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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | The Role of Non-Selective TNF Inhibitors in Demyelinating Events.
The use of non-selective tumor necrosis factor (TNF) inhibitors is well known in the treatment of inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and psoriasis. Its use in neurological disorders is limited however, due to rare adverse events of demyelination, even in patients without preceding demyelinating disease. We review here the molecular and cellular aspects of this neuroinflammatory process in light of a case of severe monophasic demyelination caused by treatment with infliximab. Focusing on the role of TNF, we review the links between CNS inflammation, demyelination, and neurodegenerative changes leading to permanent neurological deficits in a young woman, and we discuss the growing evidence for selective soluble TNF inhibitors as a new treatment approach in inflammatory and neurological diseases.
1. Introduction
The use of tumor necrosis factor (TNF) blockers has revolutionized the treatment of a number of chronic inflammatory diseases such as Crohn’s disease, ankylosing spondylitis, psoriasis, and rheumatoid arthritis.
Although TNF blockers are generally considered safe, an increasing number of neurologic adverse effects have been reported in the literature, consisting primarily of demyelination of the central nervous system (CNS) or peripheral nervous system (PNS) with a prevalence ranging from 0.050 to 0.100% [1]. These adverse events suggest a possible relationship between the use of anti-TNF biologics and demyelinating diseases [2].
TNF is a pleiotropic cytokine known to play important regulatory roles in the development and homeostasis of the healthy CNS [3]. It is produced initially as a transmembrane molecule (tmTNF) and is subsequently released from the cell as a soluble cytokine (solTNF) via regulated cleavage of tmTNF by TNF-α converting enzyme (TACE). Under normal conditions, TNF can be produced in the periphery by monocytes/macrophages, lymphocytes (T and B), natural killer cells, and dendritic cells [4], while TNF in the CNS is produced mainly by microglia [5]. Both forms of TNF are biologically active and interact with two distinct receptors—TNFR1 and TNFR2—with TNFR1 being expressed in all cell types, whereas TNFR2 is expressed mainly on immune cells, oligodendrocytes, and endothelial cells [6]. solTNF has a high affinity for TNFR1, which contains a death domain and can mediate apoptosis and chronic inflammation [7]. In the CNS, tmTNF has a higher affinity for TNFR2 and promotes mostly protective features such as cell survival and remyelination [6,7].
In animal models of multiple sclerosis (MS), such as experimental autoimmune encephalomyelitis (EAE), the administration of TNF blockers slowed the demyelinating process and improved outcome [8,9]. Ablation of TNF or TNFR1/TNFR2 combined in mice did not protect from EAE, however, and instead caused exacerbation of chronic disease [10,11,12,13]. TNFR1 ablation resulted in less severe EAE and better remyelination, while TNFR2 ablation exacerbated EAE and prevented remyelination [11,13,14]. Furthermore, mice only expressing tmTNF showed suppression of EAE [15]. These studies suggest a dichotomy between solTNF and tmTNF, in which MS is associated with the detrimental effects of solTNF via TNFR1, but tmTNF signaling via TNFR2 is important for repair and remyelination. This is supported by studies in EAE mice treated with a selective blocker of solTNF, XPro1595, which resulted in improved function, significant axonal preservation, oligodendrocyte differentiation, and remyelination [6,7]. More importantly, these differences in receptor function might explain the failed clinical trial using the non-selective TNF inhibitor Lenercept as treatment for MS [16], which was terminated due to clinical and radiological disease progression.
We present here a case of severe demyelination following treatment with infliximab, a chimeric monoclonal antibody that prevents binding of TNF to TNFR1 and TNFR2 by blocking both solTNF and tmTNF [17]. We discuss the possible underlying mechanisms of TNF blockers in CNS demyelination in the context of the current literature.
2. Case Description
The case is a 27-year-old woman with psoriatic arthritis, treated with methotrexate and infliximab. No family history of neurological disorders was reported.
After 4.5 years of treatment with infliximab, she complained of increasing fatigue, muscle pain, and mild cognitive difficulties. After a few months, she developed a subacute hemiparesis. MRI scan showed a solitary process with gadolinium ring enhancement (Figure 1—Week 0).
CSF analysis revealed no pleocytosis and normal protein levels, but did reveal oligoclonal bands and an elevated IgG index of 0.78. Initial blood tests showed a positive toxoplasmosis IgG, and PET-CT and a following biopsy from a single lymph node showed signs of granulomatous inflammation. The infliximab was discontinued, and the patient was initially treated for both toxoplasmosis and tuberculosis (Figure 1—Week 0).
Further investigations revealed no pathology on repeated PET-CT, including no pathological lymph nodes.
Repeated blood and CSF tests were found negative for toxoplasmosis, tuberculosis, varicella-zoster, Epstein–Barr, herpes simplex I+II, cytomegalovirus, Bartonella, Brucella, Aspergillus, hepatitis, and HIV. Microbiome PCR sequencing revealed no pathological DNA.
Antinuclear antibodies (ANA), Extractable Nuclear Antigen antibodies (ENA), Proteinase 3 Anti Neutrophil Cytoplasmic Antibody (C-ANCA), and Perinuclear Anti Neutrophil Cytoplasmic Antibodies (P-ANCA) were all negative.
Despite discontinuation of infliximab, the patient progressed clinically and radiologically over the next 12 weeks (Figure 1—Week 12). Clinical evaluation showed grade 4 hemiparesis on the left side and no cognitive difficulties, headache, or nausea.
Repeated CSF analysis confirmed oligoclonal bands and elevated IgG index but no increase in cell count or protein. Cytology described normal-appearing lymphocytes without pathological changes. Flow cytometry revealed 74% T cells, 7.9% polyclonal B cells, 1.6% NK cells, and CD4/CD8 of 4.1.
A biopsy was taken from the lesions in the brain, and histology showed unspecific reactive microglia and few infiltrating CD8+ T and B cells. There were no signs of tumor, lymphoma, vasculitis, progressive multifocal leukoencephalopathy, or infection with herpes, toxoplasmosis, or tuberculosis.
The patient was treated with high-dose glucocorticoid intravenously (1 g a day for 5 days) followed by five courses of plasma exchange (Figure 1—Week 12). Afterwards, MRI showed no new lesions but progression of one existing lesion and oedema, and the patient remained stable (Figure 1—Week 16). The patient continued with oral steroid therapy, which was tapered off after introduction of a two-course Rituximab treatment as a steroid-sparing agent (Figure 1—Week 16).
The following MRI showed remission, and the patient continued with a slight hemiparesis.
After 2 years (Figure 1—Week 104), the patient’s psoriatic arthritis started to deteriorate, and she was put on Secukinumab. She remained neurologically stable throughout the period and at follow-up (Figure 1—Week 134).
3. Discussion
We present a case of severe demyelination in a young woman who received infliximab as treatment for psoriatic arthritis. Because of the atypical presentation, many differential diagnoses were considered:
3.1. Infection
As the patient had been on different types of immunosuppressants since her early childhood, and at the time her symptoms developed she was treated with both infliximab and methotrexate, an infectious cause was first suspected. This was supported by the first MRI, which showed a characteristic ring enhancement comparable to cerebral toxoplasmosis, and a positive IgA test for toxoplasmosis. To further complicate the matter, a biopsy from a neck gland showed granulomatous inflammation, which could suggest tuberculosis. However, later test results for tuberculosis were negative (using interferon-gamma blood tests and microscopy of biopsy material). Although the patient received treatment for both toxoplasmosis and tuberculosis, this had no effect on the intracranial process or her clinical status. Furthermore, the CSF showed no signs of pleocytosis or elevated protein, nor did it confirm toxoplasmosis, tuberculosis, or any other form of infection.
3.2. Malignancy
Treatment with a TNF inhibitor has been suspected to increase the risk of certain malignancies, but this is still debated and may be related to the underlying autoimmune disease rather than the treatment [18,19,20,21]. On the initial PET-CT, the patient had a suspicious lymph gland. Biopsy from both this and a brain lesion showed no sign of malignant disease, just as repeated CSF cytology described normal-appearing lymphocytes without pathological changes. The clinical and radiological stabilization at 2 years follow-up also suggests a more benign disease process.
3.3. Inflammatory Demyelination
Studies suggest that patients with an autoimmune disease have an increased risk of developing other diseases with similar pathological mechanisms. Although still controversial, psoriasis has been shown to carry an increased risk of MS [22,23,24]. Reasons for this include shared genetic, environmental, and immunopathological factors (such as a strong Th1/Th17 response) in the two disorders [25]. This is further supported by the overlap in medications such as fumarate and Secukinumab [26]. As illustrated by the divergent results to anti-TNF inhibitors [16] however, the immunopathogenesis is not identical.
A register-based study from 2019 found an increased risk of MS and neuroinflammatory disease in patients with psoriatic arthritis but not rheumatoid arthritis, both with and without treatment with non-selective TNF inhibitors [27]. In view of the close relationship between autoimmune diseases, it is therefore possible that treatment with TNF blockers simply exacerbates a dormant neuroinflammatory condition like MS.
In this case, the patient remained stable without specific MS treatment, although Secukinumab was later introduced as an arthritis treatment and could in theory suppress any underlying MS activity. Secukinumab has been shown to be effective in MS [26], but it seems unlikely that an aggressive debut of MS would later stabilize completely without regular MS treatment. However, the disease course may still support a monophasic demyelinating event.
3.4. Infliximab-Induced Demyelination
As previously mentioned, the use of non-selective TNF blockers has been linked to demyelinating diseases, including MS, optic neuritis, transverse myelitis, and demyelinating neuropathies [1,28]. Furthermore, a potential link between TNF inhibitors and demyelinating disease has been suggested [29,30,31]. In view of the large number of patients treated with TNF blockers for long periods of time however, the demyelinating cases are rare and divergent [32,33]
The patient described here received infliximab for approximately 4.5 years before developing symptoms. In a 2017 review of reported cases of CNS demyelination associated with TNF inhibitors [26], the mean time of exposure was 17 months, but some patients had been treated for 6 years before developing symptoms. Our patient showed no resolution of her symptoms, consistent with 28% of the reviewed cases, and she had no prior family history of MS, which was also the case in the majority of cases reviewed. This patient thus shares many similarities with other cases of psoriatic arthritis treated with TNF blockers, supporting an initial monophasic demyelinating event that may later develop into MS, as seen in some cases with longer follow-up [28].
The mechanisms behind the potential demyelinating role of non-selective TNF blockers are not completely clear. In general, TNF blockers are large molecules that do not penetrate the intact blood–brain barrier, possibly explaining the lack of positive effects in TNF-mediated CNS diseases as opposed to other autoimmune disease such as rheumatoid and psoriatic arthritis [34,35]. Another theory is that the peripheral immunological effects of TNF blockers might alter the cytokine profile into a more proinflammatory CNS profile [28] or increase the ingress of peripheral autoreactive T-cells into the CNS through the leaky blood–brain barrier already established in active MS [34,35]
The infliximab used in this case blocks binding of TNF to TNFR1 and TNFR2 by blocking both solTNF and tmTNF [17], therefore also blocking the positive effects of TNFR2. Levels of TNF are increased in patients with MS, and studies suggest that while high levels of TNFR1 may be a risk factor for more severe disease, TNFR2 plays a more protective role [36]. As infliximab affects both pathways, the blocking of the protective features of TNFR2 and the remyelinating process could potentially lead to demyelinating events, as seen in our case. This is further supported by animal studies in which a selective blocker of solTNF resulted in improved function as well as significant axonal preservation, oligodendrocyte differentiation, and remyelination [6,7]. Therefore, selective TNF inhibition or activation of TNFR2 could lead to a new treatment approach for inflammatory disease [37,38].
4. Conclusions
This case supports the growing evidence suggesting demyelinating events as adverse effects of non-selective TNF inhibitors, but distinguishes itself by the long follow-up time and the in-depth discussion of the underlying mechanisms using selective versus non-selective TNF inhibition. As demyelination is a rare adverse event and TNF blockers are generally considered safe and effective in many chronic autoimmune disorders, this should not preclude this treatment, but rather suggests caution in patients of high risk of developing demyelinating events. With the introduction of selective solTNF inhibitors and the growing evidence of their effect, this may form the basis of a new treatment approach in inflammatory and neurological diseases.
Acknowledgments
Claire Gudex is acknowledged for proofreading the manuscript.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
L.B.K. and H.H.N. wrote the manuscript with the assistance of K.L.L., K.-E.B. and N.N. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Ethical review and approval were waived for this study, in accordance with Danish regulation since this is a case report with informed consent from the patient.
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to Danish data protection regulations.
Conflicts of Interest
K.L.L. is a member of the Lundbeck Foundation Brain Prize Council. H.H.N. is a member of the research council of the Danish Multiple Sclerosis Society and has served on scientific advisory boards and received support for congress participation, speaker honoraria, and research support from Biogen, Merck-Serono, Roche, Teva, Lundbeck, and Novartis.
Figure 1 Schematic overview of the case, showing the relationship between clinical presentation, treatment, and radiological presentation shown by MRI scans (T2, Flair, and T1+gadolinium enhancement). Created with BioRender.com. | INFLIXIMAB, METHOTREXATE, RITUXIMAB, SECUKINUMAB | DrugsGivenReaction | CC BY | 33401396 | 18,749,761 | 2021-01-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Demyelination'. | The Role of Non-Selective TNF Inhibitors in Demyelinating Events.
The use of non-selective tumor necrosis factor (TNF) inhibitors is well known in the treatment of inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and psoriasis. Its use in neurological disorders is limited however, due to rare adverse events of demyelination, even in patients without preceding demyelinating disease. We review here the molecular and cellular aspects of this neuroinflammatory process in light of a case of severe monophasic demyelination caused by treatment with infliximab. Focusing on the role of TNF, we review the links between CNS inflammation, demyelination, and neurodegenerative changes leading to permanent neurological deficits in a young woman, and we discuss the growing evidence for selective soluble TNF inhibitors as a new treatment approach in inflammatory and neurological diseases.
1. Introduction
The use of tumor necrosis factor (TNF) blockers has revolutionized the treatment of a number of chronic inflammatory diseases such as Crohn’s disease, ankylosing spondylitis, psoriasis, and rheumatoid arthritis.
Although TNF blockers are generally considered safe, an increasing number of neurologic adverse effects have been reported in the literature, consisting primarily of demyelination of the central nervous system (CNS) or peripheral nervous system (PNS) with a prevalence ranging from 0.050 to 0.100% [1]. These adverse events suggest a possible relationship between the use of anti-TNF biologics and demyelinating diseases [2].
TNF is a pleiotropic cytokine known to play important regulatory roles in the development and homeostasis of the healthy CNS [3]. It is produced initially as a transmembrane molecule (tmTNF) and is subsequently released from the cell as a soluble cytokine (solTNF) via regulated cleavage of tmTNF by TNF-α converting enzyme (TACE). Under normal conditions, TNF can be produced in the periphery by monocytes/macrophages, lymphocytes (T and B), natural killer cells, and dendritic cells [4], while TNF in the CNS is produced mainly by microglia [5]. Both forms of TNF are biologically active and interact with two distinct receptors—TNFR1 and TNFR2—with TNFR1 being expressed in all cell types, whereas TNFR2 is expressed mainly on immune cells, oligodendrocytes, and endothelial cells [6]. solTNF has a high affinity for TNFR1, which contains a death domain and can mediate apoptosis and chronic inflammation [7]. In the CNS, tmTNF has a higher affinity for TNFR2 and promotes mostly protective features such as cell survival and remyelination [6,7].
In animal models of multiple sclerosis (MS), such as experimental autoimmune encephalomyelitis (EAE), the administration of TNF blockers slowed the demyelinating process and improved outcome [8,9]. Ablation of TNF or TNFR1/TNFR2 combined in mice did not protect from EAE, however, and instead caused exacerbation of chronic disease [10,11,12,13]. TNFR1 ablation resulted in less severe EAE and better remyelination, while TNFR2 ablation exacerbated EAE and prevented remyelination [11,13,14]. Furthermore, mice only expressing tmTNF showed suppression of EAE [15]. These studies suggest a dichotomy between solTNF and tmTNF, in which MS is associated with the detrimental effects of solTNF via TNFR1, but tmTNF signaling via TNFR2 is important for repair and remyelination. This is supported by studies in EAE mice treated with a selective blocker of solTNF, XPro1595, which resulted in improved function, significant axonal preservation, oligodendrocyte differentiation, and remyelination [6,7]. More importantly, these differences in receptor function might explain the failed clinical trial using the non-selective TNF inhibitor Lenercept as treatment for MS [16], which was terminated due to clinical and radiological disease progression.
We present here a case of severe demyelination following treatment with infliximab, a chimeric monoclonal antibody that prevents binding of TNF to TNFR1 and TNFR2 by blocking both solTNF and tmTNF [17]. We discuss the possible underlying mechanisms of TNF blockers in CNS demyelination in the context of the current literature.
2. Case Description
The case is a 27-year-old woman with psoriatic arthritis, treated with methotrexate and infliximab. No family history of neurological disorders was reported.
After 4.5 years of treatment with infliximab, she complained of increasing fatigue, muscle pain, and mild cognitive difficulties. After a few months, she developed a subacute hemiparesis. MRI scan showed a solitary process with gadolinium ring enhancement (Figure 1—Week 0).
CSF analysis revealed no pleocytosis and normal protein levels, but did reveal oligoclonal bands and an elevated IgG index of 0.78. Initial blood tests showed a positive toxoplasmosis IgG, and PET-CT and a following biopsy from a single lymph node showed signs of granulomatous inflammation. The infliximab was discontinued, and the patient was initially treated for both toxoplasmosis and tuberculosis (Figure 1—Week 0).
Further investigations revealed no pathology on repeated PET-CT, including no pathological lymph nodes.
Repeated blood and CSF tests were found negative for toxoplasmosis, tuberculosis, varicella-zoster, Epstein–Barr, herpes simplex I+II, cytomegalovirus, Bartonella, Brucella, Aspergillus, hepatitis, and HIV. Microbiome PCR sequencing revealed no pathological DNA.
Antinuclear antibodies (ANA), Extractable Nuclear Antigen antibodies (ENA), Proteinase 3 Anti Neutrophil Cytoplasmic Antibody (C-ANCA), and Perinuclear Anti Neutrophil Cytoplasmic Antibodies (P-ANCA) were all negative.
Despite discontinuation of infliximab, the patient progressed clinically and radiologically over the next 12 weeks (Figure 1—Week 12). Clinical evaluation showed grade 4 hemiparesis on the left side and no cognitive difficulties, headache, or nausea.
Repeated CSF analysis confirmed oligoclonal bands and elevated IgG index but no increase in cell count or protein. Cytology described normal-appearing lymphocytes without pathological changes. Flow cytometry revealed 74% T cells, 7.9% polyclonal B cells, 1.6% NK cells, and CD4/CD8 of 4.1.
A biopsy was taken from the lesions in the brain, and histology showed unspecific reactive microglia and few infiltrating CD8+ T and B cells. There were no signs of tumor, lymphoma, vasculitis, progressive multifocal leukoencephalopathy, or infection with herpes, toxoplasmosis, or tuberculosis.
The patient was treated with high-dose glucocorticoid intravenously (1 g a day for 5 days) followed by five courses of plasma exchange (Figure 1—Week 12). Afterwards, MRI showed no new lesions but progression of one existing lesion and oedema, and the patient remained stable (Figure 1—Week 16). The patient continued with oral steroid therapy, which was tapered off after introduction of a two-course Rituximab treatment as a steroid-sparing agent (Figure 1—Week 16).
The following MRI showed remission, and the patient continued with a slight hemiparesis.
After 2 years (Figure 1—Week 104), the patient’s psoriatic arthritis started to deteriorate, and she was put on Secukinumab. She remained neurologically stable throughout the period and at follow-up (Figure 1—Week 134).
3. Discussion
We present a case of severe demyelination in a young woman who received infliximab as treatment for psoriatic arthritis. Because of the atypical presentation, many differential diagnoses were considered:
3.1. Infection
As the patient had been on different types of immunosuppressants since her early childhood, and at the time her symptoms developed she was treated with both infliximab and methotrexate, an infectious cause was first suspected. This was supported by the first MRI, which showed a characteristic ring enhancement comparable to cerebral toxoplasmosis, and a positive IgA test for toxoplasmosis. To further complicate the matter, a biopsy from a neck gland showed granulomatous inflammation, which could suggest tuberculosis. However, later test results for tuberculosis were negative (using interferon-gamma blood tests and microscopy of biopsy material). Although the patient received treatment for both toxoplasmosis and tuberculosis, this had no effect on the intracranial process or her clinical status. Furthermore, the CSF showed no signs of pleocytosis or elevated protein, nor did it confirm toxoplasmosis, tuberculosis, or any other form of infection.
3.2. Malignancy
Treatment with a TNF inhibitor has been suspected to increase the risk of certain malignancies, but this is still debated and may be related to the underlying autoimmune disease rather than the treatment [18,19,20,21]. On the initial PET-CT, the patient had a suspicious lymph gland. Biopsy from both this and a brain lesion showed no sign of malignant disease, just as repeated CSF cytology described normal-appearing lymphocytes without pathological changes. The clinical and radiological stabilization at 2 years follow-up also suggests a more benign disease process.
3.3. Inflammatory Demyelination
Studies suggest that patients with an autoimmune disease have an increased risk of developing other diseases with similar pathological mechanisms. Although still controversial, psoriasis has been shown to carry an increased risk of MS [22,23,24]. Reasons for this include shared genetic, environmental, and immunopathological factors (such as a strong Th1/Th17 response) in the two disorders [25]. This is further supported by the overlap in medications such as fumarate and Secukinumab [26]. As illustrated by the divergent results to anti-TNF inhibitors [16] however, the immunopathogenesis is not identical.
A register-based study from 2019 found an increased risk of MS and neuroinflammatory disease in patients with psoriatic arthritis but not rheumatoid arthritis, both with and without treatment with non-selective TNF inhibitors [27]. In view of the close relationship between autoimmune diseases, it is therefore possible that treatment with TNF blockers simply exacerbates a dormant neuroinflammatory condition like MS.
In this case, the patient remained stable without specific MS treatment, although Secukinumab was later introduced as an arthritis treatment and could in theory suppress any underlying MS activity. Secukinumab has been shown to be effective in MS [26], but it seems unlikely that an aggressive debut of MS would later stabilize completely without regular MS treatment. However, the disease course may still support a monophasic demyelinating event.
3.4. Infliximab-Induced Demyelination
As previously mentioned, the use of non-selective TNF blockers has been linked to demyelinating diseases, including MS, optic neuritis, transverse myelitis, and demyelinating neuropathies [1,28]. Furthermore, a potential link between TNF inhibitors and demyelinating disease has been suggested [29,30,31]. In view of the large number of patients treated with TNF blockers for long periods of time however, the demyelinating cases are rare and divergent [32,33]
The patient described here received infliximab for approximately 4.5 years before developing symptoms. In a 2017 review of reported cases of CNS demyelination associated with TNF inhibitors [26], the mean time of exposure was 17 months, but some patients had been treated for 6 years before developing symptoms. Our patient showed no resolution of her symptoms, consistent with 28% of the reviewed cases, and she had no prior family history of MS, which was also the case in the majority of cases reviewed. This patient thus shares many similarities with other cases of psoriatic arthritis treated with TNF blockers, supporting an initial monophasic demyelinating event that may later develop into MS, as seen in some cases with longer follow-up [28].
The mechanisms behind the potential demyelinating role of non-selective TNF blockers are not completely clear. In general, TNF blockers are large molecules that do not penetrate the intact blood–brain barrier, possibly explaining the lack of positive effects in TNF-mediated CNS diseases as opposed to other autoimmune disease such as rheumatoid and psoriatic arthritis [34,35]. Another theory is that the peripheral immunological effects of TNF blockers might alter the cytokine profile into a more proinflammatory CNS profile [28] or increase the ingress of peripheral autoreactive T-cells into the CNS through the leaky blood–brain barrier already established in active MS [34,35]
The infliximab used in this case blocks binding of TNF to TNFR1 and TNFR2 by blocking both solTNF and tmTNF [17], therefore also blocking the positive effects of TNFR2. Levels of TNF are increased in patients with MS, and studies suggest that while high levels of TNFR1 may be a risk factor for more severe disease, TNFR2 plays a more protective role [36]. As infliximab affects both pathways, the blocking of the protective features of TNFR2 and the remyelinating process could potentially lead to demyelinating events, as seen in our case. This is further supported by animal studies in which a selective blocker of solTNF resulted in improved function as well as significant axonal preservation, oligodendrocyte differentiation, and remyelination [6,7]. Therefore, selective TNF inhibition or activation of TNFR2 could lead to a new treatment approach for inflammatory disease [37,38].
4. Conclusions
This case supports the growing evidence suggesting demyelinating events as adverse effects of non-selective TNF inhibitors, but distinguishes itself by the long follow-up time and the in-depth discussion of the underlying mechanisms using selective versus non-selective TNF inhibition. As demyelination is a rare adverse event and TNF blockers are generally considered safe and effective in many chronic autoimmune disorders, this should not preclude this treatment, but rather suggests caution in patients of high risk of developing demyelinating events. With the introduction of selective solTNF inhibitors and the growing evidence of their effect, this may form the basis of a new treatment approach in inflammatory and neurological diseases.
Acknowledgments
Claire Gudex is acknowledged for proofreading the manuscript.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
L.B.K. and H.H.N. wrote the manuscript with the assistance of K.L.L., K.-E.B. and N.N. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Ethical review and approval were waived for this study, in accordance with Danish regulation since this is a case report with informed consent from the patient.
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to Danish data protection regulations.
Conflicts of Interest
K.L.L. is a member of the Lundbeck Foundation Brain Prize Council. H.H.N. is a member of the research council of the Danish Multiple Sclerosis Society and has served on scientific advisory boards and received support for congress participation, speaker honoraria, and research support from Biogen, Merck-Serono, Roche, Teva, Lundbeck, and Novartis.
Figure 1 Schematic overview of the case, showing the relationship between clinical presentation, treatment, and radiological presentation shown by MRI scans (T2, Flair, and T1+gadolinium enhancement). Created with BioRender.com. | INFLIXIMAB, METHOTREXATE, RITUXIMAB, SECUKINUMAB | DrugsGivenReaction | CC BY | 33401396 | 18,783,118 | 2021-01-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Psoriatic arthropathy'. | The Role of Non-Selective TNF Inhibitors in Demyelinating Events.
The use of non-selective tumor necrosis factor (TNF) inhibitors is well known in the treatment of inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and psoriasis. Its use in neurological disorders is limited however, due to rare adverse events of demyelination, even in patients without preceding demyelinating disease. We review here the molecular and cellular aspects of this neuroinflammatory process in light of a case of severe monophasic demyelination caused by treatment with infliximab. Focusing on the role of TNF, we review the links between CNS inflammation, demyelination, and neurodegenerative changes leading to permanent neurological deficits in a young woman, and we discuss the growing evidence for selective soluble TNF inhibitors as a new treatment approach in inflammatory and neurological diseases.
1. Introduction
The use of tumor necrosis factor (TNF) blockers has revolutionized the treatment of a number of chronic inflammatory diseases such as Crohn’s disease, ankylosing spondylitis, psoriasis, and rheumatoid arthritis.
Although TNF blockers are generally considered safe, an increasing number of neurologic adverse effects have been reported in the literature, consisting primarily of demyelination of the central nervous system (CNS) or peripheral nervous system (PNS) with a prevalence ranging from 0.050 to 0.100% [1]. These adverse events suggest a possible relationship between the use of anti-TNF biologics and demyelinating diseases [2].
TNF is a pleiotropic cytokine known to play important regulatory roles in the development and homeostasis of the healthy CNS [3]. It is produced initially as a transmembrane molecule (tmTNF) and is subsequently released from the cell as a soluble cytokine (solTNF) via regulated cleavage of tmTNF by TNF-α converting enzyme (TACE). Under normal conditions, TNF can be produced in the periphery by monocytes/macrophages, lymphocytes (T and B), natural killer cells, and dendritic cells [4], while TNF in the CNS is produced mainly by microglia [5]. Both forms of TNF are biologically active and interact with two distinct receptors—TNFR1 and TNFR2—with TNFR1 being expressed in all cell types, whereas TNFR2 is expressed mainly on immune cells, oligodendrocytes, and endothelial cells [6]. solTNF has a high affinity for TNFR1, which contains a death domain and can mediate apoptosis and chronic inflammation [7]. In the CNS, tmTNF has a higher affinity for TNFR2 and promotes mostly protective features such as cell survival and remyelination [6,7].
In animal models of multiple sclerosis (MS), such as experimental autoimmune encephalomyelitis (EAE), the administration of TNF blockers slowed the demyelinating process and improved outcome [8,9]. Ablation of TNF or TNFR1/TNFR2 combined in mice did not protect from EAE, however, and instead caused exacerbation of chronic disease [10,11,12,13]. TNFR1 ablation resulted in less severe EAE and better remyelination, while TNFR2 ablation exacerbated EAE and prevented remyelination [11,13,14]. Furthermore, mice only expressing tmTNF showed suppression of EAE [15]. These studies suggest a dichotomy between solTNF and tmTNF, in which MS is associated with the detrimental effects of solTNF via TNFR1, but tmTNF signaling via TNFR2 is important for repair and remyelination. This is supported by studies in EAE mice treated with a selective blocker of solTNF, XPro1595, which resulted in improved function, significant axonal preservation, oligodendrocyte differentiation, and remyelination [6,7]. More importantly, these differences in receptor function might explain the failed clinical trial using the non-selective TNF inhibitor Lenercept as treatment for MS [16], which was terminated due to clinical and radiological disease progression.
We present here a case of severe demyelination following treatment with infliximab, a chimeric monoclonal antibody that prevents binding of TNF to TNFR1 and TNFR2 by blocking both solTNF and tmTNF [17]. We discuss the possible underlying mechanisms of TNF blockers in CNS demyelination in the context of the current literature.
2. Case Description
The case is a 27-year-old woman with psoriatic arthritis, treated with methotrexate and infliximab. No family history of neurological disorders was reported.
After 4.5 years of treatment with infliximab, she complained of increasing fatigue, muscle pain, and mild cognitive difficulties. After a few months, she developed a subacute hemiparesis. MRI scan showed a solitary process with gadolinium ring enhancement (Figure 1—Week 0).
CSF analysis revealed no pleocytosis and normal protein levels, but did reveal oligoclonal bands and an elevated IgG index of 0.78. Initial blood tests showed a positive toxoplasmosis IgG, and PET-CT and a following biopsy from a single lymph node showed signs of granulomatous inflammation. The infliximab was discontinued, and the patient was initially treated for both toxoplasmosis and tuberculosis (Figure 1—Week 0).
Further investigations revealed no pathology on repeated PET-CT, including no pathological lymph nodes.
Repeated blood and CSF tests were found negative for toxoplasmosis, tuberculosis, varicella-zoster, Epstein–Barr, herpes simplex I+II, cytomegalovirus, Bartonella, Brucella, Aspergillus, hepatitis, and HIV. Microbiome PCR sequencing revealed no pathological DNA.
Antinuclear antibodies (ANA), Extractable Nuclear Antigen antibodies (ENA), Proteinase 3 Anti Neutrophil Cytoplasmic Antibody (C-ANCA), and Perinuclear Anti Neutrophil Cytoplasmic Antibodies (P-ANCA) were all negative.
Despite discontinuation of infliximab, the patient progressed clinically and radiologically over the next 12 weeks (Figure 1—Week 12). Clinical evaluation showed grade 4 hemiparesis on the left side and no cognitive difficulties, headache, or nausea.
Repeated CSF analysis confirmed oligoclonal bands and elevated IgG index but no increase in cell count or protein. Cytology described normal-appearing lymphocytes without pathological changes. Flow cytometry revealed 74% T cells, 7.9% polyclonal B cells, 1.6% NK cells, and CD4/CD8 of 4.1.
A biopsy was taken from the lesions in the brain, and histology showed unspecific reactive microglia and few infiltrating CD8+ T and B cells. There were no signs of tumor, lymphoma, vasculitis, progressive multifocal leukoencephalopathy, or infection with herpes, toxoplasmosis, or tuberculosis.
The patient was treated with high-dose glucocorticoid intravenously (1 g a day for 5 days) followed by five courses of plasma exchange (Figure 1—Week 12). Afterwards, MRI showed no new lesions but progression of one existing lesion and oedema, and the patient remained stable (Figure 1—Week 16). The patient continued with oral steroid therapy, which was tapered off after introduction of a two-course Rituximab treatment as a steroid-sparing agent (Figure 1—Week 16).
The following MRI showed remission, and the patient continued with a slight hemiparesis.
After 2 years (Figure 1—Week 104), the patient’s psoriatic arthritis started to deteriorate, and she was put on Secukinumab. She remained neurologically stable throughout the period and at follow-up (Figure 1—Week 134).
3. Discussion
We present a case of severe demyelination in a young woman who received infliximab as treatment for psoriatic arthritis. Because of the atypical presentation, many differential diagnoses were considered:
3.1. Infection
As the patient had been on different types of immunosuppressants since her early childhood, and at the time her symptoms developed she was treated with both infliximab and methotrexate, an infectious cause was first suspected. This was supported by the first MRI, which showed a characteristic ring enhancement comparable to cerebral toxoplasmosis, and a positive IgA test for toxoplasmosis. To further complicate the matter, a biopsy from a neck gland showed granulomatous inflammation, which could suggest tuberculosis. However, later test results for tuberculosis were negative (using interferon-gamma blood tests and microscopy of biopsy material). Although the patient received treatment for both toxoplasmosis and tuberculosis, this had no effect on the intracranial process or her clinical status. Furthermore, the CSF showed no signs of pleocytosis or elevated protein, nor did it confirm toxoplasmosis, tuberculosis, or any other form of infection.
3.2. Malignancy
Treatment with a TNF inhibitor has been suspected to increase the risk of certain malignancies, but this is still debated and may be related to the underlying autoimmune disease rather than the treatment [18,19,20,21]. On the initial PET-CT, the patient had a suspicious lymph gland. Biopsy from both this and a brain lesion showed no sign of malignant disease, just as repeated CSF cytology described normal-appearing lymphocytes without pathological changes. The clinical and radiological stabilization at 2 years follow-up also suggests a more benign disease process.
3.3. Inflammatory Demyelination
Studies suggest that patients with an autoimmune disease have an increased risk of developing other diseases with similar pathological mechanisms. Although still controversial, psoriasis has been shown to carry an increased risk of MS [22,23,24]. Reasons for this include shared genetic, environmental, and immunopathological factors (such as a strong Th1/Th17 response) in the two disorders [25]. This is further supported by the overlap in medications such as fumarate and Secukinumab [26]. As illustrated by the divergent results to anti-TNF inhibitors [16] however, the immunopathogenesis is not identical.
A register-based study from 2019 found an increased risk of MS and neuroinflammatory disease in patients with psoriatic arthritis but not rheumatoid arthritis, both with and without treatment with non-selective TNF inhibitors [27]. In view of the close relationship between autoimmune diseases, it is therefore possible that treatment with TNF blockers simply exacerbates a dormant neuroinflammatory condition like MS.
In this case, the patient remained stable without specific MS treatment, although Secukinumab was later introduced as an arthritis treatment and could in theory suppress any underlying MS activity. Secukinumab has been shown to be effective in MS [26], but it seems unlikely that an aggressive debut of MS would later stabilize completely without regular MS treatment. However, the disease course may still support a monophasic demyelinating event.
3.4. Infliximab-Induced Demyelination
As previously mentioned, the use of non-selective TNF blockers has been linked to demyelinating diseases, including MS, optic neuritis, transverse myelitis, and demyelinating neuropathies [1,28]. Furthermore, a potential link between TNF inhibitors and demyelinating disease has been suggested [29,30,31]. In view of the large number of patients treated with TNF blockers for long periods of time however, the demyelinating cases are rare and divergent [32,33]
The patient described here received infliximab for approximately 4.5 years before developing symptoms. In a 2017 review of reported cases of CNS demyelination associated with TNF inhibitors [26], the mean time of exposure was 17 months, but some patients had been treated for 6 years before developing symptoms. Our patient showed no resolution of her symptoms, consistent with 28% of the reviewed cases, and she had no prior family history of MS, which was also the case in the majority of cases reviewed. This patient thus shares many similarities with other cases of psoriatic arthritis treated with TNF blockers, supporting an initial monophasic demyelinating event that may later develop into MS, as seen in some cases with longer follow-up [28].
The mechanisms behind the potential demyelinating role of non-selective TNF blockers are not completely clear. In general, TNF blockers are large molecules that do not penetrate the intact blood–brain barrier, possibly explaining the lack of positive effects in TNF-mediated CNS diseases as opposed to other autoimmune disease such as rheumatoid and psoriatic arthritis [34,35]. Another theory is that the peripheral immunological effects of TNF blockers might alter the cytokine profile into a more proinflammatory CNS profile [28] or increase the ingress of peripheral autoreactive T-cells into the CNS through the leaky blood–brain barrier already established in active MS [34,35]
The infliximab used in this case blocks binding of TNF to TNFR1 and TNFR2 by blocking both solTNF and tmTNF [17], therefore also blocking the positive effects of TNFR2. Levels of TNF are increased in patients with MS, and studies suggest that while high levels of TNFR1 may be a risk factor for more severe disease, TNFR2 plays a more protective role [36]. As infliximab affects both pathways, the blocking of the protective features of TNFR2 and the remyelinating process could potentially lead to demyelinating events, as seen in our case. This is further supported by animal studies in which a selective blocker of solTNF resulted in improved function as well as significant axonal preservation, oligodendrocyte differentiation, and remyelination [6,7]. Therefore, selective TNF inhibition or activation of TNFR2 could lead to a new treatment approach for inflammatory disease [37,38].
4. Conclusions
This case supports the growing evidence suggesting demyelinating events as adverse effects of non-selective TNF inhibitors, but distinguishes itself by the long follow-up time and the in-depth discussion of the underlying mechanisms using selective versus non-selective TNF inhibition. As demyelination is a rare adverse event and TNF blockers are generally considered safe and effective in many chronic autoimmune disorders, this should not preclude this treatment, but rather suggests caution in patients of high risk of developing demyelinating events. With the introduction of selective solTNF inhibitors and the growing evidence of their effect, this may form the basis of a new treatment approach in inflammatory and neurological diseases.
Acknowledgments
Claire Gudex is acknowledged for proofreading the manuscript.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
L.B.K. and H.H.N. wrote the manuscript with the assistance of K.L.L., K.-E.B. and N.N. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Ethical review and approval were waived for this study, in accordance with Danish regulation since this is a case report with informed consent from the patient.
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to Danish data protection regulations.
Conflicts of Interest
K.L.L. is a member of the Lundbeck Foundation Brain Prize Council. H.H.N. is a member of the research council of the Danish Multiple Sclerosis Society and has served on scientific advisory boards and received support for congress participation, speaker honoraria, and research support from Biogen, Merck-Serono, Roche, Teva, Lundbeck, and Novartis.
Figure 1 Schematic overview of the case, showing the relationship between clinical presentation, treatment, and radiological presentation shown by MRI scans (T2, Flair, and T1+gadolinium enhancement). Created with BioRender.com. | INFLIXIMAB, METHOTREXATE, RITUXIMAB, SECUKINUMAB | DrugsGivenReaction | CC BY | 33401396 | 18,871,003 | 2021-01-01 |
What was the administration route of drug 'INFLIXIMAB'? | The Role of Non-Selective TNF Inhibitors in Demyelinating Events.
The use of non-selective tumor necrosis factor (TNF) inhibitors is well known in the treatment of inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and psoriasis. Its use in neurological disorders is limited however, due to rare adverse events of demyelination, even in patients without preceding demyelinating disease. We review here the molecular and cellular aspects of this neuroinflammatory process in light of a case of severe monophasic demyelination caused by treatment with infliximab. Focusing on the role of TNF, we review the links between CNS inflammation, demyelination, and neurodegenerative changes leading to permanent neurological deficits in a young woman, and we discuss the growing evidence for selective soluble TNF inhibitors as a new treatment approach in inflammatory and neurological diseases.
1. Introduction
The use of tumor necrosis factor (TNF) blockers has revolutionized the treatment of a number of chronic inflammatory diseases such as Crohn’s disease, ankylosing spondylitis, psoriasis, and rheumatoid arthritis.
Although TNF blockers are generally considered safe, an increasing number of neurologic adverse effects have been reported in the literature, consisting primarily of demyelination of the central nervous system (CNS) or peripheral nervous system (PNS) with a prevalence ranging from 0.050 to 0.100% [1]. These adverse events suggest a possible relationship between the use of anti-TNF biologics and demyelinating diseases [2].
TNF is a pleiotropic cytokine known to play important regulatory roles in the development and homeostasis of the healthy CNS [3]. It is produced initially as a transmembrane molecule (tmTNF) and is subsequently released from the cell as a soluble cytokine (solTNF) via regulated cleavage of tmTNF by TNF-α converting enzyme (TACE). Under normal conditions, TNF can be produced in the periphery by monocytes/macrophages, lymphocytes (T and B), natural killer cells, and dendritic cells [4], while TNF in the CNS is produced mainly by microglia [5]. Both forms of TNF are biologically active and interact with two distinct receptors—TNFR1 and TNFR2—with TNFR1 being expressed in all cell types, whereas TNFR2 is expressed mainly on immune cells, oligodendrocytes, and endothelial cells [6]. solTNF has a high affinity for TNFR1, which contains a death domain and can mediate apoptosis and chronic inflammation [7]. In the CNS, tmTNF has a higher affinity for TNFR2 and promotes mostly protective features such as cell survival and remyelination [6,7].
In animal models of multiple sclerosis (MS), such as experimental autoimmune encephalomyelitis (EAE), the administration of TNF blockers slowed the demyelinating process and improved outcome [8,9]. Ablation of TNF or TNFR1/TNFR2 combined in mice did not protect from EAE, however, and instead caused exacerbation of chronic disease [10,11,12,13]. TNFR1 ablation resulted in less severe EAE and better remyelination, while TNFR2 ablation exacerbated EAE and prevented remyelination [11,13,14]. Furthermore, mice only expressing tmTNF showed suppression of EAE [15]. These studies suggest a dichotomy between solTNF and tmTNF, in which MS is associated with the detrimental effects of solTNF via TNFR1, but tmTNF signaling via TNFR2 is important for repair and remyelination. This is supported by studies in EAE mice treated with a selective blocker of solTNF, XPro1595, which resulted in improved function, significant axonal preservation, oligodendrocyte differentiation, and remyelination [6,7]. More importantly, these differences in receptor function might explain the failed clinical trial using the non-selective TNF inhibitor Lenercept as treatment for MS [16], which was terminated due to clinical and radiological disease progression.
We present here a case of severe demyelination following treatment with infliximab, a chimeric monoclonal antibody that prevents binding of TNF to TNFR1 and TNFR2 by blocking both solTNF and tmTNF [17]. We discuss the possible underlying mechanisms of TNF blockers in CNS demyelination in the context of the current literature.
2. Case Description
The case is a 27-year-old woman with psoriatic arthritis, treated with methotrexate and infliximab. No family history of neurological disorders was reported.
After 4.5 years of treatment with infliximab, she complained of increasing fatigue, muscle pain, and mild cognitive difficulties. After a few months, she developed a subacute hemiparesis. MRI scan showed a solitary process with gadolinium ring enhancement (Figure 1—Week 0).
CSF analysis revealed no pleocytosis and normal protein levels, but did reveal oligoclonal bands and an elevated IgG index of 0.78. Initial blood tests showed a positive toxoplasmosis IgG, and PET-CT and a following biopsy from a single lymph node showed signs of granulomatous inflammation. The infliximab was discontinued, and the patient was initially treated for both toxoplasmosis and tuberculosis (Figure 1—Week 0).
Further investigations revealed no pathology on repeated PET-CT, including no pathological lymph nodes.
Repeated blood and CSF tests were found negative for toxoplasmosis, tuberculosis, varicella-zoster, Epstein–Barr, herpes simplex I+II, cytomegalovirus, Bartonella, Brucella, Aspergillus, hepatitis, and HIV. Microbiome PCR sequencing revealed no pathological DNA.
Antinuclear antibodies (ANA), Extractable Nuclear Antigen antibodies (ENA), Proteinase 3 Anti Neutrophil Cytoplasmic Antibody (C-ANCA), and Perinuclear Anti Neutrophil Cytoplasmic Antibodies (P-ANCA) were all negative.
Despite discontinuation of infliximab, the patient progressed clinically and radiologically over the next 12 weeks (Figure 1—Week 12). Clinical evaluation showed grade 4 hemiparesis on the left side and no cognitive difficulties, headache, or nausea.
Repeated CSF analysis confirmed oligoclonal bands and elevated IgG index but no increase in cell count or protein. Cytology described normal-appearing lymphocytes without pathological changes. Flow cytometry revealed 74% T cells, 7.9% polyclonal B cells, 1.6% NK cells, and CD4/CD8 of 4.1.
A biopsy was taken from the lesions in the brain, and histology showed unspecific reactive microglia and few infiltrating CD8+ T and B cells. There were no signs of tumor, lymphoma, vasculitis, progressive multifocal leukoencephalopathy, or infection with herpes, toxoplasmosis, or tuberculosis.
The patient was treated with high-dose glucocorticoid intravenously (1 g a day for 5 days) followed by five courses of plasma exchange (Figure 1—Week 12). Afterwards, MRI showed no new lesions but progression of one existing lesion and oedema, and the patient remained stable (Figure 1—Week 16). The patient continued with oral steroid therapy, which was tapered off after introduction of a two-course Rituximab treatment as a steroid-sparing agent (Figure 1—Week 16).
The following MRI showed remission, and the patient continued with a slight hemiparesis.
After 2 years (Figure 1—Week 104), the patient’s psoriatic arthritis started to deteriorate, and she was put on Secukinumab. She remained neurologically stable throughout the period and at follow-up (Figure 1—Week 134).
3. Discussion
We present a case of severe demyelination in a young woman who received infliximab as treatment for psoriatic arthritis. Because of the atypical presentation, many differential diagnoses were considered:
3.1. Infection
As the patient had been on different types of immunosuppressants since her early childhood, and at the time her symptoms developed she was treated with both infliximab and methotrexate, an infectious cause was first suspected. This was supported by the first MRI, which showed a characteristic ring enhancement comparable to cerebral toxoplasmosis, and a positive IgA test for toxoplasmosis. To further complicate the matter, a biopsy from a neck gland showed granulomatous inflammation, which could suggest tuberculosis. However, later test results for tuberculosis were negative (using interferon-gamma blood tests and microscopy of biopsy material). Although the patient received treatment for both toxoplasmosis and tuberculosis, this had no effect on the intracranial process or her clinical status. Furthermore, the CSF showed no signs of pleocytosis or elevated protein, nor did it confirm toxoplasmosis, tuberculosis, or any other form of infection.
3.2. Malignancy
Treatment with a TNF inhibitor has been suspected to increase the risk of certain malignancies, but this is still debated and may be related to the underlying autoimmune disease rather than the treatment [18,19,20,21]. On the initial PET-CT, the patient had a suspicious lymph gland. Biopsy from both this and a brain lesion showed no sign of malignant disease, just as repeated CSF cytology described normal-appearing lymphocytes without pathological changes. The clinical and radiological stabilization at 2 years follow-up also suggests a more benign disease process.
3.3. Inflammatory Demyelination
Studies suggest that patients with an autoimmune disease have an increased risk of developing other diseases with similar pathological mechanisms. Although still controversial, psoriasis has been shown to carry an increased risk of MS [22,23,24]. Reasons for this include shared genetic, environmental, and immunopathological factors (such as a strong Th1/Th17 response) in the two disorders [25]. This is further supported by the overlap in medications such as fumarate and Secukinumab [26]. As illustrated by the divergent results to anti-TNF inhibitors [16] however, the immunopathogenesis is not identical.
A register-based study from 2019 found an increased risk of MS and neuroinflammatory disease in patients with psoriatic arthritis but not rheumatoid arthritis, both with and without treatment with non-selective TNF inhibitors [27]. In view of the close relationship between autoimmune diseases, it is therefore possible that treatment with TNF blockers simply exacerbates a dormant neuroinflammatory condition like MS.
In this case, the patient remained stable without specific MS treatment, although Secukinumab was later introduced as an arthritis treatment and could in theory suppress any underlying MS activity. Secukinumab has been shown to be effective in MS [26], but it seems unlikely that an aggressive debut of MS would later stabilize completely without regular MS treatment. However, the disease course may still support a monophasic demyelinating event.
3.4. Infliximab-Induced Demyelination
As previously mentioned, the use of non-selective TNF blockers has been linked to demyelinating diseases, including MS, optic neuritis, transverse myelitis, and demyelinating neuropathies [1,28]. Furthermore, a potential link between TNF inhibitors and demyelinating disease has been suggested [29,30,31]. In view of the large number of patients treated with TNF blockers for long periods of time however, the demyelinating cases are rare and divergent [32,33]
The patient described here received infliximab for approximately 4.5 years before developing symptoms. In a 2017 review of reported cases of CNS demyelination associated with TNF inhibitors [26], the mean time of exposure was 17 months, but some patients had been treated for 6 years before developing symptoms. Our patient showed no resolution of her symptoms, consistent with 28% of the reviewed cases, and she had no prior family history of MS, which was also the case in the majority of cases reviewed. This patient thus shares many similarities with other cases of psoriatic arthritis treated with TNF blockers, supporting an initial monophasic demyelinating event that may later develop into MS, as seen in some cases with longer follow-up [28].
The mechanisms behind the potential demyelinating role of non-selective TNF blockers are not completely clear. In general, TNF blockers are large molecules that do not penetrate the intact blood–brain barrier, possibly explaining the lack of positive effects in TNF-mediated CNS diseases as opposed to other autoimmune disease such as rheumatoid and psoriatic arthritis [34,35]. Another theory is that the peripheral immunological effects of TNF blockers might alter the cytokine profile into a more proinflammatory CNS profile [28] or increase the ingress of peripheral autoreactive T-cells into the CNS through the leaky blood–brain barrier already established in active MS [34,35]
The infliximab used in this case blocks binding of TNF to TNFR1 and TNFR2 by blocking both solTNF and tmTNF [17], therefore also blocking the positive effects of TNFR2. Levels of TNF are increased in patients with MS, and studies suggest that while high levels of TNFR1 may be a risk factor for more severe disease, TNFR2 plays a more protective role [36]. As infliximab affects both pathways, the blocking of the protective features of TNFR2 and the remyelinating process could potentially lead to demyelinating events, as seen in our case. This is further supported by animal studies in which a selective blocker of solTNF resulted in improved function as well as significant axonal preservation, oligodendrocyte differentiation, and remyelination [6,7]. Therefore, selective TNF inhibition or activation of TNFR2 could lead to a new treatment approach for inflammatory disease [37,38].
4. Conclusions
This case supports the growing evidence suggesting demyelinating events as adverse effects of non-selective TNF inhibitors, but distinguishes itself by the long follow-up time and the in-depth discussion of the underlying mechanisms using selective versus non-selective TNF inhibition. As demyelination is a rare adverse event and TNF blockers are generally considered safe and effective in many chronic autoimmune disorders, this should not preclude this treatment, but rather suggests caution in patients of high risk of developing demyelinating events. With the introduction of selective solTNF inhibitors and the growing evidence of their effect, this may form the basis of a new treatment approach in inflammatory and neurological diseases.
Acknowledgments
Claire Gudex is acknowledged for proofreading the manuscript.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
L.B.K. and H.H.N. wrote the manuscript with the assistance of K.L.L., K.-E.B. and N.N. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Ethical review and approval were waived for this study, in accordance with Danish regulation since this is a case report with informed consent from the patient.
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to Danish data protection regulations.
Conflicts of Interest
K.L.L. is a member of the Lundbeck Foundation Brain Prize Council. H.H.N. is a member of the research council of the Danish Multiple Sclerosis Society and has served on scientific advisory boards and received support for congress participation, speaker honoraria, and research support from Biogen, Merck-Serono, Roche, Teva, Lundbeck, and Novartis.
Figure 1 Schematic overview of the case, showing the relationship between clinical presentation, treatment, and radiological presentation shown by MRI scans (T2, Flair, and T1+gadolinium enhancement). Created with BioRender.com. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33401396 | 18,783,118 | 2021-01-01 |
What was the dosage of drug 'INFLIXIMAB'? | The Role of Non-Selective TNF Inhibitors in Demyelinating Events.
The use of non-selective tumor necrosis factor (TNF) inhibitors is well known in the treatment of inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and psoriasis. Its use in neurological disorders is limited however, due to rare adverse events of demyelination, even in patients without preceding demyelinating disease. We review here the molecular and cellular aspects of this neuroinflammatory process in light of a case of severe monophasic demyelination caused by treatment with infliximab. Focusing on the role of TNF, we review the links between CNS inflammation, demyelination, and neurodegenerative changes leading to permanent neurological deficits in a young woman, and we discuss the growing evidence for selective soluble TNF inhibitors as a new treatment approach in inflammatory and neurological diseases.
1. Introduction
The use of tumor necrosis factor (TNF) blockers has revolutionized the treatment of a number of chronic inflammatory diseases such as Crohn’s disease, ankylosing spondylitis, psoriasis, and rheumatoid arthritis.
Although TNF blockers are generally considered safe, an increasing number of neurologic adverse effects have been reported in the literature, consisting primarily of demyelination of the central nervous system (CNS) or peripheral nervous system (PNS) with a prevalence ranging from 0.050 to 0.100% [1]. These adverse events suggest a possible relationship between the use of anti-TNF biologics and demyelinating diseases [2].
TNF is a pleiotropic cytokine known to play important regulatory roles in the development and homeostasis of the healthy CNS [3]. It is produced initially as a transmembrane molecule (tmTNF) and is subsequently released from the cell as a soluble cytokine (solTNF) via regulated cleavage of tmTNF by TNF-α converting enzyme (TACE). Under normal conditions, TNF can be produced in the periphery by monocytes/macrophages, lymphocytes (T and B), natural killer cells, and dendritic cells [4], while TNF in the CNS is produced mainly by microglia [5]. Both forms of TNF are biologically active and interact with two distinct receptors—TNFR1 and TNFR2—with TNFR1 being expressed in all cell types, whereas TNFR2 is expressed mainly on immune cells, oligodendrocytes, and endothelial cells [6]. solTNF has a high affinity for TNFR1, which contains a death domain and can mediate apoptosis and chronic inflammation [7]. In the CNS, tmTNF has a higher affinity for TNFR2 and promotes mostly protective features such as cell survival and remyelination [6,7].
In animal models of multiple sclerosis (MS), such as experimental autoimmune encephalomyelitis (EAE), the administration of TNF blockers slowed the demyelinating process and improved outcome [8,9]. Ablation of TNF or TNFR1/TNFR2 combined in mice did not protect from EAE, however, and instead caused exacerbation of chronic disease [10,11,12,13]. TNFR1 ablation resulted in less severe EAE and better remyelination, while TNFR2 ablation exacerbated EAE and prevented remyelination [11,13,14]. Furthermore, mice only expressing tmTNF showed suppression of EAE [15]. These studies suggest a dichotomy between solTNF and tmTNF, in which MS is associated with the detrimental effects of solTNF via TNFR1, but tmTNF signaling via TNFR2 is important for repair and remyelination. This is supported by studies in EAE mice treated with a selective blocker of solTNF, XPro1595, which resulted in improved function, significant axonal preservation, oligodendrocyte differentiation, and remyelination [6,7]. More importantly, these differences in receptor function might explain the failed clinical trial using the non-selective TNF inhibitor Lenercept as treatment for MS [16], which was terminated due to clinical and radiological disease progression.
We present here a case of severe demyelination following treatment with infliximab, a chimeric monoclonal antibody that prevents binding of TNF to TNFR1 and TNFR2 by blocking both solTNF and tmTNF [17]. We discuss the possible underlying mechanisms of TNF blockers in CNS demyelination in the context of the current literature.
2. Case Description
The case is a 27-year-old woman with psoriatic arthritis, treated with methotrexate and infliximab. No family history of neurological disorders was reported.
After 4.5 years of treatment with infliximab, she complained of increasing fatigue, muscle pain, and mild cognitive difficulties. After a few months, she developed a subacute hemiparesis. MRI scan showed a solitary process with gadolinium ring enhancement (Figure 1—Week 0).
CSF analysis revealed no pleocytosis and normal protein levels, but did reveal oligoclonal bands and an elevated IgG index of 0.78. Initial blood tests showed a positive toxoplasmosis IgG, and PET-CT and a following biopsy from a single lymph node showed signs of granulomatous inflammation. The infliximab was discontinued, and the patient was initially treated for both toxoplasmosis and tuberculosis (Figure 1—Week 0).
Further investigations revealed no pathology on repeated PET-CT, including no pathological lymph nodes.
Repeated blood and CSF tests were found negative for toxoplasmosis, tuberculosis, varicella-zoster, Epstein–Barr, herpes simplex I+II, cytomegalovirus, Bartonella, Brucella, Aspergillus, hepatitis, and HIV. Microbiome PCR sequencing revealed no pathological DNA.
Antinuclear antibodies (ANA), Extractable Nuclear Antigen antibodies (ENA), Proteinase 3 Anti Neutrophil Cytoplasmic Antibody (C-ANCA), and Perinuclear Anti Neutrophil Cytoplasmic Antibodies (P-ANCA) were all negative.
Despite discontinuation of infliximab, the patient progressed clinically and radiologically over the next 12 weeks (Figure 1—Week 12). Clinical evaluation showed grade 4 hemiparesis on the left side and no cognitive difficulties, headache, or nausea.
Repeated CSF analysis confirmed oligoclonal bands and elevated IgG index but no increase in cell count or protein. Cytology described normal-appearing lymphocytes without pathological changes. Flow cytometry revealed 74% T cells, 7.9% polyclonal B cells, 1.6% NK cells, and CD4/CD8 of 4.1.
A biopsy was taken from the lesions in the brain, and histology showed unspecific reactive microglia and few infiltrating CD8+ T and B cells. There were no signs of tumor, lymphoma, vasculitis, progressive multifocal leukoencephalopathy, or infection with herpes, toxoplasmosis, or tuberculosis.
The patient was treated with high-dose glucocorticoid intravenously (1 g a day for 5 days) followed by five courses of plasma exchange (Figure 1—Week 12). Afterwards, MRI showed no new lesions but progression of one existing lesion and oedema, and the patient remained stable (Figure 1—Week 16). The patient continued with oral steroid therapy, which was tapered off after introduction of a two-course Rituximab treatment as a steroid-sparing agent (Figure 1—Week 16).
The following MRI showed remission, and the patient continued with a slight hemiparesis.
After 2 years (Figure 1—Week 104), the patient’s psoriatic arthritis started to deteriorate, and she was put on Secukinumab. She remained neurologically stable throughout the period and at follow-up (Figure 1—Week 134).
3. Discussion
We present a case of severe demyelination in a young woman who received infliximab as treatment for psoriatic arthritis. Because of the atypical presentation, many differential diagnoses were considered:
3.1. Infection
As the patient had been on different types of immunosuppressants since her early childhood, and at the time her symptoms developed she was treated with both infliximab and methotrexate, an infectious cause was first suspected. This was supported by the first MRI, which showed a characteristic ring enhancement comparable to cerebral toxoplasmosis, and a positive IgA test for toxoplasmosis. To further complicate the matter, a biopsy from a neck gland showed granulomatous inflammation, which could suggest tuberculosis. However, later test results for tuberculosis were negative (using interferon-gamma blood tests and microscopy of biopsy material). Although the patient received treatment for both toxoplasmosis and tuberculosis, this had no effect on the intracranial process or her clinical status. Furthermore, the CSF showed no signs of pleocytosis or elevated protein, nor did it confirm toxoplasmosis, tuberculosis, or any other form of infection.
3.2. Malignancy
Treatment with a TNF inhibitor has been suspected to increase the risk of certain malignancies, but this is still debated and may be related to the underlying autoimmune disease rather than the treatment [18,19,20,21]. On the initial PET-CT, the patient had a suspicious lymph gland. Biopsy from both this and a brain lesion showed no sign of malignant disease, just as repeated CSF cytology described normal-appearing lymphocytes without pathological changes. The clinical and radiological stabilization at 2 years follow-up also suggests a more benign disease process.
3.3. Inflammatory Demyelination
Studies suggest that patients with an autoimmune disease have an increased risk of developing other diseases with similar pathological mechanisms. Although still controversial, psoriasis has been shown to carry an increased risk of MS [22,23,24]. Reasons for this include shared genetic, environmental, and immunopathological factors (such as a strong Th1/Th17 response) in the two disorders [25]. This is further supported by the overlap in medications such as fumarate and Secukinumab [26]. As illustrated by the divergent results to anti-TNF inhibitors [16] however, the immunopathogenesis is not identical.
