS syndrome after being started on leflunomide, which is not commonly associated with DRESS. The diagnostic workup comprised of monitoring inflammatory markers on laboratory work, an excisional lymph node biopsy (to rule out malignancy), and a skin biopsy (to assess the etiology of the rash). Our patient received systemic steroids, dose-adjusted based on expert opinion. Further research is required to explore the association between leflunomide and DRESS and address guidelines for the management of DRESS.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe reaction that presents itself after the initiation of a drug or offending agent.1 Its presentation varies with patient and drug; however, common symptoms are a diffuse blanching rash, multiple end-organ involvement, and lymphadenopathy.2 Immediate diagnosis and appropriate management is necessary in order to avoid progression to severe DRESS symptoms requiring critical care management.3
There have been several antiepileptics, antibiotics, and sulfa drugs that have been heavily associated with DRESS syndrome. However, leflunomide has not been commonly associated with DRESS, as there have only been a few cases, to our knowledge, that have been documented thus far. Our patient was recently started on leflunomide and came in with a diffuse rash, diarrhea, and fever. After a thorough diagnostic approach, he was diagnosed with DRESS. Due to the lack of randomized controlled trials guiding the management of DRESS syndrome, our patient was started on a steroid dose deemed appropriate by expert opinion, which led to the resolution of his symptoms.
Case Presentation
We present the case of a 52-year-old male with past medical history of rheumatoid arthritis, essential hypertension and gastroesophageal reflux disease, who presented to our hospital with chief complaints of fever, diarrhea, and a rash that had been going on for a week prior to admission. He noticed a pruritic skin rash that started at his legs and then rapidly progressed to the rest of his body. He had multiple episodes of diarrhea and 3 episodes of emesis. Review of systems was negative for any possible sick contacts, pulmonary, or other abdominal symptoms.
Four months prior to admission, our patient was worked up for polyarthralgia and was diagnosed with seropositive rheumatoid arthritis. He was started on methotrexate without avail. He was switched to leflunomide, which he started taking 2 weeks prior to admission. His only medications were leflunomide, omeprazole, and ibuprofen.
Physical examination was remarkable for a middle-aged man who appeared his age and was is acute distress. He had a generalized maculopapular blanchable rash present diffusely across the surface of his body. Inguinal lymphadenopathy was noted, with the largest lymph node at 40 mm.
In the emergency department, he was noted to be tachypneic at a rate of 26 and tachycardic at a rate of 104. His laboratory work was significant for a white blood cell count of 18.7 × 103/µL, elevated eosinophil count at 2.19 × 103/µL, neutrophilia at 14.48 × 103/µL, C-reactive protein of 82 mg/L, erythrocyte sedimentation rate of 20 mm/h, ferritin of 246 ng/mL, and a low complement C4. Rapid strep test, monospot antibody test, and Lyme antibody testing were all negative. He was resuscitated with fluids and started on antibiotics. Computed tomography scan of the thorax, abdomen, and pelvis was done (Figure 1), which showed mediastinal, upper abdominal, axillary, and paraesophageal lymphadenopathy. Rheumatology, hematology/oncology, and dermatology services were consulted.
Figure 1. Diffuse inguinal lymphadenopathy seen on computed tomography scan of the abdomen/pelvis (marked by blue arrow).
Further studies showed an elevated rheumatoid factor of 241 IU/mL, an anti-CCP of >300 units, speckled pattern antibodies elevated at 160 (/dil), and quantitative immunoglobulin (Ig) E elevated at 20 184 IU/mL. Steroid therapy was deferred until an excisional lymph node biopsy could be obtained. His eosinophil count continued to increase to a peak of 21.34 × 103/µL.
After the excisional left inguinal lymph node biopsy was performed, our patient was started on intravenous (IV) methylprednisolone 40 mg twice daily, which was subsequently increased to 60 mg twice daily. His eosinophil count trended down to 10.70 × 103/µL.