A register-based study from 2019 found an increased risk of MS and neuroinflammatory disease in patients with psoriatic arthritis but not rheumatoid arthritis, both with and without treatment with non-selective TNF inhibitors [27]. In view of the close relationship between autoimmune diseases, it is therefore possible that treatment with TNF blockers simply exacerbates a dormant neuroinflammatory condition like MS.
In this case, the patient remained stable without specific MS treatment, although Secukinumab was later introduced as an arthritis treatment and could in theory suppress any underlying MS activity. Secukinumab has been shown to be effective in MS [26], but it seems unlikely that an aggressive debut of MS would later stabilize completely without regular MS treatment. However, the disease course may still support a monophasic demyelinating event.
3.4. Infliximab-Induced Demyelination
As previously mentioned, the use of non-selective TNF blockers has been linked to demyelinating diseases, including MS, optic neuritis, transverse myelitis, and demyelinating neuropathies [1,28]. Furthermore, a potential link between TNF inhibitors and demyelinating disease has been suggested [29,30,31]. In view of the large number of patients treated with TNF blockers for long periods of time however, the demyelinating cases are rare and divergent [32,33]
The patient described here received infliximab for approximately 4.5 years before developing symptoms. In a 2017 review of reported cases of CNS demyelination associated with TNF inhibitors [26], the mean time of exposure was 17 months, but some patients had been treated for 6 years before developing symptoms. Our patient showed no resolution of her symptoms, consistent with 28% of the reviewed cases, and she had no prior family history of MS, which was also the case in the majority of cases reviewed. This patient thus shares many similarities with other cases of psoriatic arthritis treated with TNF blockers, supporting an initial monophasic demyelinating event that may later develop into MS, as seen in some cases with longer follow-up [28].
The mechanisms behind the potential demyelinating role of non-selective TNF blockers are not completely clear. In general, TNF blockers are large molecules that do not penetrate the intact blood–brain barrier, possibly explaining the lack of positive effects in TNF-mediated CNS diseases as opposed to other autoimmune disease such as rheumatoid and psoriatic arthritis [34,35]. Another theory is that the peripheral immunological effects of TNF blockers might alter the cytokine profile into a more proinflammatory CNS profile [28] or increase the ingress of peripheral autoreactive T-cells into the CNS through the leaky blood–brain barrier already established in active MS [34,35]
The infliximab used in this case blocks binding of TNF to TNFR1 and TNFR2 by blocking both solTNF and tmTNF [17], therefore also blocking the positive effects of TNFR2. Levels of TNF are increased in patients with MS, and studies suggest that while high levels of TNFR1 may be a risk factor for more severe disease, TNFR2 plays a more protective role [36]. As infliximab affects both pathways, the blocking of the protective features of TNFR2 and the remyelinating process could potentially lead to demyelinating events, as seen in our case. This is further supported by animal studies in which a selective blocker of solTNF resulted in improved function as well as significant axonal preservation, oligodendrocyte differentiation, and remyelination [6,7]. Therefore, selective TNF inhibition or activation of TNFR2 could lead to a new treatment approach for inflammatory disease [37,38].
4. Conclusions
This case supports the growing evidence suggesting demyelinating events as adverse effects of non-selective TNF inhibitors, but distinguishes itself by the long follow-up time and the in-depth discussion of the underlying mechanisms using selective versus non-selective TNF inhibition. As demyelination is a rare adverse event and TNF blockers are generally considered safe and effective in many chronic autoimmune disorders, this should not preclude this treatment, but rather suggests caution in patients of high risk of developing demyelinating events. With the introduction of selective solTNF inhibitors and the growing evidence of their effect, this may form the basis of a new treatment approach in inflammatory and neurological diseases.
Acknowledgments
Claire Gudex is acknowledged for proofreading the manuscript.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
L.B.K. and H.H.N. wrote the manuscript with the assistance of K.L.L., K.-E.B. and N.N. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Ethical review and approval were waived for this study, in accordance with Danish regulation since this is a case report with informed consent from the patient.
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to Danish data protection regulations.
Conflicts of Interest
K.L.L. is a member of the Lundbeck Foundation Brain Prize Council. H.H.N. is a member of the research council of the Danish Multiple Sclerosis Society and has served on scientific advisory boards and received support for congress participation, speaker honoraria, and research support from Biogen, Merck-Serono, Roche, Teva, Lundbeck, and Novartis.
Figure 1 Schematic overview of the case, showing the relationship between clinical presentation, treatment, and radiological presentation shown by MRI scans (T2, Flair, and T1+gadolinium enhancement). Created with BioRender.com. | UNK, 4.5 YEARS | DrugDosageText | CC BY | 33401396 | 18,800,068 | 2021-01-01 |
What was the dosage of drug 'RITUXIMAB'? | The Role of Non-Selective TNF Inhibitors in Demyelinating Events.
The use of non-selective tumor necrosis factor (TNF) inhibitors is well known in the treatment of inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and psoriasis. Its use in neurological disorders is limited however, due to rare adverse events of demyelination, even in patients without preceding demyelinating disease. We review here the molecular and cellular aspects of this neuroinflammatory process in light of a case of severe monophasic demyelination caused by treatment with infliximab. Focusing on the role of TNF, we review the links between CNS inflammation, demyelination, and neurodegenerative changes leading to permanent neurological deficits in a young woman, and we discuss the growing evidence for selective soluble TNF inhibitors as a new treatment approach in inflammatory and neurological diseases.
1. Introduction
The use of tumor necrosis factor (TNF) blockers has revolutionized the treatment of a number of chronic inflammatory diseases such as Crohn’s disease, ankylosing spondylitis, psoriasis, and rheumatoid arthritis.
Although TNF blockers are generally considered safe, an increasing number of neurologic adverse effects have been reported in the literature, consisting primarily of demyelination of the central nervous system (CNS) or peripheral nervous system (PNS) with a prevalence ranging from 0.050 to 0.100% [1]. These adverse events suggest a possible relationship between the use of anti-TNF biologics and demyelinating diseases [2].
TNF is a pleiotropic cytokine known to play important regulatory roles in the development and homeostasis of the healthy CNS [3]. It is produced initially as a transmembrane molecule (tmTNF) and is subsequently released from the cell as a soluble cytokine (solTNF) via regulated cleavage of tmTNF by TNF-α converting enzyme (TACE). Under normal conditions, TNF can be produced in the periphery by monocytes/macrophages, lymphocytes (T and B), natural killer cells, and dendritic cells [4], while TNF in the CNS is produced mainly by microglia [5]. Both forms of TNF are biologically active and interact with two distinct receptors—TNFR1 and TNFR2—with TNFR1 being expressed in all cell types, whereas TNFR2 is expressed mainly on immune cells, oligodendrocytes, and endothelial cells [6]. solTNF has a high affinity for TNFR1, which contains a death domain and can mediate apoptosis and chronic inflammation [7]. In the CNS, tmTNF has a higher affinity for TNFR2 and promotes mostly protective features such as cell survival and remyelination [6,7].
In animal models of multiple sclerosis (MS), such as experimental autoimmune encephalomyelitis (EAE), the administration of TNF blockers slowed the demyelinating process and improved outcome [8,9]. Ablation of TNF or TNFR1/TNFR2 combined in mice did not protect from EAE, however, and instead caused exacerbation of chronic disease [10,11,12,13]. TNFR1 ablation resulted in less severe EAE and better remyelination, while TNFR2 ablation exacerbated EAE and prevented remyelination [11,13,14]. Furthermore, mice only expressing tmTNF showed suppression of EAE [15]. These studies suggest a dichotomy between solTNF and tmTNF, in which MS is associated with the detrimental effects of solTNF via TNFR1, but tmTNF signaling via TNFR2 is important for repair and remyelination. This is supported by studies in EAE mice treated with a selective blocker of solTNF, XPro1595, which resulted in improved function, significant axonal preservation, oligodendrocyte differentiation, and remyelination [6,7]. More importantly, these differences in receptor function might explain the failed clinical trial using the non-selective TNF inhibitor Lenercept as treatment for MS [16], which was terminated due to clinical and radiological disease progression.
We present here a case of severe demyelination following treatment with infliximab, a chimeric monoclonal antibody that prevents binding of TNF to TNFR1 and TNFR2 by blocking both solTNF and tmTNF [17]. We discuss the possible underlying mechanisms of TNF blockers in CNS demyelination in the context of the current literature.
2. Case Description
The case is a 27-year-old woman with psoriatic arthritis, treated with methotrexate and infliximab. No family history of neurological disorders was reported.
After 4.5 years of treatment with infliximab, she complained of increasing fatigue, muscle pain, and mild cognitive difficulties. After a few months, she developed a subacute hemiparesis. MRI scan showed a solitary process with gadolinium ring enhancement (Figure 1—Week 0).
CSF analysis revealed no pleocytosis and normal protein levels, but did reveal oligoclonal bands and an elevated IgG index of 0.78. Initial blood tests showed a positive toxoplasmosis IgG, and PET-CT and a following biopsy from a single lymph node showed signs of granulomatous inflammation. The infliximab was discontinued, and the patient was initially treated for both toxoplasmosis and tuberculosis (Figure 1—Week 0).
Further investigations revealed no pathology on repeated PET-CT, including no pathological lymph nodes.
Repeated blood and CSF tests were found negative for toxoplasmosis, tuberculosis, varicella-zoster, Epstein–Barr, herpes simplex I+II, cytomegalovirus, Bartonella, Brucella, Aspergillus, hepatitis, and HIV. Microbiome PCR sequencing revealed no pathological DNA.
Antinuclear antibodies (ANA), Extractable Nuclear Antigen antibodies (ENA), Proteinase 3 Anti Neutrophil Cytoplasmic Antibody (C-ANCA), and Perinuclear Anti Neutrophil Cytoplasmic Antibodies (P-ANCA) were all negative.
Despite discontinuation of infliximab, the patient progressed clinically and radiologically over the next 12 weeks (Figure 1—Week 12). Clinical evaluation showed grade 4 hemiparesis on the left side and no cognitive difficulties, headache, or nausea.
Repeated CSF analysis confirmed oligoclonal bands and elevated IgG index but no increase in cell count or protein. Cytology described normal-appearing lymphocytes without pathological changes. Flow cytometry revealed 74% T cells, 7.9% polyclonal B cells, 1.6% NK cells, and CD4/CD8 of 4.1.
A biopsy was taken from the lesions in the brain, and histology showed unspecific reactive microglia and few infiltrating CD8+ T and B cells. There were no signs of tumor, lymphoma, vasculitis, progressive multifocal leukoencephalopathy, or infection with herpes, toxoplasmosis, or tuberculosis.
The patient was treated with high-dose glucocorticoid intravenously (1 g a day for 5 days) followed by five courses of plasma exchange (Figure 1—Week 12). Afterwards, MRI showed no new lesions but progression of one existing lesion and oedema, and the patient remained stable (Figure 1—Week 16). The patient continued with oral steroid therapy, which was tapered off after introduction of a two-course Rituximab treatment as a steroid-sparing agent (Figure 1—Week 16).
The following MRI showed remission, and the patient continued with a slight hemiparesis.
After 2 years (Figure 1—Week 104), the patient’s psoriatic arthritis started to deteriorate, and she was put on Secukinumab. She remained neurologically stable throughout the period and at follow-up (Figure 1—Week 134).
3. Discussion
We present a case of severe demyelination in a young woman who received infliximab as treatment for psoriatic arthritis. Because of the atypical presentation, many differential diagnoses were considered:
3.1. Infection
As the patient had been on different types of immunosuppressants since her early childhood, and at the time her symptoms developed she was treated with both infliximab and methotrexate, an infectious cause was first suspected. This was supported by the first MRI, which showed a characteristic ring enhancement comparable to cerebral toxoplasmosis, and a positive IgA test for toxoplasmosis. To further complicate the matter, a biopsy from a neck gland showed granulomatous inflammation, which could suggest tuberculosis. However, later test results for tuberculosis were negative (using interferon-gamma blood tests and microscopy of biopsy material). Although the patient received treatment for both toxoplasmosis and tuberculosis, this had no effect on the intracranial process or her clinical status. Furthermore, the CSF showed no signs of pleocytosis or elevated protein, nor did it confirm toxoplasmosis, tuberculosis, or any other form of infection.
3.2. Malignancy
Treatment with a TNF inhibitor has been suspected to increase the risk of certain malignancies, but this is still debated and may be related to the underlying autoimmune disease rather than the treatment [18,19,20,21]. On the initial PET-CT, the patient had a suspicious lymph gland. Biopsy from both this and a brain lesion showed no sign of malignant disease, just as repeated CSF cytology described normal-appearing lymphocytes without pathological changes. The clinical and radiological stabilization at 2 years follow-up also suggests a more benign disease process.
3.3. Inflammatory Demyelination
Studies suggest that patients with an autoimmune disease have an increased risk of developing other diseases with similar pathological mechanisms. Although still controversial, psoriasis has been shown to carry an increased risk of MS [22,23,24]. Reasons for this include shared genetic, environmental, and immunopathological factors (such as a strong Th1/Th17 response) in the two disorders [25]. This is further supported by the overlap in medications such as fumarate and Secukinumab [26]. As illustrated by the divergent results to anti-TNF inhibitors [16] however, the immunopathogenesis is not identical.
A register-based study from 2019 found an increased risk of MS and neuroinflammatory disease in patients with psoriatic arthritis but not rheumatoid arthritis, both with and without treatment with non-selective TNF inhibitors [27]. In view of the close relationship between autoimmune diseases, it is therefore possible that treatment with TNF blockers simply exacerbates a dormant neuroinflammatory condition like MS.
In this case, the patient remained stable without specific MS treatment, although Secukinumab was later introduced as an arthritis treatment and could in theory suppress any underlying MS activity. Secukinumab has been shown to be effective in MS [26], but it seems unlikely that an aggressive debut of MS would later stabilize completely without regular MS treatment. However, the disease course may still support a monophasic demyelinating event.
3.4. Infliximab-Induced Demyelination
As previously mentioned, the use of non-selective TNF blockers has been linked to demyelinating diseases, including MS, optic neuritis, transverse myelitis, and demyelinating neuropathies [1,28]. Furthermore, a potential link between TNF inhibitors and demyelinating disease has been suggested [29,30,31]. In view of the large number of patients treated with TNF blockers for long periods of time however, the demyelinating cases are rare and divergent [32,33]
The patient described here received infliximab for approximately 4.5 years before developing symptoms. In a 2017 review of reported cases of CNS demyelination associated with TNF inhibitors [26], the mean time of exposure was 17 months, but some patients had been treated for 6 years before developing symptoms. Our patient showed no resolution of her symptoms, consistent with 28% of the reviewed cases, and she had no prior family history of MS, which was also the case in the majority of cases reviewed. This patient thus shares many similarities with other cases of psoriatic arthritis treated with TNF blockers, supporting an initial monophasic demyelinating event that may later develop into MS, as seen in some cases with longer follow-up [28].
The mechanisms behind the potential demyelinating role of non-selective TNF blockers are not completely clear. In general, TNF blockers are large molecules that do not penetrate the intact blood–brain barrier, possibly explaining the lack of positive effects in TNF-mediated CNS diseases as opposed to other autoimmune disease such as rheumatoid and psoriatic arthritis [34,35]. Another theory is that the peripheral immunological effects of TNF blockers might alter the cytokine profile into a more proinflammatory CNS profile [28] or increase the ingress of peripheral autoreactive T-cells into the CNS through the leaky blood–brain barrier already established in active MS [34,35]
The infliximab used in this case blocks binding of TNF to TNFR1 and TNFR2 by blocking both solTNF and tmTNF [17], therefore also blocking the positive effects of TNFR2. Levels of TNF are increased in patients with MS, and studies suggest that while high levels of TNFR1 may be a risk factor for more severe disease, TNFR2 plays a more protective role [36]. As infliximab affects both pathways, the blocking of the protective features of TNFR2 and the remyelinating process could potentially lead to demyelinating events, as seen in our case. This is further supported by animal studies in which a selective blocker of solTNF resulted in improved function as well as significant axonal preservation, oligodendrocyte differentiation, and remyelination [6,7]. Therefore, selective TNF inhibition or activation of TNFR2 could lead to a new treatment approach for inflammatory disease [37,38].
4. Conclusions
This case supports the growing evidence suggesting demyelinating events as adverse effects of non-selective TNF inhibitors, but distinguishes itself by the long follow-up time and the in-depth discussion of the underlying mechanisms using selective versus non-selective TNF inhibition. As demyelination is a rare adverse event and TNF blockers are generally considered safe and effective in many chronic autoimmune disorders, this should not preclude this treatment, but rather suggests caution in patients of high risk of developing demyelinating events. With the introduction of selective solTNF inhibitors and the growing evidence of their effect, this may form the basis of a new treatment approach in inflammatory and neurological diseases.
Acknowledgments
Claire Gudex is acknowledged for proofreading the manuscript.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
L.B.K. and H.H.N. wrote the manuscript with the assistance of K.L.L., K.-E.B. and N.N. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Ethical review and approval were waived for this study, in accordance with Danish regulation since this is a case report with informed consent from the patient.
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to Danish data protection regulations.
Conflicts of Interest
K.L.L. is a member of the Lundbeck Foundation Brain Prize Council. H.H.N. is a member of the research council of the Danish Multiple Sclerosis Society and has served on scientific advisory boards and received support for congress participation, speaker honoraria, and research support from Biogen, Merck-Serono, Roche, Teva, Lundbeck, and Novartis.
Figure 1 Schematic overview of the case, showing the relationship between clinical presentation, treatment, and radiological presentation shown by MRI scans (T2, Flair, and T1+gadolinium enhancement). Created with BioRender.com. | UNK; (TWO?COURSE) | DrugDosageText | CC BY | 33401396 | 18,783,118 | 2021-01-01 |
What was the outcome of reaction 'Cognitive disorder'? | The Role of Non-Selective TNF Inhibitors in Demyelinating Events.
The use of non-selective tumor necrosis factor (TNF) inhibitors is well known in the treatment of inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and psoriasis. Its use in neurological disorders is limited however, due to rare adverse events of demyelination, even in patients without preceding demyelinating disease. We review here the molecular and cellular aspects of this neuroinflammatory process in light of a case of severe monophasic demyelination caused by treatment with infliximab. Focusing on the role of TNF, we review the links between CNS inflammation, demyelination, and neurodegenerative changes leading to permanent neurological deficits in a young woman, and we discuss the growing evidence for selective soluble TNF inhibitors as a new treatment approach in inflammatory and neurological diseases.
1. Introduction
The use of tumor necrosis factor (TNF) blockers has revolutionized the treatment of a number of chronic inflammatory diseases such as Crohn’s disease, ankylosing spondylitis, psoriasis, and rheumatoid arthritis.
Although TNF blockers are generally considered safe, an increasing number of neurologic adverse effects have been reported in the literature, consisting primarily of demyelination of the central nervous system (CNS) or peripheral nervous system (PNS) with a prevalence ranging from 0.050 to 0.100% [1]. These adverse events suggest a possible relationship between the use of anti-TNF biologics and demyelinating diseases [2].
TNF is a pleiotropic cytokine known to play important regulatory roles in the development and homeostasis of the healthy CNS [3]. It is produced initially as a transmembrane molecule (tmTNF) and is subsequently released from the cell as a soluble cytokine (solTNF) via regulated cleavage of tmTNF by TNF-α converting enzyme (TACE). Under normal conditions, TNF can be produced in the periphery by monocytes/macrophages, lymphocytes (T and B), natural killer cells, and dendritic cells [4], while TNF in the CNS is produced mainly by microglia [5]. Both forms of TNF are biologically active and interact with two distinct receptors—TNFR1 and TNFR2—with TNFR1 being expressed in all cell types, whereas TNFR2 is expressed mainly on immune cells, oligodendrocytes, and endothelial cells [6]. solTNF has a high affinity for TNFR1, which contains a death domain and can mediate apoptosis and chronic inflammation [7]. In the CNS, tmTNF has a higher affinity for TNFR2 and promotes mostly protective features such as cell survival and remyelination [6,7].
In animal models of multiple sclerosis (MS), such as experimental autoimmune encephalomyelitis (EAE), the administration of TNF blockers slowed the demyelinating process and improved outcome [8,9]. Ablation of TNF or TNFR1/TNFR2 combined in mice did not protect from EAE, however, and instead caused exacerbation of chronic disease [10,11,12,13]. TNFR1 ablation resulted in less severe EAE and better remyelination, while TNFR2 ablation exacerbated EAE and prevented remyelination [11,13,14]. Furthermore, mice only expressing tmTNF showed suppression of EAE [15]. These studies suggest a dichotomy between solTNF and tmTNF, in which MS is associated with the detrimental effects of solTNF via TNFR1, but tmTNF signaling via TNFR2 is important for repair and remyelination. This is supported by studies in EAE mice treated with a selective blocker of solTNF, XPro1595, which resulted in improved function, significant axonal preservation, oligodendrocyte differentiation, and remyelination [6,7]. More importantly, these differences in receptor function might explain the failed clinical trial using the non-selective TNF inhibitor Lenercept as treatment for MS [16], which was terminated due to clinical and radiological disease progression.
We present here a case of severe demyelination following treatment with infliximab, a chimeric monoclonal antibody that prevents binding of TNF to TNFR1 and TNFR2 by blocking both solTNF and tmTNF [17]. We discuss the possible underlying mechanisms of TNF blockers in CNS demyelination in the context of the current literature.
2. Case Description
The case is a 27-year-old woman with psoriatic arthritis, treated with methotrexate and infliximab. No family history of neurological disorders was reported.
After 4.5 years of treatment with infliximab, she complained of increasing fatigue, muscle pain, and mild cognitive difficulties. After a few months, she developed a subacute hemiparesis. MRI scan showed a solitary process with gadolinium ring enhancement (Figure 1—Week 0).
CSF analysis revealed no pleocytosis and normal protein levels, but did reveal oligoclonal bands and an elevated IgG index of 0.78. Initial blood tests showed a positive toxoplasmosis IgG, and PET-CT and a following biopsy from a single lymph node showed signs of granulomatous inflammation. The infliximab was discontinued, and the patient was initially treated for both toxoplasmosis and tuberculosis (Figure 1—Week 0).
Further investigations revealed no pathology on repeated PET-CT, including no pathological lymph nodes.
Repeated blood and CSF tests were found negative for toxoplasmosis, tuberculosis, varicella-zoster, Epstein–Barr, herpes simplex I+II, cytomegalovirus, Bartonella, Brucella, Aspergillus, hepatitis, and HIV. Microbiome PCR sequencing revealed no pathological DNA.
Antinuclear antibodies (ANA), Extractable Nuclear Antigen antibodies (ENA), Proteinase 3 Anti Neutrophil Cytoplasmic Antibody (C-ANCA), and Perinuclear Anti Neutrophil Cytoplasmic Antibodies (P-ANCA) were all negative.
Despite discontinuation of infliximab, the patient progressed clinically and radiologically over the next 12 weeks (Figure 1—Week 12). Clinical evaluation showed grade 4 hemiparesis on the left side and no cognitive difficulties, headache, or nausea.
Repeated CSF analysis confirmed oligoclonal bands and elevated IgG index but no increase in cell count or protein. Cytology described normal-appearing lymphocytes without pathological changes. Flow cytometry revealed 74% T cells, 7.9% polyclonal B cells, 1.6% NK cells, and CD4/CD8 of 4.1.
A biopsy was taken from the lesions in the brain, and histology showed unspecific reactive microglia and few infiltrating CD8+ T and B cells. There were no signs of tumor, lymphoma, vasculitis, progressive multifocal leukoencephalopathy, or infection with herpes, toxoplasmosis, or tuberculosis.
The patient was treated with high-dose glucocorticoid intravenously (1 g a day for 5 days) followed by five courses of plasma exchange (Figure 1—Week 12). Afterwards, MRI showed no new lesions but progression of one existing lesion and oedema, and the patient remained stable (Figure 1—Week 16). The patient continued with oral steroid therapy, which was tapered off after introduction of a two-course Rituximab treatment as a steroid-sparing agent (Figure 1—Week 16).
The following MRI showed remission, and the patient continued with a slight hemiparesis.
After 2 years (Figure 1—Week 104), the patient’s psoriatic arthritis started to deteriorate, and she was put on Secukinumab. She remained neurologically stable throughout the period and at follow-up (Figure 1—Week 134).
3. Discussion
We present a case of severe demyelination in a young woman who received infliximab as treatment for psoriatic arthritis. Because of the atypical presentation, many differential diagnoses were considered:
3.1. Infection
As the patient had been on different types of immunosuppressants since her early childhood, and at the time her symptoms developed she was treated with both infliximab and methotrexate, an infectious cause was first suspected. This was supported by the first MRI, which showed a characteristic ring enhancement comparable to cerebral toxoplasmosis, and a positive IgA test for toxoplasmosis. To further complicate the matter, a biopsy from a neck gland showed granulomatous inflammation, which could suggest tuberculosis. However, later test results for tuberculosis were negative (using interferon-gamma blood tests and microscopy of biopsy material). Although the patient received treatment for both toxoplasmosis and tuberculosis, this had no effect on the intracranial process or her clinical status. Furthermore, the CSF showed no signs of pleocytosis or elevated protein, nor did it confirm toxoplasmosis, tuberculosis, or any other form of infection.
3.2. Malignancy
Treatment with a TNF inhibitor has been suspected to increase the risk of certain malignancies, but this is still debated and may be related to the underlying autoimmune disease rather than the treatment [18,19,20,21]. On the initial PET-CT, the patient had a suspicious lymph gland. Biopsy from both this and a brain lesion showed no sign of malignant disease, just as repeated CSF cytology described normal-appearing lymphocytes without pathological changes. The clinical and radiological stabilization at 2 years follow-up also suggests a more benign disease process.
3.3. Inflammatory Demyelination
Studies suggest that patients with an autoimmune disease have an increased risk of developing other diseases with similar pathological mechanisms. Although still controversial, psoriasis has been shown to carry an increased risk of MS [22,23,24]. Reasons for this include shared genetic, environmental, and immunopathological factors (such as a strong Th1/Th17 response) in the two disorders [25]. This is further supported by the overlap in medications such as fumarate and Secukinumab [26]. As illustrated by the divergent results to anti-TNF inhibitors [16] however, the immunopathogenesis is not identical.
A register-based study from 2019 found an increased risk of MS and neuroinflammatory disease in patients with psoriatic arthritis but not rheumatoid arthritis, both with and without treatment with non-selective TNF inhibitors [27]. In view of the close relationship between autoimmune diseases, it is therefore possible that treatment with TNF blockers simply exacerbates a dormant neuroinflammatory condition like MS.
In this case, the patient remained stable without specific MS treatment, although Secukinumab was later introduced as an arthritis treatment and could in theory suppress any underlying MS activity. Secukinumab has been shown to be effective in MS [26], but it seems unlikely that an aggressive debut of MS would later stabilize completely without regular MS treatment. However, the disease course may still support a monophasic demyelinating event.
3.4. Infliximab-Induced Demyelination
As previously mentioned, the use of non-selective TNF blockers has been linked to demyelinating diseases, including MS, optic neuritis, transverse myelitis, and demyelinating neuropathies [1,28]. Furthermore, a potential link between TNF inhibitors and demyelinating disease has been suggested [29,30,31]. In view of the large number of patients treated with TNF blockers for long periods of time however, the demyelinating cases are rare and divergent [32,33]
The patient described here received infliximab for approximately 4.5 years before developing symptoms. In a 2017 review of reported cases of CNS demyelination associated with TNF inhibitors [26], the mean time of exposure was 17 months, but some patients had been treated for 6 years before developing symptoms. Our patient showed no resolution of her symptoms, consistent with 28% of the reviewed cases, and she had no prior family history of MS, which was also the case in the majority of cases reviewed. This patient thus shares many similarities with other cases of psoriatic arthritis treated with TNF blockers, supporting an initial monophasic demyelinating event that may later develop into MS, as seen in some cases with longer follow-up [28].
The mechanisms behind the potential demyelinating role of non-selective TNF blockers are not completely clear. In general, TNF blockers are large molecules that do not penetrate the intact blood–brain barrier, possibly explaining the lack of positive effects in TNF-mediated CNS diseases as opposed to other autoimmune disease such as rheumatoid and psoriatic arthritis [34,35]. Another theory is that the peripheral immunological effects of TNF blockers might alter the cytokine profile into a more proinflammatory CNS profile [28] or increase the ingress of peripheral autoreactive T-cells into the CNS through the leaky blood–brain barrier already established in active MS [34,35]
The infliximab used in this case blocks binding of TNF to TNFR1 and TNFR2 by blocking both solTNF and tmTNF [17], therefore also blocking the positive effects of TNFR2. Levels of TNF are increased in patients with MS, and studies suggest that while high levels of TNFR1 may be a risk factor for more severe disease, TNFR2 plays a more protective role [36]. As infliximab affects both pathways, the blocking of the protective features of TNFR2 and the remyelinating process could potentially lead to demyelinating events, as seen in our case. This is further supported by animal studies in which a selective blocker of solTNF resulted in improved function as well as significant axonal preservation, oligodendrocyte differentiation, and remyelination [6,7]. Therefore, selective TNF inhibition or activation of TNFR2 could lead to a new treatment approach for inflammatory disease [37,38].
4. Conclusions
This case supports the growing evidence suggesting demyelinating events as adverse effects of non-selective TNF inhibitors, but distinguishes itself by the long follow-up time and the in-depth discussion of the underlying mechanisms using selective versus non-selective TNF inhibition. As demyelination is a rare adverse event and TNF blockers are generally considered safe and effective in many chronic autoimmune disorders, this should not preclude this treatment, but rather suggests caution in patients of high risk of developing demyelinating events. With the introduction of selective solTNF inhibitors and the growing evidence of their effect, this may form the basis of a new treatment approach in inflammatory and neurological diseases.
Acknowledgments
Claire Gudex is acknowledged for proofreading the manuscript.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
L.B.K. and H.H.N. wrote the manuscript with the assistance of K.L.L., K.-E.B. and N.N. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Ethical review and approval were waived for this study, in accordance with Danish regulation since this is a case report with informed consent from the patient.
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to Danish data protection regulations.
Conflicts of Interest
K.L.L. is a member of the Lundbeck Foundation Brain Prize Council. H.H.N. is a member of the research council of the Danish Multiple Sclerosis Society and has served on scientific advisory boards and received support for congress participation, speaker honoraria, and research support from Biogen, Merck-Serono, Roche, Teva, Lundbeck, and Novartis.
Figure 1 Schematic overview of the case, showing the relationship between clinical presentation, treatment, and radiological presentation shown by MRI scans (T2, Flair, and T1+gadolinium enhancement). Created with BioRender.com. | Recovered | ReactionOutcome | CC BY | 33401396 | 18,800,068 | 2021-01-01 |
What was the outcome of reaction 'Condition aggravated'? | The Role of Non-Selective TNF Inhibitors in Demyelinating Events.
The use of non-selective tumor necrosis factor (TNF) inhibitors is well known in the treatment of inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and psoriasis. Its use in neurological disorders is limited however, due to rare adverse events of demyelination, even in patients without preceding demyelinating disease. We review here the molecular and cellular aspects of this neuroinflammatory process in light of a case of severe monophasic demyelination caused by treatment with infliximab. Focusing on the role of TNF, we review the links between CNS inflammation, demyelination, and neurodegenerative changes leading to permanent neurological deficits in a young woman, and we discuss the growing evidence for selective soluble TNF inhibitors as a new treatment approach in inflammatory and neurological diseases.
1. Introduction
The use of tumor necrosis factor (TNF) blockers has revolutionized the treatment of a number of chronic inflammatory diseases such as Crohn’s disease, ankylosing spondylitis, psoriasis, and rheumatoid arthritis.
Although TNF blockers are generally considered safe, an increasing number of neurologic adverse effects have been reported in the literature, consisting primarily of demyelination of the central nervous system (CNS) or peripheral nervous system (PNS) with a prevalence ranging from 0.050 to 0.100% [1]. These adverse events suggest a possible relationship between the use of anti-TNF biologics and demyelinating diseases [2].
TNF is a pleiotropic cytokine known to play important regulatory roles in the development and homeostasis of the healthy CNS [3]. It is produced initially as a transmembrane molecule (tmTNF) and is subsequently released from the cell as a soluble cytokine (solTNF) via regulated cleavage of tmTNF by TNF-α converting enzyme (TACE). Under normal conditions, TNF can be produced in the periphery by monocytes/macrophages, lymphocytes (T and B), natural killer cells, and dendritic cells [4], while TNF in the CNS is produced mainly by microglia [5]. Both forms of TNF are biologically active and interact with two distinct receptors—TNFR1 and TNFR2—with TNFR1 being expressed in all cell types, whereas TNFR2 is expressed mainly on immune cells, oligodendrocytes, and endothelial cells [6]. solTNF has a high affinity for TNFR1, which contains a death domain and can mediate apoptosis and chronic inflammation [7]. In the CNS, tmTNF has a higher affinity for TNFR2 and promotes mostly protective features such as cell survival and remyelination [6,7].
In animal models of multiple sclerosis (MS), such as experimental autoimmune encephalomyelitis (EAE), the administration of TNF blockers slowed the demyelinating process and improved outcome [8,9]. Ablation of TNF or TNFR1/TNFR2 combined in mice did not protect from EAE, however, and instead caused exacerbation of chronic disease [10,11,12,13]. TNFR1 ablation resulted in less severe EAE and better remyelination, while TNFR2 ablation exacerbated EAE and prevented remyelination [11,13,14]. Furthermore, mice only expressing tmTNF showed suppression of EAE [15]. These studies suggest a dichotomy between solTNF and tmTNF, in which MS is associated with the detrimental effects of solTNF via TNFR1, but tmTNF signaling via TNFR2 is important for repair and remyelination. This is supported by studies in EAE mice treated with a selective blocker of solTNF, XPro1595, which resulted in improved function, significant axonal preservation, oligodendrocyte differentiation, and remyelination [6,7]. More importantly, these differences in receptor function might explain the failed clinical trial using the non-selective TNF inhibitor Lenercept as treatment for MS [16], which was terminated due to clinical and radiological disease progression.
We present here a case of severe demyelination following treatment with infliximab, a chimeric monoclonal antibody that prevents binding of TNF to TNFR1 and TNFR2 by blocking both solTNF and tmTNF [17]. We discuss the possible underlying mechanisms of TNF blockers in CNS demyelination in the context of the current literature.
2. Case Description
The case is a 27-year-old woman with psoriatic arthritis, treated with methotrexate and infliximab. No family history of neurological disorders was reported.
After 4.5 years of treatment with infliximab, she complained of increasing fatigue, muscle pain, and mild cognitive difficulties. After a few months, she developed a subacute hemiparesis. MRI scan showed a solitary process with gadolinium ring enhancement (Figure 1—Week 0).
CSF analysis revealed no pleocytosis and normal protein levels, but did reveal oligoclonal bands and an elevated IgG index of 0.78. Initial blood tests showed a positive toxoplasmosis IgG, and PET-CT and a following biopsy from a single lymph node showed signs of granulomatous inflammation. The infliximab was discontinued, and the patient was initially treated for both toxoplasmosis and tuberculosis (Figure 1—Week 0).
Further investigations revealed no pathology on repeated PET-CT, including no pathological lymph nodes.
Repeated blood and CSF tests were found negative for toxoplasmosis, tuberculosis, varicella-zoster, Epstein–Barr, herpes simplex I+II, cytomegalovirus, Bartonella, Brucella, Aspergillus, hepatitis, and HIV. Microbiome PCR sequencing revealed no pathological DNA.
Antinuclear antibodies (ANA), Extractable Nuclear Antigen antibodies (ENA), Proteinase 3 Anti Neutrophil Cytoplasmic Antibody (C-ANCA), and Perinuclear Anti Neutrophil Cytoplasmic Antibodies (P-ANCA) were all negative.
Despite discontinuation of infliximab, the patient progressed clinically and radiologically over the next 12 weeks (Figure 1—Week 12). Clinical evaluation showed grade 4 hemiparesis on the left side and no cognitive difficulties, headache, or nausea.
Repeated CSF analysis confirmed oligoclonal bands and elevated IgG index but no increase in cell count or protein. Cytology described normal-appearing lymphocytes without pathological changes. Flow cytometry revealed 74% T cells, 7.9% polyclonal B cells, 1.6% NK cells, and CD4/CD8 of 4.1.
A biopsy was taken from the lesions in the brain, and histology showed unspecific reactive microglia and few infiltrating CD8+ T and B cells. There were no signs of tumor, lymphoma, vasculitis, progressive multifocal leukoencephalopathy, or infection with herpes, toxoplasmosis, or tuberculosis.
The patient was treated with high-dose glucocorticoid intravenously (1 g a day for 5 days) followed by five courses of plasma exchange (Figure 1—Week 12). Afterwards, MRI showed no new lesions but progression of one existing lesion and oedema, and the patient remained stable (Figure 1—Week 16). The patient continued with oral steroid therapy, which was tapered off after introduction of a two-course Rituximab treatment as a steroid-sparing agent (Figure 1—Week 16).
The following MRI showed remission, and the patient continued with a slight hemiparesis.
After 2 years (Figure 1—Week 104), the patient’s psoriatic arthritis started to deteriorate, and she was put on Secukinumab. She remained neurologically stable throughout the period and at follow-up (Figure 1—Week 134).
3. Discussion
We present a case of severe demyelination in a young woman who received infliximab as treatment for psoriatic arthritis. Because of the atypical presentation, many differential diagnoses were considered:
3.1. Infection
As the patient had been on different types of immunosuppressants since her early childhood, and at the time her symptoms developed she was treated with both infliximab and methotrexate, an infectious cause was first suspected. This was supported by the first MRI, which showed a characteristic ring enhancement comparable to cerebral toxoplasmosis, and a positive IgA test for toxoplasmosis. To further complicate the matter, a biopsy from a neck gland showed granulomatous inflammation, which could suggest tuberculosis. However, later test results for tuberculosis were negative (using interferon-gamma blood tests and microscopy of biopsy material). Although the patient received treatment for both toxoplasmosis and tuberculosis, this had no effect on the intracranial process or her clinical status. Furthermore, the CSF showed no signs of pleocytosis or elevated protein, nor did it confirm toxoplasmosis, tuberculosis, or any other form of infection.
3.2. Malignancy
Treatment with a TNF inhibitor has been suspected to increase the risk of certain malignancies, but this is still debated and may be related to the underlying autoimmune disease rather than the treatment [18,19,20,21]. On the initial PET-CT, the patient had a suspicious lymph gland. Biopsy from both this and a brain lesion showed no sign of malignant disease, just as repeated CSF cytology described normal-appearing lymphocytes without pathological changes. The clinical and radiological stabilization at 2 years follow-up also suggests a more benign disease process.
3.3. Inflammatory Demyelination
Studies suggest that patients with an autoimmune disease have an increased risk of developing other diseases with similar pathological mechanisms. Although still controversial, psoriasis has been shown to carry an increased risk of MS [22,23,24]. Reasons for this include shared genetic, environmental, and immunopathological factors (such as a strong Th1/Th17 response) in the two disorders [25]. This is further supported by the overlap in medications such as fumarate and Secukinumab [26]. As illustrated by the divergent results to anti-TNF inhibitors [16] however, the immunopathogenesis is not identical.
A register-based study from 2019 found an increased risk of MS and neuroinflammatory disease in patients with psoriatic arthritis but not rheumatoid arthritis, both with and without treatment with non-selective TNF inhibitors [27]. In view of the close relationship between autoimmune diseases, it is therefore possible that treatment with TNF blockers simply exacerbates a dormant neuroinflammatory condition like MS.
In this case, the patient remained stable without specific MS treatment, although Secukinumab was later introduced as an arthritis treatment and could in theory suppress any underlying MS activity. Secukinumab has been shown to be effective in MS [26], but it seems unlikely that an aggressive debut of MS would later stabilize completely without regular MS treatment. However, the disease course may still support a monophasic demyelinating event.
3.4. Infliximab-Induced Demyelination
As previously mentioned, the use of non-selective TNF blockers has been linked to demyelinating diseases, including MS, optic neuritis, transverse myelitis, and demyelinating neuropathies [1,28]. Furthermore, a potential link between TNF inhibitors and demyelinating disease has been suggested [29,30,31]. In view of the large number of patients treated with TNF blockers for long periods of time however, the demyelinating cases are rare and divergent [32,33]
The patient described here received infliximab for approximately 4.5 years before developing symptoms. In a 2017 review of reported cases of CNS demyelination associated with TNF inhibitors [26], the mean time of exposure was 17 months, but some patients had been treated for 6 years before developing symptoms. Our patient showed no resolution of her symptoms, consistent with 28% of the reviewed cases, and she had no prior family history of MS, which was also the case in the majority of cases reviewed. This patient thus shares many similarities with other cases of psoriatic arthritis treated with TNF blockers, supporting an initial monophasic demyelinating event that may later develop into MS, as seen in some cases with longer follow-up [28].
The mechanisms behind the potential demyelinating role of non-selective TNF blockers are not completely clear. In general, TNF blockers are large molecules that do not penetrate the intact blood–brain barrier, possibly explaining the lack of positive effects in TNF-mediated CNS diseases as opposed to other autoimmune disease such as rheumatoid and psoriatic arthritis [34,35]. Another theory is that the peripheral immunological effects of TNF blockers might alter the cytokine profile into a more proinflammatory CNS profile [28] or increase the ingress of peripheral autoreactive T-cells into the CNS through the leaky blood–brain barrier already established in active MS [34,35]
The infliximab used in this case blocks binding of TNF to TNFR1 and TNFR2 by blocking both solTNF and tmTNF [17], therefore also blocking the positive effects of TNFR2. Levels of TNF are increased in patients with MS, and studies suggest that while high levels of TNFR1 may be a risk factor for more severe disease, TNFR2 plays a more protective role [36]. As infliximab affects both pathways, the blocking of the protective features of TNFR2 and the remyelinating process could potentially lead to demyelinating events, as seen in our case. This is further supported by animal studies in which a selective blocker of solTNF resulted in improved function as well as significant axonal preservation, oligodendrocyte differentiation, and remyelination [6,7]. Therefore, selective TNF inhibition or activation of TNFR2 could lead to a new treatment approach for inflammatory disease [37,38].
4. Conclusions
This case supports the growing evidence suggesting demyelinating events as adverse effects of non-selective TNF inhibitors, but distinguishes itself by the long follow-up time and the in-depth discussion of the underlying mechanisms using selective versus non-selective TNF inhibition. As demyelination is a rare adverse event and TNF blockers are generally considered safe and effective in many chronic autoimmune disorders, this should not preclude this treatment, but rather suggests caution in patients of high risk of developing demyelinating events. With the introduction of selective solTNF inhibitors and the growing evidence of their effect, this may form the basis of a new treatment approach in inflammatory and neurological diseases.
Acknowledgments
Claire Gudex is acknowledged for proofreading the manuscript.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
L.B.K. and H.H.N. wrote the manuscript with the assistance of K.L.L., K.-E.B. and N.N. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Ethical review and approval were waived for this study, in accordance with Danish regulation since this is a case report with informed consent from the patient.
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to Danish data protection regulations.
Conflicts of Interest
K.L.L. is a member of the Lundbeck Foundation Brain Prize Council. H.H.N. is a member of the research council of the Danish Multiple Sclerosis Society and has served on scientific advisory boards and received support for congress participation, speaker honoraria, and research support from Biogen, Merck-Serono, Roche, Teva, Lundbeck, and Novartis.
Figure 1 Schematic overview of the case, showing the relationship between clinical presentation, treatment, and radiological presentation shown by MRI scans (T2, Flair, and T1+gadolinium enhancement). Created with BioRender.com. | Recovering | ReactionOutcome | CC BY | 33401396 | 18,749,761 | 2021-01-01 |
What was the outcome of reaction 'Demyelination'? | The Role of Non-Selective TNF Inhibitors in Demyelinating Events.
The use of non-selective tumor necrosis factor (TNF) inhibitors is well known in the treatment of inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and psoriasis. Its use in neurological disorders is limited however, due to rare adverse events of demyelination, even in patients without preceding demyelinating disease. We review here the molecular and cellular aspects of this neuroinflammatory process in light of a case of severe monophasic demyelination caused by treatment with infliximab. Focusing on the role of TNF, we review the links between CNS inflammation, demyelination, and neurodegenerative changes leading to permanent neurological deficits in a young woman, and we discuss the growing evidence for selective soluble TNF inhibitors as a new treatment approach in inflammatory and neurological diseases.
1. Introduction
The use of tumor necrosis factor (TNF) blockers has revolutionized the treatment of a number of chronic inflammatory diseases such as Crohn’s disease, ankylosing spondylitis, psoriasis, and rheumatoid arthritis.
Although TNF blockers are generally considered safe, an increasing number of neurologic adverse effects have been reported in the literature, consisting primarily of demyelination of the central nervous system (CNS) or peripheral nervous system (PNS) with a prevalence ranging from 0.050 to 0.100% [1]. These adverse events suggest a possible relationship between the use of anti-TNF biologics and demyelinating diseases [2].
TNF is a pleiotropic cytokine known to play important regulatory roles in the development and homeostasis of the healthy CNS [3]. It is produced initially as a transmembrane molecule (tmTNF) and is subsequently released from the cell as a soluble cytokine (solTNF) via regulated cleavage of tmTNF by TNF-α converting enzyme (TACE). Under normal conditions, TNF can be produced in the periphery by monocytes/macrophages, lymphocytes (T and B), natural killer cells, and dendritic cells [4], while TNF in the CNS is produced mainly by microglia [5]. Both forms of TNF are biologically active and interact with two distinct receptors—TNFR1 and TNFR2—with TNFR1 being expressed in all cell types, whereas TNFR2 is expressed mainly on immune cells, oligodendrocytes, and endothelial cells [6]. solTNF has a high affinity for TNFR1, which contains a death domain and can mediate apoptosis and chronic inflammation [7]. In the CNS, tmTNF has a higher affinity for TNFR2 and promotes mostly protective features such as cell survival and remyelination [6,7].
In animal models of multiple sclerosis (MS), such as experimental autoimmune encephalomyelitis (EAE), the administration of TNF blockers slowed the demyelinating process and improved outcome [8,9]. Ablation of TNF or TNFR1/TNFR2 combined in mice did not protect from EAE, however, and instead caused exacerbation of chronic disease [10,11,12,13]. TNFR1 ablation resulted in less severe EAE and better remyelination, while TNFR2 ablation exacerbated EAE and prevented remyelination [11,13,14]. Furthermore, mice only expressing tmTNF showed suppression of EAE [15]. These studies suggest a dichotomy between solTNF and tmTNF, in which MS is associated with the detrimental effects of solTNF via TNFR1, but tmTNF signaling via TNFR2 is important for repair and remyelination. This is supported by studies in EAE mice treated with a selective blocker of solTNF, XPro1595, which resulted in improved function, significant axonal preservation, oligodendrocyte differentiation, and remyelination [6,7]. More importantly, these differences in receptor function might explain the failed clinical trial using the non-selective TNF inhibitor Lenercept as treatment for MS [16], which was terminated due to clinical and radiological disease progression.
We present here a case of severe demyelination following treatment with infliximab, a chimeric monoclonal antibody that prevents binding of TNF to TNFR1 and TNFR2 by blocking both solTNF and tmTNF [17]. We discuss the possible underlying mechanisms of TNF blockers in CNS demyelination in the context of the current literature.
2. Case Description
The case is a 27-year-old woman with psoriatic arthritis, treated with methotrexate and infliximab. No family history of neurological disorders was reported.
After 4.5 years of treatment with infliximab, she complained of increasing fatigue, muscle pain, and mild cognitive difficulties. After a few months, she developed a subacute hemiparesis. MRI scan showed a solitary process with gadolinium ring enhancement (Figure 1—Week 0).
CSF analysis revealed no pleocytosis and normal protein levels, but did reveal oligoclonal bands and an elevated IgG index of 0.78. Initial blood tests showed a positive toxoplasmosis IgG, and PET-CT and a following biopsy from a single lymph node showed signs of granulomatous inflammation. The infliximab was discontinued, and the patient was initially treated for both toxoplasmosis and tuberculosis (Figure 1—Week 0).
Further investigations revealed no pathology on repeated PET-CT, including no pathological lymph nodes.
Repeated blood and CSF tests were found negative for toxoplasmosis, tuberculosis, varicella-zoster, Epstein–Barr, herpes simplex I+II, cytomegalovirus, Bartonella, Brucella, Aspergillus, hepatitis, and HIV. Microbiome PCR sequencing revealed no pathological DNA.
Antinuclear antibodies (ANA), Extractable Nuclear Antigen antibodies (ENA), Proteinase 3 Anti Neutrophil Cytoplasmic Antibody (C-ANCA), and Perinuclear Anti Neutrophil Cytoplasmic Antibodies (P-ANCA) were all negative.
Despite discontinuation of infliximab, the patient progressed clinically and radiologically over the next 12 weeks (Figure 1—Week 12). Clinical evaluation showed grade 4 hemiparesis on the left side and no cognitive difficulties, headache, or nausea.
Repeated CSF analysis confirmed oligoclonal bands and elevated IgG index but no increase in cell count or protein. Cytology described normal-appearing lymphocytes without pathological changes. Flow cytometry revealed 74% T cells, 7.9% polyclonal B cells, 1.6% NK cells, and CD4/CD8 of 4.1.
A biopsy was taken from the lesions in the brain, and histology showed unspecific reactive microglia and few infiltrating CD8+ T and B cells. There were no signs of tumor, lymphoma, vasculitis, progressive multifocal leukoencephalopathy, or infection with herpes, toxoplasmosis, or tuberculosis.
The patient was treated with high-dose glucocorticoid intravenously (1 g a day for 5 days) followed by five courses of plasma exchange (Figure 1—Week 12). Afterwards, MRI showed no new lesions but progression of one existing lesion and oedema, and the patient remained stable (Figure 1—Week 16). The patient continued with oral steroid therapy, which was tapered off after introduction of a two-course Rituximab treatment as a steroid-sparing agent (Figure 1—Week 16).
The following MRI showed remission, and the patient continued with a slight hemiparesis.
After 2 years (Figure 1—Week 104), the patient’s psoriatic arthritis started to deteriorate, and she was put on Secukinumab. She remained neurologically stable throughout the period and at follow-up (Figure 1—Week 134).
3. Discussion
We present a case of severe demyelination in a young woman who received infliximab as treatment for psoriatic arthritis. Because of the atypical presentation, many differential diagnoses were considered:
3.1. Infection
As the patient had been on different types of immunosuppressants since her early childhood, and at the time her symptoms developed she was treated with both infliximab and methotrexate, an infectious cause was first suspected. This was supported by the first MRI, which showed a characteristic ring enhancement comparable to cerebral toxoplasmosis, and a positive IgA test for toxoplasmosis. To further complicate the matter, a biopsy from a neck gland showed granulomatous inflammation, which could suggest tuberculosis. However, later test results for tuberculosis were negative (using interferon-gamma blood tests and microscopy of biopsy material). Although the patient received treatment for both toxoplasmosis and tuberculosis, this had no effect on the intracranial process or her clinical status. Furthermore, the CSF showed no signs of pleocytosis or elevated protein, nor did it confirm toxoplasmosis, tuberculosis, or any other form of infection.
3.2. Malignancy
Treatment with a TNF inhibitor has been suspected to increase the risk of certain malignancies, but this is still debated and may be related to the underlying autoimmune disease rather than the treatment [18,19,20,21]. On the initial PET-CT, the patient had a suspicious lymph gland. Biopsy from both this and a brain lesion showed no sign of malignant disease, just as repeated CSF cytology described normal-appearing lymphocytes without pathological changes. The clinical and radiological stabilization at 2 years follow-up also suggests a more benign disease process.
3.3. Inflammatory Demyelination
Studies suggest that patients with an autoimmune disease have an increased risk of developing other diseases with similar pathological mechanisms. Although still controversial, psoriasis has been shown to carry an increased risk of MS [22,23,24]. Reasons for this include shared genetic, environmental, and immunopathological factors (such as a strong Th1/Th17 response) in the two disorders [25]. This is further supported by the overlap in medications such as fumarate and Secukinumab [26]. As illustrated by the divergent results to anti-TNF inhibitors [16] however, the immunopathogenesis is not identical.
A register-based study from 2019 found an increased risk of MS and neuroinflammatory disease in patients with psoriatic arthritis but not rheumatoid arthritis, both with and without treatment with non-selective TNF inhibitors [27]. In view of the close relationship between autoimmune diseases, it is therefore possible that treatment with TNF blockers simply exacerbates a dormant neuroinflammatory condition like MS.
In this case, the patient remained stable without specific MS treatment, although Secukinumab was later introduced as an arthritis treatment and could in theory suppress any underlying MS activity. Secukinumab has been shown to be effective in MS [26], but it seems unlikely that an aggressive debut of MS would later stabilize completely without regular MS treatment. However, the disease course may still support a monophasic demyelinating event.
3.4. Infliximab-Induced Demyelination
As previously mentioned, the use of non-selective TNF blockers has been linked to demyelinating diseases, including MS, optic neuritis, transverse myelitis, and demyelinating neuropathies [1,28]. Furthermore, a potential link between TNF inhibitors and demyelinating disease has been suggested [29,30,31]. In view of the large number of patients treated with TNF blockers for long periods of time however, the demyelinating cases are rare and divergent [32,33]
The patient described here received infliximab for approximately 4.5 years before developing symptoms. In a 2017 review of reported cases of CNS demyelination associated with TNF inhibitors [26], the mean time of exposure was 17 months, but some patients had been treated for 6 years before developing symptoms. Our patient showed no resolution of her symptoms, consistent with 28% of the reviewed cases, and she had no prior family history of MS, which was also the case in the majority of cases reviewed. This patient thus shares many similarities with other cases of psoriatic arthritis treated with TNF blockers, supporting an initial monophasic demyelinating event that may later develop into MS, as seen in some cases with longer follow-up [28].
The mechanisms behind the potential demyelinating role of non-selective TNF blockers are not completely clear. In general, TNF blockers are large molecules that do not penetrate the intact blood–brain barrier, possibly explaining the lack of positive effects in TNF-mediated CNS diseases as opposed to other autoimmune disease such as rheumatoid and psoriatic arthritis [34,35]. Another theory is that the peripheral immunological effects of TNF blockers might alter the cytokine profile into a more proinflammatory CNS profile [28] or increase the ingress of peripheral autoreactive T-cells into the CNS through the leaky blood–brain barrier already established in active MS [34,35]
The infliximab used in this case blocks binding of TNF to TNFR1 and TNFR2 by blocking both solTNF and tmTNF [17], therefore also blocking the positive effects of TNFR2. Levels of TNF are increased in patients with MS, and studies suggest that while high levels of TNFR1 may be a risk factor for more severe disease, TNFR2 plays a more protective role [36]. As infliximab affects both pathways, the blocking of the protective features of TNFR2 and the remyelinating process could potentially lead to demyelinating events, as seen in our case. This is further supported by animal studies in which a selective blocker of solTNF resulted in improved function as well as significant axonal preservation, oligodendrocyte differentiation, and remyelination [6,7]. Therefore, selective TNF inhibition or activation of TNFR2 could lead to a new treatment approach for inflammatory disease [37,38].
4. Conclusions
This case supports the growing evidence suggesting demyelinating events as adverse effects of non-selective TNF inhibitors, but distinguishes itself by the long follow-up time and the in-depth discussion of the underlying mechanisms using selective versus non-selective TNF inhibition. As demyelination is a rare adverse event and TNF blockers are generally considered safe and effective in many chronic autoimmune disorders, this should not preclude this treatment, but rather suggests caution in patients of high risk of developing demyelinating events. With the introduction of selective solTNF inhibitors and the growing evidence of their effect, this may form the basis of a new treatment approach in inflammatory and neurological diseases.
Acknowledgments
Claire Gudex is acknowledged for proofreading the manuscript.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
L.B.K. and H.H.N. wrote the manuscript with the assistance of K.L.L., K.-E.B. and N.N. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Ethical review and approval were waived for this study, in accordance with Danish regulation since this is a case report with informed consent from the patient.
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to Danish data protection regulations.
Conflicts of Interest
K.L.L. is a member of the Lundbeck Foundation Brain Prize Council. H.H.N. is a member of the research council of the Danish Multiple Sclerosis Society and has served on scientific advisory boards and received support for congress participation, speaker honoraria, and research support from Biogen, Merck-Serono, Roche, Teva, Lundbeck, and Novartis.
Figure 1 Schematic overview of the case, showing the relationship between clinical presentation, treatment, and radiological presentation shown by MRI scans (T2, Flair, and T1+gadolinium enhancement). Created with BioRender.com. | Recovering | ReactionOutcome | CC BY | 33401396 | 18,783,118 | 2021-01-01 |
What was the outcome of reaction 'Hemiparesis'? | The Role of Non-Selective TNF Inhibitors in Demyelinating Events.
The use of non-selective tumor necrosis factor (TNF) inhibitors is well known in the treatment of inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and psoriasis. Its use in neurological disorders is limited however, due to rare adverse events of demyelination, even in patients without preceding demyelinating disease. We review here the molecular and cellular aspects of this neuroinflammatory process in light of a case of severe monophasic demyelination caused by treatment with infliximab. Focusing on the role of TNF, we review the links between CNS inflammation, demyelination, and neurodegenerative changes leading to permanent neurological deficits in a young woman, and we discuss the growing evidence for selective soluble TNF inhibitors as a new treatment approach in inflammatory and neurological diseases.
1. Introduction
The use of tumor necrosis factor (TNF) blockers has revolutionized the treatment of a number of chronic inflammatory diseases such as Crohn’s disease, ankylosing spondylitis, psoriasis, and rheumatoid arthritis.
Although TNF blockers are generally considered safe, an increasing number of neurologic adverse effects have been reported in the literature, consisting primarily of demyelination of the central nervous system (CNS) or peripheral nervous system (PNS) with a prevalence ranging from 0.050 to 0.100% [1]. These adverse events suggest a possible relationship between the use of anti-TNF biologics and demyelinating diseases [2].
TNF is a pleiotropic cytokine known to play important regulatory roles in the development and homeostasis of the healthy CNS [3]. It is produced initially as a transmembrane molecule (tmTNF) and is subsequently released from the cell as a soluble cytokine (solTNF) via regulated cleavage of tmTNF by TNF-α converting enzyme (TACE). Under normal conditions, TNF can be produced in the periphery by monocytes/macrophages, lymphocytes (T and B), natural killer cells, and dendritic cells [4], while TNF in the CNS is produced mainly by microglia [5]. Both forms of TNF are biologically active and interact with two distinct receptors—TNFR1 and TNFR2—with TNFR1 being expressed in all cell types, whereas TNFR2 is expressed mainly on immune cells, oligodendrocytes, and endothelial cells [6]. solTNF has a high affinity for TNFR1, which contains a death domain and can mediate apoptosis and chronic inflammation [7]. In the CNS, tmTNF has a higher affinity for TNFR2 and promotes mostly protective features such as cell survival and remyelination [6,7].
In animal models of multiple sclerosis (MS), such as experimental autoimmune encephalomyelitis (EAE), the administration of TNF blockers slowed the demyelinating process and improved outcome [8,9]. Ablation of TNF or TNFR1/TNFR2 combined in mice did not protect from EAE, however, and instead caused exacerbation of chronic disease [10,11,12,13]. TNFR1 ablation resulted in less severe EAE and better remyelination, while TNFR2 ablation exacerbated EAE and prevented remyelination [11,13,14]. Furthermore, mice only expressing tmTNF showed suppression of EAE [15]. These studies suggest a dichotomy between solTNF and tmTNF, in which MS is associated with the detrimental effects of solTNF via TNFR1, but tmTNF signaling via TNFR2 is important for repair and remyelination. This is supported by studies in EAE mice treated with a selective blocker of solTNF, XPro1595, which resulted in improved function, significant axonal preservation, oligodendrocyte differentiation, and remyelination [6,7]. More importantly, these differences in receptor function might explain the failed clinical trial using the non-selective TNF inhibitor Lenercept as treatment for MS [16], which was terminated due to clinical and radiological disease progression.
We present here a case of severe demyelination following treatment with infliximab, a chimeric monoclonal antibody that prevents binding of TNF to TNFR1 and TNFR2 by blocking both solTNF and tmTNF [17]. We discuss the possible underlying mechanisms of TNF blockers in CNS demyelination in the context of the current literature.
2. Case Description
The case is a 27-year-old woman with psoriatic arthritis, treated with methotrexate and infliximab. No family history of neurological disorders was reported.
After 4.5 years of treatment with infliximab, she complained of increasing fatigue, muscle pain, and mild cognitive difficulties. After a few months, she developed a subacute hemiparesis. MRI scan showed a solitary process with gadolinium ring enhancement (Figure 1—Week 0).
CSF analysis revealed no pleocytosis and normal protein levels, but did reveal oligoclonal bands and an elevated IgG index of 0.78. Initial blood tests showed a positive toxoplasmosis IgG, and PET-CT and a following biopsy from a single lymph node showed signs of granulomatous inflammation. The infliximab was discontinued, and the patient was initially treated for both toxoplasmosis and tuberculosis (Figure 1—Week 0).
Further investigations revealed no pathology on repeated PET-CT, including no pathological lymph nodes.
Repeated blood and CSF tests were found negative for toxoplasmosis, tuberculosis, varicella-zoster, Epstein–Barr, herpes simplex I+II, cytomegalovirus, Bartonella, Brucella, Aspergillus, hepatitis, and HIV. Microbiome PCR sequencing revealed no pathological DNA.
Antinuclear antibodies (ANA), Extractable Nuclear Antigen antibodies (ENA), Proteinase 3 Anti Neutrophil Cytoplasmic Antibody (C-ANCA), and Perinuclear Anti Neutrophil Cytoplasmic Antibodies (P-ANCA) were all negative.
Despite discontinuation of infliximab, the patient progressed clinically and radiologically over the next 12 weeks (Figure 1—Week 12). Clinical evaluation showed grade 4 hemiparesis on the left side and no cognitive difficulties, headache, or nausea.
Repeated CSF analysis confirmed oligoclonal bands and elevated IgG index but no increase in cell count or protein. Cytology described normal-appearing lymphocytes without pathological changes. Flow cytometry revealed 74% T cells, 7.9% polyclonal B cells, 1.6% NK cells, and CD4/CD8 of 4.1.
A biopsy was taken from the lesions in the brain, and histology showed unspecific reactive microglia and few infiltrating CD8+ T and B cells. There were no signs of tumor, lymphoma, vasculitis, progressive multifocal leukoencephalopathy, or infection with herpes, toxoplasmosis, or tuberculosis.
The patient was treated with high-dose glucocorticoid intravenously (1 g a day for 5 days) followed by five courses of plasma exchange (Figure 1—Week 12). Afterwards, MRI showed no new lesions but progression of one existing lesion and oedema, and the patient remained stable (Figure 1—Week 16). The patient continued with oral steroid therapy, which was tapered off after introduction of a two-course Rituximab treatment as a steroid-sparing agent (Figure 1—Week 16).
The following MRI showed remission, and the patient continued with a slight hemiparesis.
After 2 years (Figure 1—Week 104), the patient’s psoriatic arthritis started to deteriorate, and she was put on Secukinumab. She remained neurologically stable throughout the period and at follow-up (Figure 1—Week 134).
3. Discussion
We present a case of severe demyelination in a young woman who received infliximab as treatment for psoriatic arthritis. Because of the atypical presentation, many differential diagnoses were considered:
3.1. Infection
As the patient had been on different types of immunosuppressants since her early childhood, and at the time her symptoms developed she was treated with both infliximab and methotrexate, an infectious cause was first suspected. This was supported by the first MRI, which showed a characteristic ring enhancement comparable to cerebral toxoplasmosis, and a positive IgA test for toxoplasmosis. To further complicate the matter, a biopsy from a neck gland showed granulomatous inflammation, which could suggest tuberculosis. However, later test results for tuberculosis were negative (using interferon-gamma blood tests and microscopy of biopsy material). Although the patient received treatment for both toxoplasmosis and tuberculosis, this had no effect on the intracranial process or her clinical status. Furthermore, the CSF showed no signs of pleocytosis or elevated protein, nor did it confirm toxoplasmosis, tuberculosis, or any other form of infection.
3.2. Malignancy
Treatment with a TNF inhibitor has been suspected to increase the risk of certain malignancies, but this is still debated and may be related to the underlying autoimmune disease rather than the treatment [18,19,20,21]. On the initial PET-CT, the patient had a suspicious lymph gland. Biopsy from both this and a brain lesion showed no sign of malignant disease, just as repeated CSF cytology described normal-appearing lymphocytes without pathological changes. The clinical and radiological stabilization at 2 years follow-up also suggests a more benign disease process.
3.3. Inflammatory Demyelination
Studies suggest that patients with an autoimmune disease have an increased risk of developing other diseases with similar pathological mechanisms. Although still controversial, psoriasis has been shown to carry an increased risk of MS [22,23,24]. Reasons for this include shared genetic, environmental, and immunopathological factors (such as a strong Th1/Th17 response) in the two disorders [25]. This is further supported by the overlap in medications such as fumarate and Secukinumab [26]. As illustrated by the divergent results to anti-TNF inhibitors [16] however, the immunopathogenesis is not identical.
A register-based study from 2019 found an increased risk of MS and neuroinflammatory disease in patients with psoriatic arthritis but not rheumatoid arthritis, both with and without treatment with non-selective TNF inhibitors [27]. In view of the close relationship between autoimmune diseases, it is therefore possible that treatment with TNF blockers simply exacerbates a dormant neuroinflammatory condition like MS.
In this case, the patient remained stable without specific MS treatment, although Secukinumab was later introduced as an arthritis treatment and could in theory suppress any underlying MS activity. Secukinumab has been shown to be effective in MS [26], but it seems unlikely that an aggressive debut of MS would later stabilize completely without regular MS treatment. However, the disease course may still support a monophasic demyelinating event.
3.4. Infliximab-Induced Demyelination
As previously mentioned, the use of non-selective TNF blockers has been linked to demyelinating diseases, including MS, optic neuritis, transverse myelitis, and demyelinating neuropathies [1,28]. Furthermore, a potential link between TNF inhibitors and demyelinating disease has been suggested [29,30,31]. In view of the large number of patients treated with TNF blockers for long periods of time however, the demyelinating cases are rare and divergent [32,33]
The patient described here received infliximab for approximately 4.5 years before developing symptoms. In a 2017 review of reported cases of CNS demyelination associated with TNF inhibitors [26], the mean time of exposure was 17 months, but some patients had been treated for 6 years before developing symptoms. Our patient showed no resolution of her symptoms, consistent with 28% of the reviewed cases, and she had no prior family history of MS, which was also the case in the majority of cases reviewed. This patient thus shares many similarities with other cases of psoriatic arthritis treated with TNF blockers, supporting an initial monophasic demyelinating event that may later develop into MS, as seen in some cases with longer follow-up [28].
The mechanisms behind the potential demyelinating role of non-selective TNF blockers are not completely clear. In general, TNF blockers are large molecules that do not penetrate the intact blood–brain barrier, possibly explaining the lack of positive effects in TNF-mediated CNS diseases as opposed to other autoimmune disease such as rheumatoid and psoriatic arthritis [34,35]. Another theory is that the peripheral immunological effects of TNF blockers might alter the cytokine profile into a more proinflammatory CNS profile [28] or increase the ingress of peripheral autoreactive T-cells into the CNS through the leaky blood–brain barrier already established in active MS [34,35]
The infliximab used in this case blocks binding of TNF to TNFR1 and TNFR2 by blocking both solTNF and tmTNF [17], therefore also blocking the positive effects of TNFR2. Levels of TNF are increased in patients with MS, and studies suggest that while high levels of TNFR1 may be a risk factor for more severe disease, TNFR2 plays a more protective role [36]. As infliximab affects both pathways, the blocking of the protective features of TNFR2 and the remyelinating process could potentially lead to demyelinating events, as seen in our case. This is further supported by animal studies in which a selective blocker of solTNF resulted in improved function as well as significant axonal preservation, oligodendrocyte differentiation, and remyelination [6,7]. Therefore, selective TNF inhibition or activation of TNFR2 could lead to a new treatment approach for inflammatory disease [37,38].
4. Conclusions
This case supports the growing evidence suggesting demyelinating events as adverse effects of non-selective TNF inhibitors, but distinguishes itself by the long follow-up time and the in-depth discussion of the underlying mechanisms using selective versus non-selective TNF inhibition. As demyelination is a rare adverse event and TNF blockers are generally considered safe and effective in many chronic autoimmune disorders, this should not preclude this treatment, but rather suggests caution in patients of high risk of developing demyelinating events. With the introduction of selective solTNF inhibitors and the growing evidence of their effect, this may form the basis of a new treatment approach in inflammatory and neurological diseases.
Acknowledgments
Claire Gudex is acknowledged for proofreading the manuscript.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
L.B.K. and H.H.N. wrote the manuscript with the assistance of K.L.L., K.-E.B. and N.N. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Ethical review and approval were waived for this study, in accordance with Danish regulation since this is a case report with informed consent from the patient.
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to Danish data protection regulations.
Conflicts of Interest
K.L.L. is a member of the Lundbeck Foundation Brain Prize Council. H.H.N. is a member of the research council of the Danish Multiple Sclerosis Society and has served on scientific advisory boards and received support for congress participation, speaker honoraria, and research support from Biogen, Merck-Serono, Roche, Teva, Lundbeck, and Novartis.
Figure 1 Schematic overview of the case, showing the relationship between clinical presentation, treatment, and radiological presentation shown by MRI scans (T2, Flair, and T1+gadolinium enhancement). Created with BioRender.com. | Recovering | ReactionOutcome | CC BY | 33401396 | 18,800,068 | 2021-01-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Foetal death'. | Klebsiella pneumoniae Chorioamnionitis: An Underrecognized Cause of Preterm Premature Rupture of Membranes in the Second Trimester.
Klebsiella pneumoniae is a Gram-negative, rod-shaped bacterium, responsible for hospital and community acquired pneumonia, urinary tract and wound infections, and bloodstream dissemination. K. pneumoniae infection in pregnancy, leading to acute chorioamnionitis (AC), preterm premature rupture of membranes (PPROM) and early pregnancy loss in the second trimester, has been rarely reported. Herein, we present a case of K. pneumoniae AC that caused intrauterine fetal demise (IUFD) at 19 weeks + 5 days. The 36-year-old mother was admitted at 18 weeks + 1 day of gestation for threatened abortion. IUFD occurred 11 days after. Fetal postmortem showed severe AC and funisitis, neutrophils within alveoli and intestinal lumen, associated with rod-like bacteria. Fetal blood and lung cultures grew K. pneumoniae, β-lactamase-non-producing strain. Antibiogram revealed sensitivity for piperacillin/tazobactam. Three days after IUFD, the mother presented with fever (37.8 °C) which persisted for one week. Maternal blood and urine cultures were negative. According to fetal microbiological results, available 6 days after IUFD, initial treatment with amoxicillin/clavulanic acid was replaced with piperacillin/tazobactam with full patient recovery. Therefore, in the event of PPROM and IUFD, fetal microbiological investigations should always be performed to isolate the proper etiologic agent and start the correct medical treatment.
1. Introduction
Acute chorioamnionitis (AC) is defined as infiltration of neutrophils within placental chorionic plate and amniochorial membranes, usually due to ascending infection [1,2]. Although AC often occurs as subclinical condition, diagnosed only by placental histological examination [3], bacterial infection of the amniotic cavity is the main cause of preterm premature rupture of membranes (PPROM) leading to preterm delivery, respiratory distress, sepsis, and occasionally fetal/neonatal death [4,5,6,7,8]. Moreover, AC is a high risk factor for neonatal necrotising enterocolitis (NEC), retinopathy of prematurity (ROP), poor long-term neurologic outcome, and cerebral palsy [4,5,6,7,8]. The main microorganisms responsible for AC are group B Streptococcus, Fusobacterium nucleatum, Peptostreptococcus, Escherichia coli, Bacteroides species, Ureaplasma urealyticum, and Listeria monocytogenes [1,2]. The gold standard for AC diagnosis remains placental examination. [6]. However, microorganism identification, and subsequent antibiogram, relies on fetal blood and tissue cultures, placental subchorionic fibrin swab, and parenchymal cultures [9,10,11].
To date, intrauterine infection and fetal demise due to K. pneumoniae has been described in only three cases. All of them were second trimester pregnancies presented with PPROM and early pregnancy loss [12,13,14].
Herein, we report a new case of AC due to K. pneumoniae leading to fetal death at 19 weeks + 5 days of gestation. Infection was confirmed by fetal blood and tissue microbiological cultures. We also discuss maternal clinical presentation and antibiotic treatment.
2. Case Description
2.1. Mother Clinical Presentation and Treatment
A 36-year-old woman was admitted to our Institution for threatened abortion at 18 weeks + 1 day of gestation (wga) and treated with antibiotics according to international PPROM guidelines [15]. The treatment consisted of ampicillin and azithromycin for 2 days, then replaced with amoxicillin/clavulanic acid for 5 days. The patient was carefully monitored, but at day 11 after hospital admission, transabdominal ultrasound (US) revealed intrauterine fetal death (IUFD) associated with oligohydramnios. Labor was induced and a male stillborn was vaginally delivered after 36 h.
At day 12 after admission, the patient was treated with ampicillin and gentamicin.
At day 14, the patient presented with fever (37.8 °C) and elevated C-reactive protein (CRP) of 11.10 mg/dL, however blood and urine culture were negative.
At day 16, due to fever persistence and increased CRP of 17.56 mg/dL, antibiotic therapy was modified with amoxicillin/clavulanic acid.
At day 18, as the patient was still feverish with high CRP (12.06 mg/dL), the previous therapy was suspended and replaced with piperacillin/tazobactam.
The patient fully recovered with fever remission and CRP reduction, and after 3 days without fever, she was discharged (day 21).
2.2. Fetal Autopsy and Microbiological Results
IUFD was diagnosed 11 days after the patient’s admission, corresponding approximately to a gestational age of 19 weeks + 5 days.
Postmortem examination revealed a nonmacerated fetus weighing 240 g and measuring 24.5 cm in crown–heel length. The other measurements were as follows: crown–rump length 17.5 cm; foot length 3 cm; head, chest, and abdominal circumference 16 cm, 13 cm, and 12.5 cm, respectively. Overall, anthropometric measurements were consistent with 19 weeks’ gestation [16]. External examination showed a normal male fetus with mild facial and nuchal oedema. Internal examination disclosed minimal pleural and abdominal serous effusions and organ congestion. No congenital anomalies were found.
At microscopy, lungs displayed mild pneumonia with focal intra-alveolar neutrophils associated with rod-like bacteria (Figure 1). Neutrophils and rod-like bacteria were similarly observed in the lumen of the gastrointestinal tract (Figure 2). No other significant histological findings were noted except for mild pancreatic oedema (Figure 3).
Postmortem lung and blood cultures were processed according to routine procedures on selective media. Identification was performed by MALDI-ToF MS (MALDI Biotyper, Bruker Daltonik GmbH, D-28359, Bremen, Germany), while for susceptibility testing, the Phoenix 100™ system was used (Becton, Dickinson and Company, Franklin Lakes, NJ, USA) and agar diffusion (Kirby–Bauer method, according to EUCAST rules).
The isolate was identified as K. pneumoniae ssp. pneumoniae. Further phenotypical test, performed according to Brisse et al., allowed for setting the isolate in the K. pneumoniae phylogroup KpI [17].
The isolate’s susceptibility profile revealed a wild-type phenotype, being susceptible to all the antibiotics tested, except for the intrinsic resistances (Intrinsic_Resistance_and_Unusual_Phenotypes_Tables_v3.2_20200225 in https://www.eucast.org/expert_rules_and_intrinsic_resistance). No ESBL, AmpC, or carbapenemase resistance traits were phenotypically documented, according to EUCAST rules EUCAST_detection_of_resistance_mechanisms_170711, in https://www.eucast.org/resistance_mechanisms).
On blood agar, the isolate did not show the hypermucoviscosity (HMV) phenomenon, as demonstrated by the negativity on the string test, where a standard bacteriological loop was used to stretch a mucoviscous string from the bacterial colony [18].
The antibiogram revealed sensitivity for amoxicillin/clavulanic acid, gentamicin, piperacillin/tazobactam; and resistance to ampicillin (Table 1).
Microbiological results approximately arrived after 17 days of patient’s hospital admission and communicated to the clinicians. As the patient was still feverish with elevated CRP, the treatment was changed accordingly from amoxicillin/clavulanic acid to piperacillin/tazobactam.
The placenta was received fragmented and weighed 139 g. Macroscopically, recognizable strands of membranes were yellowish and opaque. Microscopically, there was severe chorioamnionitis with focal amnion necrosis (Figure 4) corresponding to a maternal inflammatory response stage 3/3 and grade 2/2 [19]. Bacterial organisms were noted at high magnification. Funisitis was also observed with neutrophilic infiltrate of the umbilical vein, one artery, and extension to Wharton’s jelly (Figure 5). These findings were consistent with fetal inflammatory response stage 2/3 and grade 2/2 [19].
The placental parenchyma was normally developed for second trimester, with mesenchymal and immature intermediate villi. Multifocal villous oedema was also identified. The decidua showed diffuse acute necrotizing deciduitis and focal laminar necrosis.
3. Materials and Methods
We searched for ((chorioamnionitis OR ((placenta OR placental) AND (infection OR inflammation)) OR PROM OR “premature rupture of membranes”) AND K. pneumoniae in Pubmed (all fields, 55 results), Scopus (Title/Abstract/Keywords, 15 results), and Web of Science (Topic/Title, 25 results) databases. No limitations were set. Titles and abstract of the results were screened to identify relevant articles. All relevant papers were obtained in full-text format and screened for additional references. The bibliographic research ended on 1 October 2020: three papers were finally included.
4. Discussion
K. pneumoniae is a Gram-negative, rod-shaped bacterium belonging to the family of Enterobacteriaceae, involved in hospital and community-acquired bacterial pneumonia, urinary tract, and wound infections [20,21].
K. pneumoniae represents the main cause of hospital-acquired infections (HAI), and as an opportunistic pathogen, typically induces infections in hospitalized or immunocompromised patients.
Behind Clostridium difficile and Staphylococcus aureus, K. pneumoniae is the third main pathogen responsible for HAI, defined as the onset of pneumonia in ≥48 h after hospital admission [22]. Mortality rate in K. pneumoniae pneumonia is high, reaching 50% [20].
Community-acquired K. pneumoniae pneumonia is usually severe, panlobar, and often diagnosed in chronic alcoholics, attributed to aspiration of gastric contents. This kind of pneumonia is also known as ‘‘Friedlander’s pneumonia’’ characterized by radiographic alterations due to severe pyogenic infection [23]. Urinary tract is often infected by K. pneumoniae, especially in patients with diabetes mellitus or neuropathic bladder, mainly occurring in a nosocomial setting [20,21]. A typical complication is catheter-associated urinary tract infections (CAUTIs) due to the bacterium ability for building biofilms and adhering to catheters [24].
K. pneumoniae may also colonize wound/surgical sites, representing almost 13% of all the infections caused.
K. pneumoniae is the second cause of bloodstream infections (BSI), triggered by Gram-negative bacteria, behind only to Escherichia coli [20,21,22].
BSI may be hospital acquired or occurring in a community setting. In the first situation, cancer is the main underlying disease. Instead, diabetes mellitus and chronic hepatic conditions are typically found in the community [25]. Bacteremia is usually caused by a secondary dissemination from a known site of infection. Typical sources include the urinary and gastrointestinal tract, intravenous or urinary catheters, and respiratory localization [26].
In the neonatal population, K. pneumoniae infection can be responsible for neonatal sepsis and meningitis and may affect premature infants and spread within pediatric wards [20,27,28].
However, to the best of our knowledge, intrauterine fetal death due to K. pneumoniae infection has been reported only in three cases [12,13,14].
Sheikh et al. [12] described a case of IUFD at 18 weeks of gestation. AC and acute villitis were found in the placenta. K. pneumoniae was isolated in maternal blood and placental cultures. Fetal autopsy was not performed. The mother was admitted to the hospital with high temperature (41 °C) and malodorous vaginal discharge. The patient had also vaginal bleeding since one day before the admission.
The PPROM presented by Omwandho et al. [13] was a spontaneous miscarriage at 15 weeks. The mother had a threatened miscarriage at 12th week of gestation with light vaginal bleeding, but then she completely recovered after staying in bed. However, at 15th week, US showed IUFD. Placental cultures were positive for K. pneumoniae, but no pathology was seen in the placenta. Fetal autopsy was also negative for infection or inflammation. Nevertheless, the authors attributed the fetal demise to K. pneumoniae placental microbiological finding. The husband suffered from K. pneumoniae prostatitis and likely infected his wife.
Torabi et al. reported [14] PPROM and IUFD at 20 weeks of gestation due to K. pneumoniae intrauterine infection as the bacterium was found in fetal blood and lung tissue cultures. Placental pathology showed severe AC, chorionic vasculitis, and funisitis. Fetal autopsy showed clusters of neutrophils and bacteria both in the lungs and in the lumen of the gastrointestinal tract. The patient was admitted to the hospital with PPROM, but she had no vaginal bleeding before, and no fever prior to or during the admission. She also denied respiratory or urinary infections for the duration of her pregnancy.
In our case, the patient was admitted for threatened abortion at 18 wga +1 day with no fever. Although she underwent antibiotic treatment (ampicillin and azithromycin for 2 days, and then amoxicillin/clavulanic acid for 5 days), IUFD was diagnosed at 19 wga + 5 days. Ampicillin and gentamicin were started. Three days after IUFD, the patient was feverish (37.8 °C) with high CRP. Fever and elevated CRP persisted for another 7 days. However, maternal blood and urine cultures were negative. First, antibiotic therapy was modified with amoxicillin/clavulanic acid with no results. Then, after 6 days since IUFD, postmortem fetal lung and blood cultures identified K. pneumoniae, β-lactamase-non-producing strain. The antibiogram showed sensitivity for amoxicillin/clavulanic acid, gentamicin, piperacillin/tazobactam; and resistance to ampicillin. Then, accordingly to these findings and 7 days after IUFD, medical treatment was replaced with piperacillin/tazobactam with complete symptom resolution and CRP reduction.
Similarly to Torabi’s case [14], placental examination showed severe AC and funisitis. Neutrophils and rod-shaped bacteria were found in fetal lungs and in the lumen of the gastrointestinal tract.
In the management of our case, microbiological cultures on fetal blood and lung tissue, including the antibiogram, were of paramount importance in identifying K. pneumoniae as the etiologic agent, and mother’s medical treatment was then changed accordingly.
However, to date, PPROM and IUFD due to K. pneumoniae have been scarcely reported. One main reason may be attributed to the lack of submitting fetal tissues for microbiological studies.
Although microbiological studies are always recommended in case of PPROM as indicated in the perinatal autopsy protocol, in common practice only fetal autopsies carried out by dedicated perinatal pathologists are performed correctly, including ancillary studies [9].
Another cause may be failure in microbiological culture, as bacteria could not grow or they may be difficult to cultivate [29].
It must be taken into account that AC may be clinically silent and the hallmark for diagnosis relies on placental histological examination [30]. In our specific case, AC and fetal infection were observed, including rod-shaped bacteria. Microbiological cultures on postmortem fetal blood and tissues, and subsequent antibiogram, grew K. pneumoniae and provided the correct maternal treatment.
In the case we described, K. pneumoniae, acquired as ascending infection, determined AC. However, bacterial specific source remained undetermined. The mother denied previous urinary or respiratory infections. In humans, K. pneumoniae is a saprophyte in the nasopharynx and in the intestinal tract. Carrier rates are variable, but isolation from stools is usually higher [22]. Carrier rates typically worsen in a hospital environment. Reported carrier rates in hospitalized patients are 77% in the stool, 19% in the pharynx, and 42% on the hands of patients. The high rates detected in hospital settings are usually associated with antibiotic therapy and progressively increase with the length of stay [20]. It is only a speculation that in our case, AC might have occurred during the hospital stay as a consequence of carrier exacerbation.
Therefore, in the event of PPROM leading to a miscarriage, microbiological cultures on fetal blood and tissues should be mandatory, in order to find the right etiologic agent, and consequent antibiotic therapy.
By and large, appropriate management of clinical chorioamnionitis has been recently reviewed by a workshop of experts [31,32]. The effort has been made to improve maternal and fetal/neonatal wellbeing in order to reduce overall morbidity and unnecessary antibiotic treatment.
First, the term “chorioamnionitis”, in a clinical setting, should be avoided and restricted to the histopathological diagnosis of amniochorial membrane inflammation and/or funisitis. Instead, the new concept of “Triple I” is introduced to indicate “Intrauterine Inflammation or Infection or both”.
Triple I is diagnosed when there is maternal fever with one or more of the following: (1) fetal tachycardia (>160 bpm for 10 min or longer); (2) maternal WBC >15,000 in absence of corticosteroid; (3) purulent fluid from the cervical or confirmed visually on speculum; (4) biochemical or microbiologic amniotic fluid (AF) consistent with amniotic infection.
Triple I should be further classified as “suspected” or “confirmed”. Triple I confirmation requires evidence of infection either in AF (positive Gram stain for bacteria, low AF glucose, high WBC count in the absence of a bloody tap, or positive AF culture results) or in placental histopathological examination (e.g., chorioamnionitis and/or funisitis). Without the previous criteria, Triple I remains as “suspected” or “isolated maternal fever”, the latter categorized as “not Triple I”. There is still controversy regarding reliable antenatal and postnatal biomarkers able to accurately detect the neonatal risk for early onset sepsis (EOS). For example, prenatal dosage of IL-6 value seems promising in assessing the severity of intrauterine infection. The hallmark for EOS still relies on neonatal blood cultures, however they can be biased by false-negative or false-positive results. Moreover, a close communication has been recommended between the obstetric and neonatal team about maternal and fetal/neonatal conditions, e.g., confirmation of Triple I, maternal antibiotic or antipyretic treatment, to name a few.
Triple I may have potential complications such as postpartum hemorrhage, wound infection, and endomyometritis [33]. Antimicrobial treatment depends on Triple I features; however, a wide spectrum therapy with ampicillin and gentamicin is usually given. In case of cesarean section, clindamycin or metronidazole should be added to cover anaerobic pathogens. Bacteremia, sepsis, and persistent fever will be taken into account to determine the duration of treatment. Newborns at risk of EOS tend to receive antibiotics for almost 5 days; conversely it is still debated in wellbeing infants if the treatment is necessary for more than 48 h.
However, a close communication between the obstetric and neonatal teams is paramount for a correct management of maternal and fetal/neonatal health care. In this context, placental examination plays a key role either in identifying the microorganism through tissue cultures or histologically confirming a Triple I [31,32].
Consequently, a good interaction between pathologists and clinicians must also be put in place, as happened in the case we described, in which isolation of K. pneumoniae in fetal blood and tissues, helped to change maternal antibiotic treatment.
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Author Contributions
M.P.B. carried out the diagnosis and wrote the manuscript—original draft preparation, review, and editing; A.P. provided the histological pictures; G.D.D. provided the draft preparation; G.C. clinically managed the patient; P.N., L.V., G.R., M.B., and E.C. carried out the microbiological diagnosis. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Our investigations were carried out following the rules of the Declaration of Helsinki of 1975, revised in 2013. According to Italian legislation, Ethical Approval for a single case is not required, as long as the data are kept anonymous and the investigations performed do not imply genetic results.
Informed Consent Statement
The current Italian legislation neither requires the family’s consent or ethical approval for a single case, as long as the data are strictly kept anonymous. Because summoning the parents was not possible as it would have badly interfered with the grieving process, parents’ consent was completely waived, according to the Italian Authority of Privacy and Data Protection ("Garante della Privacy": GDPR nr 679/2016; 9/2016 and recent law addition number 424/ 19th of July 2018; http://www.garanteprivacy.it).
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Fetal lung: a few intra-alveolar neutrophils (red arrow) associated with rod-shaped bacteria (blue arrow) (HE staining 20×).
Figure 2 Fetal small intestine: intestinal lumen filled with mucus (HE staining 4×). In the mucoid material (frame) there were neutrophils (blue arrows) intermixed with abundant clusters of rod-shaped bacteria (HE staining 20×).
Figure 3 Pancreatic acini with interacinar edema (red stars) (HE staining 4×).
Figure 4 Amniochorial membranes: severe acute chorioamnionitis with focal amnion necrosis (between blue arrows) (HE staining 10×).
Figure 5 Umbilical vein acute flebitis: the umbilical vein showed acute parietal inflammation (red star) with extension to the Wharton’s jelly (blue arrow) (HE staining 20×).
microorganisms-09-00096-t001_Table 1Table 1 Klebsiella pneumoniae antibiogram. MIC: minimum inhibitory concentration.
Antibiotic MIC µg/mL Resistance/Susceptibility
amikacin <=4 S
amoxicillin/clavulanic acid <4/4 S
ampicillin >8 R
aztreonam <=1 S
cefepime <=1 S
ceftazidime <=0.5 S
ceftriaxone <=0.5 S
ciprofloxacin <=0.25 S
colistin 0.5 S
ertapenem <=0.25 S
fosfomycin 32 S
gentamicin <=1 S
imipenem 0.5 S
levofloxacin <=0.5 S
meropenem <=0.125 S
piperacillin/tazobactam <4/4 S
tobramicyn <=1 S
trimethoprim/sulfamethoxazole <=1/19 S | AMOXICILLIN\CLAVULANIC ACID, AMPICILLIN, AZITHROMYCIN ANHYDROUS | DrugsGivenReaction | CC BY | 33401648 | 19,583,466 | 2021-01-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Foetal exposure during pregnancy'. | Klebsiella pneumoniae Chorioamnionitis: An Underrecognized Cause of Preterm Premature Rupture of Membranes in the Second Trimester.
Klebsiella pneumoniae is a Gram-negative, rod-shaped bacterium, responsible for hospital and community acquired pneumonia, urinary tract and wound infections, and bloodstream dissemination. K. pneumoniae infection in pregnancy, leading to acute chorioamnionitis (AC), preterm premature rupture of membranes (PPROM) and early pregnancy loss in the second trimester, has been rarely reported. Herein, we present a case of K. pneumoniae AC that caused intrauterine fetal demise (IUFD) at 19 weeks + 5 days. The 36-year-old mother was admitted at 18 weeks + 1 day of gestation for threatened abortion. IUFD occurred 11 days after. Fetal postmortem showed severe AC and funisitis, neutrophils within alveoli and intestinal lumen, associated with rod-like bacteria. Fetal blood and lung cultures grew K. pneumoniae, β-lactamase-non-producing strain. Antibiogram revealed sensitivity for piperacillin/tazobactam. Three days after IUFD, the mother presented with fever (37.8 °C) which persisted for one week. Maternal blood and urine cultures were negative. According to fetal microbiological results, available 6 days after IUFD, initial treatment with amoxicillin/clavulanic acid was replaced with piperacillin/tazobactam with full patient recovery. Therefore, in the event of PPROM and IUFD, fetal microbiological investigations should always be performed to isolate the proper etiologic agent and start the correct medical treatment.
1. Introduction
Acute chorioamnionitis (AC) is defined as infiltration of neutrophils within placental chorionic plate and amniochorial membranes, usually due to ascending infection [1,2]. Although AC often occurs as subclinical condition, diagnosed only by placental histological examination [3], bacterial infection of the amniotic cavity is the main cause of preterm premature rupture of membranes (PPROM) leading to preterm delivery, respiratory distress, sepsis, and occasionally fetal/neonatal death [4,5,6,7,8]. Moreover, AC is a high risk factor for neonatal necrotising enterocolitis (NEC), retinopathy of prematurity (ROP), poor long-term neurologic outcome, and cerebral palsy [4,5,6,7,8]. The main microorganisms responsible for AC are group B Streptococcus, Fusobacterium nucleatum, Peptostreptococcus, Escherichia coli, Bacteroides species, Ureaplasma urealyticum, and Listeria monocytogenes [1,2]. The gold standard for AC diagnosis remains placental examination. [6]. However, microorganism identification, and subsequent antibiogram, relies on fetal blood and tissue cultures, placental subchorionic fibrin swab, and parenchymal cultures [9,10,11].
To date, intrauterine infection and fetal demise due to K. pneumoniae has been described in only three cases. All of them were second trimester pregnancies presented with PPROM and early pregnancy loss [12,13,14].
Herein, we report a new case of AC due to K. pneumoniae leading to fetal death at 19 weeks + 5 days of gestation. Infection was confirmed by fetal blood and tissue microbiological cultures. We also discuss maternal clinical presentation and antibiotic treatment.
2. Case Description
2.1. Mother Clinical Presentation and Treatment
A 36-year-old woman was admitted to our Institution for threatened abortion at 18 weeks + 1 day of gestation (wga) and treated with antibiotics according to international PPROM guidelines [15]. The treatment consisted of ampicillin and azithromycin for 2 days, then replaced with amoxicillin/clavulanic acid for 5 days. The patient was carefully monitored, but at day 11 after hospital admission, transabdominal ultrasound (US) revealed intrauterine fetal death (IUFD) associated with oligohydramnios. Labor was induced and a male stillborn was vaginally delivered after 36 h.
At day 12 after admission, the patient was treated with ampicillin and gentamicin.
At day 14, the patient presented with fever (37.8 °C) and elevated C-reactive protein (CRP) of 11.10 mg/dL, however blood and urine culture were negative.
At day 16, due to fever persistence and increased CRP of 17.56 mg/dL, antibiotic therapy was modified with amoxicillin/clavulanic acid.
At day 18, as the patient was still feverish with high CRP (12.06 mg/dL), the previous therapy was suspended and replaced with piperacillin/tazobactam.
The patient fully recovered with fever remission and CRP reduction, and after 3 days without fever, she was discharged (day 21).
2.2. Fetal Autopsy and Microbiological Results
IUFD was diagnosed 11 days after the patient’s admission, corresponding approximately to a gestational age of 19 weeks + 5 days.
Postmortem examination revealed a nonmacerated fetus weighing 240 g and measuring 24.5 cm in crown–heel length. The other measurements were as follows: crown–rump length 17.5 cm; foot length 3 cm; head, chest, and abdominal circumference 16 cm, 13 cm, and 12.5 cm, respectively. Overall, anthropometric measurements were consistent with 19 weeks’ gestation [16]. External examination showed a normal male fetus with mild facial and nuchal oedema. Internal examination disclosed minimal pleural and abdominal serous effusions and organ congestion. No congenital anomalies were found.
At microscopy, lungs displayed mild pneumonia with focal intra-alveolar neutrophils associated with rod-like bacteria (Figure 1). Neutrophils and rod-like bacteria were similarly observed in the lumen of the gastrointestinal tract (Figure 2). No other significant histological findings were noted except for mild pancreatic oedema (Figure 3).
Postmortem lung and blood cultures were processed according to routine procedures on selective media. Identification was performed by MALDI-ToF MS (MALDI Biotyper, Bruker Daltonik GmbH, D-28359, Bremen, Germany), while for susceptibility testing, the Phoenix 100™ system was used (Becton, Dickinson and Company, Franklin Lakes, NJ, USA) and agar diffusion (Kirby–Bauer method, according to EUCAST rules).
The isolate was identified as K. pneumoniae ssp. pneumoniae. Further phenotypical test, performed according to Brisse et al., allowed for setting the isolate in the K. pneumoniae phylogroup KpI [17].
The isolate’s susceptibility profile revealed a wild-type phenotype, being susceptible to all the antibiotics tested, except for the intrinsic resistances (Intrinsic_Resistance_and_Unusual_Phenotypes_Tables_v3.2_20200225 in https://www.eucast.org/expert_rules_and_intrinsic_resistance). No ESBL, AmpC, or carbapenemase resistance traits were phenotypically documented, according to EUCAST rules EUCAST_detection_of_resistance_mechanisms_170711, in https://www.eucast.org/resistance_mechanisms).
On blood agar, the isolate did not show the hypermucoviscosity (HMV) phenomenon, as demonstrated by the negativity on the string test, where a standard bacteriological loop was used to stretch a mucoviscous string from the bacterial colony [18].
The antibiogram revealed sensitivity for amoxicillin/clavulanic acid, gentamicin, piperacillin/tazobactam; and resistance to ampicillin (Table 1).
Microbiological results approximately arrived after 17 days of patient’s hospital admission and communicated to the clinicians. As the patient was still feverish with elevated CRP, the treatment was changed accordingly from amoxicillin/clavulanic acid to piperacillin/tazobactam.
The placenta was received fragmented and weighed 139 g. Macroscopically, recognizable strands of membranes were yellowish and opaque. Microscopically, there was severe chorioamnionitis with focal amnion necrosis (Figure 4) corresponding to a maternal inflammatory response stage 3/3 and grade 2/2 [19]. Bacterial organisms were noted at high magnification. Funisitis was also observed with neutrophilic infiltrate of the umbilical vein, one artery, and extension to Wharton’s jelly (Figure 5). These findings were consistent with fetal inflammatory response stage 2/3 and grade 2/2 [19].
The placental parenchyma was normally developed for second trimester, with mesenchymal and immature intermediate villi. Multifocal villous oedema was also identified. The decidua showed diffuse acute necrotizing deciduitis and focal laminar necrosis.
3. Materials and Methods
We searched for ((chorioamnionitis OR ((placenta OR placental) AND (infection OR inflammation)) OR PROM OR “premature rupture of membranes”) AND K. pneumoniae in Pubmed (all fields, 55 results), Scopus (Title/Abstract/Keywords, 15 results), and Web of Science (Topic/Title, 25 results) databases. No limitations were set. Titles and abstract of the results were screened to identify relevant articles. All relevant papers were obtained in full-text format and screened for additional references. The bibliographic research ended on 1 October 2020: three papers were finally included.
4. Discussion
K. pneumoniae is a Gram-negative, rod-shaped bacterium belonging to the family of Enterobacteriaceae, involved in hospital and community-acquired bacterial pneumonia, urinary tract, and wound infections [20,21].
K. pneumoniae represents the main cause of hospital-acquired infections (HAI), and as an opportunistic pathogen, typically induces infections in hospitalized or immunocompromised patients.
Behind Clostridium difficile and Staphylococcus aureus, K. pneumoniae is the third main pathogen responsible for HAI, defined as the onset of pneumonia in ≥48 h after hospital admission [22]. Mortality rate in K. pneumoniae pneumonia is high, reaching 50% [20].
Community-acquired K. pneumoniae pneumonia is usually severe, panlobar, and often diagnosed in chronic alcoholics, attributed to aspiration of gastric contents. This kind of pneumonia is also known as ‘‘Friedlander’s pneumonia’’ characterized by radiographic alterations due to severe pyogenic infection [23]. Urinary tract is often infected by K. pneumoniae, especially in patients with diabetes mellitus or neuropathic bladder, mainly occurring in a nosocomial setting [20,21]. A typical complication is catheter-associated urinary tract infections (CAUTIs) due to the bacterium ability for building biofilms and adhering to catheters [24].
K. pneumoniae may also colonize wound/surgical sites, representing almost 13% of all the infections caused.
K. pneumoniae is the second cause of bloodstream infections (BSI), triggered by Gram-negative bacteria, behind only to Escherichia coli [20,21,22].
BSI may be hospital acquired or occurring in a community setting. In the first situation, cancer is the main underlying disease. Instead, diabetes mellitus and chronic hepatic conditions are typically found in the community [25]. Bacteremia is usually caused by a secondary dissemination from a known site of infection. Typical sources include the urinary and gastrointestinal tract, intravenous or urinary catheters, and respiratory localization [26].
In the neonatal population, K. pneumoniae infection can be responsible for neonatal sepsis and meningitis and may affect premature infants and spread within pediatric wards [20,27,28].
However, to the best of our knowledge, intrauterine fetal death due to K. pneumoniae infection has been reported only in three cases [12,13,14].
Sheikh et al. [12] described a case of IUFD at 18 weeks of gestation. AC and acute villitis were found in the placenta. K. pneumoniae was isolated in maternal blood and placental cultures. Fetal autopsy was not performed. The mother was admitted to the hospital with high temperature (41 °C) and malodorous vaginal discharge. The patient had also vaginal bleeding since one day before the admission.
The PPROM presented by Omwandho et al. [13] was a spontaneous miscarriage at 15 weeks. The mother had a threatened miscarriage at 12th week of gestation with light vaginal bleeding, but then she completely recovered after staying in bed. However, at 15th week, US showed IUFD. Placental cultures were positive for K. pneumoniae, but no pathology was seen in the placenta. Fetal autopsy was also negative for infection or inflammation. Nevertheless, the authors attributed the fetal demise to K. pneumoniae placental microbiological finding. The husband suffered from K. pneumoniae prostatitis and likely infected his wife.
Torabi et al. reported [14] PPROM and IUFD at 20 weeks of gestation due to K. pneumoniae intrauterine infection as the bacterium was found in fetal blood and lung tissue cultures. Placental pathology showed severe AC, chorionic vasculitis, and funisitis. Fetal autopsy showed clusters of neutrophils and bacteria both in the lungs and in the lumen of the gastrointestinal tract. The patient was admitted to the hospital with PPROM, but she had no vaginal bleeding before, and no fever prior to or during the admission. She also denied respiratory or urinary infections for the duration of her pregnancy.
In our case, the patient was admitted for threatened abortion at 18 wga +1 day with no fever. Although she underwent antibiotic treatment (ampicillin and azithromycin for 2 days, and then amoxicillin/clavulanic acid for 5 days), IUFD was diagnosed at 19 wga + 5 days. Ampicillin and gentamicin were started. Three days after IUFD, the patient was feverish (37.8 °C) with high CRP. Fever and elevated CRP persisted for another 7 days. However, maternal blood and urine cultures were negative. First, antibiotic therapy was modified with amoxicillin/clavulanic acid with no results. Then, after 6 days since IUFD, postmortem fetal lung and blood cultures identified K. pneumoniae, β-lactamase-non-producing strain. The antibiogram showed sensitivity for amoxicillin/clavulanic acid, gentamicin, piperacillin/tazobactam; and resistance to ampicillin. Then, accordingly to these findings and 7 days after IUFD, medical treatment was replaced with piperacillin/tazobactam with complete symptom resolution and CRP reduction.
Similarly to Torabi’s case [14], placental examination showed severe AC and funisitis. Neutrophils and rod-shaped bacteria were found in fetal lungs and in the lumen of the gastrointestinal tract.
In the management of our case, microbiological cultures on fetal blood and lung tissue, including the antibiogram, were of paramount importance in identifying K. pneumoniae as the etiologic agent, and mother’s medical treatment was then changed accordingly.
However, to date, PPROM and IUFD due to K. pneumoniae have been scarcely reported. One main reason may be attributed to the lack of submitting fetal tissues for microbiological studies.
Although microbiological studies are always recommended in case of PPROM as indicated in the perinatal autopsy protocol, in common practice only fetal autopsies carried out by dedicated perinatal pathologists are performed correctly, including ancillary studies [9].
Another cause may be failure in microbiological culture, as bacteria could not grow or they may be difficult to cultivate [29].
It must be taken into account that AC may be clinically silent and the hallmark for diagnosis relies on placental histological examination [30]. In our specific case, AC and fetal infection were observed, including rod-shaped bacteria. Microbiological cultures on postmortem fetal blood and tissues, and subsequent antibiogram, grew K. pneumoniae and provided the correct maternal treatment.
In the case we described, K. pneumoniae, acquired as ascending infection, determined AC. However, bacterial specific source remained undetermined. The mother denied previous urinary or respiratory infections. In humans, K. pneumoniae is a saprophyte in the nasopharynx and in the intestinal tract. Carrier rates are variable, but isolation from stools is usually higher [22]. Carrier rates typically worsen in a hospital environment. Reported carrier rates in hospitalized patients are 77% in the stool, 19% in the pharynx, and 42% on the hands of patients. The high rates detected in hospital settings are usually associated with antibiotic therapy and progressively increase with the length of stay [20]. It is only a speculation that in our case, AC might have occurred during the hospital stay as a consequence of carrier exacerbation.
Therefore, in the event of PPROM leading to a miscarriage, microbiological cultures on fetal blood and tissues should be mandatory, in order to find the right etiologic agent, and consequent antibiotic therapy.
By and large, appropriate management of clinical chorioamnionitis has been recently reviewed by a workshop of experts [31,32]. The effort has been made to improve maternal and fetal/neonatal wellbeing in order to reduce overall morbidity and unnecessary antibiotic treatment.
First, the term “chorioamnionitis”, in a clinical setting, should be avoided and restricted to the histopathological diagnosis of amniochorial membrane inflammation and/or funisitis. Instead, the new concept of “Triple I” is introduced to indicate “Intrauterine Inflammation or Infection or both”.
Triple I is diagnosed when there is maternal fever with one or more of the following: (1) fetal tachycardia (>160 bpm for 10 min or longer); (2) maternal WBC >15,000 in absence of corticosteroid; (3) purulent fluid from the cervical or confirmed visually on speculum; (4) biochemical or microbiologic amniotic fluid (AF) consistent with amniotic infection.
Triple I should be further classified as “suspected” or “confirmed”. Triple I confirmation requires evidence of infection either in AF (positive Gram stain for bacteria, low AF glucose, high WBC count in the absence of a bloody tap, or positive AF culture results) or in placental histopathological examination (e.g., chorioamnionitis and/or funisitis). Without the previous criteria, Triple I remains as “suspected” or “isolated maternal fever”, the latter categorized as “not Triple I”. There is still controversy regarding reliable antenatal and postnatal biomarkers able to accurately detect the neonatal risk for early onset sepsis (EOS). For example, prenatal dosage of IL-6 value seems promising in assessing the severity of intrauterine infection. The hallmark for EOS still relies on neonatal blood cultures, however they can be biased by false-negative or false-positive results. Moreover, a close communication has been recommended between the obstetric and neonatal team about maternal and fetal/neonatal conditions, e.g., confirmation of Triple I, maternal antibiotic or antipyretic treatment, to name a few.
Triple I may have potential complications such as postpartum hemorrhage, wound infection, and endomyometritis [33]. Antimicrobial treatment depends on Triple I features; however, a wide spectrum therapy with ampicillin and gentamicin is usually given. In case of cesarean section, clindamycin or metronidazole should be added to cover anaerobic pathogens. Bacteremia, sepsis, and persistent fever will be taken into account to determine the duration of treatment. Newborns at risk of EOS tend to receive antibiotics for almost 5 days; conversely it is still debated in wellbeing infants if the treatment is necessary for more than 48 h.
However, a close communication between the obstetric and neonatal teams is paramount for a correct management of maternal and fetal/neonatal health care. In this context, placental examination plays a key role either in identifying the microorganism through tissue cultures or histologically confirming a Triple I [31,32].
Consequently, a good interaction between pathologists and clinicians must also be put in place, as happened in the case we described, in which isolation of K. pneumoniae in fetal blood and tissues, helped to change maternal antibiotic treatment.
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Author Contributions
M.P.B. carried out the diagnosis and wrote the manuscript—original draft preparation, review, and editing; A.P. provided the histological pictures; G.D.D. provided the draft preparation; G.C. clinically managed the patient; P.N., L.V., G.R., M.B., and E.C. carried out the microbiological diagnosis. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Our investigations were carried out following the rules of the Declaration of Helsinki of 1975, revised in 2013. According to Italian legislation, Ethical Approval for a single case is not required, as long as the data are kept anonymous and the investigations performed do not imply genetic results.
Informed Consent Statement
The current Italian legislation neither requires the family’s consent or ethical approval for a single case, as long as the data are strictly kept anonymous. Because summoning the parents was not possible as it would have badly interfered with the grieving process, parents’ consent was completely waived, according to the Italian Authority of Privacy and Data Protection ("Garante della Privacy": GDPR nr 679/2016; 9/2016 and recent law addition number 424/ 19th of July 2018; http://www.garanteprivacy.it).
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Fetal lung: a few intra-alveolar neutrophils (red arrow) associated with rod-shaped bacteria (blue arrow) (HE staining 20×).
Figure 2 Fetal small intestine: intestinal lumen filled with mucus (HE staining 4×). In the mucoid material (frame) there were neutrophils (blue arrows) intermixed with abundant clusters of rod-shaped bacteria (HE staining 20×).
Figure 3 Pancreatic acini with interacinar edema (red stars) (HE staining 4×).
Figure 4 Amniochorial membranes: severe acute chorioamnionitis with focal amnion necrosis (between blue arrows) (HE staining 10×).
Figure 5 Umbilical vein acute flebitis: the umbilical vein showed acute parietal inflammation (red star) with extension to the Wharton’s jelly (blue arrow) (HE staining 20×).
microorganisms-09-00096-t001_Table 1Table 1 Klebsiella pneumoniae antibiogram. MIC: minimum inhibitory concentration.
Antibiotic MIC µg/mL Resistance/Susceptibility
amikacin <=4 S
amoxicillin/clavulanic acid <4/4 S
ampicillin >8 R
aztreonam <=1 S
cefepime <=1 S
ceftazidime <=0.5 S
ceftriaxone <=0.5 S
ciprofloxacin <=0.25 S
colistin 0.5 S
ertapenem <=0.25 S
fosfomycin 32 S
gentamicin <=1 S
imipenem 0.5 S
levofloxacin <=0.5 S
meropenem <=0.125 S
piperacillin/tazobactam <4/4 S
tobramicyn <=1 S
trimethoprim/sulfamethoxazole <=1/19 S | AMOXICILLIN\CLAVULANIC ACID, AMPICILLIN, AZITHROMYCIN ANHYDROUS | DrugsGivenReaction | CC BY | 33401648 | 19,583,466 | 2021-01-03 |
What was the administration route of drug 'AMOXICILLIN\CLAVULANIC ACID'? | Klebsiella pneumoniae Chorioamnionitis: An Underrecognized Cause of Preterm Premature Rupture of Membranes in the Second Trimester.
Klebsiella pneumoniae is a Gram-negative, rod-shaped bacterium, responsible for hospital and community acquired pneumonia, urinary tract and wound infections, and bloodstream dissemination. K. pneumoniae infection in pregnancy, leading to acute chorioamnionitis (AC), preterm premature rupture of membranes (PPROM) and early pregnancy loss in the second trimester, has been rarely reported. Herein, we present a case of K. pneumoniae AC that caused intrauterine fetal demise (IUFD) at 19 weeks + 5 days. The 36-year-old mother was admitted at 18 weeks + 1 day of gestation for threatened abortion. IUFD occurred 11 days after. Fetal postmortem showed severe AC and funisitis, neutrophils within alveoli and intestinal lumen, associated with rod-like bacteria. Fetal blood and lung cultures grew K. pneumoniae, β-lactamase-non-producing strain. Antibiogram revealed sensitivity for piperacillin/tazobactam. Three days after IUFD, the mother presented with fever (37.8 °C) which persisted for one week. Maternal blood and urine cultures were negative. According to fetal microbiological results, available 6 days after IUFD, initial treatment with amoxicillin/clavulanic acid was replaced with piperacillin/tazobactam with full patient recovery. Therefore, in the event of PPROM and IUFD, fetal microbiological investigations should always be performed to isolate the proper etiologic agent and start the correct medical treatment.
1. Introduction
Acute chorioamnionitis (AC) is defined as infiltration of neutrophils within placental chorionic plate and amniochorial membranes, usually due to ascending infection [1,2]. Although AC often occurs as subclinical condition, diagnosed only by placental histological examination [3], bacterial infection of the amniotic cavity is the main cause of preterm premature rupture of membranes (PPROM) leading to preterm delivery, respiratory distress, sepsis, and occasionally fetal/neonatal death [4,5,6,7,8]. Moreover, AC is a high risk factor for neonatal necrotising enterocolitis (NEC), retinopathy of prematurity (ROP), poor long-term neurologic outcome, and cerebral palsy [4,5,6,7,8]. The main microorganisms responsible for AC are group B Streptococcus, Fusobacterium nucleatum, Peptostreptococcus, Escherichia coli, Bacteroides species, Ureaplasma urealyticum, and Listeria monocytogenes [1,2]. The gold standard for AC diagnosis remains placental examination. [6]. However, microorganism identification, and subsequent antibiogram, relies on fetal blood and tissue cultures, placental subchorionic fibrin swab, and parenchymal cultures [9,10,11].
To date, intrauterine infection and fetal demise due to K. pneumoniae has been described in only three cases. All of them were second trimester pregnancies presented with PPROM and early pregnancy loss [12,13,14].
Herein, we report a new case of AC due to K. pneumoniae leading to fetal death at 19 weeks + 5 days of gestation. Infection was confirmed by fetal blood and tissue microbiological cultures. We also discuss maternal clinical presentation and antibiotic treatment.
2. Case Description
2.1. Mother Clinical Presentation and Treatment
A 36-year-old woman was admitted to our Institution for threatened abortion at 18 weeks + 1 day of gestation (wga) and treated with antibiotics according to international PPROM guidelines [15]. The treatment consisted of ampicillin and azithromycin for 2 days, then replaced with amoxicillin/clavulanic acid for 5 days. The patient was carefully monitored, but at day 11 after hospital admission, transabdominal ultrasound (US) revealed intrauterine fetal death (IUFD) associated with oligohydramnios. Labor was induced and a male stillborn was vaginally delivered after 36 h.
At day 12 after admission, the patient was treated with ampicillin and gentamicin.
At day 14, the patient presented with fever (37.8 °C) and elevated C-reactive protein (CRP) of 11.10 mg/dL, however blood and urine culture were negative.
At day 16, due to fever persistence and increased CRP of 17.56 mg/dL, antibiotic therapy was modified with amoxicillin/clavulanic acid.
At day 18, as the patient was still feverish with high CRP (12.06 mg/dL), the previous therapy was suspended and replaced with piperacillin/tazobactam.
The patient fully recovered with fever remission and CRP reduction, and after 3 days without fever, she was discharged (day 21).
2.2. Fetal Autopsy and Microbiological Results
IUFD was diagnosed 11 days after the patient’s admission, corresponding approximately to a gestational age of 19 weeks + 5 days.
Postmortem examination revealed a nonmacerated fetus weighing 240 g and measuring 24.5 cm in crown–heel length. The other measurements were as follows: crown–rump length 17.5 cm; foot length 3 cm; head, chest, and abdominal circumference 16 cm, 13 cm, and 12.5 cm, respectively. Overall, anthropometric measurements were consistent with 19 weeks’ gestation [16]. External examination showed a normal male fetus with mild facial and nuchal oedema. Internal examination disclosed minimal pleural and abdominal serous effusions and organ congestion. No congenital anomalies were found.
At microscopy, lungs displayed mild pneumonia with focal intra-alveolar neutrophils associated with rod-like bacteria (Figure 1). Neutrophils and rod-like bacteria were similarly observed in the lumen of the gastrointestinal tract (Figure 2). No other significant histological findings were noted except for mild pancreatic oedema (Figure 3).
Postmortem lung and blood cultures were processed according to routine procedures on selective media. Identification was performed by MALDI-ToF MS (MALDI Biotyper, Bruker Daltonik GmbH, D-28359, Bremen, Germany), while for susceptibility testing, the Phoenix 100™ system was used (Becton, Dickinson and Company, Franklin Lakes, NJ, USA) and agar diffusion (Kirby–Bauer method, according to EUCAST rules).
The isolate was identified as K. pneumoniae ssp. pneumoniae. Further phenotypical test, performed according to Brisse et al., allowed for setting the isolate in the K. pneumoniae phylogroup KpI [17].
The isolate’s susceptibility profile revealed a wild-type phenotype, being susceptible to all the antibiotics tested, except for the intrinsic resistances (Intrinsic_Resistance_and_Unusual_Phenotypes_Tables_v3.2_20200225 in https://www.eucast.org/expert_rules_and_intrinsic_resistance). No ESBL, AmpC, or carbapenemase resistance traits were phenotypically documented, according to EUCAST rules EUCAST_detection_of_resistance_mechanisms_170711, in https://www.eucast.org/resistance_mechanisms).
On blood agar, the isolate did not show the hypermucoviscosity (HMV) phenomenon, as demonstrated by the negativity on the string test, where a standard bacteriological loop was used to stretch a mucoviscous string from the bacterial colony [18].
The antibiogram revealed sensitivity for amoxicillin/clavulanic acid, gentamicin, piperacillin/tazobactam; and resistance to ampicillin (Table 1).
Microbiological results approximately arrived after 17 days of patient’s hospital admission and communicated to the clinicians. As the patient was still feverish with elevated CRP, the treatment was changed accordingly from amoxicillin/clavulanic acid to piperacillin/tazobactam.
The placenta was received fragmented and weighed 139 g. Macroscopically, recognizable strands of membranes were yellowish and opaque. Microscopically, there was severe chorioamnionitis with focal amnion necrosis (Figure 4) corresponding to a maternal inflammatory response stage 3/3 and grade 2/2 [19]. Bacterial organisms were noted at high magnification. Funisitis was also observed with neutrophilic infiltrate of the umbilical vein, one artery, and extension to Wharton’s jelly (Figure 5). These findings were consistent with fetal inflammatory response stage 2/3 and grade 2/2 [19].
The placental parenchyma was normally developed for second trimester, with mesenchymal and immature intermediate villi. Multifocal villous oedema was also identified. The decidua showed diffuse acute necrotizing deciduitis and focal laminar necrosis.
3. Materials and Methods
We searched for ((chorioamnionitis OR ((placenta OR placental) AND (infection OR inflammation)) OR PROM OR “premature rupture of membranes”) AND K. pneumoniae in Pubmed (all fields, 55 results), Scopus (Title/Abstract/Keywords, 15 results), and Web of Science (Topic/Title, 25 results) databases. No limitations were set. Titles and abstract of the results were screened to identify relevant articles. All relevant papers were obtained in full-text format and screened for additional references. The bibliographic research ended on 1 October 2020: three papers were finally included.
4. Discussion
K. pneumoniae is a Gram-negative, rod-shaped bacterium belonging to the family of Enterobacteriaceae, involved in hospital and community-acquired bacterial pneumonia, urinary tract, and wound infections [20,21].
K. pneumoniae represents the main cause of hospital-acquired infections (HAI), and as an opportunistic pathogen, typically induces infections in hospitalized or immunocompromised patients.
Behind Clostridium difficile and Staphylococcus aureus, K. pneumoniae is the third main pathogen responsible for HAI, defined as the onset of pneumonia in ≥48 h after hospital admission [22]. Mortality rate in K. pneumoniae pneumonia is high, reaching 50% [20].
Community-acquired K. pneumoniae pneumonia is usually severe, panlobar, and often diagnosed in chronic alcoholics, attributed to aspiration of gastric contents. This kind of pneumonia is also known as ‘‘Friedlander’s pneumonia’’ characterized by radiographic alterations due to severe pyogenic infection [23]. Urinary tract is often infected by K. pneumoniae, especially in patients with diabetes mellitus or neuropathic bladder, mainly occurring in a nosocomial setting [20,21]. A typical complication is catheter-associated urinary tract infections (CAUTIs) due to the bacterium ability for building biofilms and adhering to catheters [24].
K. pneumoniae may also colonize wound/surgical sites, representing almost 13% of all the infections caused.
K. pneumoniae is the second cause of bloodstream infections (BSI), triggered by Gram-negative bacteria, behind only to Escherichia coli [20,21,22].
BSI may be hospital acquired or occurring in a community setting. In the first situation, cancer is the main underlying disease. Instead, diabetes mellitus and chronic hepatic conditions are typically found in the community [25]. Bacteremia is usually caused by a secondary dissemination from a known site of infection. Typical sources include the urinary and gastrointestinal tract, intravenous or urinary catheters, and respiratory localization [26].
In the neonatal population, K. pneumoniae infection can be responsible for neonatal sepsis and meningitis and may affect premature infants and spread within pediatric wards [20,27,28].
However, to the best of our knowledge, intrauterine fetal death due to K. pneumoniae infection has been reported only in three cases [12,13,14].
Sheikh et al. [12] described a case of IUFD at 18 weeks of gestation. AC and acute villitis were found in the placenta. K. pneumoniae was isolated in maternal blood and placental cultures. Fetal autopsy was not performed. The mother was admitted to the hospital with high temperature (41 °C) and malodorous vaginal discharge. The patient had also vaginal bleeding since one day before the admission.
The PPROM presented by Omwandho et al. [13] was a spontaneous miscarriage at 15 weeks. The mother had a threatened miscarriage at 12th week of gestation with light vaginal bleeding, but then she completely recovered after staying in bed. However, at 15th week, US showed IUFD. Placental cultures were positive for K. pneumoniae, but no pathology was seen in the placenta. Fetal autopsy was also negative for infection or inflammation. Nevertheless, the authors attributed the fetal demise to K. pneumoniae placental microbiological finding. The husband suffered from K. pneumoniae prostatitis and likely infected his wife.
Torabi et al. reported [14] PPROM and IUFD at 20 weeks of gestation due to K. pneumoniae intrauterine infection as the bacterium was found in fetal blood and lung tissue cultures. Placental pathology showed severe AC, chorionic vasculitis, and funisitis. Fetal autopsy showed clusters of neutrophils and bacteria both in the lungs and in the lumen of the gastrointestinal tract. The patient was admitted to the hospital with PPROM, but she had no vaginal bleeding before, and no fever prior to or during the admission. She also denied respiratory or urinary infections for the duration of her pregnancy.
In our case, the patient was admitted for threatened abortion at 18 wga +1 day with no fever. Although she underwent antibiotic treatment (ampicillin and azithromycin for 2 days, and then amoxicillin/clavulanic acid for 5 days), IUFD was diagnosed at 19 wga + 5 days. Ampicillin and gentamicin were started. Three days after IUFD, the patient was feverish (37.8 °C) with high CRP. Fever and elevated CRP persisted for another 7 days. However, maternal blood and urine cultures were negative. First, antibiotic therapy was modified with amoxicillin/clavulanic acid with no results. Then, after 6 days since IUFD, postmortem fetal lung and blood cultures identified K. pneumoniae, β-lactamase-non-producing strain. The antibiogram showed sensitivity for amoxicillin/clavulanic acid, gentamicin, piperacillin/tazobactam; and resistance to ampicillin. Then, accordingly to these findings and 7 days after IUFD, medical treatment was replaced with piperacillin/tazobactam with complete symptom resolution and CRP reduction.