Results of the excisional biopsy showed reactive lymphoid hyperplasia with increased polyclonal IgG4+ plasma cells, immunoblasts, Langerhans cells, and histiocytes, nonspecific findings that could be seen in drug-induced lymphadenopathy (Figure 2). There was no evidence of lymphoma, infection, or IgG4 disease. CD4:CD8 ratio was 8.2, which made the possibility of neoplasm less likely.
Figure 2. Lymph node biopsy showing partial effacement of normal lymph node architecture with expansion of the paracortical areas (indicated by blue arrow) by mixed cellular proliferation (hematoxylin and eosin, 4× magnification).
Eventually a skin biopsy was done which showed focal granular perivascular C3 and fibrinogen deposition. There was no specific deposition of immunoglobulin or complement in the epidermis or dermal-epidermal junction (Figure 3).
Figure 3. Skin biopsy showing superficial perivascular inflammation (blue arrow) and mild spongiosis (red arrow). There is no interface change or overt vascular damage (hematoxylin and eosin, 4× magnification).
After receiving 7 days of IV methylprednisolone 60 mg twice daily, our patient felt a significant resolution of his rash. He was discharged on a steroid taper.
Discussion
DRESS syndrome is a rare phenomenon that has an estimated incidence of 0.9 out of every 100 000 people.4 There are certain medications that are strongly linked to this syndrome. Antiepileptic drugs such as phenytoin, carbamazepine, and lamotrigine are noted to cause DRESS syndrome. Sulfa-containing medications, minocycline, and vancomycin are antibiotics that are linked to this syndrome as well. Other drugs such as allopurinol and mexiletine are associated.3,5
Leflunomide is not usually associated with DRESS syndrome. To our knowledge, there have been very few cases that have been presented similarly.6-8 We believe that further investigation is required to explore the association between leflunomide and DRESS, so as to allow safe prescription and education of patients who require leflunomide.
Although the pathogenesis of this disease is still being studied, there are 2 competing hypotheses that aim to explain the syndrome. One hypothesis is that DRESS syndrome occurs through a delayed hypersensitivity reaction whereby CD4 and CD8 T cells are specifically activated by the offending drug to overproduce cytokines and acute phase reactants.9 Another theory is that the offending agent leads to the activation of underlying HHV6/HHV7/Epstein–Barr virus or cytomegalovirus, and the ensuing symptoms are secondary to the body’s immune system attacking the virus.10 Our patient was tested for HHV6 and Epstein–Barr virus serologies, which came back negative.
Perhaps the most prominent clinical feature of DRESS syndrome is the diffuse, pruritic rash that emerges, as was the case in our patient. The rash can start out as maculopapular and can progress to being erythematous. In severe cases, pustule formation, exfoliation, or mucosal involvement can occur. Fever and lymphadenopathy are common presenting features of the disease as well.11
The following factors are considered as part of the diagnostic criteria in the workup of DRESS syndrome: a measured fever >101.3 °F, lymphadenopathy in 2 different anatomic areas, eosinophilia and atypical lymphocytes on blood work, and skin involvement, with the inclusion of a skin biopsy. Skin biopsy would show nonspecific changes, including vascular wall damage and lymphocytic infiltrate.12 Our patient met this criteria; however, the difficulty comes in the overlap of the clinical presentation of DRESS syndrome with multiple other medical conditions. Our patient necessitated an excisional lymph node biopsy in order to rule out lymphoma. Viral infections were excluded through the viral serologies that were obtained on admission. Hyper-eosinophilic syndrome was excluded due to lack of multiorgan involvement and nonspecific findings on skin biopsy.
There is a lack of evidence-based guideline directed therapy with regard to the management of DRESS syndrome. Initially, termination of the offending agent in addition to fluid resuscitation and symptom management are crucial. For mild disease without any overt organ involvement, oral prednisone is recommended. For patients with severe DRESS syndrome, with one or more end-organ involvement, systemic steroids, IV methylprednisolone dosed at 1 mg/kg is recommended with a taper of 2 to 3 months or oral steroids after symptoms subside. Other modes of therapy include cyclosporine and intravenous immunoglobulins.13 Our patient required the initiation of IV methylprednisolone 60 mg twice daily to alleviate his symptoms of rash, and this regimen helped decrease his eosinophil count as well.