Similarly to Torabi’s case [14], placental examination showed severe AC and funisitis. Neutrophils and rod-shaped bacteria were found in fetal lungs and in the lumen of the gastrointestinal tract.
In the management of our case, microbiological cultures on fetal blood and lung tissue, including the antibiogram, were of paramount importance in identifying K. pneumoniae as the etiologic agent, and mother’s medical treatment was then changed accordingly.
However, to date, PPROM and IUFD due to K. pneumoniae have been scarcely reported. One main reason may be attributed to the lack of submitting fetal tissues for microbiological studies.
Although microbiological studies are always recommended in case of PPROM as indicated in the perinatal autopsy protocol, in common practice only fetal autopsies carried out by dedicated perinatal pathologists are performed correctly, including ancillary studies [9].
Another cause may be failure in microbiological culture, as bacteria could not grow or they may be difficult to cultivate [29].
It must be taken into account that AC may be clinically silent and the hallmark for diagnosis relies on placental histological examination [30]. In our specific case, AC and fetal infection were observed, including rod-shaped bacteria. Microbiological cultures on postmortem fetal blood and tissues, and subsequent antibiogram, grew K. pneumoniae and provided the correct maternal treatment.
In the case we described, K. pneumoniae, acquired as ascending infection, determined AC. However, bacterial specific source remained undetermined. The mother denied previous urinary or respiratory infections. In humans, K. pneumoniae is a saprophyte in the nasopharynx and in the intestinal tract. Carrier rates are variable, but isolation from stools is usually higher [22]. Carrier rates typically worsen in a hospital environment. Reported carrier rates in hospitalized patients are 77% in the stool, 19% in the pharynx, and 42% on the hands of patients. The high rates detected in hospital settings are usually associated with antibiotic therapy and progressively increase with the length of stay [20]. It is only a speculation that in our case, AC might have occurred during the hospital stay as a consequence of carrier exacerbation.
Therefore, in the event of PPROM leading to a miscarriage, microbiological cultures on fetal blood and tissues should be mandatory, in order to find the right etiologic agent, and consequent antibiotic therapy.
By and large, appropriate management of clinical chorioamnionitis has been recently reviewed by a workshop of experts [31,32]. The effort has been made to improve maternal and fetal/neonatal wellbeing in order to reduce overall morbidity and unnecessary antibiotic treatment.
First, the term “chorioamnionitis”, in a clinical setting, should be avoided and restricted to the histopathological diagnosis of amniochorial membrane inflammation and/or funisitis. Instead, the new concept of “Triple I” is introduced to indicate “Intrauterine Inflammation or Infection or both”.
Triple I is diagnosed when there is maternal fever with one or more of the following: (1) fetal tachycardia (>160 bpm for 10 min or longer); (2) maternal WBC >15,000 in absence of corticosteroid; (3) purulent fluid from the cervical or confirmed visually on speculum; (4) biochemical or microbiologic amniotic fluid (AF) consistent with amniotic infection.
Triple I should be further classified as “suspected” or “confirmed”. Triple I confirmation requires evidence of infection either in AF (positive Gram stain for bacteria, low AF glucose, high WBC count in the absence of a bloody tap, or positive AF culture results) or in placental histopathological examination (e.g., chorioamnionitis and/or funisitis). Without the previous criteria, Triple I remains as “suspected” or “isolated maternal fever”, the latter categorized as “not Triple I”. There is still controversy regarding reliable antenatal and postnatal biomarkers able to accurately detect the neonatal risk for early onset sepsis (EOS). For example, prenatal dosage of IL-6 value seems promising in assessing the severity of intrauterine infection. The hallmark for EOS still relies on neonatal blood cultures, however they can be biased by false-negative or false-positive results. Moreover, a close communication has been recommended between the obstetric and neonatal team about maternal and fetal/neonatal conditions, e.g., confirmation of Triple I, maternal antibiotic or antipyretic treatment, to name a few.
Triple I may have potential complications such as postpartum hemorrhage, wound infection, and endomyometritis [33]. Antimicrobial treatment depends on Triple I features; however, a wide spectrum therapy with ampicillin and gentamicin is usually given. In case of cesarean section, clindamycin or metronidazole should be added to cover anaerobic pathogens. Bacteremia, sepsis, and persistent fever will be taken into account to determine the duration of treatment. Newborns at risk of EOS tend to receive antibiotics for almost 5 days; conversely it is still debated in wellbeing infants if the treatment is necessary for more than 48 h.
However, a close communication between the obstetric and neonatal teams is paramount for a correct management of maternal and fetal/neonatal health care. In this context, placental examination plays a key role either in identifying the microorganism through tissue cultures or histologically confirming a Triple I [31,32].
Consequently, a good interaction between pathologists and clinicians must also be put in place, as happened in the case we described, in which isolation of K. pneumoniae in fetal blood and tissues, helped to change maternal antibiotic treatment.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
M.P.B. carried out the diagnosis and wrote the manuscript—original draft preparation, review, and editing; A.P. provided the histological pictures; G.D.D. provided the draft preparation; G.C. clinically managed the patient; P.N., L.V., G.R., M.B., and E.C. carried out the microbiological diagnosis. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Our investigations were carried out following the rules of the Declaration of Helsinki of 1975, revised in 2013. According to Italian legislation, Ethical Approval for a single case is not required, as long as the data are kept anonymous and the investigations performed do not imply genetic results.
Informed Consent Statement
The current Italian legislation neither requires the family’s consent or ethical approval for a single case, as long as the data are strictly kept anonymous. Because summoning the parents was not possible as it would have badly interfered with the grieving process, parents’ consent was completely waived, according to the Italian Authority of Privacy and Data Protection ("Garante della Privacy": GDPR nr 679/2016; 9/2016 and recent law addition number 424/ 19th of July 2018; http://www.garanteprivacy.it).
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Fetal lung: a few intra-alveolar neutrophils (red arrow) associated with rod-shaped bacteria (blue arrow) (HE staining 20×).
Figure 2 Fetal small intestine: intestinal lumen filled with mucus (HE staining 4×). In the mucoid material (frame) there were neutrophils (blue arrows) intermixed with abundant clusters of rod-shaped bacteria (HE staining 20×).
Figure 3 Pancreatic acini with interacinar edema (red stars) (HE staining 4×).
Figure 4 Amniochorial membranes: severe acute chorioamnionitis with focal amnion necrosis (between blue arrows) (HE staining 10×).
Figure 5 Umbilical vein acute flebitis: the umbilical vein showed acute parietal inflammation (red star) with extension to the Wharton’s jelly (blue arrow) (HE staining 20×).
microorganisms-09-00096-t001_Table 1Table 1 Klebsiella pneumoniae antibiogram. MIC: minimum inhibitory concentration.
Antibiotic MIC µg/mL Resistance/Susceptibility
amikacin <=4 S
amoxicillin/clavulanic acid <4/4 S
ampicillin >8 R
aztreonam <=1 S
cefepime <=1 S
ceftazidime <=0.5 S
ceftriaxone <=0.5 S
ciprofloxacin <=0.25 S
colistin 0.5 S
ertapenem <=0.25 S
fosfomycin 32 S
gentamicin <=1 S
imipenem 0.5 S
levofloxacin <=0.5 S
meropenem <=0.125 S
piperacillin/tazobactam <4/4 S
tobramicyn <=1 S
trimethoprim/sulfamethoxazole <=1/19 S | Transplacental | DrugAdministrationRoute | CC BY | 33401648 | 19,583,466 | 2021-01-03 |
What was the administration route of drug 'AMPICILLIN'? | Klebsiella pneumoniae Chorioamnionitis: An Underrecognized Cause of Preterm Premature Rupture of Membranes in the Second Trimester.
Klebsiella pneumoniae is a Gram-negative, rod-shaped bacterium, responsible for hospital and community acquired pneumonia, urinary tract and wound infections, and bloodstream dissemination. K. pneumoniae infection in pregnancy, leading to acute chorioamnionitis (AC), preterm premature rupture of membranes (PPROM) and early pregnancy loss in the second trimester, has been rarely reported. Herein, we present a case of K. pneumoniae AC that caused intrauterine fetal demise (IUFD) at 19 weeks + 5 days. The 36-year-old mother was admitted at 18 weeks + 1 day of gestation for threatened abortion. IUFD occurred 11 days after. Fetal postmortem showed severe AC and funisitis, neutrophils within alveoli and intestinal lumen, associated with rod-like bacteria. Fetal blood and lung cultures grew K. pneumoniae, β-lactamase-non-producing strain. Antibiogram revealed sensitivity for piperacillin/tazobactam. Three days after IUFD, the mother presented with fever (37.8 °C) which persisted for one week. Maternal blood and urine cultures were negative. According to fetal microbiological results, available 6 days after IUFD, initial treatment with amoxicillin/clavulanic acid was replaced with piperacillin/tazobactam with full patient recovery. Therefore, in the event of PPROM and IUFD, fetal microbiological investigations should always be performed to isolate the proper etiologic agent and start the correct medical treatment.
1. Introduction
Acute chorioamnionitis (AC) is defined as infiltration of neutrophils within placental chorionic plate and amniochorial membranes, usually due to ascending infection [1,2]. Although AC often occurs as subclinical condition, diagnosed only by placental histological examination [3], bacterial infection of the amniotic cavity is the main cause of preterm premature rupture of membranes (PPROM) leading to preterm delivery, respiratory distress, sepsis, and occasionally fetal/neonatal death [4,5,6,7,8]. Moreover, AC is a high risk factor for neonatal necrotising enterocolitis (NEC), retinopathy of prematurity (ROP), poor long-term neurologic outcome, and cerebral palsy [4,5,6,7,8]. The main microorganisms responsible for AC are group B Streptococcus, Fusobacterium nucleatum, Peptostreptococcus, Escherichia coli, Bacteroides species, Ureaplasma urealyticum, and Listeria monocytogenes [1,2]. The gold standard for AC diagnosis remains placental examination. [6]. However, microorganism identification, and subsequent antibiogram, relies on fetal blood and tissue cultures, placental subchorionic fibrin swab, and parenchymal cultures [9,10,11].
To date, intrauterine infection and fetal demise due to K. pneumoniae has been described in only three cases. All of them were second trimester pregnancies presented with PPROM and early pregnancy loss [12,13,14].
Herein, we report a new case of AC due to K. pneumoniae leading to fetal death at 19 weeks + 5 days of gestation. Infection was confirmed by fetal blood and tissue microbiological cultures. We also discuss maternal clinical presentation and antibiotic treatment.
2. Case Description
2.1. Mother Clinical Presentation and Treatment
A 36-year-old woman was admitted to our Institution for threatened abortion at 18 weeks + 1 day of gestation (wga) and treated with antibiotics according to international PPROM guidelines [15]. The treatment consisted of ampicillin and azithromycin for 2 days, then replaced with amoxicillin/clavulanic acid for 5 days. The patient was carefully monitored, but at day 11 after hospital admission, transabdominal ultrasound (US) revealed intrauterine fetal death (IUFD) associated with oligohydramnios. Labor was induced and a male stillborn was vaginally delivered after 36 h.
At day 12 after admission, the patient was treated with ampicillin and gentamicin.
At day 14, the patient presented with fever (37.8 °C) and elevated C-reactive protein (CRP) of 11.10 mg/dL, however blood and urine culture were negative.
At day 16, due to fever persistence and increased CRP of 17.56 mg/dL, antibiotic therapy was modified with amoxicillin/clavulanic acid.
At day 18, as the patient was still feverish with high CRP (12.06 mg/dL), the previous therapy was suspended and replaced with piperacillin/tazobactam.
The patient fully recovered with fever remission and CRP reduction, and after 3 days without fever, she was discharged (day 21).
2.2. Fetal Autopsy and Microbiological Results
IUFD was diagnosed 11 days after the patient’s admission, corresponding approximately to a gestational age of 19 weeks + 5 days.
Postmortem examination revealed a nonmacerated fetus weighing 240 g and measuring 24.5 cm in crown–heel length. The other measurements were as follows: crown–rump length 17.5 cm; foot length 3 cm; head, chest, and abdominal circumference 16 cm, 13 cm, and 12.5 cm, respectively. Overall, anthropometric measurements were consistent with 19 weeks’ gestation [16]. External examination showed a normal male fetus with mild facial and nuchal oedema. Internal examination disclosed minimal pleural and abdominal serous effusions and organ congestion. No congenital anomalies were found.
At microscopy, lungs displayed mild pneumonia with focal intra-alveolar neutrophils associated with rod-like bacteria (Figure 1). Neutrophils and rod-like bacteria were similarly observed in the lumen of the gastrointestinal tract (Figure 2). No other significant histological findings were noted except for mild pancreatic oedema (Figure 3).
Postmortem lung and blood cultures were processed according to routine procedures on selective media. Identification was performed by MALDI-ToF MS (MALDI Biotyper, Bruker Daltonik GmbH, D-28359, Bremen, Germany), while for susceptibility testing, the Phoenix 100™ system was used (Becton, Dickinson and Company, Franklin Lakes, NJ, USA) and agar diffusion (Kirby–Bauer method, according to EUCAST rules).
The isolate was identified as K. pneumoniae ssp. pneumoniae. Further phenotypical test, performed according to Brisse et al., allowed for setting the isolate in the K. pneumoniae phylogroup KpI [17].
The isolate’s susceptibility profile revealed a wild-type phenotype, being susceptible to all the antibiotics tested, except for the intrinsic resistances (Intrinsic_Resistance_and_Unusual_Phenotypes_Tables_v3.2_20200225 in https://www.eucast.org/expert_rules_and_intrinsic_resistance). No ESBL, AmpC, or carbapenemase resistance traits were phenotypically documented, according to EUCAST rules EUCAST_detection_of_resistance_mechanisms_170711, in https://www.eucast.org/resistance_mechanisms).
On blood agar, the isolate did not show the hypermucoviscosity (HMV) phenomenon, as demonstrated by the negativity on the string test, where a standard bacteriological loop was used to stretch a mucoviscous string from the bacterial colony [18].
The antibiogram revealed sensitivity for amoxicillin/clavulanic acid, gentamicin, piperacillin/tazobactam; and resistance to ampicillin (Table 1).
Microbiological results approximately arrived after 17 days of patient’s hospital admission and communicated to the clinicians. As the patient was still feverish with elevated CRP, the treatment was changed accordingly from amoxicillin/clavulanic acid to piperacillin/tazobactam.
The placenta was received fragmented and weighed 139 g. Macroscopically, recognizable strands of membranes were yellowish and opaque. Microscopically, there was severe chorioamnionitis with focal amnion necrosis (Figure 4) corresponding to a maternal inflammatory response stage 3/3 and grade 2/2 [19]. Bacterial organisms were noted at high magnification. Funisitis was also observed with neutrophilic infiltrate of the umbilical vein, one artery, and extension to Wharton’s jelly (Figure 5). These findings were consistent with fetal inflammatory response stage 2/3 and grade 2/2 [19].
The placental parenchyma was normally developed for second trimester, with mesenchymal and immature intermediate villi. Multifocal villous oedema was also identified. The decidua showed diffuse acute necrotizing deciduitis and focal laminar necrosis.
3. Materials and Methods
We searched for ((chorioamnionitis OR ((placenta OR placental) AND (infection OR inflammation)) OR PROM OR “premature rupture of membranes”) AND K. pneumoniae in Pubmed (all fields, 55 results), Scopus (Title/Abstract/Keywords, 15 results), and Web of Science (Topic/Title, 25 results) databases. No limitations were set. Titles and abstract of the results were screened to identify relevant articles. All relevant papers were obtained in full-text format and screened for additional references. The bibliographic research ended on 1 October 2020: three papers were finally included.
4. Discussion
K. pneumoniae is a Gram-negative, rod-shaped bacterium belonging to the family of Enterobacteriaceae, involved in hospital and community-acquired bacterial pneumonia, urinary tract, and wound infections [20,21].
K. pneumoniae represents the main cause of hospital-acquired infections (HAI), and as an opportunistic pathogen, typically induces infections in hospitalized or immunocompromised patients.
Behind Clostridium difficile and Staphylococcus aureus, K. pneumoniae is the third main pathogen responsible for HAI, defined as the onset of pneumonia in ≥48 h after hospital admission [22]. Mortality rate in K. pneumoniae pneumonia is high, reaching 50% [20].
Community-acquired K. pneumoniae pneumonia is usually severe, panlobar, and often diagnosed in chronic alcoholics, attributed to aspiration of gastric contents. This kind of pneumonia is also known as ‘‘Friedlander’s pneumonia’’ characterized by radiographic alterations due to severe pyogenic infection [23]. Urinary tract is often infected by K. pneumoniae, especially in patients with diabetes mellitus or neuropathic bladder, mainly occurring in a nosocomial setting [20,21]. A typical complication is catheter-associated urinary tract infections (CAUTIs) due to the bacterium ability for building biofilms and adhering to catheters [24].
K. pneumoniae may also colonize wound/surgical sites, representing almost 13% of all the infections caused.
K. pneumoniae is the second cause of bloodstream infections (BSI), triggered by Gram-negative bacteria, behind only to Escherichia coli [20,21,22].
BSI may be hospital acquired or occurring in a community setting. In the first situation, cancer is the main underlying disease. Instead, diabetes mellitus and chronic hepatic conditions are typically found in the community [25]. Bacteremia is usually caused by a secondary dissemination from a known site of infection. Typical sources include the urinary and gastrointestinal tract, intravenous or urinary catheters, and respiratory localization [26].
In the neonatal population, K. pneumoniae infection can be responsible for neonatal sepsis and meningitis and may affect premature infants and spread within pediatric wards [20,27,28].
However, to the best of our knowledge, intrauterine fetal death due to K. pneumoniae infection has been reported only in three cases [12,13,14].
Sheikh et al. [12] described a case of IUFD at 18 weeks of gestation. AC and acute villitis were found in the placenta. K. pneumoniae was isolated in maternal blood and placental cultures. Fetal autopsy was not performed. The mother was admitted to the hospital with high temperature (41 °C) and malodorous vaginal discharge. The patient had also vaginal bleeding since one day before the admission.
The PPROM presented by Omwandho et al. [13] was a spontaneous miscarriage at 15 weeks. The mother had a threatened miscarriage at 12th week of gestation with light vaginal bleeding, but then she completely recovered after staying in bed. However, at 15th week, US showed IUFD. Placental cultures were positive for K. pneumoniae, but no pathology was seen in the placenta. Fetal autopsy was also negative for infection or inflammation. Nevertheless, the authors attributed the fetal demise to K. pneumoniae placental microbiological finding. The husband suffered from K. pneumoniae prostatitis and likely infected his wife.
Torabi et al. reported [14] PPROM and IUFD at 20 weeks of gestation due to K. pneumoniae intrauterine infection as the bacterium was found in fetal blood and lung tissue cultures. Placental pathology showed severe AC, chorionic vasculitis, and funisitis. Fetal autopsy showed clusters of neutrophils and bacteria both in the lungs and in the lumen of the gastrointestinal tract. The patient was admitted to the hospital with PPROM, but she had no vaginal bleeding before, and no fever prior to or during the admission. She also denied respiratory or urinary infections for the duration of her pregnancy.
In our case, the patient was admitted for threatened abortion at 18 wga +1 day with no fever. Although she underwent antibiotic treatment (ampicillin and azithromycin for 2 days, and then amoxicillin/clavulanic acid for 5 days), IUFD was diagnosed at 19 wga + 5 days. Ampicillin and gentamicin were started. Three days after IUFD, the patient was feverish (37.8 °C) with high CRP. Fever and elevated CRP persisted for another 7 days. However, maternal blood and urine cultures were negative. First, antibiotic therapy was modified with amoxicillin/clavulanic acid with no results. Then, after 6 days since IUFD, postmortem fetal lung and blood cultures identified K. pneumoniae, β-lactamase-non-producing strain. The antibiogram showed sensitivity for amoxicillin/clavulanic acid, gentamicin, piperacillin/tazobactam; and resistance to ampicillin. Then, accordingly to these findings and 7 days after IUFD, medical treatment was replaced with piperacillin/tazobactam with complete symptom resolution and CRP reduction.
Similarly to Torabi’s case [14], placental examination showed severe AC and funisitis. Neutrophils and rod-shaped bacteria were found in fetal lungs and in the lumen of the gastrointestinal tract.
In the management of our case, microbiological cultures on fetal blood and lung tissue, including the antibiogram, were of paramount importance in identifying K. pneumoniae as the etiologic agent, and mother’s medical treatment was then changed accordingly.
However, to date, PPROM and IUFD due to K. pneumoniae have been scarcely reported. One main reason may be attributed to the lack of submitting fetal tissues for microbiological studies.
Although microbiological studies are always recommended in case of PPROM as indicated in the perinatal autopsy protocol, in common practice only fetal autopsies carried out by dedicated perinatal pathologists are performed correctly, including ancillary studies [9].
Another cause may be failure in microbiological culture, as bacteria could not grow or they may be difficult to cultivate [29].
It must be taken into account that AC may be clinically silent and the hallmark for diagnosis relies on placental histological examination [30]. In our specific case, AC and fetal infection were observed, including rod-shaped bacteria. Microbiological cultures on postmortem fetal blood and tissues, and subsequent antibiogram, grew K. pneumoniae and provided the correct maternal treatment.
In the case we described, K. pneumoniae, acquired as ascending infection, determined AC. However, bacterial specific source remained undetermined. The mother denied previous urinary or respiratory infections. In humans, K. pneumoniae is a saprophyte in the nasopharynx and in the intestinal tract. Carrier rates are variable, but isolation from stools is usually higher [22]. Carrier rates typically worsen in a hospital environment. Reported carrier rates in hospitalized patients are 77% in the stool, 19% in the pharynx, and 42% on the hands of patients. The high rates detected in hospital settings are usually associated with antibiotic therapy and progressively increase with the length of stay [20]. It is only a speculation that in our case, AC might have occurred during the hospital stay as a consequence of carrier exacerbation.
Therefore, in the event of PPROM leading to a miscarriage, microbiological cultures on fetal blood and tissues should be mandatory, in order to find the right etiologic agent, and consequent antibiotic therapy.
By and large, appropriate management of clinical chorioamnionitis has been recently reviewed by a workshop of experts [31,32]. The effort has been made to improve maternal and fetal/neonatal wellbeing in order to reduce overall morbidity and unnecessary antibiotic treatment.
First, the term “chorioamnionitis”, in a clinical setting, should be avoided and restricted to the histopathological diagnosis of amniochorial membrane inflammation and/or funisitis. Instead, the new concept of “Triple I” is introduced to indicate “Intrauterine Inflammation or Infection or both”.
Triple I is diagnosed when there is maternal fever with one or more of the following: (1) fetal tachycardia (>160 bpm for 10 min or longer); (2) maternal WBC >15,000 in absence of corticosteroid; (3) purulent fluid from the cervical or confirmed visually on speculum; (4) biochemical or microbiologic amniotic fluid (AF) consistent with amniotic infection.
Triple I should be further classified as “suspected” or “confirmed”. Triple I confirmation requires evidence of infection either in AF (positive Gram stain for bacteria, low AF glucose, high WBC count in the absence of a bloody tap, or positive AF culture results) or in placental histopathological examination (e.g., chorioamnionitis and/or funisitis). Without the previous criteria, Triple I remains as “suspected” or “isolated maternal fever”, the latter categorized as “not Triple I”. There is still controversy regarding reliable antenatal and postnatal biomarkers able to accurately detect the neonatal risk for early onset sepsis (EOS). For example, prenatal dosage of IL-6 value seems promising in assessing the severity of intrauterine infection. The hallmark for EOS still relies on neonatal blood cultures, however they can be biased by false-negative or false-positive results. Moreover, a close communication has been recommended between the obstetric and neonatal team about maternal and fetal/neonatal conditions, e.g., confirmation of Triple I, maternal antibiotic or antipyretic treatment, to name a few.
Triple I may have potential complications such as postpartum hemorrhage, wound infection, and endomyometritis [33]. Antimicrobial treatment depends on Triple I features; however, a wide spectrum therapy with ampicillin and gentamicin is usually given. In case of cesarean section, clindamycin or metronidazole should be added to cover anaerobic pathogens. Bacteremia, sepsis, and persistent fever will be taken into account to determine the duration of treatment. Newborns at risk of EOS tend to receive antibiotics for almost 5 days; conversely it is still debated in wellbeing infants if the treatment is necessary for more than 48 h.
However, a close communication between the obstetric and neonatal teams is paramount for a correct management of maternal and fetal/neonatal health care. In this context, placental examination plays a key role either in identifying the microorganism through tissue cultures or histologically confirming a Triple I [31,32].
Consequently, a good interaction between pathologists and clinicians must also be put in place, as happened in the case we described, in which isolation of K. pneumoniae in fetal blood and tissues, helped to change maternal antibiotic treatment.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
M.P.B. carried out the diagnosis and wrote the manuscript—original draft preparation, review, and editing; A.P. provided the histological pictures; G.D.D. provided the draft preparation; G.C. clinically managed the patient; P.N., L.V., G.R., M.B., and E.C. carried out the microbiological diagnosis. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Our investigations were carried out following the rules of the Declaration of Helsinki of 1975, revised in 2013. According to Italian legislation, Ethical Approval for a single case is not required, as long as the data are kept anonymous and the investigations performed do not imply genetic results.
Informed Consent Statement
The current Italian legislation neither requires the family’s consent or ethical approval for a single case, as long as the data are strictly kept anonymous. Because summoning the parents was not possible as it would have badly interfered with the grieving process, parents’ consent was completely waived, according to the Italian Authority of Privacy and Data Protection ("Garante della Privacy": GDPR nr 679/2016; 9/2016 and recent law addition number 424/ 19th of July 2018; http://www.garanteprivacy.it).
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Fetal lung: a few intra-alveolar neutrophils (red arrow) associated with rod-shaped bacteria (blue arrow) (HE staining 20×).
Figure 2 Fetal small intestine: intestinal lumen filled with mucus (HE staining 4×). In the mucoid material (frame) there were neutrophils (blue arrows) intermixed with abundant clusters of rod-shaped bacteria (HE staining 20×).
Figure 3 Pancreatic acini with interacinar edema (red stars) (HE staining 4×).
Figure 4 Amniochorial membranes: severe acute chorioamnionitis with focal amnion necrosis (between blue arrows) (HE staining 10×).
Figure 5 Umbilical vein acute flebitis: the umbilical vein showed acute parietal inflammation (red star) with extension to the Wharton’s jelly (blue arrow) (HE staining 20×).
microorganisms-09-00096-t001_Table 1Table 1 Klebsiella pneumoniae antibiogram. MIC: minimum inhibitory concentration.
Antibiotic MIC µg/mL Resistance/Susceptibility
amikacin <=4 S
amoxicillin/clavulanic acid <4/4 S
ampicillin >8 R
aztreonam <=1 S
cefepime <=1 S
ceftazidime <=0.5 S
ceftriaxone <=0.5 S
ciprofloxacin <=0.25 S
colistin 0.5 S
ertapenem <=0.25 S
fosfomycin 32 S
gentamicin <=1 S
imipenem 0.5 S
levofloxacin <=0.5 S
meropenem <=0.125 S
piperacillin/tazobactam <4/4 S
tobramicyn <=1 S
trimethoprim/sulfamethoxazole <=1/19 S | Transplacental | DrugAdministrationRoute | CC BY | 33401648 | 19,583,466 | 2021-01-03 |
What was the administration route of drug 'AZITHROMYCIN ANHYDROUS'? | Klebsiella pneumoniae Chorioamnionitis: An Underrecognized Cause of Preterm Premature Rupture of Membranes in the Second Trimester.
Klebsiella pneumoniae is a Gram-negative, rod-shaped bacterium, responsible for hospital and community acquired pneumonia, urinary tract and wound infections, and bloodstream dissemination. K. pneumoniae infection in pregnancy, leading to acute chorioamnionitis (AC), preterm premature rupture of membranes (PPROM) and early pregnancy loss in the second trimester, has been rarely reported. Herein, we present a case of K. pneumoniae AC that caused intrauterine fetal demise (IUFD) at 19 weeks + 5 days. The 36-year-old mother was admitted at 18 weeks + 1 day of gestation for threatened abortion. IUFD occurred 11 days after. Fetal postmortem showed severe AC and funisitis, neutrophils within alveoli and intestinal lumen, associated with rod-like bacteria. Fetal blood and lung cultures grew K. pneumoniae, β-lactamase-non-producing strain. Antibiogram revealed sensitivity for piperacillin/tazobactam. Three days after IUFD, the mother presented with fever (37.8 °C) which persisted for one week. Maternal blood and urine cultures were negative. According to fetal microbiological results, available 6 days after IUFD, initial treatment with amoxicillin/clavulanic acid was replaced with piperacillin/tazobactam with full patient recovery. Therefore, in the event of PPROM and IUFD, fetal microbiological investigations should always be performed to isolate the proper etiologic agent and start the correct medical treatment.
1. Introduction
Acute chorioamnionitis (AC) is defined as infiltration of neutrophils within placental chorionic plate and amniochorial membranes, usually due to ascending infection [1,2]. Although AC often occurs as subclinical condition, diagnosed only by placental histological examination [3], bacterial infection of the amniotic cavity is the main cause of preterm premature rupture of membranes (PPROM) leading to preterm delivery, respiratory distress, sepsis, and occasionally fetal/neonatal death [4,5,6,7,8]. Moreover, AC is a high risk factor for neonatal necrotising enterocolitis (NEC), retinopathy of prematurity (ROP), poor long-term neurologic outcome, and cerebral palsy [4,5,6,7,8]. The main microorganisms responsible for AC are group B Streptococcus, Fusobacterium nucleatum, Peptostreptococcus, Escherichia coli, Bacteroides species, Ureaplasma urealyticum, and Listeria monocytogenes [1,2]. The gold standard for AC diagnosis remains placental examination. [6]. However, microorganism identification, and subsequent antibiogram, relies on fetal blood and tissue cultures, placental subchorionic fibrin swab, and parenchymal cultures [9,10,11].
To date, intrauterine infection and fetal demise due to K. pneumoniae has been described in only three cases. All of them were second trimester pregnancies presented with PPROM and early pregnancy loss [12,13,14].
Herein, we report a new case of AC due to K. pneumoniae leading to fetal death at 19 weeks + 5 days of gestation. Infection was confirmed by fetal blood and tissue microbiological cultures. We also discuss maternal clinical presentation and antibiotic treatment.
2. Case Description
2.1. Mother Clinical Presentation and Treatment
A 36-year-old woman was admitted to our Institution for threatened abortion at 18 weeks + 1 day of gestation (wga) and treated with antibiotics according to international PPROM guidelines [15]. The treatment consisted of ampicillin and azithromycin for 2 days, then replaced with amoxicillin/clavulanic acid for 5 days. The patient was carefully monitored, but at day 11 after hospital admission, transabdominal ultrasound (US) revealed intrauterine fetal death (IUFD) associated with oligohydramnios. Labor was induced and a male stillborn was vaginally delivered after 36 h.
At day 12 after admission, the patient was treated with ampicillin and gentamicin.
At day 14, the patient presented with fever (37.8 °C) and elevated C-reactive protein (CRP) of 11.10 mg/dL, however blood and urine culture were negative.
At day 16, due to fever persistence and increased CRP of 17.56 mg/dL, antibiotic therapy was modified with amoxicillin/clavulanic acid.
At day 18, as the patient was still feverish with high CRP (12.06 mg/dL), the previous therapy was suspended and replaced with piperacillin/tazobactam.
The patient fully recovered with fever remission and CRP reduction, and after 3 days without fever, she was discharged (day 21).
2.2. Fetal Autopsy and Microbiological Results
IUFD was diagnosed 11 days after the patient’s admission, corresponding approximately to a gestational age of 19 weeks + 5 days.
Postmortem examination revealed a nonmacerated fetus weighing 240 g and measuring 24.5 cm in crown–heel length. The other measurements were as follows: crown–rump length 17.5 cm; foot length 3 cm; head, chest, and abdominal circumference 16 cm, 13 cm, and 12.5 cm, respectively. Overall, anthropometric measurements were consistent with 19 weeks’ gestation [16]. External examination showed a normal male fetus with mild facial and nuchal oedema. Internal examination disclosed minimal pleural and abdominal serous effusions and organ congestion. No congenital anomalies were found.
At microscopy, lungs displayed mild pneumonia with focal intra-alveolar neutrophils associated with rod-like bacteria (Figure 1). Neutrophils and rod-like bacteria were similarly observed in the lumen of the gastrointestinal tract (Figure 2). No other significant histological findings were noted except for mild pancreatic oedema (Figure 3).
Postmortem lung and blood cultures were processed according to routine procedures on selective media. Identification was performed by MALDI-ToF MS (MALDI Biotyper, Bruker Daltonik GmbH, D-28359, Bremen, Germany), while for susceptibility testing, the Phoenix 100™ system was used (Becton, Dickinson and Company, Franklin Lakes, NJ, USA) and agar diffusion (Kirby–Bauer method, according to EUCAST rules).
The isolate was identified as K. pneumoniae ssp. pneumoniae. Further phenotypical test, performed according to Brisse et al., allowed for setting the isolate in the K. pneumoniae phylogroup KpI [17].
The isolate’s susceptibility profile revealed a wild-type phenotype, being susceptible to all the antibiotics tested, except for the intrinsic resistances (Intrinsic_Resistance_and_Unusual_Phenotypes_Tables_v3.2_20200225 in https://www.eucast.org/expert_rules_and_intrinsic_resistance). No ESBL, AmpC, or carbapenemase resistance traits were phenotypically documented, according to EUCAST rules EUCAST_detection_of_resistance_mechanisms_170711, in https://www.eucast.org/resistance_mechanisms).
On blood agar, the isolate did not show the hypermucoviscosity (HMV) phenomenon, as demonstrated by the negativity on the string test, where a standard bacteriological loop was used to stretch a mucoviscous string from the bacterial colony [18].
The antibiogram revealed sensitivity for amoxicillin/clavulanic acid, gentamicin, piperacillin/tazobactam; and resistance to ampicillin (Table 1).
Microbiological results approximately arrived after 17 days of patient’s hospital admission and communicated to the clinicians. As the patient was still feverish with elevated CRP, the treatment was changed accordingly from amoxicillin/clavulanic acid to piperacillin/tazobactam.
The placenta was received fragmented and weighed 139 g. Macroscopically, recognizable strands of membranes were yellowish and opaque. Microscopically, there was severe chorioamnionitis with focal amnion necrosis (Figure 4) corresponding to a maternal inflammatory response stage 3/3 and grade 2/2 [19]. Bacterial organisms were noted at high magnification. Funisitis was also observed with neutrophilic infiltrate of the umbilical vein, one artery, and extension to Wharton’s jelly (Figure 5). These findings were consistent with fetal inflammatory response stage 2/3 and grade 2/2 [19].
The placental parenchyma was normally developed for second trimester, with mesenchymal and immature intermediate villi. Multifocal villous oedema was also identified. The decidua showed diffuse acute necrotizing deciduitis and focal laminar necrosis.
3. Materials and Methods
We searched for ((chorioamnionitis OR ((placenta OR placental) AND (infection OR inflammation)) OR PROM OR “premature rupture of membranes”) AND K. pneumoniae in Pubmed (all fields, 55 results), Scopus (Title/Abstract/Keywords, 15 results), and Web of Science (Topic/Title, 25 results) databases. No limitations were set. Titles and abstract of the results were screened to identify relevant articles. All relevant papers were obtained in full-text format and screened for additional references. The bibliographic research ended on 1 October 2020: three papers were finally included.
4. Discussion
K. pneumoniae is a Gram-negative, rod-shaped bacterium belonging to the family of Enterobacteriaceae, involved in hospital and community-acquired bacterial pneumonia, urinary tract, and wound infections [20,21].
K. pneumoniae represents the main cause of hospital-acquired infections (HAI), and as an opportunistic pathogen, typically induces infections in hospitalized or immunocompromised patients.
Behind Clostridium difficile and Staphylococcus aureus, K. pneumoniae is the third main pathogen responsible for HAI, defined as the onset of pneumonia in ≥48 h after hospital admission [22]. Mortality rate in K. pneumoniae pneumonia is high, reaching 50% [20].
Community-acquired K. pneumoniae pneumonia is usually severe, panlobar, and often diagnosed in chronic alcoholics, attributed to aspiration of gastric contents. This kind of pneumonia is also known as ‘‘Friedlander’s pneumonia’’ characterized by radiographic alterations due to severe pyogenic infection [23]. Urinary tract is often infected by K. pneumoniae, especially in patients with diabetes mellitus or neuropathic bladder, mainly occurring in a nosocomial setting [20,21]. A typical complication is catheter-associated urinary tract infections (CAUTIs) due to the bacterium ability for building biofilms and adhering to catheters [24].
K. pneumoniae may also colonize wound/surgical sites, representing almost 13% of all the infections caused.
K. pneumoniae is the second cause of bloodstream infections (BSI), triggered by Gram-negative bacteria, behind only to Escherichia coli [20,21,22].
BSI may be hospital acquired or occurring in a community setting. In the first situation, cancer is the main underlying disease. Instead, diabetes mellitus and chronic hepatic conditions are typically found in the community [25]. Bacteremia is usually caused by a secondary dissemination from a known site of infection. Typical sources include the urinary and gastrointestinal tract, intravenous or urinary catheters, and respiratory localization [26].
In the neonatal population, K. pneumoniae infection can be responsible for neonatal sepsis and meningitis and may affect premature infants and spread within pediatric wards [20,27,28].
However, to the best of our knowledge, intrauterine fetal death due to K. pneumoniae infection has been reported only in three cases [12,13,14].
Sheikh et al. [12] described a case of IUFD at 18 weeks of gestation. AC and acute villitis were found in the placenta. K. pneumoniae was isolated in maternal blood and placental cultures. Fetal autopsy was not performed. The mother was admitted to the hospital with high temperature (41 °C) and malodorous vaginal discharge. The patient had also vaginal bleeding since one day before the admission.
The PPROM presented by Omwandho et al. [13] was a spontaneous miscarriage at 15 weeks. The mother had a threatened miscarriage at 12th week of gestation with light vaginal bleeding, but then she completely recovered after staying in bed. However, at 15th week, US showed IUFD. Placental cultures were positive for K. pneumoniae, but no pathology was seen in the placenta. Fetal autopsy was also negative for infection or inflammation. Nevertheless, the authors attributed the fetal demise to K. pneumoniae placental microbiological finding. The husband suffered from K. pneumoniae prostatitis and likely infected his wife.
Torabi et al. reported [14] PPROM and IUFD at 20 weeks of gestation due to K. pneumoniae intrauterine infection as the bacterium was found in fetal blood and lung tissue cultures. Placental pathology showed severe AC, chorionic vasculitis, and funisitis. Fetal autopsy showed clusters of neutrophils and bacteria both in the lungs and in the lumen of the gastrointestinal tract. The patient was admitted to the hospital with PPROM, but she had no vaginal bleeding before, and no fever prior to or during the admission. She also denied respiratory or urinary infections for the duration of her pregnancy.
In our case, the patient was admitted for threatened abortion at 18 wga +1 day with no fever. Although she underwent antibiotic treatment (ampicillin and azithromycin for 2 days, and then amoxicillin/clavulanic acid for 5 days), IUFD was diagnosed at 19 wga + 5 days. Ampicillin and gentamicin were started. Three days after IUFD, the patient was feverish (37.8 °C) with high CRP. Fever and elevated CRP persisted for another 7 days. However, maternal blood and urine cultures were negative. First, antibiotic therapy was modified with amoxicillin/clavulanic acid with no results. Then, after 6 days since IUFD, postmortem fetal lung and blood cultures identified K. pneumoniae, β-lactamase-non-producing strain. The antibiogram showed sensitivity for amoxicillin/clavulanic acid, gentamicin, piperacillin/tazobactam; and resistance to ampicillin. Then, accordingly to these findings and 7 days after IUFD, medical treatment was replaced with piperacillin/tazobactam with complete symptom resolution and CRP reduction.
Similarly to Torabi’s case [14], placental examination showed severe AC and funisitis. Neutrophils and rod-shaped bacteria were found in fetal lungs and in the lumen of the gastrointestinal tract.
In the management of our case, microbiological cultures on fetal blood and lung tissue, including the antibiogram, were of paramount importance in identifying K. pneumoniae as the etiologic agent, and mother’s medical treatment was then changed accordingly.
However, to date, PPROM and IUFD due to K. pneumoniae have been scarcely reported. One main reason may be attributed to the lack of submitting fetal tissues for microbiological studies.
Although microbiological studies are always recommended in case of PPROM as indicated in the perinatal autopsy protocol, in common practice only fetal autopsies carried out by dedicated perinatal pathologists are performed correctly, including ancillary studies [9].
Another cause may be failure in microbiological culture, as bacteria could not grow or they may be difficult to cultivate [29].
It must be taken into account that AC may be clinically silent and the hallmark for diagnosis relies on placental histological examination [30]. In our specific case, AC and fetal infection were observed, including rod-shaped bacteria. Microbiological cultures on postmortem fetal blood and tissues, and subsequent antibiogram, grew K. pneumoniae and provided the correct maternal treatment.
In the case we described, K. pneumoniae, acquired as ascending infection, determined AC. However, bacterial specific source remained undetermined. The mother denied previous urinary or respiratory infections. In humans, K. pneumoniae is a saprophyte in the nasopharynx and in the intestinal tract. Carrier rates are variable, but isolation from stools is usually higher [22]. Carrier rates typically worsen in a hospital environment. Reported carrier rates in hospitalized patients are 77% in the stool, 19% in the pharynx, and 42% on the hands of patients. The high rates detected in hospital settings are usually associated with antibiotic therapy and progressively increase with the length of stay [20]. It is only a speculation that in our case, AC might have occurred during the hospital stay as a consequence of carrier exacerbation.
Therefore, in the event of PPROM leading to a miscarriage, microbiological cultures on fetal blood and tissues should be mandatory, in order to find the right etiologic agent, and consequent antibiotic therapy.
By and large, appropriate management of clinical chorioamnionitis has been recently reviewed by a workshop of experts [31,32]. The effort has been made to improve maternal and fetal/neonatal wellbeing in order to reduce overall morbidity and unnecessary antibiotic treatment.
First, the term “chorioamnionitis”, in a clinical setting, should be avoided and restricted to the histopathological diagnosis of amniochorial membrane inflammation and/or funisitis. Instead, the new concept of “Triple I” is introduced to indicate “Intrauterine Inflammation or Infection or both”.
Triple I is diagnosed when there is maternal fever with one or more of the following: (1) fetal tachycardia (>160 bpm for 10 min or longer); (2) maternal WBC >15,000 in absence of corticosteroid; (3) purulent fluid from the cervical or confirmed visually on speculum; (4) biochemical or microbiologic amniotic fluid (AF) consistent with amniotic infection.
Triple I should be further classified as “suspected” or “confirmed”. Triple I confirmation requires evidence of infection either in AF (positive Gram stain for bacteria, low AF glucose, high WBC count in the absence of a bloody tap, or positive AF culture results) or in placental histopathological examination (e.g., chorioamnionitis and/or funisitis). Without the previous criteria, Triple I remains as “suspected” or “isolated maternal fever”, the latter categorized as “not Triple I”. There is still controversy regarding reliable antenatal and postnatal biomarkers able to accurately detect the neonatal risk for early onset sepsis (EOS). For example, prenatal dosage of IL-6 value seems promising in assessing the severity of intrauterine infection. The hallmark for EOS still relies on neonatal blood cultures, however they can be biased by false-negative or false-positive results. Moreover, a close communication has been recommended between the obstetric and neonatal team about maternal and fetal/neonatal conditions, e.g., confirmation of Triple I, maternal antibiotic or antipyretic treatment, to name a few.
Triple I may have potential complications such as postpartum hemorrhage, wound infection, and endomyometritis [33]. Antimicrobial treatment depends on Triple I features; however, a wide spectrum therapy with ampicillin and gentamicin is usually given. In case of cesarean section, clindamycin or metronidazole should be added to cover anaerobic pathogens. Bacteremia, sepsis, and persistent fever will be taken into account to determine the duration of treatment. Newborns at risk of EOS tend to receive antibiotics for almost 5 days; conversely it is still debated in wellbeing infants if the treatment is necessary for more than 48 h.
However, a close communication between the obstetric and neonatal teams is paramount for a correct management of maternal and fetal/neonatal health care. In this context, placental examination plays a key role either in identifying the microorganism through tissue cultures or histologically confirming a Triple I [31,32].
Consequently, a good interaction between pathologists and clinicians must also be put in place, as happened in the case we described, in which isolation of K. pneumoniae in fetal blood and tissues, helped to change maternal antibiotic treatment.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
M.P.B. carried out the diagnosis and wrote the manuscript—original draft preparation, review, and editing; A.P. provided the histological pictures; G.D.D. provided the draft preparation; G.C. clinically managed the patient; P.N., L.V., G.R., M.B., and E.C. carried out the microbiological diagnosis. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Our investigations were carried out following the rules of the Declaration of Helsinki of 1975, revised in 2013. According to Italian legislation, Ethical Approval for a single case is not required, as long as the data are kept anonymous and the investigations performed do not imply genetic results.
Informed Consent Statement
The current Italian legislation neither requires the family’s consent or ethical approval for a single case, as long as the data are strictly kept anonymous. Because summoning the parents was not possible as it would have badly interfered with the grieving process, parents’ consent was completely waived, according to the Italian Authority of Privacy and Data Protection ("Garante della Privacy": GDPR nr 679/2016; 9/2016 and recent law addition number 424/ 19th of July 2018; http://www.garanteprivacy.it).
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Fetal lung: a few intra-alveolar neutrophils (red arrow) associated with rod-shaped bacteria (blue arrow) (HE staining 20×).
Figure 2 Fetal small intestine: intestinal lumen filled with mucus (HE staining 4×). In the mucoid material (frame) there were neutrophils (blue arrows) intermixed with abundant clusters of rod-shaped bacteria (HE staining 20×).
Figure 3 Pancreatic acini with interacinar edema (red stars) (HE staining 4×).
Figure 4 Amniochorial membranes: severe acute chorioamnionitis with focal amnion necrosis (between blue arrows) (HE staining 10×).
Figure 5 Umbilical vein acute flebitis: the umbilical vein showed acute parietal inflammation (red star) with extension to the Wharton’s jelly (blue arrow) (HE staining 20×).
microorganisms-09-00096-t001_Table 1Table 1 Klebsiella pneumoniae antibiogram. MIC: minimum inhibitory concentration.
Antibiotic MIC µg/mL Resistance/Susceptibility
amikacin <=4 S
amoxicillin/clavulanic acid <4/4 S
ampicillin >8 R
aztreonam <=1 S
cefepime <=1 S
ceftazidime <=0.5 S
ceftriaxone <=0.5 S
ciprofloxacin <=0.25 S
colistin 0.5 S
ertapenem <=0.25 S
fosfomycin 32 S
gentamicin <=1 S
imipenem 0.5 S
levofloxacin <=0.5 S
meropenem <=0.125 S
piperacillin/tazobactam <4/4 S
tobramicyn <=1 S
trimethoprim/sulfamethoxazole <=1/19 S | Transplacental | DrugAdministrationRoute | CC BY | 33401648 | 19,583,466 | 2021-01-03 |
What was the outcome of reaction 'Foetal death'? | Klebsiella pneumoniae Chorioamnionitis: An Underrecognized Cause of Preterm Premature Rupture of Membranes in the Second Trimester.
Klebsiella pneumoniae is a Gram-negative, rod-shaped bacterium, responsible for hospital and community acquired pneumonia, urinary tract and wound infections, and bloodstream dissemination. K. pneumoniae infection in pregnancy, leading to acute chorioamnionitis (AC), preterm premature rupture of membranes (PPROM) and early pregnancy loss in the second trimester, has been rarely reported. Herein, we present a case of K. pneumoniae AC that caused intrauterine fetal demise (IUFD) at 19 weeks + 5 days. The 36-year-old mother was admitted at 18 weeks + 1 day of gestation for threatened abortion. IUFD occurred 11 days after. Fetal postmortem showed severe AC and funisitis, neutrophils within alveoli and intestinal lumen, associated with rod-like bacteria. Fetal blood and lung cultures grew K. pneumoniae, β-lactamase-non-producing strain. Antibiogram revealed sensitivity for piperacillin/tazobactam. Three days after IUFD, the mother presented with fever (37.8 °C) which persisted for one week. Maternal blood and urine cultures were negative. According to fetal microbiological results, available 6 days after IUFD, initial treatment with amoxicillin/clavulanic acid was replaced with piperacillin/tazobactam with full patient recovery. Therefore, in the event of PPROM and IUFD, fetal microbiological investigations should always be performed to isolate the proper etiologic agent and start the correct medical treatment.
1. Introduction
Acute chorioamnionitis (AC) is defined as infiltration of neutrophils within placental chorionic plate and amniochorial membranes, usually due to ascending infection [1,2]. Although AC often occurs as subclinical condition, diagnosed only by placental histological examination [3], bacterial infection of the amniotic cavity is the main cause of preterm premature rupture of membranes (PPROM) leading to preterm delivery, respiratory distress, sepsis, and occasionally fetal/neonatal death [4,5,6,7,8]. Moreover, AC is a high risk factor for neonatal necrotising enterocolitis (NEC), retinopathy of prematurity (ROP), poor long-term neurologic outcome, and cerebral palsy [4,5,6,7,8]. The main microorganisms responsible for AC are group B Streptococcus, Fusobacterium nucleatum, Peptostreptococcus, Escherichia coli, Bacteroides species, Ureaplasma urealyticum, and Listeria monocytogenes [1,2]. The gold standard for AC diagnosis remains placental examination. [6]. However, microorganism identification, and subsequent antibiogram, relies on fetal blood and tissue cultures, placental subchorionic fibrin swab, and parenchymal cultures [9,10,11].
To date, intrauterine infection and fetal demise due to K. pneumoniae has been described in only three cases. All of them were second trimester pregnancies presented with PPROM and early pregnancy loss [12,13,14].
Herein, we report a new case of AC due to K. pneumoniae leading to fetal death at 19 weeks + 5 days of gestation. Infection was confirmed by fetal blood and tissue microbiological cultures. We also discuss maternal clinical presentation and antibiotic treatment.
2. Case Description
2.1. Mother Clinical Presentation and Treatment
A 36-year-old woman was admitted to our Institution for threatened abortion at 18 weeks + 1 day of gestation (wga) and treated with antibiotics according to international PPROM guidelines [15]. The treatment consisted of ampicillin and azithromycin for 2 days, then replaced with amoxicillin/clavulanic acid for 5 days. The patient was carefully monitored, but at day 11 after hospital admission, transabdominal ultrasound (US) revealed intrauterine fetal death (IUFD) associated with oligohydramnios. Labor was induced and a male stillborn was vaginally delivered after 36 h.
At day 12 after admission, the patient was treated with ampicillin and gentamicin.
At day 14, the patient presented with fever (37.8 °C) and elevated C-reactive protein (CRP) of 11.10 mg/dL, however blood and urine culture were negative.
At day 16, due to fever persistence and increased CRP of 17.56 mg/dL, antibiotic therapy was modified with amoxicillin/clavulanic acid.
At day 18, as the patient was still feverish with high CRP (12.06 mg/dL), the previous therapy was suspended and replaced with piperacillin/tazobactam.
The patient fully recovered with fever remission and CRP reduction, and after 3 days without fever, she was discharged (day 21).
2.2. Fetal Autopsy and Microbiological Results
IUFD was diagnosed 11 days after the patient’s admission, corresponding approximately to a gestational age of 19 weeks + 5 days.
Postmortem examination revealed a nonmacerated fetus weighing 240 g and measuring 24.5 cm in crown–heel length. The other measurements were as follows: crown–rump length 17.5 cm; foot length 3 cm; head, chest, and abdominal circumference 16 cm, 13 cm, and 12.5 cm, respectively. Overall, anthropometric measurements were consistent with 19 weeks’ gestation [16]. External examination showed a normal male fetus with mild facial and nuchal oedema. Internal examination disclosed minimal pleural and abdominal serous effusions and organ congestion. No congenital anomalies were found.
At microscopy, lungs displayed mild pneumonia with focal intra-alveolar neutrophils associated with rod-like bacteria (Figure 1). Neutrophils and rod-like bacteria were similarly observed in the lumen of the gastrointestinal tract (Figure 2). No other significant histological findings were noted except for mild pancreatic oedema (Figure 3).
Postmortem lung and blood cultures were processed according to routine procedures on selective media. Identification was performed by MALDI-ToF MS (MALDI Biotyper, Bruker Daltonik GmbH, D-28359, Bremen, Germany), while for susceptibility testing, the Phoenix 100™ system was used (Becton, Dickinson and Company, Franklin Lakes, NJ, USA) and agar diffusion (Kirby–Bauer method, according to EUCAST rules).
The isolate was identified as K. pneumoniae ssp. pneumoniae. Further phenotypical test, performed according to Brisse et al., allowed for setting the isolate in the K. pneumoniae phylogroup KpI [17].
The isolate’s susceptibility profile revealed a wild-type phenotype, being susceptible to all the antibiotics tested, except for the intrinsic resistances (Intrinsic_Resistance_and_Unusual_Phenotypes_Tables_v3.2_20200225 in https://www.eucast.org/expert_rules_and_intrinsic_resistance). No ESBL, AmpC, or carbapenemase resistance traits were phenotypically documented, according to EUCAST rules EUCAST_detection_of_resistance_mechanisms_170711, in https://www.eucast.org/resistance_mechanisms).
On blood agar, the isolate did not show the hypermucoviscosity (HMV) phenomenon, as demonstrated by the negativity on the string test, where a standard bacteriological loop was used to stretch a mucoviscous string from the bacterial colony [18].
The antibiogram revealed sensitivity for amoxicillin/clavulanic acid, gentamicin, piperacillin/tazobactam; and resistance to ampicillin (Table 1).
Microbiological results approximately arrived after 17 days of patient’s hospital admission and communicated to the clinicians. As the patient was still feverish with elevated CRP, the treatment was changed accordingly from amoxicillin/clavulanic acid to piperacillin/tazobactam.
The placenta was received fragmented and weighed 139 g. Macroscopically, recognizable strands of membranes were yellowish and opaque. Microscopically, there was severe chorioamnionitis with focal amnion necrosis (Figure 4) corresponding to a maternal inflammatory response stage 3/3 and grade 2/2 [19]. Bacterial organisms were noted at high magnification. Funisitis was also observed with neutrophilic infiltrate of the umbilical vein, one artery, and extension to Wharton’s jelly (Figure 5). These findings were consistent with fetal inflammatory response stage 2/3 and grade 2/2 [19].
The placental parenchyma was normally developed for second trimester, with mesenchymal and immature intermediate villi. Multifocal villous oedema was also identified. The decidua showed diffuse acute necrotizing deciduitis and focal laminar necrosis.
3. Materials and Methods
We searched for ((chorioamnionitis OR ((placenta OR placental) AND (infection OR inflammation)) OR PROM OR “premature rupture of membranes”) AND K. pneumoniae in Pubmed (all fields, 55 results), Scopus (Title/Abstract/Keywords, 15 results), and Web of Science (Topic/Title, 25 results) databases. No limitations were set. Titles and abstract of the results were screened to identify relevant articles. All relevant papers were obtained in full-text format and screened for additional references. The bibliographic research ended on 1 October 2020: three papers were finally included.
4. Discussion
K. pneumoniae is a Gram-negative, rod-shaped bacterium belonging to the family of Enterobacteriaceae, involved in hospital and community-acquired bacterial pneumonia, urinary tract, and wound infections [20,21].
K. pneumoniae represents the main cause of hospital-acquired infections (HAI), and as an opportunistic pathogen, typically induces infections in hospitalized or immunocompromised patients.
Behind Clostridium difficile and Staphylococcus aureus, K. pneumoniae is the third main pathogen responsible for HAI, defined as the onset of pneumonia in ≥48 h after hospital admission [22]. Mortality rate in K. pneumoniae pneumonia is high, reaching 50% [20].
Community-acquired K. pneumoniae pneumonia is usually severe, panlobar, and often diagnosed in chronic alcoholics, attributed to aspiration of gastric contents. This kind of pneumonia is also known as ‘‘Friedlander’s pneumonia’’ characterized by radiographic alterations due to severe pyogenic infection [23]. Urinary tract is often infected by K. pneumoniae, especially in patients with diabetes mellitus or neuropathic bladder, mainly occurring in a nosocomial setting [20,21]. A typical complication is catheter-associated urinary tract infections (CAUTIs) due to the bacterium ability for building biofilms and adhering to catheters [24].
K. pneumoniae may also colonize wound/surgical sites, representing almost 13% of all the infections caused.
K. pneumoniae is the second cause of bloodstream infections (BSI), triggered by Gram-negative bacteria, behind only to Escherichia coli [20,21,22].
BSI may be hospital acquired or occurring in a community setting. In the first situation, cancer is the main underlying disease. Instead, diabetes mellitus and chronic hepatic conditions are typically found in the community [25]. Bacteremia is usually caused by a secondary dissemination from a known site of infection. Typical sources include the urinary and gastrointestinal tract, intravenous or urinary catheters, and respiratory localization [26].
In the neonatal population, K. pneumoniae infection can be responsible for neonatal sepsis and meningitis and may affect premature infants and spread within pediatric wards [20,27,28].
However, to the best of our knowledge, intrauterine fetal death due to K. pneumoniae infection has been reported only in three cases [12,13,14].
Sheikh et al. [12] described a case of IUFD at 18 weeks of gestation. AC and acute villitis were found in the placenta. K. pneumoniae was isolated in maternal blood and placental cultures. Fetal autopsy was not performed. The mother was admitted to the hospital with high temperature (41 °C) and malodorous vaginal discharge. The patient had also vaginal bleeding since one day before the admission.
The PPROM presented by Omwandho et al. [13] was a spontaneous miscarriage at 15 weeks. The mother had a threatened miscarriage at 12th week of gestation with light vaginal bleeding, but then she completely recovered after staying in bed. However, at 15th week, US showed IUFD. Placental cultures were positive for K. pneumoniae, but no pathology was seen in the placenta. Fetal autopsy was also negative for infection or inflammation. Nevertheless, the authors attributed the fetal demise to K. pneumoniae placental microbiological finding. The husband suffered from K. pneumoniae prostatitis and likely infected his wife.
Torabi et al. reported [14] PPROM and IUFD at 20 weeks of gestation due to K. pneumoniae intrauterine infection as the bacterium was found in fetal blood and lung tissue cultures. Placental pathology showed severe AC, chorionic vasculitis, and funisitis. Fetal autopsy showed clusters of neutrophils and bacteria both in the lungs and in the lumen of the gastrointestinal tract. The patient was admitted to the hospital with PPROM, but she had no vaginal bleeding before, and no fever prior to or during the admission. She also denied respiratory or urinary infections for the duration of her pregnancy.
In our case, the patient was admitted for threatened abortion at 18 wga +1 day with no fever. Although she underwent antibiotic treatment (ampicillin and azithromycin for 2 days, and then amoxicillin/clavulanic acid for 5 days), IUFD was diagnosed at 19 wga + 5 days. Ampicillin and gentamicin were started. Three days after IUFD, the patient was feverish (37.8 °C) with high CRP. Fever and elevated CRP persisted for another 7 days. However, maternal blood and urine cultures were negative. First, antibiotic therapy was modified with amoxicillin/clavulanic acid with no results. Then, after 6 days since IUFD, postmortem fetal lung and blood cultures identified K. pneumoniae, β-lactamase-non-producing strain. The antibiogram showed sensitivity for amoxicillin/clavulanic acid, gentamicin, piperacillin/tazobactam; and resistance to ampicillin. Then, accordingly to these findings and 7 days after IUFD, medical treatment was replaced with piperacillin/tazobactam with complete symptom resolution and CRP reduction.
Similarly to Torabi’s case [14], placental examination showed severe AC and funisitis. Neutrophils and rod-shaped bacteria were found in fetal lungs and in the lumen of the gastrointestinal tract.
In the management of our case, microbiological cultures on fetal blood and lung tissue, including the antibiogram, were of paramount importance in identifying K. pneumoniae as the etiologic agent, and mother’s medical treatment was then changed accordingly.
However, to date, PPROM and IUFD due to K. pneumoniae have been scarcely reported. One main reason may be attributed to the lack of submitting fetal tissues for microbiological studies.
Although microbiological studies are always recommended in case of PPROM as indicated in the perinatal autopsy protocol, in common practice only fetal autopsies carried out by dedicated perinatal pathologists are performed correctly, including ancillary studies [9].