Conclusion
DRESS syndrome is an incredibly rare disease that results due to an adverse medication reaction. Our case details the necessity of physicians to be aware of the difficulty in appropriately diagnosing DRESS syndrome, given its overlap to several other rheumatological and hematological conditions, including malignancy. We aim to shed light on the association of leflunomide and DRESS syndrome, calling for further research to assess the strength of association between the two. Further research is required to develop guideline directed therapy for the management of DRESS syndrome.
We acknowledge the pathology department for their help in procuring the biopsy slides.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.
ORCID iD: Suman Rao https://orcid.org/0000-0003-1746-1025 | Recovered | ReactionOutcome | CC BY-NC | 33629602 | 19,046,277 | 2021 |
What was the outcome of reaction 'Tachypnoea'? | An Uncommon Presentation of DRESS Syndrome Secondary to Leflunomide Use: A Case Report.
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a constellation of symptoms that manifest as a result of certain medications. Several antipsychotics, antibiotics, and sulfa-containing drugs are known to be implicated in the etiology of DRESS syndrome. The clinical presentation of this disorder consists of a diffuse rash, lymphadenopathy, and systemic organ damage. Our patient presented with symptoms consistent with DRESS syndrome after being started on leflunomide, which is not commonly associated with DRESS. The diagnostic workup comprised of monitoring inflammatory markers on laboratory work, an excisional lymph node biopsy (to rule out malignancy), and a skin biopsy (to assess the etiology of the rash). Our patient received systemic steroids, dose-adjusted based on expert opinion. Further research is required to explore the association between leflunomide and DRESS and address guidelines for the management of DRESS.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe reaction that presents itself after the initiation of a drug or offending agent.1 Its presentation varies with patient and drug; however, common symptoms are a diffuse blanching rash, multiple end-organ involvement, and lymphadenopathy.2 Immediate diagnosis and appropriate management is necessary in order to avoid progression to severe DRESS symptoms requiring critical care management.3
There have been several antiepileptics, antibiotics, and sulfa drugs that have been heavily associated with DRESS syndrome. However, leflunomide has not been commonly associated with DRESS, as there have only been a few cases, to our knowledge, that have been documented thus far. Our patient was recently started on leflunomide and came in with a diffuse rash, diarrhea, and fever. After a thorough diagnostic approach, he was diagnosed with DRESS. Due to the lack of randomized controlled trials guiding the management of DRESS syndrome, our patient was started on a steroid dose deemed appropriate by expert opinion, which led to the resolution of his symptoms.
Case Presentation
We present the case of a 52-year-old male with past medical history of rheumatoid arthritis, essential hypertension and gastroesophageal reflux disease, who presented to our hospital with chief complaints of fever, diarrhea, and a rash that had been going on for a week prior to admission. He noticed a pruritic skin rash that started at his legs and then rapidly progressed to the rest of his body. He had multiple episodes of diarrhea and 3 episodes of emesis. Review of systems was negative for any possible sick contacts, pulmonary, or other abdominal symptoms.
Four months prior to admission, our patient was worked up for polyarthralgia and was diagnosed with seropositive rheumatoid arthritis. He was started on methotrexate without avail. He was switched to leflunomide, which he started taking 2 weeks prior to admission. His only medications were leflunomide, omeprazole, and ibuprofen.
Physical examination was remarkable for a middle-aged man who appeared his age and was is acute distress. He had a generalized maculopapular blanchable rash present diffusely across the surface of his body. Inguinal lymphadenopathy was noted, with the largest lymph node at 40 mm.