Another cause may be failure in microbiological culture, as bacteria could not grow or they may be difficult to cultivate [29].
It must be taken into account that AC may be clinically silent and the hallmark for diagnosis relies on placental histological examination [30]. In our specific case, AC and fetal infection were observed, including rod-shaped bacteria. Microbiological cultures on postmortem fetal blood and tissues, and subsequent antibiogram, grew K. pneumoniae and provided the correct maternal treatment.
In the case we described, K. pneumoniae, acquired as ascending infection, determined AC. However, bacterial specific source remained undetermined. The mother denied previous urinary or respiratory infections. In humans, K. pneumoniae is a saprophyte in the nasopharynx and in the intestinal tract. Carrier rates are variable, but isolation from stools is usually higher [22]. Carrier rates typically worsen in a hospital environment. Reported carrier rates in hospitalized patients are 77% in the stool, 19% in the pharynx, and 42% on the hands of patients. The high rates detected in hospital settings are usually associated with antibiotic therapy and progressively increase with the length of stay [20]. It is only a speculation that in our case, AC might have occurred during the hospital stay as a consequence of carrier exacerbation.
Therefore, in the event of PPROM leading to a miscarriage, microbiological cultures on fetal blood and tissues should be mandatory, in order to find the right etiologic agent, and consequent antibiotic therapy.
By and large, appropriate management of clinical chorioamnionitis has been recently reviewed by a workshop of experts [31,32]. The effort has been made to improve maternal and fetal/neonatal wellbeing in order to reduce overall morbidity and unnecessary antibiotic treatment.
First, the term “chorioamnionitis”, in a clinical setting, should be avoided and restricted to the histopathological diagnosis of amniochorial membrane inflammation and/or funisitis. Instead, the new concept of “Triple I” is introduced to indicate “Intrauterine Inflammation or Infection or both”.
Triple I is diagnosed when there is maternal fever with one or more of the following: (1) fetal tachycardia (>160 bpm for 10 min or longer); (2) maternal WBC >15,000 in absence of corticosteroid; (3) purulent fluid from the cervical or confirmed visually on speculum; (4) biochemical or microbiologic amniotic fluid (AF) consistent with amniotic infection.
Triple I should be further classified as “suspected” or “confirmed”. Triple I confirmation requires evidence of infection either in AF (positive Gram stain for bacteria, low AF glucose, high WBC count in the absence of a bloody tap, or positive AF culture results) or in placental histopathological examination (e.g., chorioamnionitis and/or funisitis). Without the previous criteria, Triple I remains as “suspected” or “isolated maternal fever”, the latter categorized as “not Triple I”. There is still controversy regarding reliable antenatal and postnatal biomarkers able to accurately detect the neonatal risk for early onset sepsis (EOS). For example, prenatal dosage of IL-6 value seems promising in assessing the severity of intrauterine infection. The hallmark for EOS still relies on neonatal blood cultures, however they can be biased by false-negative or false-positive results. Moreover, a close communication has been recommended between the obstetric and neonatal team about maternal and fetal/neonatal conditions, e.g., confirmation of Triple I, maternal antibiotic or antipyretic treatment, to name a few.
Triple I may have potential complications such as postpartum hemorrhage, wound infection, and endomyometritis [33]. Antimicrobial treatment depends on Triple I features; however, a wide spectrum therapy with ampicillin and gentamicin is usually given. In case of cesarean section, clindamycin or metronidazole should be added to cover anaerobic pathogens. Bacteremia, sepsis, and persistent fever will be taken into account to determine the duration of treatment. Newborns at risk of EOS tend to receive antibiotics for almost 5 days; conversely it is still debated in wellbeing infants if the treatment is necessary for more than 48 h.
However, a close communication between the obstetric and neonatal teams is paramount for a correct management of maternal and fetal/neonatal health care. In this context, placental examination plays a key role either in identifying the microorganism through tissue cultures or histologically confirming a Triple I [31,32].
Consequently, a good interaction between pathologists and clinicians must also be put in place, as happened in the case we described, in which isolation of K. pneumoniae in fetal blood and tissues, helped to change maternal antibiotic treatment.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
M.P.B. carried out the diagnosis and wrote the manuscript—original draft preparation, review, and editing; A.P. provided the histological pictures; G.D.D. provided the draft preparation; G.C. clinically managed the patient; P.N., L.V., G.R., M.B., and E.C. carried out the microbiological diagnosis. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Our investigations were carried out following the rules of the Declaration of Helsinki of 1975, revised in 2013. According to Italian legislation, Ethical Approval for a single case is not required, as long as the data are kept anonymous and the investigations performed do not imply genetic results.
Informed Consent Statement
The current Italian legislation neither requires the family’s consent or ethical approval for a single case, as long as the data are strictly kept anonymous. Because summoning the parents was not possible as it would have badly interfered with the grieving process, parents’ consent was completely waived, according to the Italian Authority of Privacy and Data Protection ("Garante della Privacy": GDPR nr 679/2016; 9/2016 and recent law addition number 424/ 19th of July 2018; http://www.garanteprivacy.it).
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Fetal lung: a few intra-alveolar neutrophils (red arrow) associated with rod-shaped bacteria (blue arrow) (HE staining 20×).
Figure 2 Fetal small intestine: intestinal lumen filled with mucus (HE staining 4×). In the mucoid material (frame) there were neutrophils (blue arrows) intermixed with abundant clusters of rod-shaped bacteria (HE staining 20×).
Figure 3 Pancreatic acini with interacinar edema (red stars) (HE staining 4×).
Figure 4 Amniochorial membranes: severe acute chorioamnionitis with focal amnion necrosis (between blue arrows) (HE staining 10×).
Figure 5 Umbilical vein acute flebitis: the umbilical vein showed acute parietal inflammation (red star) with extension to the Wharton’s jelly (blue arrow) (HE staining 20×).
microorganisms-09-00096-t001_Table 1Table 1 Klebsiella pneumoniae antibiogram. MIC: minimum inhibitory concentration.
Antibiotic MIC µg/mL Resistance/Susceptibility
amikacin <=4 S
amoxicillin/clavulanic acid <4/4 S
ampicillin >8 R
aztreonam <=1 S
cefepime <=1 S
ceftazidime <=0.5 S
ceftriaxone <=0.5 S
ciprofloxacin <=0.25 S
colistin 0.5 S
ertapenem <=0.25 S
fosfomycin 32 S
gentamicin <=1 S
imipenem 0.5 S
levofloxacin <=0.5 S
meropenem <=0.125 S
piperacillin/tazobactam <4/4 S
tobramicyn <=1 S
trimethoprim/sulfamethoxazole <=1/19 S | Fatal | ReactionOutcome | CC BY | 33401648 | 19,583,466 | 2021-01-03 |
What was the outcome of reaction 'Foetal exposure during pregnancy'? | Klebsiella pneumoniae Chorioamnionitis: An Underrecognized Cause of Preterm Premature Rupture of Membranes in the Second Trimester.
Klebsiella pneumoniae is a Gram-negative, rod-shaped bacterium, responsible for hospital and community acquired pneumonia, urinary tract and wound infections, and bloodstream dissemination. K. pneumoniae infection in pregnancy, leading to acute chorioamnionitis (AC), preterm premature rupture of membranes (PPROM) and early pregnancy loss in the second trimester, has been rarely reported. Herein, we present a case of K. pneumoniae AC that caused intrauterine fetal demise (IUFD) at 19 weeks + 5 days. The 36-year-old mother was admitted at 18 weeks + 1 day of gestation for threatened abortion. IUFD occurred 11 days after. Fetal postmortem showed severe AC and funisitis, neutrophils within alveoli and intestinal lumen, associated with rod-like bacteria. Fetal blood and lung cultures grew K. pneumoniae, β-lactamase-non-producing strain. Antibiogram revealed sensitivity for piperacillin/tazobactam. Three days after IUFD, the mother presented with fever (37.8 °C) which persisted for one week. Maternal blood and urine cultures were negative. According to fetal microbiological results, available 6 days after IUFD, initial treatment with amoxicillin/clavulanic acid was replaced with piperacillin/tazobactam with full patient recovery. Therefore, in the event of PPROM and IUFD, fetal microbiological investigations should always be performed to isolate the proper etiologic agent and start the correct medical treatment.
1. Introduction
Acute chorioamnionitis (AC) is defined as infiltration of neutrophils within placental chorionic plate and amniochorial membranes, usually due to ascending infection [1,2]. Although AC often occurs as subclinical condition, diagnosed only by placental histological examination [3], bacterial infection of the amniotic cavity is the main cause of preterm premature rupture of membranes (PPROM) leading to preterm delivery, respiratory distress, sepsis, and occasionally fetal/neonatal death [4,5,6,7,8]. Moreover, AC is a high risk factor for neonatal necrotising enterocolitis (NEC), retinopathy of prematurity (ROP), poor long-term neurologic outcome, and cerebral palsy [4,5,6,7,8]. The main microorganisms responsible for AC are group B Streptococcus, Fusobacterium nucleatum, Peptostreptococcus, Escherichia coli, Bacteroides species, Ureaplasma urealyticum, and Listeria monocytogenes [1,2]. The gold standard for AC diagnosis remains placental examination. [6]. However, microorganism identification, and subsequent antibiogram, relies on fetal blood and tissue cultures, placental subchorionic fibrin swab, and parenchymal cultures [9,10,11].
To date, intrauterine infection and fetal demise due to K. pneumoniae has been described in only three cases. All of them were second trimester pregnancies presented with PPROM and early pregnancy loss [12,13,14].
Herein, we report a new case of AC due to K. pneumoniae leading to fetal death at 19 weeks + 5 days of gestation. Infection was confirmed by fetal blood and tissue microbiological cultures. We also discuss maternal clinical presentation and antibiotic treatment.
2. Case Description
2.1. Mother Clinical Presentation and Treatment
A 36-year-old woman was admitted to our Institution for threatened abortion at 18 weeks + 1 day of gestation (wga) and treated with antibiotics according to international PPROM guidelines [15]. The treatment consisted of ampicillin and azithromycin for 2 days, then replaced with amoxicillin/clavulanic acid for 5 days. The patient was carefully monitored, but at day 11 after hospital admission, transabdominal ultrasound (US) revealed intrauterine fetal death (IUFD) associated with oligohydramnios. Labor was induced and a male stillborn was vaginally delivered after 36 h.
At day 12 after admission, the patient was treated with ampicillin and gentamicin.
At day 14, the patient presented with fever (37.8 °C) and elevated C-reactive protein (CRP) of 11.10 mg/dL, however blood and urine culture were negative.
At day 16, due to fever persistence and increased CRP of 17.56 mg/dL, antibiotic therapy was modified with amoxicillin/clavulanic acid.
At day 18, as the patient was still feverish with high CRP (12.06 mg/dL), the previous therapy was suspended and replaced with piperacillin/tazobactam.
The patient fully recovered with fever remission and CRP reduction, and after 3 days without fever, she was discharged (day 21).
2.2. Fetal Autopsy and Microbiological Results
IUFD was diagnosed 11 days after the patient’s admission, corresponding approximately to a gestational age of 19 weeks + 5 days.
Postmortem examination revealed a nonmacerated fetus weighing 240 g and measuring 24.5 cm in crown–heel length. The other measurements were as follows: crown–rump length 17.5 cm; foot length 3 cm; head, chest, and abdominal circumference 16 cm, 13 cm, and 12.5 cm, respectively. Overall, anthropometric measurements were consistent with 19 weeks’ gestation [16]. External examination showed a normal male fetus with mild facial and nuchal oedema. Internal examination disclosed minimal pleural and abdominal serous effusions and organ congestion. No congenital anomalies were found.
At microscopy, lungs displayed mild pneumonia with focal intra-alveolar neutrophils associated with rod-like bacteria (Figure 1). Neutrophils and rod-like bacteria were similarly observed in the lumen of the gastrointestinal tract (Figure 2). No other significant histological findings were noted except for mild pancreatic oedema (Figure 3).
Postmortem lung and blood cultures were processed according to routine procedures on selective media. Identification was performed by MALDI-ToF MS (MALDI Biotyper, Bruker Daltonik GmbH, D-28359, Bremen, Germany), while for susceptibility testing, the Phoenix 100™ system was used (Becton, Dickinson and Company, Franklin Lakes, NJ, USA) and agar diffusion (Kirby–Bauer method, according to EUCAST rules).
The isolate was identified as K. pneumoniae ssp. pneumoniae. Further phenotypical test, performed according to Brisse et al., allowed for setting the isolate in the K. pneumoniae phylogroup KpI [17].
The isolate’s susceptibility profile revealed a wild-type phenotype, being susceptible to all the antibiotics tested, except for the intrinsic resistances (Intrinsic_Resistance_and_Unusual_Phenotypes_Tables_v3.2_20200225 in https://www.eucast.org/expert_rules_and_intrinsic_resistance). No ESBL, AmpC, or carbapenemase resistance traits were phenotypically documented, according to EUCAST rules EUCAST_detection_of_resistance_mechanisms_170711, in https://www.eucast.org/resistance_mechanisms).
On blood agar, the isolate did not show the hypermucoviscosity (HMV) phenomenon, as demonstrated by the negativity on the string test, where a standard bacteriological loop was used to stretch a mucoviscous string from the bacterial colony [18].
The antibiogram revealed sensitivity for amoxicillin/clavulanic acid, gentamicin, piperacillin/tazobactam; and resistance to ampicillin (Table 1).
Microbiological results approximately arrived after 17 days of patient’s hospital admission and communicated to the clinicians. As the patient was still feverish with elevated CRP, the treatment was changed accordingly from amoxicillin/clavulanic acid to piperacillin/tazobactam.
The placenta was received fragmented and weighed 139 g. Macroscopically, recognizable strands of membranes were yellowish and opaque. Microscopically, there was severe chorioamnionitis with focal amnion necrosis (Figure 4) corresponding to a maternal inflammatory response stage 3/3 and grade 2/2 [19]. Bacterial organisms were noted at high magnification. Funisitis was also observed with neutrophilic infiltrate of the umbilical vein, one artery, and extension to Wharton’s jelly (Figure 5). These findings were consistent with fetal inflammatory response stage 2/3 and grade 2/2 [19].
The placental parenchyma was normally developed for second trimester, with mesenchymal and immature intermediate villi. Multifocal villous oedema was also identified. The decidua showed diffuse acute necrotizing deciduitis and focal laminar necrosis.
3. Materials and Methods
We searched for ((chorioamnionitis OR ((placenta OR placental) AND (infection OR inflammation)) OR PROM OR “premature rupture of membranes”) AND K. pneumoniae in Pubmed (all fields, 55 results), Scopus (Title/Abstract/Keywords, 15 results), and Web of Science (Topic/Title, 25 results) databases. No limitations were set. Titles and abstract of the results were screened to identify relevant articles. All relevant papers were obtained in full-text format and screened for additional references. The bibliographic research ended on 1 October 2020: three papers were finally included.
4. Discussion
K. pneumoniae is a Gram-negative, rod-shaped bacterium belonging to the family of Enterobacteriaceae, involved in hospital and community-acquired bacterial pneumonia, urinary tract, and wound infections [20,21].
K. pneumoniae represents the main cause of hospital-acquired infections (HAI), and as an opportunistic pathogen, typically induces infections in hospitalized or immunocompromised patients.
Behind Clostridium difficile and Staphylococcus aureus, K. pneumoniae is the third main pathogen responsible for HAI, defined as the onset of pneumonia in ≥48 h after hospital admission [22]. Mortality rate in K. pneumoniae pneumonia is high, reaching 50% [20].
Community-acquired K. pneumoniae pneumonia is usually severe, panlobar, and often diagnosed in chronic alcoholics, attributed to aspiration of gastric contents. This kind of pneumonia is also known as ‘‘Friedlander’s pneumonia’’ characterized by radiographic alterations due to severe pyogenic infection [23]. Urinary tract is often infected by K. pneumoniae, especially in patients with diabetes mellitus or neuropathic bladder, mainly occurring in a nosocomial setting [20,21]. A typical complication is catheter-associated urinary tract infections (CAUTIs) due to the bacterium ability for building biofilms and adhering to catheters [24].
K. pneumoniae may also colonize wound/surgical sites, representing almost 13% of all the infections caused.
K. pneumoniae is the second cause of bloodstream infections (BSI), triggered by Gram-negative bacteria, behind only to Escherichia coli [20,21,22].
BSI may be hospital acquired or occurring in a community setting. In the first situation, cancer is the main underlying disease. Instead, diabetes mellitus and chronic hepatic conditions are typically found in the community [25]. Bacteremia is usually caused by a secondary dissemination from a known site of infection. Typical sources include the urinary and gastrointestinal tract, intravenous or urinary catheters, and respiratory localization [26].
In the neonatal population, K. pneumoniae infection can be responsible for neonatal sepsis and meningitis and may affect premature infants and spread within pediatric wards [20,27,28].
However, to the best of our knowledge, intrauterine fetal death due to K. pneumoniae infection has been reported only in three cases [12,13,14].
Sheikh et al. [12] described a case of IUFD at 18 weeks of gestation. AC and acute villitis were found in the placenta. K. pneumoniae was isolated in maternal blood and placental cultures. Fetal autopsy was not performed. The mother was admitted to the hospital with high temperature (41 °C) and malodorous vaginal discharge. The patient had also vaginal bleeding since one day before the admission.
The PPROM presented by Omwandho et al. [13] was a spontaneous miscarriage at 15 weeks. The mother had a threatened miscarriage at 12th week of gestation with light vaginal bleeding, but then she completely recovered after staying in bed. However, at 15th week, US showed IUFD. Placental cultures were positive for K. pneumoniae, but no pathology was seen in the placenta. Fetal autopsy was also negative for infection or inflammation. Nevertheless, the authors attributed the fetal demise to K. pneumoniae placental microbiological finding. The husband suffered from K. pneumoniae prostatitis and likely infected his wife.
Torabi et al. reported [14] PPROM and IUFD at 20 weeks of gestation due to K. pneumoniae intrauterine infection as the bacterium was found in fetal blood and lung tissue cultures. Placental pathology showed severe AC, chorionic vasculitis, and funisitis. Fetal autopsy showed clusters of neutrophils and bacteria both in the lungs and in the lumen of the gastrointestinal tract. The patient was admitted to the hospital with PPROM, but she had no vaginal bleeding before, and no fever prior to or during the admission. She also denied respiratory or urinary infections for the duration of her pregnancy.
In our case, the patient was admitted for threatened abortion at 18 wga +1 day with no fever. Although she underwent antibiotic treatment (ampicillin and azithromycin for 2 days, and then amoxicillin/clavulanic acid for 5 days), IUFD was diagnosed at 19 wga + 5 days. Ampicillin and gentamicin were started. Three days after IUFD, the patient was feverish (37.8 °C) with high CRP. Fever and elevated CRP persisted for another 7 days. However, maternal blood and urine cultures were negative. First, antibiotic therapy was modified with amoxicillin/clavulanic acid with no results. Then, after 6 days since IUFD, postmortem fetal lung and blood cultures identified K. pneumoniae, β-lactamase-non-producing strain. The antibiogram showed sensitivity for amoxicillin/clavulanic acid, gentamicin, piperacillin/tazobactam; and resistance to ampicillin. Then, accordingly to these findings and 7 days after IUFD, medical treatment was replaced with piperacillin/tazobactam with complete symptom resolution and CRP reduction.
Similarly to Torabi’s case [14], placental examination showed severe AC and funisitis. Neutrophils and rod-shaped bacteria were found in fetal lungs and in the lumen of the gastrointestinal tract.
In the management of our case, microbiological cultures on fetal blood and lung tissue, including the antibiogram, were of paramount importance in identifying K. pneumoniae as the etiologic agent, and mother’s medical treatment was then changed accordingly.
However, to date, PPROM and IUFD due to K. pneumoniae have been scarcely reported. One main reason may be attributed to the lack of submitting fetal tissues for microbiological studies.
Although microbiological studies are always recommended in case of PPROM as indicated in the perinatal autopsy protocol, in common practice only fetal autopsies carried out by dedicated perinatal pathologists are performed correctly, including ancillary studies [9].
Another cause may be failure in microbiological culture, as bacteria could not grow or they may be difficult to cultivate [29].
It must be taken into account that AC may be clinically silent and the hallmark for diagnosis relies on placental histological examination [30]. In our specific case, AC and fetal infection were observed, including rod-shaped bacteria. Microbiological cultures on postmortem fetal blood and tissues, and subsequent antibiogram, grew K. pneumoniae and provided the correct maternal treatment.
In the case we described, K. pneumoniae, acquired as ascending infection, determined AC. However, bacterial specific source remained undetermined. The mother denied previous urinary or respiratory infections. In humans, K. pneumoniae is a saprophyte in the nasopharynx and in the intestinal tract. Carrier rates are variable, but isolation from stools is usually higher [22]. Carrier rates typically worsen in a hospital environment. Reported carrier rates in hospitalized patients are 77% in the stool, 19% in the pharynx, and 42% on the hands of patients. The high rates detected in hospital settings are usually associated with antibiotic therapy and progressively increase with the length of stay [20]. It is only a speculation that in our case, AC might have occurred during the hospital stay as a consequence of carrier exacerbation.
Therefore, in the event of PPROM leading to a miscarriage, microbiological cultures on fetal blood and tissues should be mandatory, in order to find the right etiologic agent, and consequent antibiotic therapy.
By and large, appropriate management of clinical chorioamnionitis has been recently reviewed by a workshop of experts [31,32]. The effort has been made to improve maternal and fetal/neonatal wellbeing in order to reduce overall morbidity and unnecessary antibiotic treatment.
First, the term “chorioamnionitis”, in a clinical setting, should be avoided and restricted to the histopathological diagnosis of amniochorial membrane inflammation and/or funisitis. Instead, the new concept of “Triple I” is introduced to indicate “Intrauterine Inflammation or Infection or both”.
Triple I is diagnosed when there is maternal fever with one or more of the following: (1) fetal tachycardia (>160 bpm for 10 min or longer); (2) maternal WBC >15,000 in absence of corticosteroid; (3) purulent fluid from the cervical or confirmed visually on speculum; (4) biochemical or microbiologic amniotic fluid (AF) consistent with amniotic infection.
Triple I should be further classified as “suspected” or “confirmed”. Triple I confirmation requires evidence of infection either in AF (positive Gram stain for bacteria, low AF glucose, high WBC count in the absence of a bloody tap, or positive AF culture results) or in placental histopathological examination (e.g., chorioamnionitis and/or funisitis). Without the previous criteria, Triple I remains as “suspected” or “isolated maternal fever”, the latter categorized as “not Triple I”. There is still controversy regarding reliable antenatal and postnatal biomarkers able to accurately detect the neonatal risk for early onset sepsis (EOS). For example, prenatal dosage of IL-6 value seems promising in assessing the severity of intrauterine infection. The hallmark for EOS still relies on neonatal blood cultures, however they can be biased by false-negative or false-positive results. Moreover, a close communication has been recommended between the obstetric and neonatal team about maternal and fetal/neonatal conditions, e.g., confirmation of Triple I, maternal antibiotic or antipyretic treatment, to name a few.
Triple I may have potential complications such as postpartum hemorrhage, wound infection, and endomyometritis [33]. Antimicrobial treatment depends on Triple I features; however, a wide spectrum therapy with ampicillin and gentamicin is usually given. In case of cesarean section, clindamycin or metronidazole should be added to cover anaerobic pathogens. Bacteremia, sepsis, and persistent fever will be taken into account to determine the duration of treatment. Newborns at risk of EOS tend to receive antibiotics for almost 5 days; conversely it is still debated in wellbeing infants if the treatment is necessary for more than 48 h.
However, a close communication between the obstetric and neonatal teams is paramount for a correct management of maternal and fetal/neonatal health care. In this context, placental examination plays a key role either in identifying the microorganism through tissue cultures or histologically confirming a Triple I [31,32].
Consequently, a good interaction between pathologists and clinicians must also be put in place, as happened in the case we described, in which isolation of K. pneumoniae in fetal blood and tissues, helped to change maternal antibiotic treatment.
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Author Contributions
M.P.B. carried out the diagnosis and wrote the manuscript—original draft preparation, review, and editing; A.P. provided the histological pictures; G.D.D. provided the draft preparation; G.C. clinically managed the patient; P.N., L.V., G.R., M.B., and E.C. carried out the microbiological diagnosis. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Our investigations were carried out following the rules of the Declaration of Helsinki of 1975, revised in 2013. According to Italian legislation, Ethical Approval for a single case is not required, as long as the data are kept anonymous and the investigations performed do not imply genetic results.
Informed Consent Statement
The current Italian legislation neither requires the family’s consent or ethical approval for a single case, as long as the data are strictly kept anonymous. Because summoning the parents was not possible as it would have badly interfered with the grieving process, parents’ consent was completely waived, according to the Italian Authority of Privacy and Data Protection ("Garante della Privacy": GDPR nr 679/2016; 9/2016 and recent law addition number 424/ 19th of July 2018; http://www.garanteprivacy.it).
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Fetal lung: a few intra-alveolar neutrophils (red arrow) associated with rod-shaped bacteria (blue arrow) (HE staining 20×).
Figure 2 Fetal small intestine: intestinal lumen filled with mucus (HE staining 4×). In the mucoid material (frame) there were neutrophils (blue arrows) intermixed with abundant clusters of rod-shaped bacteria (HE staining 20×).
Figure 3 Pancreatic acini with interacinar edema (red stars) (HE staining 4×).
Figure 4 Amniochorial membranes: severe acute chorioamnionitis with focal amnion necrosis (between blue arrows) (HE staining 10×).
Figure 5 Umbilical vein acute flebitis: the umbilical vein showed acute parietal inflammation (red star) with extension to the Wharton’s jelly (blue arrow) (HE staining 20×).
microorganisms-09-00096-t001_Table 1Table 1 Klebsiella pneumoniae antibiogram. MIC: minimum inhibitory concentration.
Antibiotic MIC µg/mL Resistance/Susceptibility
amikacin <=4 S
amoxicillin/clavulanic acid <4/4 S
ampicillin >8 R
aztreonam <=1 S
cefepime <=1 S
ceftazidime <=0.5 S
ceftriaxone <=0.5 S
ciprofloxacin <=0.25 S
colistin 0.5 S
ertapenem <=0.25 S
fosfomycin 32 S
gentamicin <=1 S
imipenem 0.5 S
levofloxacin <=0.5 S
meropenem <=0.125 S
piperacillin/tazobactam <4/4 S
tobramicyn <=1 S
trimethoprim/sulfamethoxazole <=1/19 S | Recovered | ReactionOutcome | CC BY | 33401648 | 19,583,466 | 2021-01-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Clostridium difficile colitis'. | Clostridium difficile appendicitis in an immunocompromised patient: a case report and review of the literature.
BACKGROUND
Clostridium difficile (C. difficile) is a common cause of infectious colitis in individuals with prior antibiotic or hospital exposure. Extraintestinal manifestations of C. difficile infections, however, are rare. Here we present a case of C. difficile appendicitis in an immunocompromised patient.
METHODS
A 53-year-old Caucasian male presented to the emergency room for two days of lower abdominal pain associated with nausea and subjective fevers. He otherwise denied having diarrhea or hematochezia. He did not have any recent hospitalizations, nursing home stays, or antibiotic exposure. His past medical history was notable for stage III tonsillar squamous cell carcinoma for which he was status post tonsillectomy, radiation therapy, and chemotherapy (cisplatin 4 days prior to presentation). He was afebrile with tenderness to palpation in the bilateral lower quadrants, right greater than left. His white blood cell (WBC) count was 15.6 × 103 cells/μL. Computed tomography (CT) of the abdomen and pelvis showed marked edema and inflammation of the cecum and ascending colon as well as an enlarged appendix with surrounding inflammatory changes with a small amount of free fluid in the right paracolic gutter. He was treated non-surgically with antibiotics. He did not clinically improve and on hospital day 3, he developed diarrhea for which C. difficile stool polymerase chain reaction was sent. Repeat CT of the abdomen and pelvis was performed which showed progression to pan-colitis and persistent appendicitis. C. difficile testing later resulted positive, for which oral vancomycin was started. The patient markedly improved with medical management alone and was subsequently discharged on oral vancomycin.
CONCLUSIONS
Our case highlights the importance of maintaining a high index of suspicion for C. difficile in a patient presenting with both appendicitis and colitis, with prompt diagnosis and treatment being essential.
Background
Clostridium difficile (C. difficile) is an anaerobic, gram-positive spore-forming bacillus that is commonly found as part of the human colonic flora. It is one of the most common causes of healthcare—associated infections in the United States, with recent estimates suggesting an estimated 450,000 individuals affected annually [1]. While C. difficile infection (CDI) is commonly associated with colitis, extraintestinal manifestations account for just 0.17% of cases, with many of these patients having significant comorbidities, a history of prior antibiotic use, and/or concurrent intestinal involvement [2]. Given the paucity of data, the role of C. difficile in the pathogenesis of extraintestinal infections remains unclear. Here we present a rare case of C. difficile appendicitis in an immunocompromised patient.
Case presentation
A 53-year-old Caucasian male presented to the emergency room for two days of lower abdominal pain associated with nausea, non-bilious vomiting, and subjective fevers. He otherwise denied having diarrhea, hematochezia, melena, or dysuria. He did not have any recent hospitalizations, nursing home stays, or antibiotic exposure. He denied recent travel, sick contacts, or dietary changes. His past medical history is notable for stage III tonsillar squamous cell carcinoma for which he was status post tonsillectomy, radiation therapy, and chemotherapy (cisplatin 4 days prior to presentation).
He was afebrile (36.9 °C) with a pulse of 110 beats per minute and blood pressure of 134/94 mmHg. Physical exam was notable for a non-distended abdomen, tenderness to palpation in the bilateral lower quadrants (right greater than left), and no rebound or guarding.
Laboratory examination was pertinent for a white blood cell (WBC) count of 15.6 × 103 cells/μL (reference range 4.5–10 cells/μL), blood urea nitrogen (BUN) 24 mg/dL (reference range 8–20 mg/dL), creatinine of 1.35 mg/dL (reference range 0.64–1.27 mg/dL), and lactate 2.6 mmol/L (reference range 0.5–2.2 mmol/L). Computed tomography (CT) with contrast of the abdomen and pelvis showed marked edema and inflammation of the cecum and ascending colon as well as an enlarged appendix with surrounding inflammatory changes with a small amount of free fluid in the right paracolic gutter. The patient was fluid resuscitated and started on broad spectrum antibiotics with cefepime and metronidazole. Surgery was consulted due to concern for appendicitis. They deferred surgical intervention given that it was unclear if this represented colitis with secondary inflammation of the appendix rather than a direct appendiceal source. Conservative treatment with antibiotics was recommended with plans for operative management if the patient failed to improve.
On hospital days 1–2, the patient continued to have significant abdominal pain, which started to localize more to the right lower quadrant. He continued to deny any diarrhea and remained afebrile. His WBC count remained elevated, but his creatinine improved after fluids. On hospital day 3, the patient started having diarrhea for which C. difficile testing was sent. Because the patient was not clinically improving, repeat CT of the abdomen and pelvis with contrast (Fig. 1) was performed which showed progression of his colitis, now extending from the cecum to the rectum as well as findings concerning for appendicitis as seen on the prior CT scan. C. difficile testing was positive for which the patient was started on oral vancomycin. On hospital days 4–6, the patient’s symptoms and exam markedly improved with normalization of his WBC count. Surgery continued to recommend non-surgical management given significant clinical improvement with antibiotics alone. The patient was discharged on hospital day 7 with oral vancomycin.Figure 1 Coronal (a) and sagittal (b) CT of the abdomen and pelvis with contrast demonstrating enlargement of the appendix with wall thickening and enhancement (red arrows). Periappendiceal inflammation is also present (yellow arrow)
Discussion
Extraintestinal CDI is rare and has been described in only a limited number of reports. Examples of extraintestinal manifestations that have been reported include bacteremia (with one patient having C. difficile isolated in an abdominal aneurysm), intra-abdominal abscess, peritonitis, cellulitis, reactive arthritis, osteomyelitis, brain abscess, and empyema [2, 3]. Acute appendicitis is another one of the rare extracolonic manifestation of CDI as we have described here in our case. From review of the literature, there have been very few reported cases of C. difficile appendicitis [4-7].
C. difficile has generally been known as a pathogen responsible for colitis, particularly in the setting of prior antibiotic or hospital exposure. Recent chemotherapy is also another important risk factor [8], which was the case in our patient as he was actively undergoing treatment for his tonsillar cancer. It has been hypothesized that the disruption of the gut microbiota allows for the proliferation of toxigenic C. difficile and subsequent infection. C. difficile colitis is a process mediated by bacterial release of Toxins A and B, whose role is to inactivate members of the Rho family of guanosine triphosphatases (GTPases), which leads to colonocyte death, inflammation, and loss of the intestinal epithelial barrier function [9]. The pathogenesis of extraintestinal CDI, however, remains unclear. However, given his concurrent pancolitis, it is likely that direct spread of C. difficile from the intestinal lumen resulted in his appendicitis. This is in opposition to C. difficile isolated from distant sites described in other case series, where it is thought that bacterium enters through blood circulation [2].
Two possible mechanisms for C. difficile appendicitis have been suggested: direct infection from the toxin itself versus obstruction of the appendiceal lumen from the adjacent colitis [5]. It is plausible that both of these processes play a role, as the luminal obstruction can lead to ischemia and compromise of the mucosal barrier, resulting in bacterial invasion of the appendix by intraluminal bacteria [10]. When this occurs, a mix of aerobic and anaerobic organisms, particularly Escherichia coli and Bacteroides spp., are typically implicated [11], as opposed to C. difficile which is exceedingly uncommon as detailed in our case.
We should also note that the role of C. difficile in causing extraintestinal infections have been questioned. One case series showed that many isolates were either part of polymicrobial flora or intra-abdominal fluid collections near the colon in the setting of recent fecal spillage [3]. Furthermore, it has been found that not all extraintestinal C. difficile isolates produce toxins [3], which is essential in the pathogenesis of C. difficile colitis as discussed above (therefore, culture, while the most sensitive test for C. difficile infection [8], has largely been replaced by methods that detect toxigenic strains). While it is certainly possible that the patient’s C. difficile colitis (as confirmed by stool PCR testing) and his appendicitis represented distinct and unrelated processes, the clinical presentation, radiographic features, and overwhelming response to C. difficile directed antibiotic therapy suggests that C. difficile was the most likely underlying etiology.
Given the rarity of C. difficile appendicitis, no specific treatment guidelines exist. We performed a literature review to explore the demographics, management, and outcomes of those with C. difficile appendicitis (see Table 1). Using PubMed, we searched for articles with both keywords of “clostridium difficile” and “appendicitis,” which yielded 25 results. We reviewed each individual article further to ensure that the case report was of appendicitis that was attributable to C. difficile. We reviewed a total of six cases of C. difficile appendicitis and found that none of the patients were immunocompromised. Interestingly, five out of the six cases of C. difficile appendicitis involved patients over 50 years-old. All six patients initially survived; however, one had a recurrent episode leading to septic shock and death. Three patients eventually underwent surgical intervention, two of which survived. Management was not specified in two of the cases. As described above, we, in conjunction with our surgical colleagues, opted for medical therapy alone given the patient’s significant clinical improvement. We should note, however, that given the limited number of reported cases, further studies on optimal treatment is still needed.Table 1 Literature review of cases of C. difficile appendicitis
Author (Year) Age (yo) Gender Immunocompromised Co-Morbidities Treatment Outcome
Garcia-Lechuz et al. (2001) 53 Male No Hypothyroidism Imipenem
Appendectomy
Survived
Brown et al. (2007) 72 Male No COPD Metronidazole
Appendectomy
Survived
Mattila et al. (2013) 97 Female Unknown Breast cancer
Dementia
Unknown Survived
Mattila et al. (2013) 59 Female No Epilepsy Unknown Survived
Ridha et al. (2017) 30 Male No None Metronidazole
Levofloxacin
Oral vancomycin
Survived
Coyne et al. (1997) 76 Female No ESRD on HD 1st episode: Metronidazole
2nd episode (4 weeks later): proctocolectomy
1st episode: Survived
2nd episode: death from septic shock
Conclusions
Acute appendicitis is a rare extraintestinal manifestation of CDI. While the exact pathogenesis remains unclear, its significance cannot be overlooked. Our case highlights the importance of maintaining a high index of suspicion for C. difficile in a patient presenting with both appendicitis and colitis, as prompt diagnosis and treatment are essential.
Abbreviations
C. difficileClostridium difficile
WBCWhite blood cell
CTComputed tomography
BUNBlood urea nitrogen
CDIC. difficile Infection
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors would like to acknowledge the patient for allowing us to share his case with the medical community.
Authors’ contributions
CP and DH both contributed to the data collection, literature review, and drafting of the manuscript. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | CISPLATIN | DrugsGivenReaction | CC BY | 33402156 | 18,799,214 | 2021-01-05 |
What was the administration route of drug 'VANCOMYCIN'? | Clostridium difficile appendicitis in an immunocompromised patient: a case report and review of the literature.
BACKGROUND
Clostridium difficile (C. difficile) is a common cause of infectious colitis in individuals with prior antibiotic or hospital exposure. Extraintestinal manifestations of C. difficile infections, however, are rare. Here we present a case of C. difficile appendicitis in an immunocompromised patient.
METHODS
A 53-year-old Caucasian male presented to the emergency room for two days of lower abdominal pain associated with nausea and subjective fevers. He otherwise denied having diarrhea or hematochezia. He did not have any recent hospitalizations, nursing home stays, or antibiotic exposure. His past medical history was notable for stage III tonsillar squamous cell carcinoma for which he was status post tonsillectomy, radiation therapy, and chemotherapy (cisplatin 4 days prior to presentation). He was afebrile with tenderness to palpation in the bilateral lower quadrants, right greater than left. His white blood cell (WBC) count was 15.6 × 103 cells/μL. Computed tomography (CT) of the abdomen and pelvis showed marked edema and inflammation of the cecum and ascending colon as well as an enlarged appendix with surrounding inflammatory changes with a small amount of free fluid in the right paracolic gutter. He was treated non-surgically with antibiotics. He did not clinically improve and on hospital day 3, he developed diarrhea for which C. difficile stool polymerase chain reaction was sent. Repeat CT of the abdomen and pelvis was performed which showed progression to pan-colitis and persistent appendicitis. C. difficile testing later resulted positive, for which oral vancomycin was started. The patient markedly improved with medical management alone and was subsequently discharged on oral vancomycin.
CONCLUSIONS
Our case highlights the importance of maintaining a high index of suspicion for C. difficile in a patient presenting with both appendicitis and colitis, with prompt diagnosis and treatment being essential.
Background
Clostridium difficile (C. difficile) is an anaerobic, gram-positive spore-forming bacillus that is commonly found as part of the human colonic flora. It is one of the most common causes of healthcare—associated infections in the United States, with recent estimates suggesting an estimated 450,000 individuals affected annually [1]. While C. difficile infection (CDI) is commonly associated with colitis, extraintestinal manifestations account for just 0.17% of cases, with many of these patients having significant comorbidities, a history of prior antibiotic use, and/or concurrent intestinal involvement [2]. Given the paucity of data, the role of C. difficile in the pathogenesis of extraintestinal infections remains unclear. Here we present a rare case of C. difficile appendicitis in an immunocompromised patient.
Case presentation
A 53-year-old Caucasian male presented to the emergency room for two days of lower abdominal pain associated with nausea, non-bilious vomiting, and subjective fevers. He otherwise denied having diarrhea, hematochezia, melena, or dysuria. He did not have any recent hospitalizations, nursing home stays, or antibiotic exposure. He denied recent travel, sick contacts, or dietary changes. His past medical history is notable for stage III tonsillar squamous cell carcinoma for which he was status post tonsillectomy, radiation therapy, and chemotherapy (cisplatin 4 days prior to presentation).
He was afebrile (36.9 °C) with a pulse of 110 beats per minute and blood pressure of 134/94 mmHg. Physical exam was notable for a non-distended abdomen, tenderness to palpation in the bilateral lower quadrants (right greater than left), and no rebound or guarding.
Laboratory examination was pertinent for a white blood cell (WBC) count of 15.6 × 103 cells/μL (reference range 4.5–10 cells/μL), blood urea nitrogen (BUN) 24 mg/dL (reference range 8–20 mg/dL), creatinine of 1.35 mg/dL (reference range 0.64–1.27 mg/dL), and lactate 2.6 mmol/L (reference range 0.5–2.2 mmol/L). Computed tomography (CT) with contrast of the abdomen and pelvis showed marked edema and inflammation of the cecum and ascending colon as well as an enlarged appendix with surrounding inflammatory changes with a small amount of free fluid in the right paracolic gutter. The patient was fluid resuscitated and started on broad spectrum antibiotics with cefepime and metronidazole. Surgery was consulted due to concern for appendicitis. They deferred surgical intervention given that it was unclear if this represented colitis with secondary inflammation of the appendix rather than a direct appendiceal source. Conservative treatment with antibiotics was recommended with plans for operative management if the patient failed to improve.
On hospital days 1–2, the patient continued to have significant abdominal pain, which started to localize more to the right lower quadrant. He continued to deny any diarrhea and remained afebrile. His WBC count remained elevated, but his creatinine improved after fluids. On hospital day 3, the patient started having diarrhea for which C. difficile testing was sent. Because the patient was not clinically improving, repeat CT of the abdomen and pelvis with contrast (Fig. 1) was performed which showed progression of his colitis, now extending from the cecum to the rectum as well as findings concerning for appendicitis as seen on the prior CT scan. C. difficile testing was positive for which the patient was started on oral vancomycin. On hospital days 4–6, the patient’s symptoms and exam markedly improved with normalization of his WBC count. Surgery continued to recommend non-surgical management given significant clinical improvement with antibiotics alone. The patient was discharged on hospital day 7 with oral vancomycin.Figure 1 Coronal (a) and sagittal (b) CT of the abdomen and pelvis with contrast demonstrating enlargement of the appendix with wall thickening and enhancement (red arrows). Periappendiceal inflammation is also present (yellow arrow)
Discussion
Extraintestinal CDI is rare and has been described in only a limited number of reports. Examples of extraintestinal manifestations that have been reported include bacteremia (with one patient having C. difficile isolated in an abdominal aneurysm), intra-abdominal abscess, peritonitis, cellulitis, reactive arthritis, osteomyelitis, brain abscess, and empyema [2, 3]. Acute appendicitis is another one of the rare extracolonic manifestation of CDI as we have described here in our case. From review of the literature, there have been very few reported cases of C. difficile appendicitis [4-7].
C. difficile has generally been known as a pathogen responsible for colitis, particularly in the setting of prior antibiotic or hospital exposure. Recent chemotherapy is also another important risk factor [8], which was the case in our patient as he was actively undergoing treatment for his tonsillar cancer. It has been hypothesized that the disruption of the gut microbiota allows for the proliferation of toxigenic C. difficile and subsequent infection. C. difficile colitis is a process mediated by bacterial release of Toxins A and B, whose role is to inactivate members of the Rho family of guanosine triphosphatases (GTPases), which leads to colonocyte death, inflammation, and loss of the intestinal epithelial barrier function [9]. The pathogenesis of extraintestinal CDI, however, remains unclear. However, given his concurrent pancolitis, it is likely that direct spread of C. difficile from the intestinal lumen resulted in his appendicitis. This is in opposition to C. difficile isolated from distant sites described in other case series, where it is thought that bacterium enters through blood circulation [2].
Two possible mechanisms for C. difficile appendicitis have been suggested: direct infection from the toxin itself versus obstruction of the appendiceal lumen from the adjacent colitis [5]. It is plausible that both of these processes play a role, as the luminal obstruction can lead to ischemia and compromise of the mucosal barrier, resulting in bacterial invasion of the appendix by intraluminal bacteria [10]. When this occurs, a mix of aerobic and anaerobic organisms, particularly Escherichia coli and Bacteroides spp., are typically implicated [11], as opposed to C. difficile which is exceedingly uncommon as detailed in our case.
We should also note that the role of C. difficile in causing extraintestinal infections have been questioned. One case series showed that many isolates were either part of polymicrobial flora or intra-abdominal fluid collections near the colon in the setting of recent fecal spillage [3]. Furthermore, it has been found that not all extraintestinal C. difficile isolates produce toxins [3], which is essential in the pathogenesis of C. difficile colitis as discussed above (therefore, culture, while the most sensitive test for C. difficile infection [8], has largely been replaced by methods that detect toxigenic strains). While it is certainly possible that the patient’s C. difficile colitis (as confirmed by stool PCR testing) and his appendicitis represented distinct and unrelated processes, the clinical presentation, radiographic features, and overwhelming response to C. difficile directed antibiotic therapy suggests that C. difficile was the most likely underlying etiology.
Given the rarity of C. difficile appendicitis, no specific treatment guidelines exist. We performed a literature review to explore the demographics, management, and outcomes of those with C. difficile appendicitis (see Table 1). Using PubMed, we searched for articles with both keywords of “clostridium difficile” and “appendicitis,” which yielded 25 results. We reviewed each individual article further to ensure that the case report was of appendicitis that was attributable to C. difficile. We reviewed a total of six cases of C. difficile appendicitis and found that none of the patients were immunocompromised. Interestingly, five out of the six cases of C. difficile appendicitis involved patients over 50 years-old. All six patients initially survived; however, one had a recurrent episode leading to septic shock and death. Three patients eventually underwent surgical intervention, two of which survived. Management was not specified in two of the cases. As described above, we, in conjunction with our surgical colleagues, opted for medical therapy alone given the patient’s significant clinical improvement. We should note, however, that given the limited number of reported cases, further studies on optimal treatment is still needed.Table 1 Literature review of cases of C. difficile appendicitis
Author (Year) Age (yo) Gender Immunocompromised Co-Morbidities Treatment Outcome
Garcia-Lechuz et al. (2001) 53 Male No Hypothyroidism Imipenem
Appendectomy
Survived
Brown et al. (2007) 72 Male No COPD Metronidazole
Appendectomy
Survived
Mattila et al. (2013) 97 Female Unknown Breast cancer
Dementia
Unknown Survived
Mattila et al. (2013) 59 Female No Epilepsy Unknown Survived
Ridha et al. (2017) 30 Male No None Metronidazole
Levofloxacin
Oral vancomycin
Survived
Coyne et al. (1997) 76 Female No ESRD on HD 1st episode: Metronidazole
2nd episode (4 weeks later): proctocolectomy
1st episode: Survived
2nd episode: death from septic shock
Conclusions
Acute appendicitis is a rare extraintestinal manifestation of CDI. While the exact pathogenesis remains unclear, its significance cannot be overlooked. Our case highlights the importance of maintaining a high index of suspicion for C. difficile in a patient presenting with both appendicitis and colitis, as prompt diagnosis and treatment are essential.
Abbreviations
C. difficileClostridium difficile
WBCWhite blood cell
CTComputed tomography
BUNBlood urea nitrogen
CDIC. difficile Infection
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors would like to acknowledge the patient for allowing us to share his case with the medical community.
Authors’ contributions
CP and DH both contributed to the data collection, literature review, and drafting of the manuscript. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY | 33402156 | 18,870,745 | 2021-01-05 |
What was the dosage of drug 'CISPLATIN'? | Clostridium difficile appendicitis in an immunocompromised patient: a case report and review of the literature.
BACKGROUND
Clostridium difficile (C. difficile) is a common cause of infectious colitis in individuals with prior antibiotic or hospital exposure. Extraintestinal manifestations of C. difficile infections, however, are rare. Here we present a case of C. difficile appendicitis in an immunocompromised patient.
METHODS
A 53-year-old Caucasian male presented to the emergency room for two days of lower abdominal pain associated with nausea and subjective fevers. He otherwise denied having diarrhea or hematochezia. He did not have any recent hospitalizations, nursing home stays, or antibiotic exposure. His past medical history was notable for stage III tonsillar squamous cell carcinoma for which he was status post tonsillectomy, radiation therapy, and chemotherapy (cisplatin 4 days prior to presentation). He was afebrile with tenderness to palpation in the bilateral lower quadrants, right greater than left. His white blood cell (WBC) count was 15.6 × 103 cells/μL. Computed tomography (CT) of the abdomen and pelvis showed marked edema and inflammation of the cecum and ascending colon as well as an enlarged appendix with surrounding inflammatory changes with a small amount of free fluid in the right paracolic gutter. He was treated non-surgically with antibiotics. He did not clinically improve and on hospital day 3, he developed diarrhea for which C. difficile stool polymerase chain reaction was sent. Repeat CT of the abdomen and pelvis was performed which showed progression to pan-colitis and persistent appendicitis. C. difficile testing later resulted positive, for which oral vancomycin was started. The patient markedly improved with medical management alone and was subsequently discharged on oral vancomycin.
CONCLUSIONS
Our case highlights the importance of maintaining a high index of suspicion for C. difficile in a patient presenting with both appendicitis and colitis, with prompt diagnosis and treatment being essential.
Background
Clostridium difficile (C. difficile) is an anaerobic, gram-positive spore-forming bacillus that is commonly found as part of the human colonic flora. It is one of the most common causes of healthcare—associated infections in the United States, with recent estimates suggesting an estimated 450,000 individuals affected annually [1]. While C. difficile infection (CDI) is commonly associated with colitis, extraintestinal manifestations account for just 0.17% of cases, with many of these patients having significant comorbidities, a history of prior antibiotic use, and/or concurrent intestinal involvement [2]. Given the paucity of data, the role of C. difficile in the pathogenesis of extraintestinal infections remains unclear. Here we present a rare case of C. difficile appendicitis in an immunocompromised patient.
Case presentation
A 53-year-old Caucasian male presented to the emergency room for two days of lower abdominal pain associated with nausea, non-bilious vomiting, and subjective fevers. He otherwise denied having diarrhea, hematochezia, melena, or dysuria. He did not have any recent hospitalizations, nursing home stays, or antibiotic exposure. He denied recent travel, sick contacts, or dietary changes. His past medical history is notable for stage III tonsillar squamous cell carcinoma for which he was status post tonsillectomy, radiation therapy, and chemotherapy (cisplatin 4 days prior to presentation).
He was afebrile (36.9 °C) with a pulse of 110 beats per minute and blood pressure of 134/94 mmHg. Physical exam was notable for a non-distended abdomen, tenderness to palpation in the bilateral lower quadrants (right greater than left), and no rebound or guarding.
Laboratory examination was pertinent for a white blood cell (WBC) count of 15.6 × 103 cells/μL (reference range 4.5–10 cells/μL), blood urea nitrogen (BUN) 24 mg/dL (reference range 8–20 mg/dL), creatinine of 1.35 mg/dL (reference range 0.64–1.27 mg/dL), and lactate 2.6 mmol/L (reference range 0.5–2.2 mmol/L). Computed tomography (CT) with contrast of the abdomen and pelvis showed marked edema and inflammation of the cecum and ascending colon as well as an enlarged appendix with surrounding inflammatory changes with a small amount of free fluid in the right paracolic gutter. The patient was fluid resuscitated and started on broad spectrum antibiotics with cefepime and metronidazole. Surgery was consulted due to concern for appendicitis. They deferred surgical intervention given that it was unclear if this represented colitis with secondary inflammation of the appendix rather than a direct appendiceal source. Conservative treatment with antibiotics was recommended with plans for operative management if the patient failed to improve.
On hospital days 1–2, the patient continued to have significant abdominal pain, which started to localize more to the right lower quadrant. He continued to deny any diarrhea and remained afebrile. His WBC count remained elevated, but his creatinine improved after fluids. On hospital day 3, the patient started having diarrhea for which C. difficile testing was sent. Because the patient was not clinically improving, repeat CT of the abdomen and pelvis with contrast (Fig. 1) was performed which showed progression of his colitis, now extending from the cecum to the rectum as well as findings concerning for appendicitis as seen on the prior CT scan. C. difficile testing was positive for which the patient was started on oral vancomycin. On hospital days 4–6, the patient’s symptoms and exam markedly improved with normalization of his WBC count. Surgery continued to recommend non-surgical management given significant clinical improvement with antibiotics alone. The patient was discharged on hospital day 7 with oral vancomycin.Figure 1 Coronal (a) and sagittal (b) CT of the abdomen and pelvis with contrast demonstrating enlargement of the appendix with wall thickening and enhancement (red arrows). Periappendiceal inflammation is also present (yellow arrow)
Discussion
Extraintestinal CDI is rare and has been described in only a limited number of reports. Examples of extraintestinal manifestations that have been reported include bacteremia (with one patient having C. difficile isolated in an abdominal aneurysm), intra-abdominal abscess, peritonitis, cellulitis, reactive arthritis, osteomyelitis, brain abscess, and empyema [2, 3]. Acute appendicitis is another one of the rare extracolonic manifestation of CDI as we have described here in our case. From review of the literature, there have been very few reported cases of C. difficile appendicitis [4-7].
C. difficile has generally been known as a pathogen responsible for colitis, particularly in the setting of prior antibiotic or hospital exposure. Recent chemotherapy is also another important risk factor [8], which was the case in our patient as he was actively undergoing treatment for his tonsillar cancer. It has been hypothesized that the disruption of the gut microbiota allows for the proliferation of toxigenic C. difficile and subsequent infection. C. difficile colitis is a process mediated by bacterial release of Toxins A and B, whose role is to inactivate members of the Rho family of guanosine triphosphatases (GTPases), which leads to colonocyte death, inflammation, and loss of the intestinal epithelial barrier function [9]. The pathogenesis of extraintestinal CDI, however, remains unclear. However, given his concurrent pancolitis, it is likely that direct spread of C. difficile from the intestinal lumen resulted in his appendicitis. This is in opposition to C. difficile isolated from distant sites described in other case series, where it is thought that bacterium enters through blood circulation [2].
Two possible mechanisms for C. difficile appendicitis have been suggested: direct infection from the toxin itself versus obstruction of the appendiceal lumen from the adjacent colitis [5]. It is plausible that both of these processes play a role, as the luminal obstruction can lead to ischemia and compromise of the mucosal barrier, resulting in bacterial invasion of the appendix by intraluminal bacteria [10]. When this occurs, a mix of aerobic and anaerobic organisms, particularly Escherichia coli and Bacteroides spp., are typically implicated [11], as opposed to C. difficile which is exceedingly uncommon as detailed in our case.
We should also note that the role of C. difficile in causing extraintestinal infections have been questioned. One case series showed that many isolates were either part of polymicrobial flora or intra-abdominal fluid collections near the colon in the setting of recent fecal spillage [3]. Furthermore, it has been found that not all extraintestinal C. difficile isolates produce toxins [3], which is essential in the pathogenesis of C. difficile colitis as discussed above (therefore, culture, while the most sensitive test for C. difficile infection [8], has largely been replaced by methods that detect toxigenic strains). While it is certainly possible that the patient’s C. difficile colitis (as confirmed by stool PCR testing) and his appendicitis represented distinct and unrelated processes, the clinical presentation, radiographic features, and overwhelming response to C. difficile directed antibiotic therapy suggests that C. difficile was the most likely underlying etiology.
Given the rarity of C. difficile appendicitis, no specific treatment guidelines exist. We performed a literature review to explore the demographics, management, and outcomes of those with C. difficile appendicitis (see Table 1). Using PubMed, we searched for articles with both keywords of “clostridium difficile” and “appendicitis,” which yielded 25 results. We reviewed each individual article further to ensure that the case report was of appendicitis that was attributable to C. difficile. We reviewed a total of six cases of C. difficile appendicitis and found that none of the patients were immunocompromised. Interestingly, five out of the six cases of C. difficile appendicitis involved patients over 50 years-old. All six patients initially survived; however, one had a recurrent episode leading to septic shock and death. Three patients eventually underwent surgical intervention, two of which survived. Management was not specified in two of the cases. As described above, we, in conjunction with our surgical colleagues, opted for medical therapy alone given the patient’s significant clinical improvement. We should note, however, that given the limited number of reported cases, further studies on optimal treatment is still needed.Table 1 Literature review of cases of C. difficile appendicitis
Author (Year) Age (yo) Gender Immunocompromised Co-Morbidities Treatment Outcome
Garcia-Lechuz et al. (2001) 53 Male No Hypothyroidism Imipenem
Appendectomy
Survived
Brown et al. (2007) 72 Male No COPD Metronidazole
Appendectomy
Survived
Mattila et al. (2013) 97 Female Unknown Breast cancer
Dementia
Unknown Survived
Mattila et al. (2013) 59 Female No Epilepsy Unknown Survived
Ridha et al. (2017) 30 Male No None Metronidazole
Levofloxacin
Oral vancomycin
Survived
Coyne et al. (1997) 76 Female No ESRD on HD 1st episode: Metronidazole
2nd episode (4 weeks later): proctocolectomy
1st episode: Survived
2nd episode: death from septic shock
Conclusions
Acute appendicitis is a rare extraintestinal manifestation of CDI. While the exact pathogenesis remains unclear, its significance cannot be overlooked. Our case highlights the importance of maintaining a high index of suspicion for C. difficile in a patient presenting with both appendicitis and colitis, as prompt diagnosis and treatment are essential.
Abbreviations
C. difficileClostridium difficile
WBCWhite blood cell
CTComputed tomography
BUNBlood urea nitrogen
CDIC. difficile Infection
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors would like to acknowledge the patient for allowing us to share his case with the medical community.
Authors’ contributions
CP and DH both contributed to the data collection, literature review, and drafting of the manuscript. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | UNKNOWN | DrugDosageText | CC BY | 33402156 | 18,799,214 | 2021-01-05 |
What was the outcome of reaction 'Clostridium difficile colitis'? | Clostridium difficile appendicitis in an immunocompromised patient: a case report and review of the literature.
BACKGROUND
Clostridium difficile (C. difficile) is a common cause of infectious colitis in individuals with prior antibiotic or hospital exposure. Extraintestinal manifestations of C. difficile infections, however, are rare. Here we present a case of C. difficile appendicitis in an immunocompromised patient.
METHODS
A 53-year-old Caucasian male presented to the emergency room for two days of lower abdominal pain associated with nausea and subjective fevers. He otherwise denied having diarrhea or hematochezia. He did not have any recent hospitalizations, nursing home stays, or antibiotic exposure. His past medical history was notable for stage III tonsillar squamous cell carcinoma for which he was status post tonsillectomy, radiation therapy, and chemotherapy (cisplatin 4 days prior to presentation). He was afebrile with tenderness to palpation in the bilateral lower quadrants, right greater than left. His white blood cell (WBC) count was 15.6 × 103 cells/μL. Computed tomography (CT) of the abdomen and pelvis showed marked edema and inflammation of the cecum and ascending colon as well as an enlarged appendix with surrounding inflammatory changes with a small amount of free fluid in the right paracolic gutter. He was treated non-surgically with antibiotics. He did not clinically improve and on hospital day 3, he developed diarrhea for which C. difficile stool polymerase chain reaction was sent. Repeat CT of the abdomen and pelvis was performed which showed progression to pan-colitis and persistent appendicitis. C. difficile testing later resulted positive, for which oral vancomycin was started. The patient markedly improved with medical management alone and was subsequently discharged on oral vancomycin.
CONCLUSIONS
Our case highlights the importance of maintaining a high index of suspicion for C. difficile in a patient presenting with both appendicitis and colitis, with prompt diagnosis and treatment being essential.
Background
Clostridium difficile (C. difficile) is an anaerobic, gram-positive spore-forming bacillus that is commonly found as part of the human colonic flora. It is one of the most common causes of healthcare—associated infections in the United States, with recent estimates suggesting an estimated 450,000 individuals affected annually [1]. While C. difficile infection (CDI) is commonly associated with colitis, extraintestinal manifestations account for just 0.17% of cases, with many of these patients having significant comorbidities, a history of prior antibiotic use, and/or concurrent intestinal involvement [2]. Given the paucity of data, the role of C. difficile in the pathogenesis of extraintestinal infections remains unclear. Here we present a rare case of C. difficile appendicitis in an immunocompromised patient.
Case presentation
A 53-year-old Caucasian male presented to the emergency room for two days of lower abdominal pain associated with nausea, non-bilious vomiting, and subjective fevers. He otherwise denied having diarrhea, hematochezia, melena, or dysuria. He did not have any recent hospitalizations, nursing home stays, or antibiotic exposure. He denied recent travel, sick contacts, or dietary changes. His past medical history is notable for stage III tonsillar squamous cell carcinoma for which he was status post tonsillectomy, radiation therapy, and chemotherapy (cisplatin 4 days prior to presentation).
He was afebrile (36.9 °C) with a pulse of 110 beats per minute and blood pressure of 134/94 mmHg. Physical exam was notable for a non-distended abdomen, tenderness to palpation in the bilateral lower quadrants (right greater than left), and no rebound or guarding.