In the emergency department, he was noted to be tachypneic at a rate of 26 and tachycardic at a rate of 104. His laboratory work was significant for a white blood cell count of 18.7 × 103/µL, elevated eosinophil count at 2.19 × 103/µL, neutrophilia at 14.48 × 103/µL, C-reactive protein of 82 mg/L, erythrocyte sedimentation rate of 20 mm/h, ferritin of 246 ng/mL, and a low complement C4. Rapid strep test, monospot antibody test, and Lyme antibody testing were all negative. He was resuscitated with fluids and started on antibiotics. Computed tomography scan of the thorax, abdomen, and pelvis was done (Figure 1), which showed mediastinal, upper abdominal, axillary, and paraesophageal lymphadenopathy. Rheumatology, hematology/oncology, and dermatology services were consulted.
Figure 1. Diffuse inguinal lymphadenopathy seen on computed tomography scan of the abdomen/pelvis (marked by blue arrow).
Further studies showed an elevated rheumatoid factor of 241 IU/mL, an anti-CCP of >300 units, speckled pattern antibodies elevated at 160 (/dil), and quantitative immunoglobulin (Ig) E elevated at 20 184 IU/mL. Steroid therapy was deferred until an excisional lymph node biopsy could be obtained. His eosinophil count continued to increase to a peak of 21.34 × 103/µL.
After the excisional left inguinal lymph node biopsy was performed, our patient was started on intravenous (IV) methylprednisolone 40 mg twice daily, which was subsequently increased to 60 mg twice daily. His eosinophil count trended down to 10.70 × 103/µL.
Results of the excisional biopsy showed reactive lymphoid hyperplasia with increased polyclonal IgG4+ plasma cells, immunoblasts, Langerhans cells, and histiocytes, nonspecific findings that could be seen in drug-induced lymphadenopathy (Figure 2). There was no evidence of lymphoma, infection, or IgG4 disease. CD4:CD8 ratio was 8.2, which made the possibility of neoplasm less likely.
Figure 2. Lymph node biopsy showing partial effacement of normal lymph node architecture with expansion of the paracortical areas (indicated by blue arrow) by mixed cellular proliferation (hematoxylin and eosin, 4× magnification).
Eventually a skin biopsy was done which showed focal granular perivascular C3 and fibrinogen deposition. There was no specific deposition of immunoglobulin or complement in the epidermis or dermal-epidermal junction (Figure 3).
Figure 3. Skin biopsy showing superficial perivascular inflammation (blue arrow) and mild spongiosis (red arrow). There is no interface change or overt vascular damage (hematoxylin and eosin, 4× magnification).
After receiving 7 days of IV methylprednisolone 60 mg twice daily, our patient felt a significant resolution of his rash. He was discharged on a steroid taper.
Discussion
DRESS syndrome is a rare phenomenon that has an estimated incidence of 0.9 out of every 100 000 people.4 There are certain medications that are strongly linked to this syndrome. Antiepileptic drugs such as phenytoin, carbamazepine, and lamotrigine are noted to cause DRESS syndrome. Sulfa-containing medications, minocycline, and vancomycin are antibiotics that are linked to this syndrome as well. Other drugs such as allopurinol and mexiletine are associated.3,5
Leflunomide is not usually associated with DRESS syndrome. To our knowledge, there have been very few cases that have been presented similarly.6-8 We believe that further investigation is required to explore the association between leflunomide and DRESS, so as to allow safe prescription and education of patients who require leflunomide.
Although the pathogenesis of this disease is still being studied, there are 2 competing hypotheses that aim to explain the syndrome. One hypothesis is that DRESS syndrome occurs through a delayed hypersensitivity reaction whereby CD4 and CD8 T cells are specifically activated by the offending drug to overproduce cytokines and acute phase reactants.9 Another theory is that the offending agent leads to the activation of underlying HHV6/HHV7/Epstein–Barr virus or cytomegalovirus, and the ensuing symptoms are secondary to the body’s immune system attacking the virus.10 Our patient was tested for HHV6 and Epstein–Barr virus serologies, which came back negative.