Laboratory examination was pertinent for a white blood cell (WBC) count of 15.6 × 103 cells/μL (reference range 4.5–10 cells/μL), blood urea nitrogen (BUN) 24 mg/dL (reference range 8–20 mg/dL), creatinine of 1.35 mg/dL (reference range 0.64–1.27 mg/dL), and lactate 2.6 mmol/L (reference range 0.5–2.2 mmol/L). Computed tomography (CT) with contrast of the abdomen and pelvis showed marked edema and inflammation of the cecum and ascending colon as well as an enlarged appendix with surrounding inflammatory changes with a small amount of free fluid in the right paracolic gutter. The patient was fluid resuscitated and started on broad spectrum antibiotics with cefepime and metronidazole. Surgery was consulted due to concern for appendicitis. They deferred surgical intervention given that it was unclear if this represented colitis with secondary inflammation of the appendix rather than a direct appendiceal source. Conservative treatment with antibiotics was recommended with plans for operative management if the patient failed to improve.
On hospital days 1–2, the patient continued to have significant abdominal pain, which started to localize more to the right lower quadrant. He continued to deny any diarrhea and remained afebrile. His WBC count remained elevated, but his creatinine improved after fluids. On hospital day 3, the patient started having diarrhea for which C. difficile testing was sent. Because the patient was not clinically improving, repeat CT of the abdomen and pelvis with contrast (Fig. 1) was performed which showed progression of his colitis, now extending from the cecum to the rectum as well as findings concerning for appendicitis as seen on the prior CT scan. C. difficile testing was positive for which the patient was started on oral vancomycin. On hospital days 4–6, the patient’s symptoms and exam markedly improved with normalization of his WBC count. Surgery continued to recommend non-surgical management given significant clinical improvement with antibiotics alone. The patient was discharged on hospital day 7 with oral vancomycin.Figure 1 Coronal (a) and sagittal (b) CT of the abdomen and pelvis with contrast demonstrating enlargement of the appendix with wall thickening and enhancement (red arrows). Periappendiceal inflammation is also present (yellow arrow)
Discussion
Extraintestinal CDI is rare and has been described in only a limited number of reports. Examples of extraintestinal manifestations that have been reported include bacteremia (with one patient having C. difficile isolated in an abdominal aneurysm), intra-abdominal abscess, peritonitis, cellulitis, reactive arthritis, osteomyelitis, brain abscess, and empyema [2, 3]. Acute appendicitis is another one of the rare extracolonic manifestation of CDI as we have described here in our case. From review of the literature, there have been very few reported cases of C. difficile appendicitis [4-7].
C. difficile has generally been known as a pathogen responsible for colitis, particularly in the setting of prior antibiotic or hospital exposure. Recent chemotherapy is also another important risk factor [8], which was the case in our patient as he was actively undergoing treatment for his tonsillar cancer. It has been hypothesized that the disruption of the gut microbiota allows for the proliferation of toxigenic C. difficile and subsequent infection. C. difficile colitis is a process mediated by bacterial release of Toxins A and B, whose role is to inactivate members of the Rho family of guanosine triphosphatases (GTPases), which leads to colonocyte death, inflammation, and loss of the intestinal epithelial barrier function [9]. The pathogenesis of extraintestinal CDI, however, remains unclear. However, given his concurrent pancolitis, it is likely that direct spread of C. difficile from the intestinal lumen resulted in his appendicitis. This is in opposition to C. difficile isolated from distant sites described in other case series, where it is thought that bacterium enters through blood circulation [2].
Two possible mechanisms for C. difficile appendicitis have been suggested: direct infection from the toxin itself versus obstruction of the appendiceal lumen from the adjacent colitis [5]. It is plausible that both of these processes play a role, as the luminal obstruction can lead to ischemia and compromise of the mucosal barrier, resulting in bacterial invasion of the appendix by intraluminal bacteria [10]. When this occurs, a mix of aerobic and anaerobic organisms, particularly Escherichia coli and Bacteroides spp., are typically implicated [11], as opposed to C. difficile which is exceedingly uncommon as detailed in our case.
We should also note that the role of C. difficile in causing extraintestinal infections have been questioned. One case series showed that many isolates were either part of polymicrobial flora or intra-abdominal fluid collections near the colon in the setting of recent fecal spillage [3]. Furthermore, it has been found that not all extraintestinal C. difficile isolates produce toxins [3], which is essential in the pathogenesis of C. difficile colitis as discussed above (therefore, culture, while the most sensitive test for C. difficile infection [8], has largely been replaced by methods that detect toxigenic strains). While it is certainly possible that the patient’s C. difficile colitis (as confirmed by stool PCR testing) and his appendicitis represented distinct and unrelated processes, the clinical presentation, radiographic features, and overwhelming response to C. difficile directed antibiotic therapy suggests that C. difficile was the most likely underlying etiology.
Given the rarity of C. difficile appendicitis, no specific treatment guidelines exist. We performed a literature review to explore the demographics, management, and outcomes of those with C. difficile appendicitis (see Table 1). Using PubMed, we searched for articles with both keywords of “clostridium difficile” and “appendicitis,” which yielded 25 results. We reviewed each individual article further to ensure that the case report was of appendicitis that was attributable to C. difficile. We reviewed a total of six cases of C. difficile appendicitis and found that none of the patients were immunocompromised. Interestingly, five out of the six cases of C. difficile appendicitis involved patients over 50 years-old. All six patients initially survived; however, one had a recurrent episode leading to septic shock and death. Three patients eventually underwent surgical intervention, two of which survived. Management was not specified in two of the cases. As described above, we, in conjunction with our surgical colleagues, opted for medical therapy alone given the patient’s significant clinical improvement. We should note, however, that given the limited number of reported cases, further studies on optimal treatment is still needed.Table 1 Literature review of cases of C. difficile appendicitis
Author (Year) Age (yo) Gender Immunocompromised Co-Morbidities Treatment Outcome
Garcia-Lechuz et al. (2001) 53 Male No Hypothyroidism Imipenem
Appendectomy
Survived
Brown et al. (2007) 72 Male No COPD Metronidazole
Appendectomy
Survived
Mattila et al. (2013) 97 Female Unknown Breast cancer
Dementia
Unknown Survived
Mattila et al. (2013) 59 Female No Epilepsy Unknown Survived
Ridha et al. (2017) 30 Male No None Metronidazole
Levofloxacin
Oral vancomycin
Survived
Coyne et al. (1997) 76 Female No ESRD on HD 1st episode: Metronidazole
2nd episode (4 weeks later): proctocolectomy
1st episode: Survived
2nd episode: death from septic shock
Conclusions
Acute appendicitis is a rare extraintestinal manifestation of CDI. While the exact pathogenesis remains unclear, its significance cannot be overlooked. Our case highlights the importance of maintaining a high index of suspicion for C. difficile in a patient presenting with both appendicitis and colitis, as prompt diagnosis and treatment are essential.
Abbreviations
C. difficileClostridium difficile
WBCWhite blood cell
CTComputed tomography
BUNBlood urea nitrogen
CDIC. difficile Infection
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors would like to acknowledge the patient for allowing us to share his case with the medical community.
Authors’ contributions
CP and DH both contributed to the data collection, literature review, and drafting of the manuscript. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovering | ReactionOutcome | CC BY | 33402156 | 18,799,214 | 2021-01-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Calcification of muscle'. | A severe case of thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly syndrome with myocardial and skeletal muscle calcification despite hypocalcemia: a case report.
BACKGROUND
TAFRO (thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly) syndrome is a recently recognized disease with a variety of presentations of variable severity. In acute settings, this disease also involves organ dysfunction because of the associated systemic inflammation. However, cases of TAFRO syndrome with myocardial and/or skeletal muscle calcification have never been reported.
METHODS
A 24-year-old healthy young Asian man was admitted with intermittent epigastric pain and fever for 2 weeks. Computed tomography revealed pleural effusion, ascites and systemic lymphadenopathy. Laboratory tests showed thrombocytopenia, elevated C-reactive protein, hypoalbuminemia, anemia and renal dysfunction. Based on these findings and bone marrow biopsy, we diagnosed his disease as TAFRO syndrome and commenced hemodialysis for the renal dysfunction. However, he developed refractory hypocalcemia with unstable vital signs, for which we administered calcium gluconate hydrate. Thereafter, myocardial and skeletal muscle calcification was revealed radiologically, with the myocardial calcification causing sick sinus syndrome. He was treated with tocilizumab and finally discharged in an ambulatory condition after prolonged hospitalization, with residual calcific lesions.
CONCLUSIONS
This is the first report of a patient with TAFRO syndrome and the complication of organ calcification. The etiology of calcification in this case is not clear. Systemic inflammation with possible hypercytokinemia might have been involved in the unexpected complication of systemic calcification. It is important to carefully handle the general management of TAFRO syndrome because of the possibility of various complications.
Background
TAFRO (thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, organomegaly) syndrome is a systemic inflammatory disease first reported by Takai et al. in 2010 [1], and is categorized as a subtype of idiopathic multicentric Castleman’s disease (iMCD). TAFRO syndrome follows a particularly aggressive clinical course compared to unicentric Castleman’s disease or other subtypes of iMCD. Therefore, clinicians often experience difficulty in treating this condition. Since its earliest description, reports of cases of TAFRO syndrome have been described worldwide, and guidelines for its treatment have been proposed [2–5]. Since organ dysfunction is commonly seen with TAFRO syndrome, temporary hemodialysis is often necessary during the course of treatment of this condition [2], although no case reports have described calcific deposits associated with hemodialysis. Additionally, although several cases with severe cardiac dysfunction due to chemotherapy, hypercytokinemia and massive ascites have been reported [6–8], there have been no cases of gross calcification recognized radiologically, either in the myocardium or in skeletal muscles.
We report a case of TAFRO syndrome with myocardial and skeletal muscle calcification, who was finally discharged from the hospital in an ambulatory condition following tocilizumab therapy. Our patient also presented with severe hypocalcemia during his clinical course, the treatment of which might have eventually triggered systemic calcification. Although it is difficult to completely understand the etiological mechanism in this case, our experience will contribute to understanding the pathophysiology and general management of TAFRO syndrome.
Case presentation
A previously healthy 24-year-old Asian man without significant family medical history presented with intermittent severe epigastric pain and fever for two weeks. Since a computed tomography (CT) scan at another hospital had only revealed systemic lymphadenopathy and could not detect any cause for his symptoms, he was referred to our hospital for further investigation. On admission, he was febrile (37.4 °C). Physical examination showed epigastric tenderness without signs of peritoneal irritation, and pitting edema on the lower extremities. His laboratory test results on admission are shown in Table 1. Contrast-enhanced CT scan revealed cervical, supraclavicular, axillary, paraaortic and inguinal lymphadenopathies, bilateral pleural effusion, ascites and hepatosplenomegaly. Soon after his admission, hemodialysis and mechanical ventilation were initiated due to the development of anuria and dyspnea, and methylprednisolone pulse therapy (1 g/day) was administered for three days after ruling out bacterial infections on hospital day 9, followed by intravenous methylprednisolone (50 mg/day) as maintenance therapy. Laboratory data on hospital day 11 are shown in Table 2. In spite of hemodialysis and ventilatory support, his vital signs were unstable, necessitating temporary use of catecholamines to maintain his blood pressure. Additionally, his plasma calcium level decreased (ionized calcium: 0.78 mmol/L) with a high level of phosphorus (9.6 mg/dL) on hospital day 17. Subsequently, we intravenously administered calcium gluconate hydrate for a total of eight days because the hypocalcemia was refractory to therapy. Laboratory data indicated low vitamin D and high intact parathyroid hormone levels, as seen in patients with chronic kidney disease. Finally, his plasma calcium levels were maintained within the normal range (Fig. 1). Bone marrow biopsy revealed hypercellular marrow with an increased number of megakaryocytes (Fig. 2). Based on these findings and exclusion criteria, we diagnosed his condition as TAFRO syndrome according to the diagnostic criteria proposed in 2015 [3].Table 1 Laboratory data on admission
Complete blood cell count Blood chemistry
WBC 14,100 /μL Total protein 5.1 g/dL
Seg 83 % Albumin 1.8 g/dL
Eosino 1 % T.Bil 1.0 mg/dL
Lympho 7 % AST 29 IU/L
Mono 9 % ALT 14 IU/L
RBC 413 104/μL LDH 370 IU/L
Hgb 13.5 g/dL ALP 265 IU/L
MCV 86.2 fL γ-GTP 105 IU/L
Platelet 46.8 104/μL BUN 43.1 mg/dL
Cr 1.62 mg/dL
Coagulation system eGFR 46 mL/min/1.73m2
PT 18.2 sec CRP 25.37 mg/dL
PT-INR 1.51 Glu 78 mg/dL
APTT (standard: 26-36) 47.9 sec AMY 39 IU/L
Fibrinogen >600 mg/dL
D-dimer 26.9 μg/mL
WBC White blood cell, RBC Red blood cell, Hgb Hemoglobin, MCV Mean corpuscular volume, PT Prothrombin time, PT-INR Prothrombin time-international normalized ratio, APTT Activated partial thromboplastin time, T.Bil Total Bilirubin, AST Aspartate aminotransferase, ALT Alanine aminotransferase, LDH Lactate dehydrogenase, ALP Alkaline phosphatase, BUN Blood urea nitrogen, Cr Creatinine, CRP C-reactive protein, AMY Amylase
Table 2 Laboratory data at the time of diagnosis of TAFRO syndrome
Complete blood cell count Blood chemistry Immunologic test
WBC 23,600 /μL Albumin 1.5 g/dL IgG 1385 mg/dL
Band 6 % T.Bil 0.4 mg/dL IgG4 66 mg/dL
Seg 88 % AST 33 IU/L IgA 187 mg/dL
Lympho 3 % ALT 12 IU/L IgM 62 mg/dL
Mono 3 % LDH 471 IU/L ANA <40 times
RBC 348 104/μL γ-GTP 266 IU/L anti-RNP Ab –
Hgb 9.9 g/dL ALP 400 IU/L anti-ds-DNA IgG –
MCV 86.8 fL BUN 119.5 mg/dL anti-SS-A Ab –
Platelet 7.5 104/μL Cr 7.77 mg/dL RF <3 IU/mL
ESR 87 mm/hr CRP 36.35 mg/dL PR3-ANCA <1 IU/mL
Ferritin 1873 ng/mL MPO-ANCA <1 IU/mL
ACE 7.6 IU/L Coombs test –
Haptoglobin 311 mg/dL PA-IgG 70 ng/107cells
Infectious diseases ADAMTS-13 28 %
EBV VCA IgG + Coagulation system anti-GBM Ab <2 U/mL
EBV VCA IgM - PT 19 Sec sIL-2R 1260 U/mL
EBNA IgG + PT-INR 1.59 IL-6 65.1 pg/mL
CMV C7-HRP - APTT >80 Sec VEGF 1030 pg/mL
(Standard: 26-36)
HIV antigen/Ab - Fibrinogen >600 mg/dL
HHV-8 DNA (WBC106cells) <20 AT-III 58 %
IGRA – FDP 66 μg/mL
WBC White blood cell, RBC Red blood cell, Hgb Hemoglobin, MCV Mean corpuscular volume, ESR Erythrocyte sedimentation rate, EBV Epstein–Barr virus, VCA Virus capsid antigen, EBNA Epstein–Barr virus nuclear antigen, CMV Cytomegalovirus, HIV Human immunodeficiency virus, Ab Antibody, HHV-8 Human herpesvirus-8, IGRA Interferon-gamma releasing assay, T.Bil Total Bilirubin, AST Aspartate aminotransferase, ALT Alanine aminotransferase, LDH Lactate dehydrogenase, γ-GTP Gamma-glutamyl transpeptidase, ALP Alkaline phosphatase, BUN Blood urea nitrogen, Cr Creatinine, CRP C-reactive protein, ACE Angiotensin-converting enzyme, PT Prothrombin time, PT-INR Prothrombin time-international normalized ratio, APTT Activated partial thromboplastin time, AT-III Antithrombin III, FDP Fibrin/fibrinogen degradation products, ANA Antinuclear antibody, anti-RNP-antibody Anti-ribonucleoprotein antibody, anti-ds-DNA IgG Anti-double-stranded deoxyribonuclein acid immunoglobulin G, anti-SS-A antibody Anti-Sjören's syndrome A antibody, RF Rheumatoid factor, PR3-ANCA Proteinase 3-anti-neutrophil cytoplasmic antibody, MPO-ANCA Myeloperoxidase-anti-neutrophil cytoplasmic antibody, PA-IgG Platelet-associated immunoglobulin G, anti-GBM antibody Anti-glomerular basement membrane antibody, sIL-2R Soluble interleukin-2 receptor, IL-6 Interleukin-6, VEGF Vascular endothelial growth factor
Fig. 1 Transition of ionized calcium. Hypocalcemia appeared after the initiation of dialysis, and myocardial/skeletal muscle calcification was revealed on CT scans after the recovery from hypocalcemia with administration of calcium gluconate hydrate
Fig. 2 Histological findings on bone marrow biopsy. a, b Hypercellular marrow with increased megakaryocytes are seen. (Hematoxylin and eosin staining). (Scale bar, 100 μm)
We initiated weekly treatment with the biologic tocilizumab (8 mg/kg), which is a recombinant, humanized, anti-human interleukin-6 (IL-6) receptor monoclonal antibody, along with tapering glucocorticoids on hospital day 32. However, on hospital day 76, he presented with syncope due to sick sinus syndrome. We first recognized myocardial and skeletal muscle calcification by CT scans on hospital day 47 (Fig. 3). Subsequent CTs showed progressive worsening of the degree of calcification in the first few months (Fig. 4). At this time, we could not perform temporary pacing because of the risk of hemorrhage due to persistently low platelet levels and coagulopathy.Fig. 3 Myocardial and skeletal muscle calcification noted on computed tomography scans for the first time. a High density areas were present on the myocardium (arrows). b, c The rectus abdominis muscle and those of the thigh (arrows) showed high density bilaterally
Fig. 4 Chronological changes in myocardial and skeletal muscle (rectus abdominis) calcification on computed tomography images. Computed tomography was performed on (a, e) day 47, (b, f) day 123, (c, g) day 177 and (d, h) day 345. The degree of calcification showed progressive worsening during the first few months; subsequently, myocardial calcification remained unchanged, while that in the skeletal muscle gradually diminished
Although he repeatedly suffered from various infections (such as catheter related blood stream infection, pyothorax, intraabdominal abscess and infectious endocarditis), we basically continued use of tocilizumab, except when the infection was very severe. We initiated romiplostim, an analog of thrombopoietin, on day 173 because his platelet count remained persistently low, which soon resulted in recovery of platelet count to within the normal range. In addition, urine volume began to gradually increase five months after the onset of anuria. Thereafter, calcification of the rectus abdominis muscle also began to gradually diminish, as observed by CT scans, although there were no remarkable changes in that of the myocardium (Fig. 4).
Although there were many life-threatening events throughout his prolonged hospitalization, he was finally discharged from the hospital in an ambulatory condition on hospital day 410 (his complete clinical course is shown in Fig. 5). Sick sinus syndrome resolved together with improvement in his general condition, so permanent pacemaker implantation was deemed unnecessary. Currently, he receives regular hemodialysis and intravenous tocilizumab every three weeks without evidence of recurrence for one year after discharge.Fig. 5 Clinical course from admission until discharge. PLT platelets, CRP C-reactive protein, mPSL methylprednisolone, TCZ tocilizumab, HD hemodialysis, CRBSI catheter-related blood stream infection, IE infectious endocarditis, SSS sick sinus syndrome
Discussion
TAFRO syndrome and cardiac events
TAFRO syndrome is defined as a subtype of idiopathic multicentric Castleman’s disease (iMCD) that has been recognized as having a severe clinical course. Masaki et al. proposed the diagnostic criteria and severity classification in 2015, and there have been several recently reported clinicopathological analyses and consensus guidelines for the treatment of iMCD based on the accumulated data [2–5]. Our case fulfilled the diagnostic criteria of TAFRO syndrome according to the guideline, and was classified as grade 4 (severe) severity. Our case is rare not only because of many life-threating events such as repetitive severe infections, sick sinus syndrome and cardiac arrest, but also because of the myocardial and skeletal muscle calcification that occurred two months after his disease onset. Other cases have also survived despite a very severe clinical course [9–11], although none of them experienced systemic calcification.
Many TAFRO syndrome cases have recovered with the use of biological products (such as tocilizumab or rituximab), glucocorticoids, immunosuppressants (such as cyclosporine A or sirolimus), and occasionally, with chemotherapy. In terms of cardiac dysfunction, Yasuda et al. reported two cases of TAFRO syndrome with cardiomyopathy and lowered ejection fraction (EF) [6]. They performed CHOP (cyclophosphamide, adriamycin, vincristine and prednisolone) therapy as treatment, and assumed that the cardiomyopathy was an adverse effect of adriamycin. Hiramatsu et al. showed a case of TAFRO syndrome with reversible cardiomyopathy, in which they opined that the high concentration of plasma IL-6 was the cause of cardiomyopathy [7]. However, these cases did not have any associated calcification.
The etiology of myocardial/systemic calcification
Myocardial calcification itself only occurs very rarely. There are traditionally two pathways causing myocardial calcification: metastatic and dystrophic. Metastatic calcification occurs with hypercalcemia and/or abnormality of calcium/phosphate metabolism [12]. This form of calcification can occur anywhere in the body, but is more likely in areas of high alkalinity, such as the gastric mucosa or systemic arteries; therefore, calcification due to this etiology can exist systemically. On the other hand, dystrophic calcification occurs secondary to cellular damage and necrosis, with calcium deposits replacing necrotizing cells. Other etiologies of dystrophic calcification include trauma, infections, inflammation, neoplasms and drugs [12]. Myocardial infarction is a common cause of myocardial calcification. Septic shock is also a cause of this form of calcification; hypotension during shock and catecholamine use can cause myocardial damage, which eventually results in calcium deposits even if plasma calcium concentration is normal [12, 13]. In our case, the etiology of myocardial and skeletal muscle calcification was considered more likely to be metastatic than dystrophic due to the following reasons. First, there was a failure of calcium/phosphate metabolism due to the presence of progressive renal dysfunction with hemodialysis and low vitamin D levels. There was also excessive replenishment of calcium, with an amount of 7.8 mmol of calcium gluconate hydrate per day on average, which could have accelerated calcium deposition in systemic tissues. We did not administer intravenous vitamin D agents, except for the minimal amount of vitamins administered through total parenteral nutrition, which might have been a possible cause for prolonged low calcium levels. Second, both myocardial and skeletal muscle calcification were detected on CT scans at the same time, which was within a month after the initial identification of hypocalcemia and subsequent overloading of calcium (Fig. 3). Third, although we temporarily used catecholamines, there were no other conditions explaining the dystrophic calcification, such as septic shock or myocardial infarction. Fourth, hypercytokinemia, including elevated IL-6 caused by TAFRO syndrome, could also have contributed to this unusual situation. Plasma calcium levels remained low and were almost unchanged when calcium gluconate hydrate was administered, which suggested that the administered calcium probably leaked out of the vessels and was absorbed by peripheral tissues. Increase of vasopermeability is another possible etiology for the calcified deposits, which could explain its occurrence in the absence of hypercalcemia.
In conclusion, this case of TAFRO syndrome achieved a successful recovery with tocilizumab therapy along with prolonged hospitalization, although he experienced the unexpected complication of myocardial and skeletal muscle calcification probably via a metastatic pathway triggered by drug administration. In acute clinical settings, the tendency is to urgently correct abnormal laboratory data, especially electrolyte abnormalities. However, TAFRO syndrome is known to be associated with hypercytokinemia and organ dysfunction with an unknown pathophysiology; hence, the general management of such cases should be carefully handled, anticipating unexpected complications.
Abbreviations
TAFROThrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly
iMCDIdiopathic multicentric Castleman’s disease
CTComputed tomography
IL-6Interleukin-6
CHOPCyclophosphamide, adriamycin, vincristine and prednisolone
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors thank Forte Science Communications (www.forte-science.co.jp) for their assistance in proofreading this article.
Authors’ contributions
SM treated this patient, reviewed literature, interpreted the patient data about the etiology in this patient, and contributed to writing the manuscript. YF reviewed literature, wrote the manuscript, and managed this research. SS treated this patient and wrote the manuscript. AT provided professional opinions regarding patient care and treatment, and revised the manuscript. KN revised the manuscript and currently cares for this patient at the outpatient clinic. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Ethics approval and consent for submitting case reports is usually waived by the ethics review committee of Musashino Red Cross Hospital. We followed the principles of the Declaration of Helsinki and paid cautious attention to protecting the patient’s identity.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | CALCIUM GLUCONATE, METHYLPREDNISOLONE, TOCILIZUMAB | DrugsGivenReaction | CC BY | 33402219 | 19,396,568 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myocardial calcification'. | A severe case of thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly syndrome with myocardial and skeletal muscle calcification despite hypocalcemia: a case report.
BACKGROUND
TAFRO (thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly) syndrome is a recently recognized disease with a variety of presentations of variable severity. In acute settings, this disease also involves organ dysfunction because of the associated systemic inflammation. However, cases of TAFRO syndrome with myocardial and/or skeletal muscle calcification have never been reported.
METHODS
A 24-year-old healthy young Asian man was admitted with intermittent epigastric pain and fever for 2 weeks. Computed tomography revealed pleural effusion, ascites and systemic lymphadenopathy. Laboratory tests showed thrombocytopenia, elevated C-reactive protein, hypoalbuminemia, anemia and renal dysfunction. Based on these findings and bone marrow biopsy, we diagnosed his disease as TAFRO syndrome and commenced hemodialysis for the renal dysfunction. However, he developed refractory hypocalcemia with unstable vital signs, for which we administered calcium gluconate hydrate. Thereafter, myocardial and skeletal muscle calcification was revealed radiologically, with the myocardial calcification causing sick sinus syndrome. He was treated with tocilizumab and finally discharged in an ambulatory condition after prolonged hospitalization, with residual calcific lesions.
CONCLUSIONS
This is the first report of a patient with TAFRO syndrome and the complication of organ calcification. The etiology of calcification in this case is not clear. Systemic inflammation with possible hypercytokinemia might have been involved in the unexpected complication of systemic calcification. It is important to carefully handle the general management of TAFRO syndrome because of the possibility of various complications.
Background
TAFRO (thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, organomegaly) syndrome is a systemic inflammatory disease first reported by Takai et al. in 2010 [1], and is categorized as a subtype of idiopathic multicentric Castleman’s disease (iMCD). TAFRO syndrome follows a particularly aggressive clinical course compared to unicentric Castleman’s disease or other subtypes of iMCD. Therefore, clinicians often experience difficulty in treating this condition. Since its earliest description, reports of cases of TAFRO syndrome have been described worldwide, and guidelines for its treatment have been proposed [2–5]. Since organ dysfunction is commonly seen with TAFRO syndrome, temporary hemodialysis is often necessary during the course of treatment of this condition [2], although no case reports have described calcific deposits associated with hemodialysis. Additionally, although several cases with severe cardiac dysfunction due to chemotherapy, hypercytokinemia and massive ascites have been reported [6–8], there have been no cases of gross calcification recognized radiologically, either in the myocardium or in skeletal muscles.
We report a case of TAFRO syndrome with myocardial and skeletal muscle calcification, who was finally discharged from the hospital in an ambulatory condition following tocilizumab therapy. Our patient also presented with severe hypocalcemia during his clinical course, the treatment of which might have eventually triggered systemic calcification. Although it is difficult to completely understand the etiological mechanism in this case, our experience will contribute to understanding the pathophysiology and general management of TAFRO syndrome.
Case presentation
A previously healthy 24-year-old Asian man without significant family medical history presented with intermittent severe epigastric pain and fever for two weeks. Since a computed tomography (CT) scan at another hospital had only revealed systemic lymphadenopathy and could not detect any cause for his symptoms, he was referred to our hospital for further investigation. On admission, he was febrile (37.4 °C). Physical examination showed epigastric tenderness without signs of peritoneal irritation, and pitting edema on the lower extremities. His laboratory test results on admission are shown in Table 1. Contrast-enhanced CT scan revealed cervical, supraclavicular, axillary, paraaortic and inguinal lymphadenopathies, bilateral pleural effusion, ascites and hepatosplenomegaly. Soon after his admission, hemodialysis and mechanical ventilation were initiated due to the development of anuria and dyspnea, and methylprednisolone pulse therapy (1 g/day) was administered for three days after ruling out bacterial infections on hospital day 9, followed by intravenous methylprednisolone (50 mg/day) as maintenance therapy. Laboratory data on hospital day 11 are shown in Table 2. In spite of hemodialysis and ventilatory support, his vital signs were unstable, necessitating temporary use of catecholamines to maintain his blood pressure. Additionally, his plasma calcium level decreased (ionized calcium: 0.78 mmol/L) with a high level of phosphorus (9.6 mg/dL) on hospital day 17. Subsequently, we intravenously administered calcium gluconate hydrate for a total of eight days because the hypocalcemia was refractory to therapy. Laboratory data indicated low vitamin D and high intact parathyroid hormone levels, as seen in patients with chronic kidney disease. Finally, his plasma calcium levels were maintained within the normal range (Fig. 1). Bone marrow biopsy revealed hypercellular marrow with an increased number of megakaryocytes (Fig. 2). Based on these findings and exclusion criteria, we diagnosed his condition as TAFRO syndrome according to the diagnostic criteria proposed in 2015 [3].Table 1 Laboratory data on admission
Complete blood cell count Blood chemistry
WBC 14,100 /μL Total protein 5.1 g/dL
Seg 83 % Albumin 1.8 g/dL
Eosino 1 % T.Bil 1.0 mg/dL
Lympho 7 % AST 29 IU/L
Mono 9 % ALT 14 IU/L
RBC 413 104/μL LDH 370 IU/L
Hgb 13.5 g/dL ALP 265 IU/L
MCV 86.2 fL γ-GTP 105 IU/L
Platelet 46.8 104/μL BUN 43.1 mg/dL
Cr 1.62 mg/dL
Coagulation system eGFR 46 mL/min/1.73m2
PT 18.2 sec CRP 25.37 mg/dL
PT-INR 1.51 Glu 78 mg/dL
APTT (standard: 26-36) 47.9 sec AMY 39 IU/L
Fibrinogen >600 mg/dL
D-dimer 26.9 μg/mL
WBC White blood cell, RBC Red blood cell, Hgb Hemoglobin, MCV Mean corpuscular volume, PT Prothrombin time, PT-INR Prothrombin time-international normalized ratio, APTT Activated partial thromboplastin time, T.Bil Total Bilirubin, AST Aspartate aminotransferase, ALT Alanine aminotransferase, LDH Lactate dehydrogenase, ALP Alkaline phosphatase, BUN Blood urea nitrogen, Cr Creatinine, CRP C-reactive protein, AMY Amylase
Table 2 Laboratory data at the time of diagnosis of TAFRO syndrome
Complete blood cell count Blood chemistry Immunologic test
WBC 23,600 /μL Albumin 1.5 g/dL IgG 1385 mg/dL
Band 6 % T.Bil 0.4 mg/dL IgG4 66 mg/dL
Seg 88 % AST 33 IU/L IgA 187 mg/dL
Lympho 3 % ALT 12 IU/L IgM 62 mg/dL
Mono 3 % LDH 471 IU/L ANA <40 times
RBC 348 104/μL γ-GTP 266 IU/L anti-RNP Ab –
Hgb 9.9 g/dL ALP 400 IU/L anti-ds-DNA IgG –
MCV 86.8 fL BUN 119.5 mg/dL anti-SS-A Ab –
Platelet 7.5 104/μL Cr 7.77 mg/dL RF <3 IU/mL
ESR 87 mm/hr CRP 36.35 mg/dL PR3-ANCA <1 IU/mL
Ferritin 1873 ng/mL MPO-ANCA <1 IU/mL
ACE 7.6 IU/L Coombs test –
Haptoglobin 311 mg/dL PA-IgG 70 ng/107cells
Infectious diseases ADAMTS-13 28 %
EBV VCA IgG + Coagulation system anti-GBM Ab <2 U/mL
EBV VCA IgM - PT 19 Sec sIL-2R 1260 U/mL
EBNA IgG + PT-INR 1.59 IL-6 65.1 pg/mL
CMV C7-HRP - APTT >80 Sec VEGF 1030 pg/mL
(Standard: 26-36)
HIV antigen/Ab - Fibrinogen >600 mg/dL
HHV-8 DNA (WBC106cells) <20 AT-III 58 %
IGRA – FDP 66 μg/mL
WBC White blood cell, RBC Red blood cell, Hgb Hemoglobin, MCV Mean corpuscular volume, ESR Erythrocyte sedimentation rate, EBV Epstein–Barr virus, VCA Virus capsid antigen, EBNA Epstein–Barr virus nuclear antigen, CMV Cytomegalovirus, HIV Human immunodeficiency virus, Ab Antibody, HHV-8 Human herpesvirus-8, IGRA Interferon-gamma releasing assay, T.Bil Total Bilirubin, AST Aspartate aminotransferase, ALT Alanine aminotransferase, LDH Lactate dehydrogenase, γ-GTP Gamma-glutamyl transpeptidase, ALP Alkaline phosphatase, BUN Blood urea nitrogen, Cr Creatinine, CRP C-reactive protein, ACE Angiotensin-converting enzyme, PT Prothrombin time, PT-INR Prothrombin time-international normalized ratio, APTT Activated partial thromboplastin time, AT-III Antithrombin III, FDP Fibrin/fibrinogen degradation products, ANA Antinuclear antibody, anti-RNP-antibody Anti-ribonucleoprotein antibody, anti-ds-DNA IgG Anti-double-stranded deoxyribonuclein acid immunoglobulin G, anti-SS-A antibody Anti-Sjören's syndrome A antibody, RF Rheumatoid factor, PR3-ANCA Proteinase 3-anti-neutrophil cytoplasmic antibody, MPO-ANCA Myeloperoxidase-anti-neutrophil cytoplasmic antibody, PA-IgG Platelet-associated immunoglobulin G, anti-GBM antibody Anti-glomerular basement membrane antibody, sIL-2R Soluble interleukin-2 receptor, IL-6 Interleukin-6, VEGF Vascular endothelial growth factor
Fig. 1 Transition of ionized calcium. Hypocalcemia appeared after the initiation of dialysis, and myocardial/skeletal muscle calcification was revealed on CT scans after the recovery from hypocalcemia with administration of calcium gluconate hydrate
Fig. 2 Histological findings on bone marrow biopsy. a, b Hypercellular marrow with increased megakaryocytes are seen. (Hematoxylin and eosin staining). (Scale bar, 100 μm)
We initiated weekly treatment with the biologic tocilizumab (8 mg/kg), which is a recombinant, humanized, anti-human interleukin-6 (IL-6) receptor monoclonal antibody, along with tapering glucocorticoids on hospital day 32. However, on hospital day 76, he presented with syncope due to sick sinus syndrome. We first recognized myocardial and skeletal muscle calcification by CT scans on hospital day 47 (Fig. 3). Subsequent CTs showed progressive worsening of the degree of calcification in the first few months (Fig. 4). At this time, we could not perform temporary pacing because of the risk of hemorrhage due to persistently low platelet levels and coagulopathy.Fig. 3 Myocardial and skeletal muscle calcification noted on computed tomography scans for the first time. a High density areas were present on the myocardium (arrows). b, c The rectus abdominis muscle and those of the thigh (arrows) showed high density bilaterally
Fig. 4 Chronological changes in myocardial and skeletal muscle (rectus abdominis) calcification on computed tomography images. Computed tomography was performed on (a, e) day 47, (b, f) day 123, (c, g) day 177 and (d, h) day 345. The degree of calcification showed progressive worsening during the first few months; subsequently, myocardial calcification remained unchanged, while that in the skeletal muscle gradually diminished
Although he repeatedly suffered from various infections (such as catheter related blood stream infection, pyothorax, intraabdominal abscess and infectious endocarditis), we basically continued use of tocilizumab, except when the infection was very severe. We initiated romiplostim, an analog of thrombopoietin, on day 173 because his platelet count remained persistently low, which soon resulted in recovery of platelet count to within the normal range. In addition, urine volume began to gradually increase five months after the onset of anuria. Thereafter, calcification of the rectus abdominis muscle also began to gradually diminish, as observed by CT scans, although there were no remarkable changes in that of the myocardium (Fig. 4).
Although there were many life-threatening events throughout his prolonged hospitalization, he was finally discharged from the hospital in an ambulatory condition on hospital day 410 (his complete clinical course is shown in Fig. 5). Sick sinus syndrome resolved together with improvement in his general condition, so permanent pacemaker implantation was deemed unnecessary. Currently, he receives regular hemodialysis and intravenous tocilizumab every three weeks without evidence of recurrence for one year after discharge.Fig. 5 Clinical course from admission until discharge. PLT platelets, CRP C-reactive protein, mPSL methylprednisolone, TCZ tocilizumab, HD hemodialysis, CRBSI catheter-related blood stream infection, IE infectious endocarditis, SSS sick sinus syndrome
Discussion
TAFRO syndrome and cardiac events
TAFRO syndrome is defined as a subtype of idiopathic multicentric Castleman’s disease (iMCD) that has been recognized as having a severe clinical course. Masaki et al. proposed the diagnostic criteria and severity classification in 2015, and there have been several recently reported clinicopathological analyses and consensus guidelines for the treatment of iMCD based on the accumulated data [2–5]. Our case fulfilled the diagnostic criteria of TAFRO syndrome according to the guideline, and was classified as grade 4 (severe) severity. Our case is rare not only because of many life-threating events such as repetitive severe infections, sick sinus syndrome and cardiac arrest, but also because of the myocardial and skeletal muscle calcification that occurred two months after his disease onset. Other cases have also survived despite a very severe clinical course [9–11], although none of them experienced systemic calcification.
Many TAFRO syndrome cases have recovered with the use of biological products (such as tocilizumab or rituximab), glucocorticoids, immunosuppressants (such as cyclosporine A or sirolimus), and occasionally, with chemotherapy. In terms of cardiac dysfunction, Yasuda et al. reported two cases of TAFRO syndrome with cardiomyopathy and lowered ejection fraction (EF) [6]. They performed CHOP (cyclophosphamide, adriamycin, vincristine and prednisolone) therapy as treatment, and assumed that the cardiomyopathy was an adverse effect of adriamycin. Hiramatsu et al. showed a case of TAFRO syndrome with reversible cardiomyopathy, in which they opined that the high concentration of plasma IL-6 was the cause of cardiomyopathy [7]. However, these cases did not have any associated calcification.
The etiology of myocardial/systemic calcification
Myocardial calcification itself only occurs very rarely. There are traditionally two pathways causing myocardial calcification: metastatic and dystrophic. Metastatic calcification occurs with hypercalcemia and/or abnormality of calcium/phosphate metabolism [12]. This form of calcification can occur anywhere in the body, but is more likely in areas of high alkalinity, such as the gastric mucosa or systemic arteries; therefore, calcification due to this etiology can exist systemically. On the other hand, dystrophic calcification occurs secondary to cellular damage and necrosis, with calcium deposits replacing necrotizing cells. Other etiologies of dystrophic calcification include trauma, infections, inflammation, neoplasms and drugs [12]. Myocardial infarction is a common cause of myocardial calcification. Septic shock is also a cause of this form of calcification; hypotension during shock and catecholamine use can cause myocardial damage, which eventually results in calcium deposits even if plasma calcium concentration is normal [12, 13]. In our case, the etiology of myocardial and skeletal muscle calcification was considered more likely to be metastatic than dystrophic due to the following reasons. First, there was a failure of calcium/phosphate metabolism due to the presence of progressive renal dysfunction with hemodialysis and low vitamin D levels. There was also excessive replenishment of calcium, with an amount of 7.8 mmol of calcium gluconate hydrate per day on average, which could have accelerated calcium deposition in systemic tissues. We did not administer intravenous vitamin D agents, except for the minimal amount of vitamins administered through total parenteral nutrition, which might have been a possible cause for prolonged low calcium levels. Second, both myocardial and skeletal muscle calcification were detected on CT scans at the same time, which was within a month after the initial identification of hypocalcemia and subsequent overloading of calcium (Fig. 3). Third, although we temporarily used catecholamines, there were no other conditions explaining the dystrophic calcification, such as septic shock or myocardial infarction. Fourth, hypercytokinemia, including elevated IL-6 caused by TAFRO syndrome, could also have contributed to this unusual situation. Plasma calcium levels remained low and were almost unchanged when calcium gluconate hydrate was administered, which suggested that the administered calcium probably leaked out of the vessels and was absorbed by peripheral tissues. Increase of vasopermeability is another possible etiology for the calcified deposits, which could explain its occurrence in the absence of hypercalcemia.
In conclusion, this case of TAFRO syndrome achieved a successful recovery with tocilizumab therapy along with prolonged hospitalization, although he experienced the unexpected complication of myocardial and skeletal muscle calcification probably via a metastatic pathway triggered by drug administration. In acute clinical settings, the tendency is to urgently correct abnormal laboratory data, especially electrolyte abnormalities. However, TAFRO syndrome is known to be associated with hypercytokinemia and organ dysfunction with an unknown pathophysiology; hence, the general management of such cases should be carefully handled, anticipating unexpected complications.
Abbreviations
TAFROThrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly
iMCDIdiopathic multicentric Castleman’s disease
CTComputed tomography
IL-6Interleukin-6
CHOPCyclophosphamide, adriamycin, vincristine and prednisolone
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors thank Forte Science Communications (www.forte-science.co.jp) for their assistance in proofreading this article.
Authors’ contributions
SM treated this patient, reviewed literature, interpreted the patient data about the etiology in this patient, and contributed to writing the manuscript. YF reviewed literature, wrote the manuscript, and managed this research. SS treated this patient and wrote the manuscript. AT provided professional opinions regarding patient care and treatment, and revised the manuscript. KN revised the manuscript and currently cares for this patient at the outpatient clinic. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Ethics approval and consent for submitting case reports is usually waived by the ethics review committee of Musashino Red Cross Hospital. We followed the principles of the Declaration of Helsinki and paid cautious attention to protecting the patient’s identity.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | CALCIUM GLUCONATE, METHYLPREDNISOLONE, TOCILIZUMAB | DrugsGivenReaction | CC BY | 33402219 | 19,396,568 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sinus node dysfunction'. | A severe case of thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly syndrome with myocardial and skeletal muscle calcification despite hypocalcemia: a case report.
BACKGROUND
TAFRO (thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly) syndrome is a recently recognized disease with a variety of presentations of variable severity. In acute settings, this disease also involves organ dysfunction because of the associated systemic inflammation. However, cases of TAFRO syndrome with myocardial and/or skeletal muscle calcification have never been reported.
METHODS
A 24-year-old healthy young Asian man was admitted with intermittent epigastric pain and fever for 2 weeks. Computed tomography revealed pleural effusion, ascites and systemic lymphadenopathy. Laboratory tests showed thrombocytopenia, elevated C-reactive protein, hypoalbuminemia, anemia and renal dysfunction. Based on these findings and bone marrow biopsy, we diagnosed his disease as TAFRO syndrome and commenced hemodialysis for the renal dysfunction. However, he developed refractory hypocalcemia with unstable vital signs, for which we administered calcium gluconate hydrate. Thereafter, myocardial and skeletal muscle calcification was revealed radiologically, with the myocardial calcification causing sick sinus syndrome. He was treated with tocilizumab and finally discharged in an ambulatory condition after prolonged hospitalization, with residual calcific lesions.
CONCLUSIONS
This is the first report of a patient with TAFRO syndrome and the complication of organ calcification. The etiology of calcification in this case is not clear. Systemic inflammation with possible hypercytokinemia might have been involved in the unexpected complication of systemic calcification. It is important to carefully handle the general management of TAFRO syndrome because of the possibility of various complications.
Background
TAFRO (thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, organomegaly) syndrome is a systemic inflammatory disease first reported by Takai et al. in 2010 [1], and is categorized as a subtype of idiopathic multicentric Castleman’s disease (iMCD). TAFRO syndrome follows a particularly aggressive clinical course compared to unicentric Castleman’s disease or other subtypes of iMCD. Therefore, clinicians often experience difficulty in treating this condition. Since its earliest description, reports of cases of TAFRO syndrome have been described worldwide, and guidelines for its treatment have been proposed [2–5]. Since organ dysfunction is commonly seen with TAFRO syndrome, temporary hemodialysis is often necessary during the course of treatment of this condition [2], although no case reports have described calcific deposits associated with hemodialysis. Additionally, although several cases with severe cardiac dysfunction due to chemotherapy, hypercytokinemia and massive ascites have been reported [6–8], there have been no cases of gross calcification recognized radiologically, either in the myocardium or in skeletal muscles.
We report a case of TAFRO syndrome with myocardial and skeletal muscle calcification, who was finally discharged from the hospital in an ambulatory condition following tocilizumab therapy. Our patient also presented with severe hypocalcemia during his clinical course, the treatment of which might have eventually triggered systemic calcification. Although it is difficult to completely understand the etiological mechanism in this case, our experience will contribute to understanding the pathophysiology and general management of TAFRO syndrome.
Case presentation
A previously healthy 24-year-old Asian man without significant family medical history presented with intermittent severe epigastric pain and fever for two weeks. Since a computed tomography (CT) scan at another hospital had only revealed systemic lymphadenopathy and could not detect any cause for his symptoms, he was referred to our hospital for further investigation. On admission, he was febrile (37.4 °C). Physical examination showed epigastric tenderness without signs of peritoneal irritation, and pitting edema on the lower extremities. His laboratory test results on admission are shown in Table 1. Contrast-enhanced CT scan revealed cervical, supraclavicular, axillary, paraaortic and inguinal lymphadenopathies, bilateral pleural effusion, ascites and hepatosplenomegaly. Soon after his admission, hemodialysis and mechanical ventilation were initiated due to the development of anuria and dyspnea, and methylprednisolone pulse therapy (1 g/day) was administered for three days after ruling out bacterial infections on hospital day 9, followed by intravenous methylprednisolone (50 mg/day) as maintenance therapy. Laboratory data on hospital day 11 are shown in Table 2. In spite of hemodialysis and ventilatory support, his vital signs were unstable, necessitating temporary use of catecholamines to maintain his blood pressure. Additionally, his plasma calcium level decreased (ionized calcium: 0.78 mmol/L) with a high level of phosphorus (9.6 mg/dL) on hospital day 17. Subsequently, we intravenously administered calcium gluconate hydrate for a total of eight days because the hypocalcemia was refractory to therapy. Laboratory data indicated low vitamin D and high intact parathyroid hormone levels, as seen in patients with chronic kidney disease. Finally, his plasma calcium levels were maintained within the normal range (Fig. 1). Bone marrow biopsy revealed hypercellular marrow with an increased number of megakaryocytes (Fig. 2). Based on these findings and exclusion criteria, we diagnosed his condition as TAFRO syndrome according to the diagnostic criteria proposed in 2015 [3].Table 1 Laboratory data on admission
Complete blood cell count Blood chemistry
WBC 14,100 /μL Total protein 5.1 g/dL
Seg 83 % Albumin 1.8 g/dL
Eosino 1 % T.Bil 1.0 mg/dL
Lympho 7 % AST 29 IU/L
Mono 9 % ALT 14 IU/L
RBC 413 104/μL LDH 370 IU/L
Hgb 13.5 g/dL ALP 265 IU/L
MCV 86.2 fL γ-GTP 105 IU/L
Platelet 46.8 104/μL BUN 43.1 mg/dL
Cr 1.62 mg/dL
Coagulation system eGFR 46 mL/min/1.73m2
PT 18.2 sec CRP 25.37 mg/dL
PT-INR 1.51 Glu 78 mg/dL
APTT (standard: 26-36) 47.9 sec AMY 39 IU/L
Fibrinogen >600 mg/dL
D-dimer 26.9 μg/mL
WBC White blood cell, RBC Red blood cell, Hgb Hemoglobin, MCV Mean corpuscular volume, PT Prothrombin time, PT-INR Prothrombin time-international normalized ratio, APTT Activated partial thromboplastin time, T.Bil Total Bilirubin, AST Aspartate aminotransferase, ALT Alanine aminotransferase, LDH Lactate dehydrogenase, ALP Alkaline phosphatase, BUN Blood urea nitrogen, Cr Creatinine, CRP C-reactive protein, AMY Amylase
Table 2 Laboratory data at the time of diagnosis of TAFRO syndrome
Complete blood cell count Blood chemistry Immunologic test
WBC 23,600 /μL Albumin 1.5 g/dL IgG 1385 mg/dL
Band 6 % T.Bil 0.4 mg/dL IgG4 66 mg/dL
Seg 88 % AST 33 IU/L IgA 187 mg/dL
Lympho 3 % ALT 12 IU/L IgM 62 mg/dL
Mono 3 % LDH 471 IU/L ANA <40 times
RBC 348 104/μL γ-GTP 266 IU/L anti-RNP Ab –
Hgb 9.9 g/dL ALP 400 IU/L anti-ds-DNA IgG –
MCV 86.8 fL BUN 119.5 mg/dL anti-SS-A Ab –
Platelet 7.5 104/μL Cr 7.77 mg/dL RF <3 IU/mL
ESR 87 mm/hr CRP 36.35 mg/dL PR3-ANCA <1 IU/mL
Ferritin 1873 ng/mL MPO-ANCA <1 IU/mL
ACE 7.6 IU/L Coombs test –
Haptoglobin 311 mg/dL PA-IgG 70 ng/107cells
Infectious diseases ADAMTS-13 28 %
EBV VCA IgG + Coagulation system anti-GBM Ab <2 U/mL
EBV VCA IgM - PT 19 Sec sIL-2R 1260 U/mL
EBNA IgG + PT-INR 1.59 IL-6 65.1 pg/mL
CMV C7-HRP - APTT >80 Sec VEGF 1030 pg/mL
(Standard: 26-36)
HIV antigen/Ab - Fibrinogen >600 mg/dL
HHV-8 DNA (WBC106cells) <20 AT-III 58 %
IGRA – FDP 66 μg/mL
WBC White blood cell, RBC Red blood cell, Hgb Hemoglobin, MCV Mean corpuscular volume, ESR Erythrocyte sedimentation rate, EBV Epstein–Barr virus, VCA Virus capsid antigen, EBNA Epstein–Barr virus nuclear antigen, CMV Cytomegalovirus, HIV Human immunodeficiency virus, Ab Antibody, HHV-8 Human herpesvirus-8, IGRA Interferon-gamma releasing assay, T.Bil Total Bilirubin, AST Aspartate aminotransferase, ALT Alanine aminotransferase, LDH Lactate dehydrogenase, γ-GTP Gamma-glutamyl transpeptidase, ALP Alkaline phosphatase, BUN Blood urea nitrogen, Cr Creatinine, CRP C-reactive protein, ACE Angiotensin-converting enzyme, PT Prothrombin time, PT-INR Prothrombin time-international normalized ratio, APTT Activated partial thromboplastin time, AT-III Antithrombin III, FDP Fibrin/fibrinogen degradation products, ANA Antinuclear antibody, anti-RNP-antibody Anti-ribonucleoprotein antibody, anti-ds-DNA IgG Anti-double-stranded deoxyribonuclein acid immunoglobulin G, anti-SS-A antibody Anti-Sjören's syndrome A antibody, RF Rheumatoid factor, PR3-ANCA Proteinase 3-anti-neutrophil cytoplasmic antibody, MPO-ANCA Myeloperoxidase-anti-neutrophil cytoplasmic antibody, PA-IgG Platelet-associated immunoglobulin G, anti-GBM antibody Anti-glomerular basement membrane antibody, sIL-2R Soluble interleukin-2 receptor, IL-6 Interleukin-6, VEGF Vascular endothelial growth factor
Fig. 1 Transition of ionized calcium. Hypocalcemia appeared after the initiation of dialysis, and myocardial/skeletal muscle calcification was revealed on CT scans after the recovery from hypocalcemia with administration of calcium gluconate hydrate
Fig. 2 Histological findings on bone marrow biopsy. a, b Hypercellular marrow with increased megakaryocytes are seen. (Hematoxylin and eosin staining). (Scale bar, 100 μm)
We initiated weekly treatment with the biologic tocilizumab (8 mg/kg), which is a recombinant, humanized, anti-human interleukin-6 (IL-6) receptor monoclonal antibody, along with tapering glucocorticoids on hospital day 32. However, on hospital day 76, he presented with syncope due to sick sinus syndrome. We first recognized myocardial and skeletal muscle calcification by CT scans on hospital day 47 (Fig. 3). Subsequent CTs showed progressive worsening of the degree of calcification in the first few months (Fig. 4). At this time, we could not perform temporary pacing because of the risk of hemorrhage due to persistently low platelet levels and coagulopathy.Fig. 3 Myocardial and skeletal muscle calcification noted on computed tomography scans for the first time. a High density areas were present on the myocardium (arrows). b, c The rectus abdominis muscle and those of the thigh (arrows) showed high density bilaterally
Fig. 4 Chronological changes in myocardial and skeletal muscle (rectus abdominis) calcification on computed tomography images. Computed tomography was performed on (a, e) day 47, (b, f) day 123, (c, g) day 177 and (d, h) day 345. The degree of calcification showed progressive worsening during the first few months; subsequently, myocardial calcification remained unchanged, while that in the skeletal muscle gradually diminished
Although he repeatedly suffered from various infections (such as catheter related blood stream infection, pyothorax, intraabdominal abscess and infectious endocarditis), we basically continued use of tocilizumab, except when the infection was very severe. We initiated romiplostim, an analog of thrombopoietin, on day 173 because his platelet count remained persistently low, which soon resulted in recovery of platelet count to within the normal range. In addition, urine volume began to gradually increase five months after the onset of anuria. Thereafter, calcification of the rectus abdominis muscle also began to gradually diminish, as observed by CT scans, although there were no remarkable changes in that of the myocardium (Fig. 4).
Although there were many life-threatening events throughout his prolonged hospitalization, he was finally discharged from the hospital in an ambulatory condition on hospital day 410 (his complete clinical course is shown in Fig. 5). Sick sinus syndrome resolved together with improvement in his general condition, so permanent pacemaker implantation was deemed unnecessary. Currently, he receives regular hemodialysis and intravenous tocilizumab every three weeks without evidence of recurrence for one year after discharge.Fig. 5 Clinical course from admission until discharge. PLT platelets, CRP C-reactive protein, mPSL methylprednisolone, TCZ tocilizumab, HD hemodialysis, CRBSI catheter-related blood stream infection, IE infectious endocarditis, SSS sick sinus syndrome
Discussion
TAFRO syndrome and cardiac events
TAFRO syndrome is defined as a subtype of idiopathic multicentric Castleman’s disease (iMCD) that has been recognized as having a severe clinical course. Masaki et al. proposed the diagnostic criteria and severity classification in 2015, and there have been several recently reported clinicopathological analyses and consensus guidelines for the treatment of iMCD based on the accumulated data [2–5]. Our case fulfilled the diagnostic criteria of TAFRO syndrome according to the guideline, and was classified as grade 4 (severe) severity. Our case is rare not only because of many life-threating events such as repetitive severe infections, sick sinus syndrome and cardiac arrest, but also because of the myocardial and skeletal muscle calcification that occurred two months after his disease onset. Other cases have also survived despite a very severe clinical course [9–11], although none of them experienced systemic calcification.
Many TAFRO syndrome cases have recovered with the use of biological products (such as tocilizumab or rituximab), glucocorticoids, immunosuppressants (such as cyclosporine A or sirolimus), and occasionally, with chemotherapy. In terms of cardiac dysfunction, Yasuda et al. reported two cases of TAFRO syndrome with cardiomyopathy and lowered ejection fraction (EF) [6]. They performed CHOP (cyclophosphamide, adriamycin, vincristine and prednisolone) therapy as treatment, and assumed that the cardiomyopathy was an adverse effect of adriamycin. Hiramatsu et al. showed a case of TAFRO syndrome with reversible cardiomyopathy, in which they opined that the high concentration of plasma IL-6 was the cause of cardiomyopathy [7]. However, these cases did not have any associated calcification.
The etiology of myocardial/systemic calcification
Myocardial calcification itself only occurs very rarely. There are traditionally two pathways causing myocardial calcification: metastatic and dystrophic. Metastatic calcification occurs with hypercalcemia and/or abnormality of calcium/phosphate metabolism [12]. This form of calcification can occur anywhere in the body, but is more likely in areas of high alkalinity, such as the gastric mucosa or systemic arteries; therefore, calcification due to this etiology can exist systemically. On the other hand, dystrophic calcification occurs secondary to cellular damage and necrosis, with calcium deposits replacing necrotizing cells. Other etiologies of dystrophic calcification include trauma, infections, inflammation, neoplasms and drugs [12]. Myocardial infarction is a common cause of myocardial calcification. Septic shock is also a cause of this form of calcification; hypotension during shock and catecholamine use can cause myocardial damage, which eventually results in calcium deposits even if plasma calcium concentration is normal [12, 13]. In our case, the etiology of myocardial and skeletal muscle calcification was considered more likely to be metastatic than dystrophic due to the following reasons. First, there was a failure of calcium/phosphate metabolism due to the presence of progressive renal dysfunction with hemodialysis and low vitamin D levels. There was also excessive replenishment of calcium, with an amount of 7.8 mmol of calcium gluconate hydrate per day on average, which could have accelerated calcium deposition in systemic tissues. We did not administer intravenous vitamin D agents, except for the minimal amount of vitamins administered through total parenteral nutrition, which might have been a possible cause for prolonged low calcium levels. Second, both myocardial and skeletal muscle calcification were detected on CT scans at the same time, which was within a month after the initial identification of hypocalcemia and subsequent overloading of calcium (Fig. 3). Third, although we temporarily used catecholamines, there were no other conditions explaining the dystrophic calcification, such as septic shock or myocardial infarction. Fourth, hypercytokinemia, including elevated IL-6 caused by TAFRO syndrome, could also have contributed to this unusual situation. Plasma calcium levels remained low and were almost unchanged when calcium gluconate hydrate was administered, which suggested that the administered calcium probably leaked out of the vessels and was absorbed by peripheral tissues. Increase of vasopermeability is another possible etiology for the calcified deposits, which could explain its occurrence in the absence of hypercalcemia.
In conclusion, this case of TAFRO syndrome achieved a successful recovery with tocilizumab therapy along with prolonged hospitalization, although he experienced the unexpected complication of myocardial and skeletal muscle calcification probably via a metastatic pathway triggered by drug administration. In acute clinical settings, the tendency is to urgently correct abnormal laboratory data, especially electrolyte abnormalities. However, TAFRO syndrome is known to be associated with hypercytokinemia and organ dysfunction with an unknown pathophysiology; hence, the general management of such cases should be carefully handled, anticipating unexpected complications.
Abbreviations
TAFROThrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly
iMCDIdiopathic multicentric Castleman’s disease
CTComputed tomography
IL-6Interleukin-6
CHOPCyclophosphamide, adriamycin, vincristine and prednisolone
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors thank Forte Science Communications (www.forte-science.co.jp) for their assistance in proofreading this article.
Authors’ contributions
SM treated this patient, reviewed literature, interpreted the patient data about the etiology in this patient, and contributed to writing the manuscript. YF reviewed literature, wrote the manuscript, and managed this research. SS treated this patient and wrote the manuscript. AT provided professional opinions regarding patient care and treatment, and revised the manuscript. KN revised the manuscript and currently cares for this patient at the outpatient clinic. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Ethics approval and consent for submitting case reports is usually waived by the ethics review committee of Musashino Red Cross Hospital. We followed the principles of the Declaration of Helsinki and paid cautious attention to protecting the patient’s identity.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | CALCIUM GLUCONATE, METHYLPREDNISOLONE, TOCILIZUMAB | DrugsGivenReaction | CC BY | 33402219 | 19,396,568 | 2021-01-06 |
What was the administration route of drug 'CALCIUM GLUCONATE'? | A severe case of thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly syndrome with myocardial and skeletal muscle calcification despite hypocalcemia: a case report.
BACKGROUND
TAFRO (thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly) syndrome is a recently recognized disease with a variety of presentations of variable severity. In acute settings, this disease also involves organ dysfunction because of the associated systemic inflammation. However, cases of TAFRO syndrome with myocardial and/or skeletal muscle calcification have never been reported.
METHODS
A 24-year-old healthy young Asian man was admitted with intermittent epigastric pain and fever for 2 weeks. Computed tomography revealed pleural effusion, ascites and systemic lymphadenopathy. Laboratory tests showed thrombocytopenia, elevated C-reactive protein, hypoalbuminemia, anemia and renal dysfunction. Based on these findings and bone marrow biopsy, we diagnosed his disease as TAFRO syndrome and commenced hemodialysis for the renal dysfunction. However, he developed refractory hypocalcemia with unstable vital signs, for which we administered calcium gluconate hydrate. Thereafter, myocardial and skeletal muscle calcification was revealed radiologically, with the myocardial calcification causing sick sinus syndrome. He was treated with tocilizumab and finally discharged in an ambulatory condition after prolonged hospitalization, with residual calcific lesions.