Perhaps the most prominent clinical feature of DRESS syndrome is the diffuse, pruritic rash that emerges, as was the case in our patient. The rash can start out as maculopapular and can progress to being erythematous. In severe cases, pustule formation, exfoliation, or mucosal involvement can occur. Fever and lymphadenopathy are common presenting features of the disease as well.11
The following factors are considered as part of the diagnostic criteria in the workup of DRESS syndrome: a measured fever >101.3 °F, lymphadenopathy in 2 different anatomic areas, eosinophilia and atypical lymphocytes on blood work, and skin involvement, with the inclusion of a skin biopsy. Skin biopsy would show nonspecific changes, including vascular wall damage and lymphocytic infiltrate.12 Our patient met this criteria; however, the difficulty comes in the overlap of the clinical presentation of DRESS syndrome with multiple other medical conditions. Our patient necessitated an excisional lymph node biopsy in order to rule out lymphoma. Viral infections were excluded through the viral serologies that were obtained on admission. Hyper-eosinophilic syndrome was excluded due to lack of multiorgan involvement and nonspecific findings on skin biopsy.
There is a lack of evidence-based guideline directed therapy with regard to the management of DRESS syndrome. Initially, termination of the offending agent in addition to fluid resuscitation and symptom management are crucial. For mild disease without any overt organ involvement, oral prednisone is recommended. For patients with severe DRESS syndrome, with one or more end-organ involvement, systemic steroids, IV methylprednisolone dosed at 1 mg/kg is recommended with a taper of 2 to 3 months or oral steroids after symptoms subside. Other modes of therapy include cyclosporine and intravenous immunoglobulins.13 Our patient required the initiation of IV methylprednisolone 60 mg twice daily to alleviate his symptoms of rash, and this regimen helped decrease his eosinophil count as well.
Conclusion
DRESS syndrome is an incredibly rare disease that results due to an adverse medication reaction. Our case details the necessity of physicians to be aware of the difficulty in appropriately diagnosing DRESS syndrome, given its overlap to several other rheumatological and hematological conditions, including malignancy. We aim to shed light on the association of leflunomide and DRESS syndrome, calling for further research to assess the strength of association between the two. Further research is required to develop guideline directed therapy for the management of DRESS syndrome.
We acknowledge the pathology department for their help in procuring the biopsy slides.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.
ORCID iD: Suman Rao https://orcid.org/0000-0003-1746-1025 | Recovered | ReactionOutcome | CC BY-NC | 33629602 | 19,046,277 | 2021 |
What was the outcome of reaction 'Vomiting'? | An Uncommon Presentation of DRESS Syndrome Secondary to Leflunomide Use: A Case Report.
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a constellation of symptoms that manifest as a result of certain medications. Several antipsychotics, antibiotics, and sulfa-containing drugs are known to be implicated in the etiology of DRESS syndrome. The clinical presentation of this disorder consists of a diffuse rash, lymphadenopathy, and systemic organ damage. Our patient presented with symptoms consistent with DRESS syndrome after being started on leflunomide, which is not commonly associated with DRESS. The diagnostic workup comprised of monitoring inflammatory markers on laboratory work, an excisional lymph node biopsy (to rule out malignancy), and a skin biopsy (to assess the etiology of the rash). Our patient received systemic steroids, dose-adjusted based on expert opinion. Further research is required to explore the association between leflunomide and DRESS and address guidelines for the management of DRESS.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe reaction that presents itself after the initiation of a drug or offending agent.1 Its presentation varies with patient and drug; however, common symptoms are a diffuse blanching rash, multiple end-organ involvement, and lymphadenopathy.2 Immediate diagnosis and appropriate management is necessary in order to avoid progression to severe DRESS symptoms requiring critical care management.3
There have been several antiepileptics, antibiotics, and sulfa drugs that have been heavily associated with DRESS syndrome. However, leflunomide has not been commonly associated with DRESS, as there have only been a few cases, to our knowledge, that have been documented thus far. Our patient was recently started on leflunomide and came in with a diffuse rash, diarrhea, and fever. After a thorough diagnostic approach, he was diagnosed with DRESS. Due to the lack of randomized controlled trials guiding the management of DRESS syndrome, our patient was started on a steroid dose deemed appropriate by expert opinion, which led to the resolution of his symptoms.
Case Presentation
We present the case of a 52-year-old male with past medical history of rheumatoid arthritis, essential hypertension and gastroesophageal reflux disease, who presented to our hospital with chief complaints of fever, diarrhea, and a rash that had been going on for a week prior to admission. He noticed a pruritic skin rash that started at his legs and then rapidly progressed to the rest of his body. He had multiple episodes of diarrhea and 3 episodes of emesis. Review of systems was negative for any possible sick contacts, pulmonary, or other abdominal symptoms.
Four months prior to admission, our patient was worked up for polyarthralgia and was diagnosed with seropositive rheumatoid arthritis. He was started on methotrexate without avail. He was switched to leflunomide, which he started taking 2 weeks prior to admission. His only medications were leflunomide, omeprazole, and ibuprofen.
Physical examination was remarkable for a middle-aged man who appeared his age and was is acute distress. He had a generalized maculopapular blanchable rash present diffusely across the surface of his body. Inguinal lymphadenopathy was noted, with the largest lymph node at 40 mm.
In the emergency department, he was noted to be tachypneic at a rate of 26 and tachycardic at a rate of 104. His laboratory work was significant for a white blood cell count of 18.7 × 103/µL, elevated eosinophil count at 2.19 × 103/µL, neutrophilia at 14.48 × 103/µL, C-reactive protein of 82 mg/L, erythrocyte sedimentation rate of 20 mm/h, ferritin of 246 ng/mL, and a low complement C4. Rapid strep test, monospot antibody test, and Lyme antibody testing were all negative. He was resuscitated with fluids and started on antibiotics. Computed tomography scan of the thorax, abdomen, and pelvis was done (Figure 1), which showed mediastinal, upper abdominal, axillary, and paraesophageal lymphadenopathy. Rheumatology, hematology/oncology, and dermatology services were consulted.
Figure 1. Diffuse inguinal lymphadenopathy seen on computed tomography scan of the abdomen/pelvis (marked by blue arrow).
Further studies showed an elevated rheumatoid factor of 241 IU/mL, an anti-CCP of >300 units, speckled pattern antibodies elevated at 160 (/dil), and quantitative immunoglobulin (Ig) E elevated at 20 184 IU/mL. Steroid therapy was deferred until an excisional lymph node biopsy could be obtained. His eosinophil count continued to increase to a peak of 21.34 × 103/µL.
After the excisional left inguinal lymph node biopsy was performed, our patient was started on intravenous (IV) methylprednisolone 40 mg twice daily, which was subsequently increased to 60 mg twice daily. His eosinophil count trended down to 10.70 × 103/µL.
Results of the excisional biopsy showed reactive lymphoid hyperplasia with increased polyclonal IgG4+ plasma cells, immunoblasts, Langerhans cells, and histiocytes, nonspecific findings that could be seen in drug-induced lymphadenopathy (Figure 2). There was no evidence of lymphoma, infection, or IgG4 disease. CD4:CD8 ratio was 8.2, which made the possibility of neoplasm less likely.
Figure 2. Lymph node biopsy showing partial effacement of normal lymph node architecture with expansion of the paracortical areas (indicated by blue arrow) by mixed cellular proliferation (hematoxylin and eosin, 4× magnification).
Eventually a skin biopsy was done which showed focal granular perivascular C3 and fibrinogen deposition. There was no specific deposition of immunoglobulin or complement in the epidermis or dermal-epidermal junction (Figure 3).
Figure 3. Skin biopsy showing superficial perivascular inflammation (blue arrow) and mild spongiosis (red arrow). There is no interface change or overt vascular damage (hematoxylin and eosin, 4× magnification).