CONCLUSIONS
This is the first report of a patient with TAFRO syndrome and the complication of organ calcification. The etiology of calcification in this case is not clear. Systemic inflammation with possible hypercytokinemia might have been involved in the unexpected complication of systemic calcification. It is important to carefully handle the general management of TAFRO syndrome because of the possibility of various complications.
Background
TAFRO (thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, organomegaly) syndrome is a systemic inflammatory disease first reported by Takai et al. in 2010 [1], and is categorized as a subtype of idiopathic multicentric Castleman’s disease (iMCD). TAFRO syndrome follows a particularly aggressive clinical course compared to unicentric Castleman’s disease or other subtypes of iMCD. Therefore, clinicians often experience difficulty in treating this condition. Since its earliest description, reports of cases of TAFRO syndrome have been described worldwide, and guidelines for its treatment have been proposed [2–5]. Since organ dysfunction is commonly seen with TAFRO syndrome, temporary hemodialysis is often necessary during the course of treatment of this condition [2], although no case reports have described calcific deposits associated with hemodialysis. Additionally, although several cases with severe cardiac dysfunction due to chemotherapy, hypercytokinemia and massive ascites have been reported [6–8], there have been no cases of gross calcification recognized radiologically, either in the myocardium or in skeletal muscles.
We report a case of TAFRO syndrome with myocardial and skeletal muscle calcification, who was finally discharged from the hospital in an ambulatory condition following tocilizumab therapy. Our patient also presented with severe hypocalcemia during his clinical course, the treatment of which might have eventually triggered systemic calcification. Although it is difficult to completely understand the etiological mechanism in this case, our experience will contribute to understanding the pathophysiology and general management of TAFRO syndrome.
Case presentation
A previously healthy 24-year-old Asian man without significant family medical history presented with intermittent severe epigastric pain and fever for two weeks. Since a computed tomography (CT) scan at another hospital had only revealed systemic lymphadenopathy and could not detect any cause for his symptoms, he was referred to our hospital for further investigation. On admission, he was febrile (37.4 °C). Physical examination showed epigastric tenderness without signs of peritoneal irritation, and pitting edema on the lower extremities. His laboratory test results on admission are shown in Table 1. Contrast-enhanced CT scan revealed cervical, supraclavicular, axillary, paraaortic and inguinal lymphadenopathies, bilateral pleural effusion, ascites and hepatosplenomegaly. Soon after his admission, hemodialysis and mechanical ventilation were initiated due to the development of anuria and dyspnea, and methylprednisolone pulse therapy (1 g/day) was administered for three days after ruling out bacterial infections on hospital day 9, followed by intravenous methylprednisolone (50 mg/day) as maintenance therapy. Laboratory data on hospital day 11 are shown in Table 2. In spite of hemodialysis and ventilatory support, his vital signs were unstable, necessitating temporary use of catecholamines to maintain his blood pressure. Additionally, his plasma calcium level decreased (ionized calcium: 0.78 mmol/L) with a high level of phosphorus (9.6 mg/dL) on hospital day 17. Subsequently, we intravenously administered calcium gluconate hydrate for a total of eight days because the hypocalcemia was refractory to therapy. Laboratory data indicated low vitamin D and high intact parathyroid hormone levels, as seen in patients with chronic kidney disease. Finally, his plasma calcium levels were maintained within the normal range (Fig. 1). Bone marrow biopsy revealed hypercellular marrow with an increased number of megakaryocytes (Fig. 2). Based on these findings and exclusion criteria, we diagnosed his condition as TAFRO syndrome according to the diagnostic criteria proposed in 2015 [3].Table 1 Laboratory data on admission
Complete blood cell count Blood chemistry
WBC 14,100 /μL Total protein 5.1 g/dL
Seg 83 % Albumin 1.8 g/dL
Eosino 1 % T.Bil 1.0 mg/dL
Lympho 7 % AST 29 IU/L
Mono 9 % ALT 14 IU/L
RBC 413 104/μL LDH 370 IU/L
Hgb 13.5 g/dL ALP 265 IU/L
MCV 86.2 fL γ-GTP 105 IU/L
Platelet 46.8 104/μL BUN 43.1 mg/dL
Cr 1.62 mg/dL
Coagulation system eGFR 46 mL/min/1.73m2
PT 18.2 sec CRP 25.37 mg/dL
PT-INR 1.51 Glu 78 mg/dL
APTT (standard: 26-36) 47.9 sec AMY 39 IU/L
Fibrinogen >600 mg/dL
D-dimer 26.9 μg/mL
WBC White blood cell, RBC Red blood cell, Hgb Hemoglobin, MCV Mean corpuscular volume, PT Prothrombin time, PT-INR Prothrombin time-international normalized ratio, APTT Activated partial thromboplastin time, T.Bil Total Bilirubin, AST Aspartate aminotransferase, ALT Alanine aminotransferase, LDH Lactate dehydrogenase, ALP Alkaline phosphatase, BUN Blood urea nitrogen, Cr Creatinine, CRP C-reactive protein, AMY Amylase
Table 2 Laboratory data at the time of diagnosis of TAFRO syndrome
Complete blood cell count Blood chemistry Immunologic test
WBC 23,600 /μL Albumin 1.5 g/dL IgG 1385 mg/dL
Band 6 % T.Bil 0.4 mg/dL IgG4 66 mg/dL
Seg 88 % AST 33 IU/L IgA 187 mg/dL
Lympho 3 % ALT 12 IU/L IgM 62 mg/dL
Mono 3 % LDH 471 IU/L ANA <40 times
RBC 348 104/μL γ-GTP 266 IU/L anti-RNP Ab –
Hgb 9.9 g/dL ALP 400 IU/L anti-ds-DNA IgG –
MCV 86.8 fL BUN 119.5 mg/dL anti-SS-A Ab –
Platelet 7.5 104/μL Cr 7.77 mg/dL RF <3 IU/mL
ESR 87 mm/hr CRP 36.35 mg/dL PR3-ANCA <1 IU/mL
Ferritin 1873 ng/mL MPO-ANCA <1 IU/mL
ACE 7.6 IU/L Coombs test –
Haptoglobin 311 mg/dL PA-IgG 70 ng/107cells
Infectious diseases ADAMTS-13 28 %
EBV VCA IgG + Coagulation system anti-GBM Ab <2 U/mL
EBV VCA IgM - PT 19 Sec sIL-2R 1260 U/mL
EBNA IgG + PT-INR 1.59 IL-6 65.1 pg/mL
CMV C7-HRP - APTT >80 Sec VEGF 1030 pg/mL
(Standard: 26-36)
HIV antigen/Ab - Fibrinogen >600 mg/dL
HHV-8 DNA (WBC106cells) <20 AT-III 58 %
IGRA – FDP 66 μg/mL
WBC White blood cell, RBC Red blood cell, Hgb Hemoglobin, MCV Mean corpuscular volume, ESR Erythrocyte sedimentation rate, EBV Epstein–Barr virus, VCA Virus capsid antigen, EBNA Epstein–Barr virus nuclear antigen, CMV Cytomegalovirus, HIV Human immunodeficiency virus, Ab Antibody, HHV-8 Human herpesvirus-8, IGRA Interferon-gamma releasing assay, T.Bil Total Bilirubin, AST Aspartate aminotransferase, ALT Alanine aminotransferase, LDH Lactate dehydrogenase, γ-GTP Gamma-glutamyl transpeptidase, ALP Alkaline phosphatase, BUN Blood urea nitrogen, Cr Creatinine, CRP C-reactive protein, ACE Angiotensin-converting enzyme, PT Prothrombin time, PT-INR Prothrombin time-international normalized ratio, APTT Activated partial thromboplastin time, AT-III Antithrombin III, FDP Fibrin/fibrinogen degradation products, ANA Antinuclear antibody, anti-RNP-antibody Anti-ribonucleoprotein antibody, anti-ds-DNA IgG Anti-double-stranded deoxyribonuclein acid immunoglobulin G, anti-SS-A antibody Anti-Sjören's syndrome A antibody, RF Rheumatoid factor, PR3-ANCA Proteinase 3-anti-neutrophil cytoplasmic antibody, MPO-ANCA Myeloperoxidase-anti-neutrophil cytoplasmic antibody, PA-IgG Platelet-associated immunoglobulin G, anti-GBM antibody Anti-glomerular basement membrane antibody, sIL-2R Soluble interleukin-2 receptor, IL-6 Interleukin-6, VEGF Vascular endothelial growth factor
Fig. 1 Transition of ionized calcium. Hypocalcemia appeared after the initiation of dialysis, and myocardial/skeletal muscle calcification was revealed on CT scans after the recovery from hypocalcemia with administration of calcium gluconate hydrate
Fig. 2 Histological findings on bone marrow biopsy. a, b Hypercellular marrow with increased megakaryocytes are seen. (Hematoxylin and eosin staining). (Scale bar, 100 μm)
We initiated weekly treatment with the biologic tocilizumab (8 mg/kg), which is a recombinant, humanized, anti-human interleukin-6 (IL-6) receptor monoclonal antibody, along with tapering glucocorticoids on hospital day 32. However, on hospital day 76, he presented with syncope due to sick sinus syndrome. We first recognized myocardial and skeletal muscle calcification by CT scans on hospital day 47 (Fig. 3). Subsequent CTs showed progressive worsening of the degree of calcification in the first few months (Fig. 4). At this time, we could not perform temporary pacing because of the risk of hemorrhage due to persistently low platelet levels and coagulopathy.Fig. 3 Myocardial and skeletal muscle calcification noted on computed tomography scans for the first time. a High density areas were present on the myocardium (arrows). b, c The rectus abdominis muscle and those of the thigh (arrows) showed high density bilaterally
Fig. 4 Chronological changes in myocardial and skeletal muscle (rectus abdominis) calcification on computed tomography images. Computed tomography was performed on (a, e) day 47, (b, f) day 123, (c, g) day 177 and (d, h) day 345. The degree of calcification showed progressive worsening during the first few months; subsequently, myocardial calcification remained unchanged, while that in the skeletal muscle gradually diminished
Although he repeatedly suffered from various infections (such as catheter related blood stream infection, pyothorax, intraabdominal abscess and infectious endocarditis), we basically continued use of tocilizumab, except when the infection was very severe. We initiated romiplostim, an analog of thrombopoietin, on day 173 because his platelet count remained persistently low, which soon resulted in recovery of platelet count to within the normal range. In addition, urine volume began to gradually increase five months after the onset of anuria. Thereafter, calcification of the rectus abdominis muscle also began to gradually diminish, as observed by CT scans, although there were no remarkable changes in that of the myocardium (Fig. 4).
Although there were many life-threatening events throughout his prolonged hospitalization, he was finally discharged from the hospital in an ambulatory condition on hospital day 410 (his complete clinical course is shown in Fig. 5). Sick sinus syndrome resolved together with improvement in his general condition, so permanent pacemaker implantation was deemed unnecessary. Currently, he receives regular hemodialysis and intravenous tocilizumab every three weeks without evidence of recurrence for one year after discharge.Fig. 5 Clinical course from admission until discharge. PLT platelets, CRP C-reactive protein, mPSL methylprednisolone, TCZ tocilizumab, HD hemodialysis, CRBSI catheter-related blood stream infection, IE infectious endocarditis, SSS sick sinus syndrome
Discussion
TAFRO syndrome and cardiac events
TAFRO syndrome is defined as a subtype of idiopathic multicentric Castleman’s disease (iMCD) that has been recognized as having a severe clinical course. Masaki et al. proposed the diagnostic criteria and severity classification in 2015, and there have been several recently reported clinicopathological analyses and consensus guidelines for the treatment of iMCD based on the accumulated data [2–5]. Our case fulfilled the diagnostic criteria of TAFRO syndrome according to the guideline, and was classified as grade 4 (severe) severity. Our case is rare not only because of many life-threating events such as repetitive severe infections, sick sinus syndrome and cardiac arrest, but also because of the myocardial and skeletal muscle calcification that occurred two months after his disease onset. Other cases have also survived despite a very severe clinical course [9–11], although none of them experienced systemic calcification.
Many TAFRO syndrome cases have recovered with the use of biological products (such as tocilizumab or rituximab), glucocorticoids, immunosuppressants (such as cyclosporine A or sirolimus), and occasionally, with chemotherapy. In terms of cardiac dysfunction, Yasuda et al. reported two cases of TAFRO syndrome with cardiomyopathy and lowered ejection fraction (EF) [6]. They performed CHOP (cyclophosphamide, adriamycin, vincristine and prednisolone) therapy as treatment, and assumed that the cardiomyopathy was an adverse effect of adriamycin. Hiramatsu et al. showed a case of TAFRO syndrome with reversible cardiomyopathy, in which they opined that the high concentration of plasma IL-6 was the cause of cardiomyopathy [7]. However, these cases did not have any associated calcification.
The etiology of myocardial/systemic calcification
Myocardial calcification itself only occurs very rarely. There are traditionally two pathways causing myocardial calcification: metastatic and dystrophic. Metastatic calcification occurs with hypercalcemia and/or abnormality of calcium/phosphate metabolism [12]. This form of calcification can occur anywhere in the body, but is more likely in areas of high alkalinity, such as the gastric mucosa or systemic arteries; therefore, calcification due to this etiology can exist systemically. On the other hand, dystrophic calcification occurs secondary to cellular damage and necrosis, with calcium deposits replacing necrotizing cells. Other etiologies of dystrophic calcification include trauma, infections, inflammation, neoplasms and drugs [12]. Myocardial infarction is a common cause of myocardial calcification. Septic shock is also a cause of this form of calcification; hypotension during shock and catecholamine use can cause myocardial damage, which eventually results in calcium deposits even if plasma calcium concentration is normal [12, 13]. In our case, the etiology of myocardial and skeletal muscle calcification was considered more likely to be metastatic than dystrophic due to the following reasons. First, there was a failure of calcium/phosphate metabolism due to the presence of progressive renal dysfunction with hemodialysis and low vitamin D levels. There was also excessive replenishment of calcium, with an amount of 7.8 mmol of calcium gluconate hydrate per day on average, which could have accelerated calcium deposition in systemic tissues. We did not administer intravenous vitamin D agents, except for the minimal amount of vitamins administered through total parenteral nutrition, which might have been a possible cause for prolonged low calcium levels. Second, both myocardial and skeletal muscle calcification were detected on CT scans at the same time, which was within a month after the initial identification of hypocalcemia and subsequent overloading of calcium (Fig. 3). Third, although we temporarily used catecholamines, there were no other conditions explaining the dystrophic calcification, such as septic shock or myocardial infarction. Fourth, hypercytokinemia, including elevated IL-6 caused by TAFRO syndrome, could also have contributed to this unusual situation. Plasma calcium levels remained low and were almost unchanged when calcium gluconate hydrate was administered, which suggested that the administered calcium probably leaked out of the vessels and was absorbed by peripheral tissues. Increase of vasopermeability is another possible etiology for the calcified deposits, which could explain its occurrence in the absence of hypercalcemia.
In conclusion, this case of TAFRO syndrome achieved a successful recovery with tocilizumab therapy along with prolonged hospitalization, although he experienced the unexpected complication of myocardial and skeletal muscle calcification probably via a metastatic pathway triggered by drug administration. In acute clinical settings, the tendency is to urgently correct abnormal laboratory data, especially electrolyte abnormalities. However, TAFRO syndrome is known to be associated with hypercytokinemia and organ dysfunction with an unknown pathophysiology; hence, the general management of such cases should be carefully handled, anticipating unexpected complications.
Abbreviations
TAFROThrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly
iMCDIdiopathic multicentric Castleman’s disease
CTComputed tomography
IL-6Interleukin-6
CHOPCyclophosphamide, adriamycin, vincristine and prednisolone
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors thank Forte Science Communications (www.forte-science.co.jp) for their assistance in proofreading this article.
Authors’ contributions
SM treated this patient, reviewed literature, interpreted the patient data about the etiology in this patient, and contributed to writing the manuscript. YF reviewed literature, wrote the manuscript, and managed this research. SS treated this patient and wrote the manuscript. AT provided professional opinions regarding patient care and treatment, and revised the manuscript. KN revised the manuscript and currently cares for this patient at the outpatient clinic. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Ethics approval and consent for submitting case reports is usually waived by the ethics review committee of Musashino Red Cross Hospital. We followed the principles of the Declaration of Helsinki and paid cautious attention to protecting the patient’s identity.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33402219 | 19,396,568 | 2021-01-06 |
What was the administration route of drug 'METHYLPREDNISOLONE'? | A severe case of thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly syndrome with myocardial and skeletal muscle calcification despite hypocalcemia: a case report.
BACKGROUND
TAFRO (thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly) syndrome is a recently recognized disease with a variety of presentations of variable severity. In acute settings, this disease also involves organ dysfunction because of the associated systemic inflammation. However, cases of TAFRO syndrome with myocardial and/or skeletal muscle calcification have never been reported.
METHODS
A 24-year-old healthy young Asian man was admitted with intermittent epigastric pain and fever for 2 weeks. Computed tomography revealed pleural effusion, ascites and systemic lymphadenopathy. Laboratory tests showed thrombocytopenia, elevated C-reactive protein, hypoalbuminemia, anemia and renal dysfunction. Based on these findings and bone marrow biopsy, we diagnosed his disease as TAFRO syndrome and commenced hemodialysis for the renal dysfunction. However, he developed refractory hypocalcemia with unstable vital signs, for which we administered calcium gluconate hydrate. Thereafter, myocardial and skeletal muscle calcification was revealed radiologically, with the myocardial calcification causing sick sinus syndrome. He was treated with tocilizumab and finally discharged in an ambulatory condition after prolonged hospitalization, with residual calcific lesions.
CONCLUSIONS
This is the first report of a patient with TAFRO syndrome and the complication of organ calcification. The etiology of calcification in this case is not clear. Systemic inflammation with possible hypercytokinemia might have been involved in the unexpected complication of systemic calcification. It is important to carefully handle the general management of TAFRO syndrome because of the possibility of various complications.
Background
TAFRO (thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, organomegaly) syndrome is a systemic inflammatory disease first reported by Takai et al. in 2010 [1], and is categorized as a subtype of idiopathic multicentric Castleman’s disease (iMCD). TAFRO syndrome follows a particularly aggressive clinical course compared to unicentric Castleman’s disease or other subtypes of iMCD. Therefore, clinicians often experience difficulty in treating this condition. Since its earliest description, reports of cases of TAFRO syndrome have been described worldwide, and guidelines for its treatment have been proposed [2–5]. Since organ dysfunction is commonly seen with TAFRO syndrome, temporary hemodialysis is often necessary during the course of treatment of this condition [2], although no case reports have described calcific deposits associated with hemodialysis. Additionally, although several cases with severe cardiac dysfunction due to chemotherapy, hypercytokinemia and massive ascites have been reported [6–8], there have been no cases of gross calcification recognized radiologically, either in the myocardium or in skeletal muscles.
We report a case of TAFRO syndrome with myocardial and skeletal muscle calcification, who was finally discharged from the hospital in an ambulatory condition following tocilizumab therapy. Our patient also presented with severe hypocalcemia during his clinical course, the treatment of which might have eventually triggered systemic calcification. Although it is difficult to completely understand the etiological mechanism in this case, our experience will contribute to understanding the pathophysiology and general management of TAFRO syndrome.
Case presentation
A previously healthy 24-year-old Asian man without significant family medical history presented with intermittent severe epigastric pain and fever for two weeks. Since a computed tomography (CT) scan at another hospital had only revealed systemic lymphadenopathy and could not detect any cause for his symptoms, he was referred to our hospital for further investigation. On admission, he was febrile (37.4 °C). Physical examination showed epigastric tenderness without signs of peritoneal irritation, and pitting edema on the lower extremities. His laboratory test results on admission are shown in Table 1. Contrast-enhanced CT scan revealed cervical, supraclavicular, axillary, paraaortic and inguinal lymphadenopathies, bilateral pleural effusion, ascites and hepatosplenomegaly. Soon after his admission, hemodialysis and mechanical ventilation were initiated due to the development of anuria and dyspnea, and methylprednisolone pulse therapy (1 g/day) was administered for three days after ruling out bacterial infections on hospital day 9, followed by intravenous methylprednisolone (50 mg/day) as maintenance therapy. Laboratory data on hospital day 11 are shown in Table 2. In spite of hemodialysis and ventilatory support, his vital signs were unstable, necessitating temporary use of catecholamines to maintain his blood pressure. Additionally, his plasma calcium level decreased (ionized calcium: 0.78 mmol/L) with a high level of phosphorus (9.6 mg/dL) on hospital day 17. Subsequently, we intravenously administered calcium gluconate hydrate for a total of eight days because the hypocalcemia was refractory to therapy. Laboratory data indicated low vitamin D and high intact parathyroid hormone levels, as seen in patients with chronic kidney disease. Finally, his plasma calcium levels were maintained within the normal range (Fig. 1). Bone marrow biopsy revealed hypercellular marrow with an increased number of megakaryocytes (Fig. 2). Based on these findings and exclusion criteria, we diagnosed his condition as TAFRO syndrome according to the diagnostic criteria proposed in 2015 [3].Table 1 Laboratory data on admission
Complete blood cell count Blood chemistry
WBC 14,100 /μL Total protein 5.1 g/dL
Seg 83 % Albumin 1.8 g/dL
Eosino 1 % T.Bil 1.0 mg/dL
Lympho 7 % AST 29 IU/L
Mono 9 % ALT 14 IU/L
RBC 413 104/μL LDH 370 IU/L
Hgb 13.5 g/dL ALP 265 IU/L
MCV 86.2 fL γ-GTP 105 IU/L
Platelet 46.8 104/μL BUN 43.1 mg/dL
Cr 1.62 mg/dL
Coagulation system eGFR 46 mL/min/1.73m2
PT 18.2 sec CRP 25.37 mg/dL
PT-INR 1.51 Glu 78 mg/dL
APTT (standard: 26-36) 47.9 sec AMY 39 IU/L
Fibrinogen >600 mg/dL
D-dimer 26.9 μg/mL
WBC White blood cell, RBC Red blood cell, Hgb Hemoglobin, MCV Mean corpuscular volume, PT Prothrombin time, PT-INR Prothrombin time-international normalized ratio, APTT Activated partial thromboplastin time, T.Bil Total Bilirubin, AST Aspartate aminotransferase, ALT Alanine aminotransferase, LDH Lactate dehydrogenase, ALP Alkaline phosphatase, BUN Blood urea nitrogen, Cr Creatinine, CRP C-reactive protein, AMY Amylase
Table 2 Laboratory data at the time of diagnosis of TAFRO syndrome
Complete blood cell count Blood chemistry Immunologic test
WBC 23,600 /μL Albumin 1.5 g/dL IgG 1385 mg/dL
Band 6 % T.Bil 0.4 mg/dL IgG4 66 mg/dL
Seg 88 % AST 33 IU/L IgA 187 mg/dL
Lympho 3 % ALT 12 IU/L IgM 62 mg/dL
Mono 3 % LDH 471 IU/L ANA <40 times
RBC 348 104/μL γ-GTP 266 IU/L anti-RNP Ab –
Hgb 9.9 g/dL ALP 400 IU/L anti-ds-DNA IgG –
MCV 86.8 fL BUN 119.5 mg/dL anti-SS-A Ab –
Platelet 7.5 104/μL Cr 7.77 mg/dL RF <3 IU/mL
ESR 87 mm/hr CRP 36.35 mg/dL PR3-ANCA <1 IU/mL
Ferritin 1873 ng/mL MPO-ANCA <1 IU/mL
ACE 7.6 IU/L Coombs test –
Haptoglobin 311 mg/dL PA-IgG 70 ng/107cells
Infectious diseases ADAMTS-13 28 %
EBV VCA IgG + Coagulation system anti-GBM Ab <2 U/mL
EBV VCA IgM - PT 19 Sec sIL-2R 1260 U/mL
EBNA IgG + PT-INR 1.59 IL-6 65.1 pg/mL
CMV C7-HRP - APTT >80 Sec VEGF 1030 pg/mL
(Standard: 26-36)
HIV antigen/Ab - Fibrinogen >600 mg/dL
HHV-8 DNA (WBC106cells) <20 AT-III 58 %
IGRA – FDP 66 μg/mL
WBC White blood cell, RBC Red blood cell, Hgb Hemoglobin, MCV Mean corpuscular volume, ESR Erythrocyte sedimentation rate, EBV Epstein–Barr virus, VCA Virus capsid antigen, EBNA Epstein–Barr virus nuclear antigen, CMV Cytomegalovirus, HIV Human immunodeficiency virus, Ab Antibody, HHV-8 Human herpesvirus-8, IGRA Interferon-gamma releasing assay, T.Bil Total Bilirubin, AST Aspartate aminotransferase, ALT Alanine aminotransferase, LDH Lactate dehydrogenase, γ-GTP Gamma-glutamyl transpeptidase, ALP Alkaline phosphatase, BUN Blood urea nitrogen, Cr Creatinine, CRP C-reactive protein, ACE Angiotensin-converting enzyme, PT Prothrombin time, PT-INR Prothrombin time-international normalized ratio, APTT Activated partial thromboplastin time, AT-III Antithrombin III, FDP Fibrin/fibrinogen degradation products, ANA Antinuclear antibody, anti-RNP-antibody Anti-ribonucleoprotein antibody, anti-ds-DNA IgG Anti-double-stranded deoxyribonuclein acid immunoglobulin G, anti-SS-A antibody Anti-Sjören's syndrome A antibody, RF Rheumatoid factor, PR3-ANCA Proteinase 3-anti-neutrophil cytoplasmic antibody, MPO-ANCA Myeloperoxidase-anti-neutrophil cytoplasmic antibody, PA-IgG Platelet-associated immunoglobulin G, anti-GBM antibody Anti-glomerular basement membrane antibody, sIL-2R Soluble interleukin-2 receptor, IL-6 Interleukin-6, VEGF Vascular endothelial growth factor
Fig. 1 Transition of ionized calcium. Hypocalcemia appeared after the initiation of dialysis, and myocardial/skeletal muscle calcification was revealed on CT scans after the recovery from hypocalcemia with administration of calcium gluconate hydrate
Fig. 2 Histological findings on bone marrow biopsy. a, b Hypercellular marrow with increased megakaryocytes are seen. (Hematoxylin and eosin staining). (Scale bar, 100 μm)
We initiated weekly treatment with the biologic tocilizumab (8 mg/kg), which is a recombinant, humanized, anti-human interleukin-6 (IL-6) receptor monoclonal antibody, along with tapering glucocorticoids on hospital day 32. However, on hospital day 76, he presented with syncope due to sick sinus syndrome. We first recognized myocardial and skeletal muscle calcification by CT scans on hospital day 47 (Fig. 3). Subsequent CTs showed progressive worsening of the degree of calcification in the first few months (Fig. 4). At this time, we could not perform temporary pacing because of the risk of hemorrhage due to persistently low platelet levels and coagulopathy.Fig. 3 Myocardial and skeletal muscle calcification noted on computed tomography scans for the first time. a High density areas were present on the myocardium (arrows). b, c The rectus abdominis muscle and those of the thigh (arrows) showed high density bilaterally
Fig. 4 Chronological changes in myocardial and skeletal muscle (rectus abdominis) calcification on computed tomography images. Computed tomography was performed on (a, e) day 47, (b, f) day 123, (c, g) day 177 and (d, h) day 345. The degree of calcification showed progressive worsening during the first few months; subsequently, myocardial calcification remained unchanged, while that in the skeletal muscle gradually diminished
Although he repeatedly suffered from various infections (such as catheter related blood stream infection, pyothorax, intraabdominal abscess and infectious endocarditis), we basically continued use of tocilizumab, except when the infection was very severe. We initiated romiplostim, an analog of thrombopoietin, on day 173 because his platelet count remained persistently low, which soon resulted in recovery of platelet count to within the normal range. In addition, urine volume began to gradually increase five months after the onset of anuria. Thereafter, calcification of the rectus abdominis muscle also began to gradually diminish, as observed by CT scans, although there were no remarkable changes in that of the myocardium (Fig. 4).
Although there were many life-threatening events throughout his prolonged hospitalization, he was finally discharged from the hospital in an ambulatory condition on hospital day 410 (his complete clinical course is shown in Fig. 5). Sick sinus syndrome resolved together with improvement in his general condition, so permanent pacemaker implantation was deemed unnecessary. Currently, he receives regular hemodialysis and intravenous tocilizumab every three weeks without evidence of recurrence for one year after discharge.Fig. 5 Clinical course from admission until discharge. PLT platelets, CRP C-reactive protein, mPSL methylprednisolone, TCZ tocilizumab, HD hemodialysis, CRBSI catheter-related blood stream infection, IE infectious endocarditis, SSS sick sinus syndrome
Discussion
TAFRO syndrome and cardiac events
TAFRO syndrome is defined as a subtype of idiopathic multicentric Castleman’s disease (iMCD) that has been recognized as having a severe clinical course. Masaki et al. proposed the diagnostic criteria and severity classification in 2015, and there have been several recently reported clinicopathological analyses and consensus guidelines for the treatment of iMCD based on the accumulated data [2–5]. Our case fulfilled the diagnostic criteria of TAFRO syndrome according to the guideline, and was classified as grade 4 (severe) severity. Our case is rare not only because of many life-threating events such as repetitive severe infections, sick sinus syndrome and cardiac arrest, but also because of the myocardial and skeletal muscle calcification that occurred two months after his disease onset. Other cases have also survived despite a very severe clinical course [9–11], although none of them experienced systemic calcification.
Many TAFRO syndrome cases have recovered with the use of biological products (such as tocilizumab or rituximab), glucocorticoids, immunosuppressants (such as cyclosporine A or sirolimus), and occasionally, with chemotherapy. In terms of cardiac dysfunction, Yasuda et al. reported two cases of TAFRO syndrome with cardiomyopathy and lowered ejection fraction (EF) [6]. They performed CHOP (cyclophosphamide, adriamycin, vincristine and prednisolone) therapy as treatment, and assumed that the cardiomyopathy was an adverse effect of adriamycin. Hiramatsu et al. showed a case of TAFRO syndrome with reversible cardiomyopathy, in which they opined that the high concentration of plasma IL-6 was the cause of cardiomyopathy [7]. However, these cases did not have any associated calcification.
The etiology of myocardial/systemic calcification
Myocardial calcification itself only occurs very rarely. There are traditionally two pathways causing myocardial calcification: metastatic and dystrophic. Metastatic calcification occurs with hypercalcemia and/or abnormality of calcium/phosphate metabolism [12]. This form of calcification can occur anywhere in the body, but is more likely in areas of high alkalinity, such as the gastric mucosa or systemic arteries; therefore, calcification due to this etiology can exist systemically. On the other hand, dystrophic calcification occurs secondary to cellular damage and necrosis, with calcium deposits replacing necrotizing cells. Other etiologies of dystrophic calcification include trauma, infections, inflammation, neoplasms and drugs [12]. Myocardial infarction is a common cause of myocardial calcification. Septic shock is also a cause of this form of calcification; hypotension during shock and catecholamine use can cause myocardial damage, which eventually results in calcium deposits even if plasma calcium concentration is normal [12, 13]. In our case, the etiology of myocardial and skeletal muscle calcification was considered more likely to be metastatic than dystrophic due to the following reasons. First, there was a failure of calcium/phosphate metabolism due to the presence of progressive renal dysfunction with hemodialysis and low vitamin D levels. There was also excessive replenishment of calcium, with an amount of 7.8 mmol of calcium gluconate hydrate per day on average, which could have accelerated calcium deposition in systemic tissues. We did not administer intravenous vitamin D agents, except for the minimal amount of vitamins administered through total parenteral nutrition, which might have been a possible cause for prolonged low calcium levels. Second, both myocardial and skeletal muscle calcification were detected on CT scans at the same time, which was within a month after the initial identification of hypocalcemia and subsequent overloading of calcium (Fig. 3). Third, although we temporarily used catecholamines, there were no other conditions explaining the dystrophic calcification, such as septic shock or myocardial infarction. Fourth, hypercytokinemia, including elevated IL-6 caused by TAFRO syndrome, could also have contributed to this unusual situation. Plasma calcium levels remained low and were almost unchanged when calcium gluconate hydrate was administered, which suggested that the administered calcium probably leaked out of the vessels and was absorbed by peripheral tissues. Increase of vasopermeability is another possible etiology for the calcified deposits, which could explain its occurrence in the absence of hypercalcemia.
In conclusion, this case of TAFRO syndrome achieved a successful recovery with tocilizumab therapy along with prolonged hospitalization, although he experienced the unexpected complication of myocardial and skeletal muscle calcification probably via a metastatic pathway triggered by drug administration. In acute clinical settings, the tendency is to urgently correct abnormal laboratory data, especially electrolyte abnormalities. However, TAFRO syndrome is known to be associated with hypercytokinemia and organ dysfunction with an unknown pathophysiology; hence, the general management of such cases should be carefully handled, anticipating unexpected complications.
Abbreviations
TAFROThrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly
iMCDIdiopathic multicentric Castleman’s disease
CTComputed tomography
IL-6Interleukin-6
CHOPCyclophosphamide, adriamycin, vincristine and prednisolone
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors thank Forte Science Communications (www.forte-science.co.jp) for their assistance in proofreading this article.
Authors’ contributions
SM treated this patient, reviewed literature, interpreted the patient data about the etiology in this patient, and contributed to writing the manuscript. YF reviewed literature, wrote the manuscript, and managed this research. SS treated this patient and wrote the manuscript. AT provided professional opinions regarding patient care and treatment, and revised the manuscript. KN revised the manuscript and currently cares for this patient at the outpatient clinic. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Ethics approval and consent for submitting case reports is usually waived by the ethics review committee of Musashino Red Cross Hospital. We followed the principles of the Declaration of Helsinki and paid cautious attention to protecting the patient’s identity.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33402219 | 19,396,568 | 2021-01-06 |
What was the dosage of drug 'METHYLPREDNISOLONE'? | A severe case of thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly syndrome with myocardial and skeletal muscle calcification despite hypocalcemia: a case report.
BACKGROUND
TAFRO (thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly) syndrome is a recently recognized disease with a variety of presentations of variable severity. In acute settings, this disease also involves organ dysfunction because of the associated systemic inflammation. However, cases of TAFRO syndrome with myocardial and/or skeletal muscle calcification have never been reported.
METHODS
A 24-year-old healthy young Asian man was admitted with intermittent epigastric pain and fever for 2 weeks. Computed tomography revealed pleural effusion, ascites and systemic lymphadenopathy. Laboratory tests showed thrombocytopenia, elevated C-reactive protein, hypoalbuminemia, anemia and renal dysfunction. Based on these findings and bone marrow biopsy, we diagnosed his disease as TAFRO syndrome and commenced hemodialysis for the renal dysfunction. However, he developed refractory hypocalcemia with unstable vital signs, for which we administered calcium gluconate hydrate. Thereafter, myocardial and skeletal muscle calcification was revealed radiologically, with the myocardial calcification causing sick sinus syndrome. He was treated with tocilizumab and finally discharged in an ambulatory condition after prolonged hospitalization, with residual calcific lesions.
CONCLUSIONS
This is the first report of a patient with TAFRO syndrome and the complication of organ calcification. The etiology of calcification in this case is not clear. Systemic inflammation with possible hypercytokinemia might have been involved in the unexpected complication of systemic calcification. It is important to carefully handle the general management of TAFRO syndrome because of the possibility of various complications.
Background
TAFRO (thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, organomegaly) syndrome is a systemic inflammatory disease first reported by Takai et al. in 2010 [1], and is categorized as a subtype of idiopathic multicentric Castleman’s disease (iMCD). TAFRO syndrome follows a particularly aggressive clinical course compared to unicentric Castleman’s disease or other subtypes of iMCD. Therefore, clinicians often experience difficulty in treating this condition. Since its earliest description, reports of cases of TAFRO syndrome have been described worldwide, and guidelines for its treatment have been proposed [2–5]. Since organ dysfunction is commonly seen with TAFRO syndrome, temporary hemodialysis is often necessary during the course of treatment of this condition [2], although no case reports have described calcific deposits associated with hemodialysis. Additionally, although several cases with severe cardiac dysfunction due to chemotherapy, hypercytokinemia and massive ascites have been reported [6–8], there have been no cases of gross calcification recognized radiologically, either in the myocardium or in skeletal muscles.
We report a case of TAFRO syndrome with myocardial and skeletal muscle calcification, who was finally discharged from the hospital in an ambulatory condition following tocilizumab therapy. Our patient also presented with severe hypocalcemia during his clinical course, the treatment of which might have eventually triggered systemic calcification. Although it is difficult to completely understand the etiological mechanism in this case, our experience will contribute to understanding the pathophysiology and general management of TAFRO syndrome.
Case presentation
A previously healthy 24-year-old Asian man without significant family medical history presented with intermittent severe epigastric pain and fever for two weeks. Since a computed tomography (CT) scan at another hospital had only revealed systemic lymphadenopathy and could not detect any cause for his symptoms, he was referred to our hospital for further investigation. On admission, he was febrile (37.4 °C). Physical examination showed epigastric tenderness without signs of peritoneal irritation, and pitting edema on the lower extremities. His laboratory test results on admission are shown in Table 1. Contrast-enhanced CT scan revealed cervical, supraclavicular, axillary, paraaortic and inguinal lymphadenopathies, bilateral pleural effusion, ascites and hepatosplenomegaly. Soon after his admission, hemodialysis and mechanical ventilation were initiated due to the development of anuria and dyspnea, and methylprednisolone pulse therapy (1 g/day) was administered for three days after ruling out bacterial infections on hospital day 9, followed by intravenous methylprednisolone (50 mg/day) as maintenance therapy. Laboratory data on hospital day 11 are shown in Table 2. In spite of hemodialysis and ventilatory support, his vital signs were unstable, necessitating temporary use of catecholamines to maintain his blood pressure. Additionally, his plasma calcium level decreased (ionized calcium: 0.78 mmol/L) with a high level of phosphorus (9.6 mg/dL) on hospital day 17. Subsequently, we intravenously administered calcium gluconate hydrate for a total of eight days because the hypocalcemia was refractory to therapy. Laboratory data indicated low vitamin D and high intact parathyroid hormone levels, as seen in patients with chronic kidney disease. Finally, his plasma calcium levels were maintained within the normal range (Fig. 1). Bone marrow biopsy revealed hypercellular marrow with an increased number of megakaryocytes (Fig. 2). Based on these findings and exclusion criteria, we diagnosed his condition as TAFRO syndrome according to the diagnostic criteria proposed in 2015 [3].Table 1 Laboratory data on admission
Complete blood cell count Blood chemistry
WBC 14,100 /μL Total protein 5.1 g/dL
Seg 83 % Albumin 1.8 g/dL
Eosino 1 % T.Bil 1.0 mg/dL
Lympho 7 % AST 29 IU/L
Mono 9 % ALT 14 IU/L
RBC 413 104/μL LDH 370 IU/L
Hgb 13.5 g/dL ALP 265 IU/L
MCV 86.2 fL γ-GTP 105 IU/L
Platelet 46.8 104/μL BUN 43.1 mg/dL
Cr 1.62 mg/dL
Coagulation system eGFR 46 mL/min/1.73m2
PT 18.2 sec CRP 25.37 mg/dL
PT-INR 1.51 Glu 78 mg/dL
APTT (standard: 26-36) 47.9 sec AMY 39 IU/L
Fibrinogen >600 mg/dL
D-dimer 26.9 μg/mL
WBC White blood cell, RBC Red blood cell, Hgb Hemoglobin, MCV Mean corpuscular volume, PT Prothrombin time, PT-INR Prothrombin time-international normalized ratio, APTT Activated partial thromboplastin time, T.Bil Total Bilirubin, AST Aspartate aminotransferase, ALT Alanine aminotransferase, LDH Lactate dehydrogenase, ALP Alkaline phosphatase, BUN Blood urea nitrogen, Cr Creatinine, CRP C-reactive protein, AMY Amylase
Table 2 Laboratory data at the time of diagnosis of TAFRO syndrome
Complete blood cell count Blood chemistry Immunologic test
WBC 23,600 /μL Albumin 1.5 g/dL IgG 1385 mg/dL
Band 6 % T.Bil 0.4 mg/dL IgG4 66 mg/dL
Seg 88 % AST 33 IU/L IgA 187 mg/dL
Lympho 3 % ALT 12 IU/L IgM 62 mg/dL
Mono 3 % LDH 471 IU/L ANA <40 times
RBC 348 104/μL γ-GTP 266 IU/L anti-RNP Ab –
Hgb 9.9 g/dL ALP 400 IU/L anti-ds-DNA IgG –
MCV 86.8 fL BUN 119.5 mg/dL anti-SS-A Ab –
Platelet 7.5 104/μL Cr 7.77 mg/dL RF <3 IU/mL
ESR 87 mm/hr CRP 36.35 mg/dL PR3-ANCA <1 IU/mL
Ferritin 1873 ng/mL MPO-ANCA <1 IU/mL
ACE 7.6 IU/L Coombs test –
Haptoglobin 311 mg/dL PA-IgG 70 ng/107cells
Infectious diseases ADAMTS-13 28 %
EBV VCA IgG + Coagulation system anti-GBM Ab <2 U/mL
EBV VCA IgM - PT 19 Sec sIL-2R 1260 U/mL
EBNA IgG + PT-INR 1.59 IL-6 65.1 pg/mL
CMV C7-HRP - APTT >80 Sec VEGF 1030 pg/mL
(Standard: 26-36)
HIV antigen/Ab - Fibrinogen >600 mg/dL
HHV-8 DNA (WBC106cells) <20 AT-III 58 %
IGRA – FDP 66 μg/mL
WBC White blood cell, RBC Red blood cell, Hgb Hemoglobin, MCV Mean corpuscular volume, ESR Erythrocyte sedimentation rate, EBV Epstein–Barr virus, VCA Virus capsid antigen, EBNA Epstein–Barr virus nuclear antigen, CMV Cytomegalovirus, HIV Human immunodeficiency virus, Ab Antibody, HHV-8 Human herpesvirus-8, IGRA Interferon-gamma releasing assay, T.Bil Total Bilirubin, AST Aspartate aminotransferase, ALT Alanine aminotransferase, LDH Lactate dehydrogenase, γ-GTP Gamma-glutamyl transpeptidase, ALP Alkaline phosphatase, BUN Blood urea nitrogen, Cr Creatinine, CRP C-reactive protein, ACE Angiotensin-converting enzyme, PT Prothrombin time, PT-INR Prothrombin time-international normalized ratio, APTT Activated partial thromboplastin time, AT-III Antithrombin III, FDP Fibrin/fibrinogen degradation products, ANA Antinuclear antibody, anti-RNP-antibody Anti-ribonucleoprotein antibody, anti-ds-DNA IgG Anti-double-stranded deoxyribonuclein acid immunoglobulin G, anti-SS-A antibody Anti-Sjören's syndrome A antibody, RF Rheumatoid factor, PR3-ANCA Proteinase 3-anti-neutrophil cytoplasmic antibody, MPO-ANCA Myeloperoxidase-anti-neutrophil cytoplasmic antibody, PA-IgG Platelet-associated immunoglobulin G, anti-GBM antibody Anti-glomerular basement membrane antibody, sIL-2R Soluble interleukin-2 receptor, IL-6 Interleukin-6, VEGF Vascular endothelial growth factor
Fig. 1 Transition of ionized calcium. Hypocalcemia appeared after the initiation of dialysis, and myocardial/skeletal muscle calcification was revealed on CT scans after the recovery from hypocalcemia with administration of calcium gluconate hydrate
Fig. 2 Histological findings on bone marrow biopsy. a, b Hypercellular marrow with increased megakaryocytes are seen. (Hematoxylin and eosin staining). (Scale bar, 100 μm)
We initiated weekly treatment with the biologic tocilizumab (8 mg/kg), which is a recombinant, humanized, anti-human interleukin-6 (IL-6) receptor monoclonal antibody, along with tapering glucocorticoids on hospital day 32. However, on hospital day 76, he presented with syncope due to sick sinus syndrome. We first recognized myocardial and skeletal muscle calcification by CT scans on hospital day 47 (Fig. 3). Subsequent CTs showed progressive worsening of the degree of calcification in the first few months (Fig. 4). At this time, we could not perform temporary pacing because of the risk of hemorrhage due to persistently low platelet levels and coagulopathy.Fig. 3 Myocardial and skeletal muscle calcification noted on computed tomography scans for the first time. a High density areas were present on the myocardium (arrows). b, c The rectus abdominis muscle and those of the thigh (arrows) showed high density bilaterally
Fig. 4 Chronological changes in myocardial and skeletal muscle (rectus abdominis) calcification on computed tomography images. Computed tomography was performed on (a, e) day 47, (b, f) day 123, (c, g) day 177 and (d, h) day 345. The degree of calcification showed progressive worsening during the first few months; subsequently, myocardial calcification remained unchanged, while that in the skeletal muscle gradually diminished
Although he repeatedly suffered from various infections (such as catheter related blood stream infection, pyothorax, intraabdominal abscess and infectious endocarditis), we basically continued use of tocilizumab, except when the infection was very severe. We initiated romiplostim, an analog of thrombopoietin, on day 173 because his platelet count remained persistently low, which soon resulted in recovery of platelet count to within the normal range. In addition, urine volume began to gradually increase five months after the onset of anuria. Thereafter, calcification of the rectus abdominis muscle also began to gradually diminish, as observed by CT scans, although there were no remarkable changes in that of the myocardium (Fig. 4).
Although there were many life-threatening events throughout his prolonged hospitalization, he was finally discharged from the hospital in an ambulatory condition on hospital day 410 (his complete clinical course is shown in Fig. 5). Sick sinus syndrome resolved together with improvement in his general condition, so permanent pacemaker implantation was deemed unnecessary. Currently, he receives regular hemodialysis and intravenous tocilizumab every three weeks without evidence of recurrence for one year after discharge.Fig. 5 Clinical course from admission until discharge. PLT platelets, CRP C-reactive protein, mPSL methylprednisolone, TCZ tocilizumab, HD hemodialysis, CRBSI catheter-related blood stream infection, IE infectious endocarditis, SSS sick sinus syndrome
Discussion
TAFRO syndrome and cardiac events
TAFRO syndrome is defined as a subtype of idiopathic multicentric Castleman’s disease (iMCD) that has been recognized as having a severe clinical course. Masaki et al. proposed the diagnostic criteria and severity classification in 2015, and there have been several recently reported clinicopathological analyses and consensus guidelines for the treatment of iMCD based on the accumulated data [2–5]. Our case fulfilled the diagnostic criteria of TAFRO syndrome according to the guideline, and was classified as grade 4 (severe) severity. Our case is rare not only because of many life-threating events such as repetitive severe infections, sick sinus syndrome and cardiac arrest, but also because of the myocardial and skeletal muscle calcification that occurred two months after his disease onset. Other cases have also survived despite a very severe clinical course [9–11], although none of them experienced systemic calcification.
Many TAFRO syndrome cases have recovered with the use of biological products (such as tocilizumab or rituximab), glucocorticoids, immunosuppressants (such as cyclosporine A or sirolimus), and occasionally, with chemotherapy. In terms of cardiac dysfunction, Yasuda et al. reported two cases of TAFRO syndrome with cardiomyopathy and lowered ejection fraction (EF) [6]. They performed CHOP (cyclophosphamide, adriamycin, vincristine and prednisolone) therapy as treatment, and assumed that the cardiomyopathy was an adverse effect of adriamycin. Hiramatsu et al. showed a case of TAFRO syndrome with reversible cardiomyopathy, in which they opined that the high concentration of plasma IL-6 was the cause of cardiomyopathy [7]. However, these cases did not have any associated calcification.
The etiology of myocardial/systemic calcification
Myocardial calcification itself only occurs very rarely. There are traditionally two pathways causing myocardial calcification: metastatic and dystrophic. Metastatic calcification occurs with hypercalcemia and/or abnormality of calcium/phosphate metabolism [12]. This form of calcification can occur anywhere in the body, but is more likely in areas of high alkalinity, such as the gastric mucosa or systemic arteries; therefore, calcification due to this etiology can exist systemically. On the other hand, dystrophic calcification occurs secondary to cellular damage and necrosis, with calcium deposits replacing necrotizing cells. Other etiologies of dystrophic calcification include trauma, infections, inflammation, neoplasms and drugs [12]. Myocardial infarction is a common cause of myocardial calcification. Septic shock is also a cause of this form of calcification; hypotension during shock and catecholamine use can cause myocardial damage, which eventually results in calcium deposits even if plasma calcium concentration is normal [12, 13]. In our case, the etiology of myocardial and skeletal muscle calcification was considered more likely to be metastatic than dystrophic due to the following reasons. First, there was a failure of calcium/phosphate metabolism due to the presence of progressive renal dysfunction with hemodialysis and low vitamin D levels. There was also excessive replenishment of calcium, with an amount of 7.8 mmol of calcium gluconate hydrate per day on average, which could have accelerated calcium deposition in systemic tissues. We did not administer intravenous vitamin D agents, except for the minimal amount of vitamins administered through total parenteral nutrition, which might have been a possible cause for prolonged low calcium levels. Second, both myocardial and skeletal muscle calcification were detected on CT scans at the same time, which was within a month after the initial identification of hypocalcemia and subsequent overloading of calcium (Fig. 3). Third, although we temporarily used catecholamines, there were no other conditions explaining the dystrophic calcification, such as septic shock or myocardial infarction. Fourth, hypercytokinemia, including elevated IL-6 caused by TAFRO syndrome, could also have contributed to this unusual situation. Plasma calcium levels remained low and were almost unchanged when calcium gluconate hydrate was administered, which suggested that the administered calcium probably leaked out of the vessels and was absorbed by peripheral tissues. Increase of vasopermeability is another possible etiology for the calcified deposits, which could explain its occurrence in the absence of hypercalcemia.
In conclusion, this case of TAFRO syndrome achieved a successful recovery with tocilizumab therapy along with prolonged hospitalization, although he experienced the unexpected complication of myocardial and skeletal muscle calcification probably via a metastatic pathway triggered by drug administration. In acute clinical settings, the tendency is to urgently correct abnormal laboratory data, especially electrolyte abnormalities. However, TAFRO syndrome is known to be associated with hypercytokinemia and organ dysfunction with an unknown pathophysiology; hence, the general management of such cases should be carefully handled, anticipating unexpected complications.
Abbreviations
TAFROThrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly
iMCDIdiopathic multicentric Castleman’s disease
CTComputed tomography
IL-6Interleukin-6
CHOPCyclophosphamide, adriamycin, vincristine and prednisolone
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors thank Forte Science Communications (www.forte-science.co.jp) for their assistance in proofreading this article.
Authors’ contributions
SM treated this patient, reviewed literature, interpreted the patient data about the etiology in this patient, and contributed to writing the manuscript. YF reviewed literature, wrote the manuscript, and managed this research. SS treated this patient and wrote the manuscript. AT provided professional opinions regarding patient care and treatment, and revised the manuscript. KN revised the manuscript and currently cares for this patient at the outpatient clinic. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Ethics approval and consent for submitting case reports is usually waived by the ethics review committee of Musashino Red Cross Hospital. We followed the principles of the Declaration of Helsinki and paid cautious attention to protecting the patient’s identity.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | PULSE THERAPY | DrugDosageText | CC BY | 33402219 | 19,396,568 | 2021-01-06 |
What was the outcome of reaction 'Calcification of muscle'? | A severe case of thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly syndrome with myocardial and skeletal muscle calcification despite hypocalcemia: a case report.
BACKGROUND
TAFRO (thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly) syndrome is a recently recognized disease with a variety of presentations of variable severity. In acute settings, this disease also involves organ dysfunction because of the associated systemic inflammation. However, cases of TAFRO syndrome with myocardial and/or skeletal muscle calcification have never been reported.
METHODS
A 24-year-old healthy young Asian man was admitted with intermittent epigastric pain and fever for 2 weeks. Computed tomography revealed pleural effusion, ascites and systemic lymphadenopathy. Laboratory tests showed thrombocytopenia, elevated C-reactive protein, hypoalbuminemia, anemia and renal dysfunction. Based on these findings and bone marrow biopsy, we diagnosed his disease as TAFRO syndrome and commenced hemodialysis for the renal dysfunction. However, he developed refractory hypocalcemia with unstable vital signs, for which we administered calcium gluconate hydrate. Thereafter, myocardial and skeletal muscle calcification was revealed radiologically, with the myocardial calcification causing sick sinus syndrome. He was treated with tocilizumab and finally discharged in an ambulatory condition after prolonged hospitalization, with residual calcific lesions.
CONCLUSIONS
This is the first report of a patient with TAFRO syndrome and the complication of organ calcification. The etiology of calcification in this case is not clear. Systemic inflammation with possible hypercytokinemia might have been involved in the unexpected complication of systemic calcification. It is important to carefully handle the general management of TAFRO syndrome because of the possibility of various complications.
Background
TAFRO (thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, organomegaly) syndrome is a systemic inflammatory disease first reported by Takai et al. in 2010 [1], and is categorized as a subtype of idiopathic multicentric Castleman’s disease (iMCD). TAFRO syndrome follows a particularly aggressive clinical course compared to unicentric Castleman’s disease or other subtypes of iMCD. Therefore, clinicians often experience difficulty in treating this condition. Since its earliest description, reports of cases of TAFRO syndrome have been described worldwide, and guidelines for its treatment have been proposed [2–5]. Since organ dysfunction is commonly seen with TAFRO syndrome, temporary hemodialysis is often necessary during the course of treatment of this condition [2], although no case reports have described calcific deposits associated with hemodialysis. Additionally, although several cases with severe cardiac dysfunction due to chemotherapy, hypercytokinemia and massive ascites have been reported [6–8], there have been no cases of gross calcification recognized radiologically, either in the myocardium or in skeletal muscles.
We report a case of TAFRO syndrome with myocardial and skeletal muscle calcification, who was finally discharged from the hospital in an ambulatory condition following tocilizumab therapy. Our patient also presented with severe hypocalcemia during his clinical course, the treatment of which might have eventually triggered systemic calcification. Although it is difficult to completely understand the etiological mechanism in this case, our experience will contribute to understanding the pathophysiology and general management of TAFRO syndrome.
Case presentation
A previously healthy 24-year-old Asian man without significant family medical history presented with intermittent severe epigastric pain and fever for two weeks. Since a computed tomography (CT) scan at another hospital had only revealed systemic lymphadenopathy and could not detect any cause for his symptoms, he was referred to our hospital for further investigation. On admission, he was febrile (37.4 °C). Physical examination showed epigastric tenderness without signs of peritoneal irritation, and pitting edema on the lower extremities. His laboratory test results on admission are shown in Table 1. Contrast-enhanced CT scan revealed cervical, supraclavicular, axillary, paraaortic and inguinal lymphadenopathies, bilateral pleural effusion, ascites and hepatosplenomegaly. Soon after his admission, hemodialysis and mechanical ventilation were initiated due to the development of anuria and dyspnea, and methylprednisolone pulse therapy (1 g/day) was administered for three days after ruling out bacterial infections on hospital day 9, followed by intravenous methylprednisolone (50 mg/day) as maintenance therapy. Laboratory data on hospital day 11 are shown in Table 2. In spite of hemodialysis and ventilatory support, his vital signs were unstable, necessitating temporary use of catecholamines to maintain his blood pressure. Additionally, his plasma calcium level decreased (ionized calcium: 0.78 mmol/L) with a high level of phosphorus (9.6 mg/dL) on hospital day 17. Subsequently, we intravenously administered calcium gluconate hydrate for a total of eight days because the hypocalcemia was refractory to therapy. Laboratory data indicated low vitamin D and high intact parathyroid hormone levels, as seen in patients with chronic kidney disease. Finally, his plasma calcium levels were maintained within the normal range (Fig. 1). Bone marrow biopsy revealed hypercellular marrow with an increased number of megakaryocytes (Fig. 2). Based on these findings and exclusion criteria, we diagnosed his condition as TAFRO syndrome according to the diagnostic criteria proposed in 2015 [3].Table 1 Laboratory data on admission
Complete blood cell count Blood chemistry
WBC 14,100 /μL Total protein 5.1 g/dL
Seg 83 % Albumin 1.8 g/dL
Eosino 1 % T.Bil 1.0 mg/dL
Lympho 7 % AST 29 IU/L
Mono 9 % ALT 14 IU/L
RBC 413 104/μL LDH 370 IU/L
Hgb 13.5 g/dL ALP 265 IU/L
MCV 86.2 fL γ-GTP 105 IU/L
Platelet 46.8 104/μL BUN 43.1 mg/dL
Cr 1.62 mg/dL
Coagulation system eGFR 46 mL/min/1.73m2
PT 18.2 sec CRP 25.37 mg/dL
PT-INR 1.51 Glu 78 mg/dL
APTT (standard: 26-36) 47.9 sec AMY 39 IU/L
Fibrinogen >600 mg/dL
D-dimer 26.9 μg/mL
WBC White blood cell, RBC Red blood cell, Hgb Hemoglobin, MCV Mean corpuscular volume, PT Prothrombin time, PT-INR Prothrombin time-international normalized ratio, APTT Activated partial thromboplastin time, T.Bil Total Bilirubin, AST Aspartate aminotransferase, ALT Alanine aminotransferase, LDH Lactate dehydrogenase, ALP Alkaline phosphatase, BUN Blood urea nitrogen, Cr Creatinine, CRP C-reactive protein, AMY Amylase
Table 2 Laboratory data at the time of diagnosis of TAFRO syndrome
Complete blood cell count Blood chemistry Immunologic test
WBC 23,600 /μL Albumin 1.5 g/dL IgG 1385 mg/dL
Band 6 % T.Bil 0.4 mg/dL IgG4 66 mg/dL
Seg 88 % AST 33 IU/L IgA 187 mg/dL
Lympho 3 % ALT 12 IU/L IgM 62 mg/dL
Mono 3 % LDH 471 IU/L ANA <40 times
RBC 348 104/μL γ-GTP 266 IU/L anti-RNP Ab –
Hgb 9.9 g/dL ALP 400 IU/L anti-ds-DNA IgG –
MCV 86.8 fL BUN 119.5 mg/dL anti-SS-A Ab –
Platelet 7.5 104/μL Cr 7.77 mg/dL RF <3 IU/mL
ESR 87 mm/hr CRP 36.35 mg/dL PR3-ANCA <1 IU/mL
Ferritin 1873 ng/mL MPO-ANCA <1 IU/mL
ACE 7.6 IU/L Coombs test –
Haptoglobin 311 mg/dL PA-IgG 70 ng/107cells
Infectious diseases ADAMTS-13 28 %
EBV VCA IgG + Coagulation system anti-GBM Ab <2 U/mL
EBV VCA IgM - PT 19 Sec sIL-2R 1260 U/mL
EBNA IgG + PT-INR 1.59 IL-6 65.1 pg/mL
CMV C7-HRP - APTT >80 Sec VEGF 1030 pg/mL
(Standard: 26-36)
HIV antigen/Ab - Fibrinogen >600 mg/dL
HHV-8 DNA (WBC106cells) <20 AT-III 58 %
IGRA – FDP 66 μg/mL
WBC White blood cell, RBC Red blood cell, Hgb Hemoglobin, MCV Mean corpuscular volume, ESR Erythrocyte sedimentation rate, EBV Epstein–Barr virus, VCA Virus capsid antigen, EBNA Epstein–Barr virus nuclear antigen, CMV Cytomegalovirus, HIV Human immunodeficiency virus, Ab Antibody, HHV-8 Human herpesvirus-8, IGRA Interferon-gamma releasing assay, T.Bil Total Bilirubin, AST Aspartate aminotransferase, ALT Alanine aminotransferase, LDH Lactate dehydrogenase, γ-GTP Gamma-glutamyl transpeptidase, ALP Alkaline phosphatase, BUN Blood urea nitrogen, Cr Creatinine, CRP C-reactive protein, ACE Angiotensin-converting enzyme, PT Prothrombin time, PT-INR Prothrombin time-international normalized ratio, APTT Activated partial thromboplastin time, AT-III Antithrombin III, FDP Fibrin/fibrinogen degradation products, ANA Antinuclear antibody, anti-RNP-antibody Anti-ribonucleoprotein antibody, anti-ds-DNA IgG Anti-double-stranded deoxyribonuclein acid immunoglobulin G, anti-SS-A antibody Anti-Sjören's syndrome A antibody, RF Rheumatoid factor, PR3-ANCA Proteinase 3-anti-neutrophil cytoplasmic antibody, MPO-ANCA Myeloperoxidase-anti-neutrophil cytoplasmic antibody, PA-IgG Platelet-associated immunoglobulin G, anti-GBM antibody Anti-glomerular basement membrane antibody, sIL-2R Soluble interleukin-2 receptor, IL-6 Interleukin-6, VEGF Vascular endothelial growth factor
Fig. 1 Transition of ionized calcium. Hypocalcemia appeared after the initiation of dialysis, and myocardial/skeletal muscle calcification was revealed on CT scans after the recovery from hypocalcemia with administration of calcium gluconate hydrate
Fig. 2 Histological findings on bone marrow biopsy. a, b Hypercellular marrow with increased megakaryocytes are seen. (Hematoxylin and eosin staining). (Scale bar, 100 μm)
We initiated weekly treatment with the biologic tocilizumab (8 mg/kg), which is a recombinant, humanized, anti-human interleukin-6 (IL-6) receptor monoclonal antibody, along with tapering glucocorticoids on hospital day 32. However, on hospital day 76, he presented with syncope due to sick sinus syndrome. We first recognized myocardial and skeletal muscle calcification by CT scans on hospital day 47 (Fig. 3). Subsequent CTs showed progressive worsening of the degree of calcification in the first few months (Fig. 4). At this time, we could not perform temporary pacing because of the risk of hemorrhage due to persistently low platelet levels and coagulopathy.Fig. 3 Myocardial and skeletal muscle calcification noted on computed tomography scans for the first time. a High density areas were present on the myocardium (arrows). b, c The rectus abdominis muscle and those of the thigh (arrows) showed high density bilaterally
Fig. 4 Chronological changes in myocardial and skeletal muscle (rectus abdominis) calcification on computed tomography images. Computed tomography was performed on (a, e) day 47, (b, f) day 123, (c, g) day 177 and (d, h) day 345. The degree of calcification showed progressive worsening during the first few months; subsequently, myocardial calcification remained unchanged, while that in the skeletal muscle gradually diminished
Although he repeatedly suffered from various infections (such as catheter related blood stream infection, pyothorax, intraabdominal abscess and infectious endocarditis), we basically continued use of tocilizumab, except when the infection was very severe. We initiated romiplostim, an analog of thrombopoietin, on day 173 because his platelet count remained persistently low, which soon resulted in recovery of platelet count to within the normal range. In addition, urine volume began to gradually increase five months after the onset of anuria. Thereafter, calcification of the rectus abdominis muscle also began to gradually diminish, as observed by CT scans, although there were no remarkable changes in that of the myocardium (Fig. 4).