After receiving 7 days of IV methylprednisolone 60 mg twice daily, our patient felt a significant resolution of his rash. He was discharged on a steroid taper.
Discussion
DRESS syndrome is a rare phenomenon that has an estimated incidence of 0.9 out of every 100 000 people.4 There are certain medications that are strongly linked to this syndrome. Antiepileptic drugs such as phenytoin, carbamazepine, and lamotrigine are noted to cause DRESS syndrome. Sulfa-containing medications, minocycline, and vancomycin are antibiotics that are linked to this syndrome as well. Other drugs such as allopurinol and mexiletine are associated.3,5
Leflunomide is not usually associated with DRESS syndrome. To our knowledge, there have been very few cases that have been presented similarly.6-8 We believe that further investigation is required to explore the association between leflunomide and DRESS, so as to allow safe prescription and education of patients who require leflunomide.
Although the pathogenesis of this disease is still being studied, there are 2 competing hypotheses that aim to explain the syndrome. One hypothesis is that DRESS syndrome occurs through a delayed hypersensitivity reaction whereby CD4 and CD8 T cells are specifically activated by the offending drug to overproduce cytokines and acute phase reactants.9 Another theory is that the offending agent leads to the activation of underlying HHV6/HHV7/Epstein–Barr virus or cytomegalovirus, and the ensuing symptoms are secondary to the body’s immune system attacking the virus.10 Our patient was tested for HHV6 and Epstein–Barr virus serologies, which came back negative.
Perhaps the most prominent clinical feature of DRESS syndrome is the diffuse, pruritic rash that emerges, as was the case in our patient. The rash can start out as maculopapular and can progress to being erythematous. In severe cases, pustule formation, exfoliation, or mucosal involvement can occur. Fever and lymphadenopathy are common presenting features of the disease as well.11
The following factors are considered as part of the diagnostic criteria in the workup of DRESS syndrome: a measured fever >101.3 °F, lymphadenopathy in 2 different anatomic areas, eosinophilia and atypical lymphocytes on blood work, and skin involvement, with the inclusion of a skin biopsy. Skin biopsy would show nonspecific changes, including vascular wall damage and lymphocytic infiltrate.12 Our patient met this criteria; however, the difficulty comes in the overlap of the clinical presentation of DRESS syndrome with multiple other medical conditions. Our patient necessitated an excisional lymph node biopsy in order to rule out lymphoma. Viral infections were excluded through the viral serologies that were obtained on admission. Hyper-eosinophilic syndrome was excluded due to lack of multiorgan involvement and nonspecific findings on skin biopsy.
There is a lack of evidence-based guideline directed therapy with regard to the management of DRESS syndrome. Initially, termination of the offending agent in addition to fluid resuscitation and symptom management are crucial. For mild disease without any overt organ involvement, oral prednisone is recommended. For patients with severe DRESS syndrome, with one or more end-organ involvement, systemic steroids, IV methylprednisolone dosed at 1 mg/kg is recommended with a taper of 2 to 3 months or oral steroids after symptoms subside. Other modes of therapy include cyclosporine and intravenous immunoglobulins.13 Our patient required the initiation of IV methylprednisolone 60 mg twice daily to alleviate his symptoms of rash, and this regimen helped decrease his eosinophil count as well.
Conclusion
DRESS syndrome is an incredibly rare disease that results due to an adverse medication reaction. Our case details the necessity of physicians to be aware of the difficulty in appropriately diagnosing DRESS syndrome, given its overlap to several other rheumatological and hematological conditions, including malignancy. We aim to shed light on the association of leflunomide and DRESS syndrome, calling for further research to assess the strength of association between the two. Further research is required to develop guideline directed therapy for the management of DRESS syndrome.
We acknowledge the pathology department for their help in procuring the biopsy slides.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.
ORCID iD: Suman Rao https://orcid.org/0000-0003-1746-1025 | Recovered | ReactionOutcome | CC BY-NC | 33629602 | 19,046,277 | 2021 |
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