Although there were many life-threatening events throughout his prolonged hospitalization, he was finally discharged from the hospital in an ambulatory condition on hospital day 410 (his complete clinical course is shown in Fig. 5). Sick sinus syndrome resolved together with improvement in his general condition, so permanent pacemaker implantation was deemed unnecessary. Currently, he receives regular hemodialysis and intravenous tocilizumab every three weeks without evidence of recurrence for one year after discharge.Fig. 5 Clinical course from admission until discharge. PLT platelets, CRP C-reactive protein, mPSL methylprednisolone, TCZ tocilizumab, HD hemodialysis, CRBSI catheter-related blood stream infection, IE infectious endocarditis, SSS sick sinus syndrome
Discussion
TAFRO syndrome and cardiac events
TAFRO syndrome is defined as a subtype of idiopathic multicentric Castleman’s disease (iMCD) that has been recognized as having a severe clinical course. Masaki et al. proposed the diagnostic criteria and severity classification in 2015, and there have been several recently reported clinicopathological analyses and consensus guidelines for the treatment of iMCD based on the accumulated data [2–5]. Our case fulfilled the diagnostic criteria of TAFRO syndrome according to the guideline, and was classified as grade 4 (severe) severity. Our case is rare not only because of many life-threating events such as repetitive severe infections, sick sinus syndrome and cardiac arrest, but also because of the myocardial and skeletal muscle calcification that occurred two months after his disease onset. Other cases have also survived despite a very severe clinical course [9–11], although none of them experienced systemic calcification.
Many TAFRO syndrome cases have recovered with the use of biological products (such as tocilizumab or rituximab), glucocorticoids, immunosuppressants (such as cyclosporine A or sirolimus), and occasionally, with chemotherapy. In terms of cardiac dysfunction, Yasuda et al. reported two cases of TAFRO syndrome with cardiomyopathy and lowered ejection fraction (EF) [6]. They performed CHOP (cyclophosphamide, adriamycin, vincristine and prednisolone) therapy as treatment, and assumed that the cardiomyopathy was an adverse effect of adriamycin. Hiramatsu et al. showed a case of TAFRO syndrome with reversible cardiomyopathy, in which they opined that the high concentration of plasma IL-6 was the cause of cardiomyopathy [7]. However, these cases did not have any associated calcification.
The etiology of myocardial/systemic calcification
Myocardial calcification itself only occurs very rarely. There are traditionally two pathways causing myocardial calcification: metastatic and dystrophic. Metastatic calcification occurs with hypercalcemia and/or abnormality of calcium/phosphate metabolism [12]. This form of calcification can occur anywhere in the body, but is more likely in areas of high alkalinity, such as the gastric mucosa or systemic arteries; therefore, calcification due to this etiology can exist systemically. On the other hand, dystrophic calcification occurs secondary to cellular damage and necrosis, with calcium deposits replacing necrotizing cells. Other etiologies of dystrophic calcification include trauma, infections, inflammation, neoplasms and drugs [12]. Myocardial infarction is a common cause of myocardial calcification. Septic shock is also a cause of this form of calcification; hypotension during shock and catecholamine use can cause myocardial damage, which eventually results in calcium deposits even if plasma calcium concentration is normal [12, 13]. In our case, the etiology of myocardial and skeletal muscle calcification was considered more likely to be metastatic than dystrophic due to the following reasons. First, there was a failure of calcium/phosphate metabolism due to the presence of progressive renal dysfunction with hemodialysis and low vitamin D levels. There was also excessive replenishment of calcium, with an amount of 7.8 mmol of calcium gluconate hydrate per day on average, which could have accelerated calcium deposition in systemic tissues. We did not administer intravenous vitamin D agents, except for the minimal amount of vitamins administered through total parenteral nutrition, which might have been a possible cause for prolonged low calcium levels. Second, both myocardial and skeletal muscle calcification were detected on CT scans at the same time, which was within a month after the initial identification of hypocalcemia and subsequent overloading of calcium (Fig. 3). Third, although we temporarily used catecholamines, there were no other conditions explaining the dystrophic calcification, such as septic shock or myocardial infarction. Fourth, hypercytokinemia, including elevated IL-6 caused by TAFRO syndrome, could also have contributed to this unusual situation. Plasma calcium levels remained low and were almost unchanged when calcium gluconate hydrate was administered, which suggested that the administered calcium probably leaked out of the vessels and was absorbed by peripheral tissues. Increase of vasopermeability is another possible etiology for the calcified deposits, which could explain its occurrence in the absence of hypercalcemia.
In conclusion, this case of TAFRO syndrome achieved a successful recovery with tocilizumab therapy along with prolonged hospitalization, although he experienced the unexpected complication of myocardial and skeletal muscle calcification probably via a metastatic pathway triggered by drug administration. In acute clinical settings, the tendency is to urgently correct abnormal laboratory data, especially electrolyte abnormalities. However, TAFRO syndrome is known to be associated with hypercytokinemia and organ dysfunction with an unknown pathophysiology; hence, the general management of such cases should be carefully handled, anticipating unexpected complications.
Abbreviations
TAFROThrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly
iMCDIdiopathic multicentric Castleman’s disease
CTComputed tomography
IL-6Interleukin-6
CHOPCyclophosphamide, adriamycin, vincristine and prednisolone
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors thank Forte Science Communications (www.forte-science.co.jp) for their assistance in proofreading this article.
Authors’ contributions
SM treated this patient, reviewed literature, interpreted the patient data about the etiology in this patient, and contributed to writing the manuscript. YF reviewed literature, wrote the manuscript, and managed this research. SS treated this patient and wrote the manuscript. AT provided professional opinions regarding patient care and treatment, and revised the manuscript. KN revised the manuscript and currently cares for this patient at the outpatient clinic. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Ethics approval and consent for submitting case reports is usually waived by the ethics review committee of Musashino Red Cross Hospital. We followed the principles of the Declaration of Helsinki and paid cautious attention to protecting the patient’s identity.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33402219 | 19,396,568 | 2021-01-06 |
What was the outcome of reaction 'Myocardial calcification'? | A severe case of thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly syndrome with myocardial and skeletal muscle calcification despite hypocalcemia: a case report.
BACKGROUND
TAFRO (thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly) syndrome is a recently recognized disease with a variety of presentations of variable severity. In acute settings, this disease also involves organ dysfunction because of the associated systemic inflammation. However, cases of TAFRO syndrome with myocardial and/or skeletal muscle calcification have never been reported.
METHODS
A 24-year-old healthy young Asian man was admitted with intermittent epigastric pain and fever for 2 weeks. Computed tomography revealed pleural effusion, ascites and systemic lymphadenopathy. Laboratory tests showed thrombocytopenia, elevated C-reactive protein, hypoalbuminemia, anemia and renal dysfunction. Based on these findings and bone marrow biopsy, we diagnosed his disease as TAFRO syndrome and commenced hemodialysis for the renal dysfunction. However, he developed refractory hypocalcemia with unstable vital signs, for which we administered calcium gluconate hydrate. Thereafter, myocardial and skeletal muscle calcification was revealed radiologically, with the myocardial calcification causing sick sinus syndrome. He was treated with tocilizumab and finally discharged in an ambulatory condition after prolonged hospitalization, with residual calcific lesions.
CONCLUSIONS
This is the first report of a patient with TAFRO syndrome and the complication of organ calcification. The etiology of calcification in this case is not clear. Systemic inflammation with possible hypercytokinemia might have been involved in the unexpected complication of systemic calcification. It is important to carefully handle the general management of TAFRO syndrome because of the possibility of various complications.
Background
TAFRO (thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, organomegaly) syndrome is a systemic inflammatory disease first reported by Takai et al. in 2010 [1], and is categorized as a subtype of idiopathic multicentric Castleman’s disease (iMCD). TAFRO syndrome follows a particularly aggressive clinical course compared to unicentric Castleman’s disease or other subtypes of iMCD. Therefore, clinicians often experience difficulty in treating this condition. Since its earliest description, reports of cases of TAFRO syndrome have been described worldwide, and guidelines for its treatment have been proposed [2–5]. Since organ dysfunction is commonly seen with TAFRO syndrome, temporary hemodialysis is often necessary during the course of treatment of this condition [2], although no case reports have described calcific deposits associated with hemodialysis. Additionally, although several cases with severe cardiac dysfunction due to chemotherapy, hypercytokinemia and massive ascites have been reported [6–8], there have been no cases of gross calcification recognized radiologically, either in the myocardium or in skeletal muscles.
We report a case of TAFRO syndrome with myocardial and skeletal muscle calcification, who was finally discharged from the hospital in an ambulatory condition following tocilizumab therapy. Our patient also presented with severe hypocalcemia during his clinical course, the treatment of which might have eventually triggered systemic calcification. Although it is difficult to completely understand the etiological mechanism in this case, our experience will contribute to understanding the pathophysiology and general management of TAFRO syndrome.
Case presentation
A previously healthy 24-year-old Asian man without significant family medical history presented with intermittent severe epigastric pain and fever for two weeks. Since a computed tomography (CT) scan at another hospital had only revealed systemic lymphadenopathy and could not detect any cause for his symptoms, he was referred to our hospital for further investigation. On admission, he was febrile (37.4 °C). Physical examination showed epigastric tenderness without signs of peritoneal irritation, and pitting edema on the lower extremities. His laboratory test results on admission are shown in Table 1. Contrast-enhanced CT scan revealed cervical, supraclavicular, axillary, paraaortic and inguinal lymphadenopathies, bilateral pleural effusion, ascites and hepatosplenomegaly. Soon after his admission, hemodialysis and mechanical ventilation were initiated due to the development of anuria and dyspnea, and methylprednisolone pulse therapy (1 g/day) was administered for three days after ruling out bacterial infections on hospital day 9, followed by intravenous methylprednisolone (50 mg/day) as maintenance therapy. Laboratory data on hospital day 11 are shown in Table 2. In spite of hemodialysis and ventilatory support, his vital signs were unstable, necessitating temporary use of catecholamines to maintain his blood pressure. Additionally, his plasma calcium level decreased (ionized calcium: 0.78 mmol/L) with a high level of phosphorus (9.6 mg/dL) on hospital day 17. Subsequently, we intravenously administered calcium gluconate hydrate for a total of eight days because the hypocalcemia was refractory to therapy. Laboratory data indicated low vitamin D and high intact parathyroid hormone levels, as seen in patients with chronic kidney disease. Finally, his plasma calcium levels were maintained within the normal range (Fig. 1). Bone marrow biopsy revealed hypercellular marrow with an increased number of megakaryocytes (Fig. 2). Based on these findings and exclusion criteria, we diagnosed his condition as TAFRO syndrome according to the diagnostic criteria proposed in 2015 [3].Table 1 Laboratory data on admission
Complete blood cell count Blood chemistry
WBC 14,100 /μL Total protein 5.1 g/dL
Seg 83 % Albumin 1.8 g/dL
Eosino 1 % T.Bil 1.0 mg/dL
Lympho 7 % AST 29 IU/L
Mono 9 % ALT 14 IU/L
RBC 413 104/μL LDH 370 IU/L
Hgb 13.5 g/dL ALP 265 IU/L
MCV 86.2 fL γ-GTP 105 IU/L
Platelet 46.8 104/μL BUN 43.1 mg/dL
Cr 1.62 mg/dL
Coagulation system eGFR 46 mL/min/1.73m2
PT 18.2 sec CRP 25.37 mg/dL
PT-INR 1.51 Glu 78 mg/dL
APTT (standard: 26-36) 47.9 sec AMY 39 IU/L
Fibrinogen >600 mg/dL
D-dimer 26.9 μg/mL
WBC White blood cell, RBC Red blood cell, Hgb Hemoglobin, MCV Mean corpuscular volume, PT Prothrombin time, PT-INR Prothrombin time-international normalized ratio, APTT Activated partial thromboplastin time, T.Bil Total Bilirubin, AST Aspartate aminotransferase, ALT Alanine aminotransferase, LDH Lactate dehydrogenase, ALP Alkaline phosphatase, BUN Blood urea nitrogen, Cr Creatinine, CRP C-reactive protein, AMY Amylase
Table 2 Laboratory data at the time of diagnosis of TAFRO syndrome
Complete blood cell count Blood chemistry Immunologic test
WBC 23,600 /μL Albumin 1.5 g/dL IgG 1385 mg/dL
Band 6 % T.Bil 0.4 mg/dL IgG4 66 mg/dL
Seg 88 % AST 33 IU/L IgA 187 mg/dL
Lympho 3 % ALT 12 IU/L IgM 62 mg/dL
Mono 3 % LDH 471 IU/L ANA <40 times
RBC 348 104/μL γ-GTP 266 IU/L anti-RNP Ab –
Hgb 9.9 g/dL ALP 400 IU/L anti-ds-DNA IgG –
MCV 86.8 fL BUN 119.5 mg/dL anti-SS-A Ab –
Platelet 7.5 104/μL Cr 7.77 mg/dL RF <3 IU/mL
ESR 87 mm/hr CRP 36.35 mg/dL PR3-ANCA <1 IU/mL
Ferritin 1873 ng/mL MPO-ANCA <1 IU/mL
ACE 7.6 IU/L Coombs test –
Haptoglobin 311 mg/dL PA-IgG 70 ng/107cells
Infectious diseases ADAMTS-13 28 %
EBV VCA IgG + Coagulation system anti-GBM Ab <2 U/mL
EBV VCA IgM - PT 19 Sec sIL-2R 1260 U/mL
EBNA IgG + PT-INR 1.59 IL-6 65.1 pg/mL
CMV C7-HRP - APTT >80 Sec VEGF 1030 pg/mL
(Standard: 26-36)
HIV antigen/Ab - Fibrinogen >600 mg/dL
HHV-8 DNA (WBC106cells) <20 AT-III 58 %
IGRA – FDP 66 μg/mL
WBC White blood cell, RBC Red blood cell, Hgb Hemoglobin, MCV Mean corpuscular volume, ESR Erythrocyte sedimentation rate, EBV Epstein–Barr virus, VCA Virus capsid antigen, EBNA Epstein–Barr virus nuclear antigen, CMV Cytomegalovirus, HIV Human immunodeficiency virus, Ab Antibody, HHV-8 Human herpesvirus-8, IGRA Interferon-gamma releasing assay, T.Bil Total Bilirubin, AST Aspartate aminotransferase, ALT Alanine aminotransferase, LDH Lactate dehydrogenase, γ-GTP Gamma-glutamyl transpeptidase, ALP Alkaline phosphatase, BUN Blood urea nitrogen, Cr Creatinine, CRP C-reactive protein, ACE Angiotensin-converting enzyme, PT Prothrombin time, PT-INR Prothrombin time-international normalized ratio, APTT Activated partial thromboplastin time, AT-III Antithrombin III, FDP Fibrin/fibrinogen degradation products, ANA Antinuclear antibody, anti-RNP-antibody Anti-ribonucleoprotein antibody, anti-ds-DNA IgG Anti-double-stranded deoxyribonuclein acid immunoglobulin G, anti-SS-A antibody Anti-Sjören's syndrome A antibody, RF Rheumatoid factor, PR3-ANCA Proteinase 3-anti-neutrophil cytoplasmic antibody, MPO-ANCA Myeloperoxidase-anti-neutrophil cytoplasmic antibody, PA-IgG Platelet-associated immunoglobulin G, anti-GBM antibody Anti-glomerular basement membrane antibody, sIL-2R Soluble interleukin-2 receptor, IL-6 Interleukin-6, VEGF Vascular endothelial growth factor
Fig. 1 Transition of ionized calcium. Hypocalcemia appeared after the initiation of dialysis, and myocardial/skeletal muscle calcification was revealed on CT scans after the recovery from hypocalcemia with administration of calcium gluconate hydrate
Fig. 2 Histological findings on bone marrow biopsy. a, b Hypercellular marrow with increased megakaryocytes are seen. (Hematoxylin and eosin staining). (Scale bar, 100 μm)
We initiated weekly treatment with the biologic tocilizumab (8 mg/kg), which is a recombinant, humanized, anti-human interleukin-6 (IL-6) receptor monoclonal antibody, along with tapering glucocorticoids on hospital day 32. However, on hospital day 76, he presented with syncope due to sick sinus syndrome. We first recognized myocardial and skeletal muscle calcification by CT scans on hospital day 47 (Fig. 3). Subsequent CTs showed progressive worsening of the degree of calcification in the first few months (Fig. 4). At this time, we could not perform temporary pacing because of the risk of hemorrhage due to persistently low platelet levels and coagulopathy.Fig. 3 Myocardial and skeletal muscle calcification noted on computed tomography scans for the first time. a High density areas were present on the myocardium (arrows). b, c The rectus abdominis muscle and those of the thigh (arrows) showed high density bilaterally
Fig. 4 Chronological changes in myocardial and skeletal muscle (rectus abdominis) calcification on computed tomography images. Computed tomography was performed on (a, e) day 47, (b, f) day 123, (c, g) day 177 and (d, h) day 345. The degree of calcification showed progressive worsening during the first few months; subsequently, myocardial calcification remained unchanged, while that in the skeletal muscle gradually diminished
Although he repeatedly suffered from various infections (such as catheter related blood stream infection, pyothorax, intraabdominal abscess and infectious endocarditis), we basically continued use of tocilizumab, except when the infection was very severe. We initiated romiplostim, an analog of thrombopoietin, on day 173 because his platelet count remained persistently low, which soon resulted in recovery of platelet count to within the normal range. In addition, urine volume began to gradually increase five months after the onset of anuria. Thereafter, calcification of the rectus abdominis muscle also began to gradually diminish, as observed by CT scans, although there were no remarkable changes in that of the myocardium (Fig. 4).
Although there were many life-threatening events throughout his prolonged hospitalization, he was finally discharged from the hospital in an ambulatory condition on hospital day 410 (his complete clinical course is shown in Fig. 5). Sick sinus syndrome resolved together with improvement in his general condition, so permanent pacemaker implantation was deemed unnecessary. Currently, he receives regular hemodialysis and intravenous tocilizumab every three weeks without evidence of recurrence for one year after discharge.Fig. 5 Clinical course from admission until discharge. PLT platelets, CRP C-reactive protein, mPSL methylprednisolone, TCZ tocilizumab, HD hemodialysis, CRBSI catheter-related blood stream infection, IE infectious endocarditis, SSS sick sinus syndrome
Discussion
TAFRO syndrome and cardiac events
TAFRO syndrome is defined as a subtype of idiopathic multicentric Castleman’s disease (iMCD) that has been recognized as having a severe clinical course. Masaki et al. proposed the diagnostic criteria and severity classification in 2015, and there have been several recently reported clinicopathological analyses and consensus guidelines for the treatment of iMCD based on the accumulated data [2–5]. Our case fulfilled the diagnostic criteria of TAFRO syndrome according to the guideline, and was classified as grade 4 (severe) severity. Our case is rare not only because of many life-threating events such as repetitive severe infections, sick sinus syndrome and cardiac arrest, but also because of the myocardial and skeletal muscle calcification that occurred two months after his disease onset. Other cases have also survived despite a very severe clinical course [9–11], although none of them experienced systemic calcification.
Many TAFRO syndrome cases have recovered with the use of biological products (such as tocilizumab or rituximab), glucocorticoids, immunosuppressants (such as cyclosporine A or sirolimus), and occasionally, with chemotherapy. In terms of cardiac dysfunction, Yasuda et al. reported two cases of TAFRO syndrome with cardiomyopathy and lowered ejection fraction (EF) [6]. They performed CHOP (cyclophosphamide, adriamycin, vincristine and prednisolone) therapy as treatment, and assumed that the cardiomyopathy was an adverse effect of adriamycin. Hiramatsu et al. showed a case of TAFRO syndrome with reversible cardiomyopathy, in which they opined that the high concentration of plasma IL-6 was the cause of cardiomyopathy [7]. However, these cases did not have any associated calcification.
The etiology of myocardial/systemic calcification
Myocardial calcification itself only occurs very rarely. There are traditionally two pathways causing myocardial calcification: metastatic and dystrophic. Metastatic calcification occurs with hypercalcemia and/or abnormality of calcium/phosphate metabolism [12]. This form of calcification can occur anywhere in the body, but is more likely in areas of high alkalinity, such as the gastric mucosa or systemic arteries; therefore, calcification due to this etiology can exist systemically. On the other hand, dystrophic calcification occurs secondary to cellular damage and necrosis, with calcium deposits replacing necrotizing cells. Other etiologies of dystrophic calcification include trauma, infections, inflammation, neoplasms and drugs [12]. Myocardial infarction is a common cause of myocardial calcification. Septic shock is also a cause of this form of calcification; hypotension during shock and catecholamine use can cause myocardial damage, which eventually results in calcium deposits even if plasma calcium concentration is normal [12, 13]. In our case, the etiology of myocardial and skeletal muscle calcification was considered more likely to be metastatic than dystrophic due to the following reasons. First, there was a failure of calcium/phosphate metabolism due to the presence of progressive renal dysfunction with hemodialysis and low vitamin D levels. There was also excessive replenishment of calcium, with an amount of 7.8 mmol of calcium gluconate hydrate per day on average, which could have accelerated calcium deposition in systemic tissues. We did not administer intravenous vitamin D agents, except for the minimal amount of vitamins administered through total parenteral nutrition, which might have been a possible cause for prolonged low calcium levels. Second, both myocardial and skeletal muscle calcification were detected on CT scans at the same time, which was within a month after the initial identification of hypocalcemia and subsequent overloading of calcium (Fig. 3). Third, although we temporarily used catecholamines, there were no other conditions explaining the dystrophic calcification, such as septic shock or myocardial infarction. Fourth, hypercytokinemia, including elevated IL-6 caused by TAFRO syndrome, could also have contributed to this unusual situation. Plasma calcium levels remained low and were almost unchanged when calcium gluconate hydrate was administered, which suggested that the administered calcium probably leaked out of the vessels and was absorbed by peripheral tissues. Increase of vasopermeability is another possible etiology for the calcified deposits, which could explain its occurrence in the absence of hypercalcemia.
In conclusion, this case of TAFRO syndrome achieved a successful recovery with tocilizumab therapy along with prolonged hospitalization, although he experienced the unexpected complication of myocardial and skeletal muscle calcification probably via a metastatic pathway triggered by drug administration. In acute clinical settings, the tendency is to urgently correct abnormal laboratory data, especially electrolyte abnormalities. However, TAFRO syndrome is known to be associated with hypercytokinemia and organ dysfunction with an unknown pathophysiology; hence, the general management of such cases should be carefully handled, anticipating unexpected complications.
Abbreviations
TAFROThrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly
iMCDIdiopathic multicentric Castleman’s disease
CTComputed tomography
IL-6Interleukin-6
CHOPCyclophosphamide, adriamycin, vincristine and prednisolone
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Acknowledgements
The authors thank Forte Science Communications (www.forte-science.co.jp) for their assistance in proofreading this article.
Authors’ contributions
SM treated this patient, reviewed literature, interpreted the patient data about the etiology in this patient, and contributed to writing the manuscript. YF reviewed literature, wrote the manuscript, and managed this research. SS treated this patient and wrote the manuscript. AT provided professional opinions regarding patient care and treatment, and revised the manuscript. KN revised the manuscript and currently cares for this patient at the outpatient clinic. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Ethics approval and consent for submitting case reports is usually waived by the ethics review committee of Musashino Red Cross Hospital. We followed the principles of the Declaration of Helsinki and paid cautious attention to protecting the patient’s identity.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33402219 | 19,396,568 | 2021-01-06 |
What was the outcome of reaction 'Sinus node dysfunction'? | A severe case of thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly syndrome with myocardial and skeletal muscle calcification despite hypocalcemia: a case report.
BACKGROUND
TAFRO (thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly) syndrome is a recently recognized disease with a variety of presentations of variable severity. In acute settings, this disease also involves organ dysfunction because of the associated systemic inflammation. However, cases of TAFRO syndrome with myocardial and/or skeletal muscle calcification have never been reported.
METHODS
A 24-year-old healthy young Asian man was admitted with intermittent epigastric pain and fever for 2 weeks. Computed tomography revealed pleural effusion, ascites and systemic lymphadenopathy. Laboratory tests showed thrombocytopenia, elevated C-reactive protein, hypoalbuminemia, anemia and renal dysfunction. Based on these findings and bone marrow biopsy, we diagnosed his disease as TAFRO syndrome and commenced hemodialysis for the renal dysfunction. However, he developed refractory hypocalcemia with unstable vital signs, for which we administered calcium gluconate hydrate. Thereafter, myocardial and skeletal muscle calcification was revealed radiologically, with the myocardial calcification causing sick sinus syndrome. He was treated with tocilizumab and finally discharged in an ambulatory condition after prolonged hospitalization, with residual calcific lesions.
CONCLUSIONS
This is the first report of a patient with TAFRO syndrome and the complication of organ calcification. The etiology of calcification in this case is not clear. Systemic inflammation with possible hypercytokinemia might have been involved in the unexpected complication of systemic calcification. It is important to carefully handle the general management of TAFRO syndrome because of the possibility of various complications.
Background
TAFRO (thrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, organomegaly) syndrome is a systemic inflammatory disease first reported by Takai et al. in 2010 [1], and is categorized as a subtype of idiopathic multicentric Castleman’s disease (iMCD). TAFRO syndrome follows a particularly aggressive clinical course compared to unicentric Castleman’s disease or other subtypes of iMCD. Therefore, clinicians often experience difficulty in treating this condition. Since its earliest description, reports of cases of TAFRO syndrome have been described worldwide, and guidelines for its treatment have been proposed [2–5]. Since organ dysfunction is commonly seen with TAFRO syndrome, temporary hemodialysis is often necessary during the course of treatment of this condition [2], although no case reports have described calcific deposits associated with hemodialysis. Additionally, although several cases with severe cardiac dysfunction due to chemotherapy, hypercytokinemia and massive ascites have been reported [6–8], there have been no cases of gross calcification recognized radiologically, either in the myocardium or in skeletal muscles.
We report a case of TAFRO syndrome with myocardial and skeletal muscle calcification, who was finally discharged from the hospital in an ambulatory condition following tocilizumab therapy. Our patient also presented with severe hypocalcemia during his clinical course, the treatment of which might have eventually triggered systemic calcification. Although it is difficult to completely understand the etiological mechanism in this case, our experience will contribute to understanding the pathophysiology and general management of TAFRO syndrome.
Case presentation
A previously healthy 24-year-old Asian man without significant family medical history presented with intermittent severe epigastric pain and fever for two weeks. Since a computed tomography (CT) scan at another hospital had only revealed systemic lymphadenopathy and could not detect any cause for his symptoms, he was referred to our hospital for further investigation. On admission, he was febrile (37.4 °C). Physical examination showed epigastric tenderness without signs of peritoneal irritation, and pitting edema on the lower extremities. His laboratory test results on admission are shown in Table 1. Contrast-enhanced CT scan revealed cervical, supraclavicular, axillary, paraaortic and inguinal lymphadenopathies, bilateral pleural effusion, ascites and hepatosplenomegaly. Soon after his admission, hemodialysis and mechanical ventilation were initiated due to the development of anuria and dyspnea, and methylprednisolone pulse therapy (1 g/day) was administered for three days after ruling out bacterial infections on hospital day 9, followed by intravenous methylprednisolone (50 mg/day) as maintenance therapy. Laboratory data on hospital day 11 are shown in Table 2. In spite of hemodialysis and ventilatory support, his vital signs were unstable, necessitating temporary use of catecholamines to maintain his blood pressure. Additionally, his plasma calcium level decreased (ionized calcium: 0.78 mmol/L) with a high level of phosphorus (9.6 mg/dL) on hospital day 17. Subsequently, we intravenously administered calcium gluconate hydrate for a total of eight days because the hypocalcemia was refractory to therapy. Laboratory data indicated low vitamin D and high intact parathyroid hormone levels, as seen in patients with chronic kidney disease. Finally, his plasma calcium levels were maintained within the normal range (Fig. 1). Bone marrow biopsy revealed hypercellular marrow with an increased number of megakaryocytes (Fig. 2). Based on these findings and exclusion criteria, we diagnosed his condition as TAFRO syndrome according to the diagnostic criteria proposed in 2015 [3].Table 1 Laboratory data on admission
Complete blood cell count Blood chemistry
WBC 14,100 /μL Total protein 5.1 g/dL
Seg 83 % Albumin 1.8 g/dL
Eosino 1 % T.Bil 1.0 mg/dL
Lympho 7 % AST 29 IU/L
Mono 9 % ALT 14 IU/L
RBC 413 104/μL LDH 370 IU/L
Hgb 13.5 g/dL ALP 265 IU/L
MCV 86.2 fL γ-GTP 105 IU/L
Platelet 46.8 104/μL BUN 43.1 mg/dL
Cr 1.62 mg/dL
Coagulation system eGFR 46 mL/min/1.73m2
PT 18.2 sec CRP 25.37 mg/dL
PT-INR 1.51 Glu 78 mg/dL
APTT (standard: 26-36) 47.9 sec AMY 39 IU/L
Fibrinogen >600 mg/dL
D-dimer 26.9 μg/mL
WBC White blood cell, RBC Red blood cell, Hgb Hemoglobin, MCV Mean corpuscular volume, PT Prothrombin time, PT-INR Prothrombin time-international normalized ratio, APTT Activated partial thromboplastin time, T.Bil Total Bilirubin, AST Aspartate aminotransferase, ALT Alanine aminotransferase, LDH Lactate dehydrogenase, ALP Alkaline phosphatase, BUN Blood urea nitrogen, Cr Creatinine, CRP C-reactive protein, AMY Amylase
Table 2 Laboratory data at the time of diagnosis of TAFRO syndrome
Complete blood cell count Blood chemistry Immunologic test
WBC 23,600 /μL Albumin 1.5 g/dL IgG 1385 mg/dL
Band 6 % T.Bil 0.4 mg/dL IgG4 66 mg/dL
Seg 88 % AST 33 IU/L IgA 187 mg/dL
Lympho 3 % ALT 12 IU/L IgM 62 mg/dL
Mono 3 % LDH 471 IU/L ANA <40 times
RBC 348 104/μL γ-GTP 266 IU/L anti-RNP Ab –
Hgb 9.9 g/dL ALP 400 IU/L anti-ds-DNA IgG –
MCV 86.8 fL BUN 119.5 mg/dL anti-SS-A Ab –
Platelet 7.5 104/μL Cr 7.77 mg/dL RF <3 IU/mL
ESR 87 mm/hr CRP 36.35 mg/dL PR3-ANCA <1 IU/mL
Ferritin 1873 ng/mL MPO-ANCA <1 IU/mL
ACE 7.6 IU/L Coombs test –
Haptoglobin 311 mg/dL PA-IgG 70 ng/107cells
Infectious diseases ADAMTS-13 28 %
EBV VCA IgG + Coagulation system anti-GBM Ab <2 U/mL
EBV VCA IgM - PT 19 Sec sIL-2R 1260 U/mL
EBNA IgG + PT-INR 1.59 IL-6 65.1 pg/mL
CMV C7-HRP - APTT >80 Sec VEGF 1030 pg/mL
(Standard: 26-36)
HIV antigen/Ab - Fibrinogen >600 mg/dL
HHV-8 DNA (WBC106cells) <20 AT-III 58 %
IGRA – FDP 66 μg/mL
WBC White blood cell, RBC Red blood cell, Hgb Hemoglobin, MCV Mean corpuscular volume, ESR Erythrocyte sedimentation rate, EBV Epstein–Barr virus, VCA Virus capsid antigen, EBNA Epstein–Barr virus nuclear antigen, CMV Cytomegalovirus, HIV Human immunodeficiency virus, Ab Antibody, HHV-8 Human herpesvirus-8, IGRA Interferon-gamma releasing assay, T.Bil Total Bilirubin, AST Aspartate aminotransferase, ALT Alanine aminotransferase, LDH Lactate dehydrogenase, γ-GTP Gamma-glutamyl transpeptidase, ALP Alkaline phosphatase, BUN Blood urea nitrogen, Cr Creatinine, CRP C-reactive protein, ACE Angiotensin-converting enzyme, PT Prothrombin time, PT-INR Prothrombin time-international normalized ratio, APTT Activated partial thromboplastin time, AT-III Antithrombin III, FDP Fibrin/fibrinogen degradation products, ANA Antinuclear antibody, anti-RNP-antibody Anti-ribonucleoprotein antibody, anti-ds-DNA IgG Anti-double-stranded deoxyribonuclein acid immunoglobulin G, anti-SS-A antibody Anti-Sjören's syndrome A antibody, RF Rheumatoid factor, PR3-ANCA Proteinase 3-anti-neutrophil cytoplasmic antibody, MPO-ANCA Myeloperoxidase-anti-neutrophil cytoplasmic antibody, PA-IgG Platelet-associated immunoglobulin G, anti-GBM antibody Anti-glomerular basement membrane antibody, sIL-2R Soluble interleukin-2 receptor, IL-6 Interleukin-6, VEGF Vascular endothelial growth factor
Fig. 1 Transition of ionized calcium. Hypocalcemia appeared after the initiation of dialysis, and myocardial/skeletal muscle calcification was revealed on CT scans after the recovery from hypocalcemia with administration of calcium gluconate hydrate
Fig. 2 Histological findings on bone marrow biopsy. a, b Hypercellular marrow with increased megakaryocytes are seen. (Hematoxylin and eosin staining). (Scale bar, 100 μm)
We initiated weekly treatment with the biologic tocilizumab (8 mg/kg), which is a recombinant, humanized, anti-human interleukin-6 (IL-6) receptor monoclonal antibody, along with tapering glucocorticoids on hospital day 32. However, on hospital day 76, he presented with syncope due to sick sinus syndrome. We first recognized myocardial and skeletal muscle calcification by CT scans on hospital day 47 (Fig. 3). Subsequent CTs showed progressive worsening of the degree of calcification in the first few months (Fig. 4). At this time, we could not perform temporary pacing because of the risk of hemorrhage due to persistently low platelet levels and coagulopathy.Fig. 3 Myocardial and skeletal muscle calcification noted on computed tomography scans for the first time. a High density areas were present on the myocardium (arrows). b, c The rectus abdominis muscle and those of the thigh (arrows) showed high density bilaterally
Fig. 4 Chronological changes in myocardial and skeletal muscle (rectus abdominis) calcification on computed tomography images. Computed tomography was performed on (a, e) day 47, (b, f) day 123, (c, g) day 177 and (d, h) day 345. The degree of calcification showed progressive worsening during the first few months; subsequently, myocardial calcification remained unchanged, while that in the skeletal muscle gradually diminished
Although he repeatedly suffered from various infections (such as catheter related blood stream infection, pyothorax, intraabdominal abscess and infectious endocarditis), we basically continued use of tocilizumab, except when the infection was very severe. We initiated romiplostim, an analog of thrombopoietin, on day 173 because his platelet count remained persistently low, which soon resulted in recovery of platelet count to within the normal range. In addition, urine volume began to gradually increase five months after the onset of anuria. Thereafter, calcification of the rectus abdominis muscle also began to gradually diminish, as observed by CT scans, although there were no remarkable changes in that of the myocardium (Fig. 4).
Although there were many life-threatening events throughout his prolonged hospitalization, he was finally discharged from the hospital in an ambulatory condition on hospital day 410 (his complete clinical course is shown in Fig. 5). Sick sinus syndrome resolved together with improvement in his general condition, so permanent pacemaker implantation was deemed unnecessary. Currently, he receives regular hemodialysis and intravenous tocilizumab every three weeks without evidence of recurrence for one year after discharge.Fig. 5 Clinical course from admission until discharge. PLT platelets, CRP C-reactive protein, mPSL methylprednisolone, TCZ tocilizumab, HD hemodialysis, CRBSI catheter-related blood stream infection, IE infectious endocarditis, SSS sick sinus syndrome
Discussion
TAFRO syndrome and cardiac events
TAFRO syndrome is defined as a subtype of idiopathic multicentric Castleman’s disease (iMCD) that has been recognized as having a severe clinical course. Masaki et al. proposed the diagnostic criteria and severity classification in 2015, and there have been several recently reported clinicopathological analyses and consensus guidelines for the treatment of iMCD based on the accumulated data [2–5]. Our case fulfilled the diagnostic criteria of TAFRO syndrome according to the guideline, and was classified as grade 4 (severe) severity. Our case is rare not only because of many life-threating events such as repetitive severe infections, sick sinus syndrome and cardiac arrest, but also because of the myocardial and skeletal muscle calcification that occurred two months after his disease onset. Other cases have also survived despite a very severe clinical course [9–11], although none of them experienced systemic calcification.
Many TAFRO syndrome cases have recovered with the use of biological products (such as tocilizumab or rituximab), glucocorticoids, immunosuppressants (such as cyclosporine A or sirolimus), and occasionally, with chemotherapy. In terms of cardiac dysfunction, Yasuda et al. reported two cases of TAFRO syndrome with cardiomyopathy and lowered ejection fraction (EF) [6]. They performed CHOP (cyclophosphamide, adriamycin, vincristine and prednisolone) therapy as treatment, and assumed that the cardiomyopathy was an adverse effect of adriamycin. Hiramatsu et al. showed a case of TAFRO syndrome with reversible cardiomyopathy, in which they opined that the high concentration of plasma IL-6 was the cause of cardiomyopathy [7]. However, these cases did not have any associated calcification.
The etiology of myocardial/systemic calcification
Myocardial calcification itself only occurs very rarely. There are traditionally two pathways causing myocardial calcification: metastatic and dystrophic. Metastatic calcification occurs with hypercalcemia and/or abnormality of calcium/phosphate metabolism [12]. This form of calcification can occur anywhere in the body, but is more likely in areas of high alkalinity, such as the gastric mucosa or systemic arteries; therefore, calcification due to this etiology can exist systemically. On the other hand, dystrophic calcification occurs secondary to cellular damage and necrosis, with calcium deposits replacing necrotizing cells. Other etiologies of dystrophic calcification include trauma, infections, inflammation, neoplasms and drugs [12]. Myocardial infarction is a common cause of myocardial calcification. Septic shock is also a cause of this form of calcification; hypotension during shock and catecholamine use can cause myocardial damage, which eventually results in calcium deposits even if plasma calcium concentration is normal [12, 13]. In our case, the etiology of myocardial and skeletal muscle calcification was considered more likely to be metastatic than dystrophic due to the following reasons. First, there was a failure of calcium/phosphate metabolism due to the presence of progressive renal dysfunction with hemodialysis and low vitamin D levels. There was also excessive replenishment of calcium, with an amount of 7.8 mmol of calcium gluconate hydrate per day on average, which could have accelerated calcium deposition in systemic tissues. We did not administer intravenous vitamin D agents, except for the minimal amount of vitamins administered through total parenteral nutrition, which might have been a possible cause for prolonged low calcium levels. Second, both myocardial and skeletal muscle calcification were detected on CT scans at the same time, which was within a month after the initial identification of hypocalcemia and subsequent overloading of calcium (Fig. 3). Third, although we temporarily used catecholamines, there were no other conditions explaining the dystrophic calcification, such as septic shock or myocardial infarction. Fourth, hypercytokinemia, including elevated IL-6 caused by TAFRO syndrome, could also have contributed to this unusual situation. Plasma calcium levels remained low and were almost unchanged when calcium gluconate hydrate was administered, which suggested that the administered calcium probably leaked out of the vessels and was absorbed by peripheral tissues. Increase of vasopermeability is another possible etiology for the calcified deposits, which could explain its occurrence in the absence of hypercalcemia.
In conclusion, this case of TAFRO syndrome achieved a successful recovery with tocilizumab therapy along with prolonged hospitalization, although he experienced the unexpected complication of myocardial and skeletal muscle calcification probably via a metastatic pathway triggered by drug administration. In acute clinical settings, the tendency is to urgently correct abnormal laboratory data, especially electrolyte abnormalities. However, TAFRO syndrome is known to be associated with hypercytokinemia and organ dysfunction with an unknown pathophysiology; hence, the general management of such cases should be carefully handled, anticipating unexpected complications.
Abbreviations
TAFROThrombocytopenia, anasarca, fever, renal insufficiency or reticulin fibrosis, and organomegaly
iMCDIdiopathic multicentric Castleman’s disease
CTComputed tomography
IL-6Interleukin-6
CHOPCyclophosphamide, adriamycin, vincristine and prednisolone
Publisher's Note
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Acknowledgements
The authors thank Forte Science Communications (www.forte-science.co.jp) for their assistance in proofreading this article.
Authors’ contributions
SM treated this patient, reviewed literature, interpreted the patient data about the etiology in this patient, and contributed to writing the manuscript. YF reviewed literature, wrote the manuscript, and managed this research. SS treated this patient and wrote the manuscript. AT provided professional opinions regarding patient care and treatment, and revised the manuscript. KN revised the manuscript and currently cares for this patient at the outpatient clinic. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Ethics approval and consent for submitting case reports is usually waived by the ethics review committee of Musashino Red Cross Hospital. We followed the principles of the Declaration of Helsinki and paid cautious attention to protecting the patient’s identity.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33402219 | 19,396,568 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute kidney injury'. | Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
Background
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder associated with mature B-cell dysfunction, hypogammaglobulinaemia and T-cell abnormalities. In Europe and North America, CLL is the most common leukaemia, with median age of diagnosis of 70 years.1 Treatment is indicated only for symptomatic disease, such as anaemia <100 g/L and/or thrombocytopenia <100×109/L, massive splenomegaly, lymphadenopathy or constitutional symptoms.2
Infection is a frequent cause of morbidity and mortality in CLL. Roughly 30%–50% of all CLL patients suffer infections, with a high subsequent mortality rate.3 While the majority of infections affect more often the respiratory track, or skin and the gastrointestinal tract.4 The most frequent organisms causing infections are bacteria like Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. This increased susceptibility to infection stems from B-cells with impaired immunoglobulin production capability and dysfunctional T-helper cells, which also assist in antibody production. This impaired capability to produce immunoglobulins, termed hypogammaglobulinaemia, affects 85% of CLL patients, particularly in advanced disease.4
Antineoplastic agents recommended for the treatment of CLL are also immunosuppressive and further increase the risk of infections.5 These include opportunistic micro-organisms such as Candida, Pneumocystis jirovecii, listeria, nocardia and atypical mycobacteria. In addition, patients have increased risk of viral diseases such as herpes simplex, Epstein-Barr and cytomegalovirus (CMV). Additional infectious complications may include hepatitis B reactivation and progressive multifocal leucoencephalopathy. In spite of the immunosuppressive risk, chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the standard risk therapy in fit patients below 65 years of age with CLL, in absence of 17 p deletion, or TP53 mutation, and with immunoglobulin heavy chain V (IGHV)-mutated.6
To reduce risk of infection, immunoglobulin levels should also be routinely monitored, particularly with rituximab, which reduces the number of B-cells expressing CD20. It is postulated that monitoring immunoglobulins while being treated with rituximab may reduce the risk of serious infections.4
Herein, we present a unique case of a woman treated for CLL who experienced severe pancytopenia and immunosuppression at the completion of her chemo-immunotherapy. She subsequently experienced triple concurrent viral infections, which posed a therapeutic challenge due to her pancytopenia.
Case presentation
A previously healthy 58-year-old woman was diagnosed with CLL through a routine blood test in 2015. Her physical examination was unremarkable and her lymphocyte counts were at 12.36×109 cells/L. Bone marrow biopsy with immunohistochemistry was suggestive of CLL and stained positive for BCL2, CD5 (aberrant T-cell marker), CD20, CD23, CD43 and CD79a (B-cell markers) while BCL6 was negative. The PCR amplification study showed immunoglobulin heavy chain gene rearrangement along with IgG kappa light chain gene arrangement. No t(14;18) BCL2/JH or t(11;14) BCL1/JH gene rearrangements were observed. As she was asymptomatic, and positron emission tomography (PET) scan showed low grade metabolic activity in lymph nodes in cervical, axillary and iliac areas, no therapy was initiated (figure 1). She was followed every 6 months.
Figure 1 Positron emission tomography scan (right) and corresponding CT images (left) of multiple low-grade hypermetabolic lymph nodes in 2017, 2 years after diagnosis of chronic lymphocytic leukaemia. (A) Multiple small low-grade hypermetabolic lymph nodes in bilateral neck regions predominantly in the posterior triangles. SUV of 1.9 in the left and right upper posterior triangles. (B) Hypermetabolic lymph nodes in the left axillary regions, SUV 1.8. (C) Left external iliac lymph node SUV of 3. SUV, Standardized uptake value.
In November 2017 the patient had symptom of a rapid bilateral enlargement of the cervical lymph nodes accompanied by persistent fatigue, night sweats and decreased weight. Lyme disease, HIV, hepatitis B and C and syphilis serologies were performed, and all tests yielded negative results. Repeat PET/CT scan, cytogenetics and bone marrow biopsy demonstrated no evidence of Richter’s transformation into a diffuse large cell lymphoma. Due to significant bulky disease and enlarged adenopathy with B constitutional symptoms, chemo-immunotherapy with FCR was considered. This was furthermore rationalised as she was a fit patient younger than 65 years of age with standard risk for CLL due to the absence of 17 p deletion, or TP53 mutation, and with IGHV being mutated.7
She received six cycles of FCR which was completed uneventfully on 11 November 2019. During FCR therapy, she received oral valacyclovir 500 mg two times per day for herpes prophylaxis as well as Septra DS (160 mg trimethoprim and 800 mg sulfamethoxazole) one tablet Mondays, Wednesdays and Fridays for P. jirovecii prophylaxis. On 18 November, she presented to the emergency room of the McGill University Health Centre (MUHC) with haematuria, suprapubic pain and fever. She was admitted and treated for a urine infection and slowly improved after different antibiotics such as ciprofloxacin, trimethoprim-sulfamethoxazole and ceftriaxone and blood and urinary bacterial cultures were negative. A CT urogram showed moderate bilateral hydroureteronephrosis with diffuse urolithelial and bladder thickening (figure 2). As a whole, these findings were suggestive of an inflammatory or infectious process evoking pyleoureteritis and cystitis.
Figure 2 CT urogram on admission in November 2019, demonstrating (A) poorly distended bladder and marked thickening of bladder walls (green arrow) and (B) moderate dilation of both ureters and collection ducts with marked thickening and enhancement of the urothelium associated with moderate periureteric fat stranding.
Investigations
On admission, she was mildly pancytopenic (table 1). As the patient partially improved and had negative urine cultures, a cyclophosphamide-induced haemorrhagic cystitis was considered, and she was placed on continuous bladder irrigation.
Table 1 Summary of the patient’s serological and microbiological test results during the course of her neutropenia and triple viremia
Laboratory results Reference ranges 20 March 2019 11 November 2019 26 November 2019 25 December 2019 01 January 2020 23 January 2020 01 February 2020 07 February 2020 03 March 2020
Time of intervention First dose FCR Last dose FCR Meropenem started Virology investigated Begins cidofovir+GCSF Cidofovir changed to Ganciclovir Ganciclovir transitioned to valganciclovir Discharge Follow-up
WBC (109/L) 4.0–10.0 30.90 5.90 3.00 1.00 0.60 2.40 6.10 2.40 2.00
Neutrophils 2.0–7.0 3.75 4.18 2.46 0.80 0.36 1.19 5.09 1.73 1.35
Lymphocytes 1.5–4.5 26.26 0.87 0.23 0.08 0.11 0.23 0.46 0.33 0.44
Plt (109/L) 150–450 145 158 123 48 19 54 17 12 39
Hb (g/L) 120–150 142 129 99 63 80 70 70 71 99
Creatinine (umol/L) 50–90 71 68 125 128 118 75 74 69 75
CMV (copies/mL) – – – – 7320 3170 1291 153 149 0
Adenovirus (copies/mL) – – – – – 7.44 log10 4.86 log10 3.74 log10 – 3.30 log10
BK virus urine (copies/mL) – – – – – 2.26×107 – 3.20×108 –
BK virus blood (copies/mL) – – – – – – – – – 3.91×103
CMV, cytomegalovirus; FCR, fludarabine, cyclophosphamide and rituximab; Hb, haemoglobin; Plt, platelet; WBC, white blood cell.
On 1 December 2019 she developed a pancytopenia that required platelet and packed red blood cell transfusions. She remained persistently febrile despite repeated negative bacterial blood and urine cultures. Due to her CLL, pancytopenia and the consideration of immunosuppression induced by FCR chemotherapy, viral infections were investigated. PCR for adenovirus showed 22.4 copies/mL in blood, and positive in urine; PCR for polyoma virus showed 8.81 million copies/mL blood; and PCR for CMV showed 358 copies/mL in blood, confirming viral invasive infections (figure 3). To further investigate her pancytopenia, serology for parvovirus B 19 was carried out and was negative for IgM.
Figure 3 Cytomegalovirus (CMV) and BK viremia (A) and adeno-viremia (B) over the course of treatment.
On 18 December 2019 the patient underwent a double J-stent insertion for bilateral hydronephrosis. Pelvic pain persisted and she continued to pass clots in her urine. Repeat CMV PCR testing on 25 December 2019 showed 7320 copies/mL while an ophthalmological assessment revealed no evidence of CMV retinitis or keratitis. Bone marrow biopsy results showed pancytopenia without transformation (figure 4).
Figure 4 Histology and immunochemistry of bone marrow smear (A) and biopsy (B). Bone marrow biopsy demonstrating hypocellularity. Moderate left shift of the myeloid series and mild left shift of the erythroid series. No lymphocytosis or lymphoma, no definite diagnosis of myelodysplastic syndrome (B).
Treatment
On 1 January 2020, cidofovir was administered to treat the three viral infections of BK polyomavirus, adenovirus and CMV. Cidofovir was given at the dose of 1 mg/kg intravenously three times a week instead of a weekly dose given her kidney injury and high creatinine levels. She received probenecid 2 g orally 1 hour before cidofovir, then 2 hours and 8 hours after the end of infusion to increase cidofovir levels in the blood. For renal protection, she was hydrated with 1 L of 0.9% normal saline during cidofovir infusion. Filgrastim (G-CSF) was initiated for her neutropenia, darbepoetin for her anaemia, and intravenous IgG was infused three times at 4-week intervals for her hypogammaglobulinumia.
Neutropenia worsen despite filgrastim, and CMV viral load continued to increase. Due to cidofovir myelotoxicity, a decision was made to focus treatment on CMV infection, while ignoring the BK and adenovirus. To this end, the patient was changed to ganciclovir 250 mg intravenous two times per day on 23 January 2020 and her urinary symptoms improved for the first time. On 1 February 2020, she was transitioned to oral valganciclovir 450 mg daily and was discharged to home 1 week later, after 101 days in hospital.
Outcome and follow-up
A bone marrow biopsy on 27 January 2020 showed a hypocellular marrow with focal area up to 20%–30% haematopoietic tissue. No evidence of lymphocytosis or lymphoma and no dysplastic changes in morphology were observed. Immunohistochemistry showed <5% CD117, and was negative for CD20, CD34 and PAX5. The histological appearance represented haematopoietic regeneration post-chemotherapy. On 3 March 2020 follow-up, CMV load was undetectable, adenovirus load was 5000 copies/mL, BK load was 3.2×108 copies/mL (table 1). She was switched on CMV prophylaxis with resolved haemorrhagic cystitis and received valganciclovir 450 mg p.o. daily for another 3 months and until her absolute lymphocyte count recovers above 109 cells/L. She continued trimethoprim-sulfamethaxole prophylaxis for 6 months post-chemotherapy. Her double-J stents remain in place. While clinically improved, her neutropenia improved on low dose filgrastim until 4 April 2020. Her blood counts normalised 1 month after and she is followed as an outpatient with Haematology, Infectious Diseases, and Urology services at the MUHC.
Discussion
FCR chemo-immunotherapy is considered the treatment for standard risk CLL patients under the age of 65,7 with a high overall response rate. However, the predominant complication is myelosuppression.8 Persistent neutropenia was reported in 19% and late infections in 9% of patients.9 The frequency of cytopenias was 35% at 3 months and 12% at 9 months after completion of therapy, respectively. Another side effect is prolonged lymphoid immunodeficiency.
Human adenovirus infections usually present as a keratoconjunctivitis or respiratory tract infection. In most healthy individuals the infection is usually self-limited. However, in immunosuppressed patients, infection may disseminate and become potentially life-threatening. Disseminated adenovirus infection can result from either de novo infection or a reactivation of clinically silent infection.10
BK virus is a member of the polyomavirus family. BK virus reactivation occurs only in immunosuppressed patients and can lead to nephropathy, ureteral stenosis, tubular interstitial damage and haemorrhagic cystitis. Viremia occurs in 20%–60% of this population. There is no specific treatment for BK virus-associated nephropathy, therefore viral replication can only be controlled through modulating the immunosuppressive condition.11
CMV is a herpes virus with a large double-stranded DNA that remains latent in the host after primary infection. Immunocompromised patients can have reactivation of their latent infection. Diagnosis of viral reactivation is made through CMV PCR in blood, tissue or body fluid. Manifestations of CMV infection occur most often in the gastrointestinal tract, lungs, liver and retina.12 As we did not observe the typical owl’s eye tissue lesion in the second bone marrow biopsy, we considered that CMV reactivation was a contributing factor for the pancytopenia, and treatment may have prevented such tissue lesion to develop. First line treatment of CMV infection includes intravenous ganciclovir or its oral prodrug valganciclovir, which are DNA polymerase inhibitors. The major side effect of these drugs is myelosuppression, including neutropenia.4
In our patient, the prolonged pancytopenias secondary to FCR was associated with haematuria with an ureteral mass. To date, only two observations on the use of cidofovir to simultaneously treat BK-virus associated haemorrhagic cystitis and CMV reactivation have been reported. However, in the case report by Held et al, the patient had received a bone marrow transplant for chronic myeloid leukaemia, whereas our patient had CLL.
Cidofovir has been suggested in some cases for the treatment of BK virus-associated haemorrhagic cystitis.13 Cidofovir and foscarnet are second-line therapies in patients with CMV that are either resistant or refractory to ganciclovir. Cidofovir is a non-cyclic analogue of cytidine monophosphate that terminates CMV DNA synthesis. In vitro studies showed effectiveness against herpes viruses, including CMV, herpes simplex viruses 1 and 2, varicella-zoster, Epstein-Barr virus, human papillomavirus and adenovirus. The main adverse effect is nephrotoxicity, causing proximal tubular injury. Serum creatinine and urine protein measurements are recommended during administration.14 Probenecid decreases intratubular secretion and maintains a sufficient plasma concentration to allow for once weekly dosing at 5 mg/kg to reduce its nephrotoxicity.13 An alternate dosing regimen, initially used in our patient, was three times per week dosing at 3 mg/kg. In the study performed by Philippe et al, intravenous cidofovir achieve remission in 81.5% of the 22 patients.13
The patient reported by Held et al recovered fully with cidofovir15; however, our patient was switched to ganciclovir due to persistent neutropenia. Bone marrow biopsy was consistent with secondary treatment-related myelosuppression syndrome, without evidence of myelodysplasia or lymphoproliferative infiltration. Myelosuppression is a major side effect of ganciclovir. However, the antiviral effects far outweigh these risks and therefore ganciclovir and its oral prodrug valganciclovir should be considered for patients with pancytopenia secondary to CMV reactivation.
In summary, this unique case of triple-viremia induced haemorrhagic cystitis in an immunosuppressed CLL patient posed both a diagnostic and therapeutic challenge as treatments are nephrotoxic and further increase immunosuppression.
The major learning point is to exercise caution when prescribing FCR chemotherapy on its long-term immunosuppressive effects. It is expected that novel immuno-chemotherapy for CLL should control the disease with reduced immunosuppressive effects.16
Patient’s perspective
Translation from French
I was diagnosed with CLL in November 2015. Started the treatments with FCR protocol in April 2019 (six treatments of three consecutive days each). At the end of the fourth treatment, I was not well. I had fever and a large fatigue with no energy. I finished treatments on the 13th of November 2019. On the week of 18 November, the symptoms appeared: fever, incontinent of urine with blood, no appetite, fatigue.
I visited MUHC emergency, 12 hours wait before I had a doctor’s room. I stayed the night and the next day I saw the doctor, but they did not know what I had. On the 22nd of November I returned to emergency with a lot of fever and other symptoms. I passed the night in an emergency room. On Saturday they released me, had fever and falls.
On the 24th I returned to emergency, fever and incontinence, etc. I was placed in the corridor in a stretcher with a commode next to the whole world. There was nowhere else for me, I had to go through the doors to go to the public toilet and I urinated every 5 min. I stayed in emergency 5 days before I was admitted to Internal Medicine.
It was a bad experience the three times I was in emergency. On 29 November, I had my own room. I was there till 07 February 2020.
The staff took charge rapidly. There were many tests during this long period to find out the cause of my problems. Everything came from the chemotherapy. Many departments were involved: urology, otolaryngology, haematology, internal medicine, infectious diseases.
There were several healthcare workers who spoke on behalf of other departments.
Very good service with the nursing staffs and the préposé (aux bénéficiaires). On my part, my immune system was severely damaged.
Learning points
Infections in immunosuppressed patients remain a diagnostic and therapeutic challenge.
In patient treated for chronic lymphocytic leukaemia, haematuria can be related to viral infections like BK virus, adenovirus and cytomegalovirus (CMV).
BK infection is diagnosed with a high index of suspicion, however, combined CMV and adenovirus infections renders the diagnosis more difficult.
Treatment of these viral infections remains difficult as medications are associated with myelotoxicity (ganciclovir) and renal insufficiency (cidofovir).
The authors would like to thank Dr Malek Merdad and Dr Isabelle Malhamé for their inspiration to write this article.
Contributors: MK and J-PR devised the project, main conceptual ideas and proof outlines. MK took the lead in writing the manuscript the supervision of J-PR. MK created all the images and translated the patient’s perspective from French to English. J-PR and JL provided critical feedback and helped shape analysis and manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | CIDOFOVIR, CYCLOPHOSPHAMIDE, FILGRASTIM, FLUDARABINE PHOSPHATE, HUMAN IMMUNOGLOBULIN G, PROBENECID, RITUXIMAB, SODIUM CHLORIDE, SULFAMETHOXAZOLE\TRIMETHOPRIM, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33402369 | 19,066,566 | 2021-01-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Adenovirus infection'. | Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
Background
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder associated with mature B-cell dysfunction, hypogammaglobulinaemia and T-cell abnormalities. In Europe and North America, CLL is the most common leukaemia, with median age of diagnosis of 70 years.1 Treatment is indicated only for symptomatic disease, such as anaemia <100 g/L and/or thrombocytopenia <100×109/L, massive splenomegaly, lymphadenopathy or constitutional symptoms.2
Infection is a frequent cause of morbidity and mortality in CLL. Roughly 30%–50% of all CLL patients suffer infections, with a high subsequent mortality rate.3 While the majority of infections affect more often the respiratory track, or skin and the gastrointestinal tract.4 The most frequent organisms causing infections are bacteria like Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. This increased susceptibility to infection stems from B-cells with impaired immunoglobulin production capability and dysfunctional T-helper cells, which also assist in antibody production. This impaired capability to produce immunoglobulins, termed hypogammaglobulinaemia, affects 85% of CLL patients, particularly in advanced disease.4
Antineoplastic agents recommended for the treatment of CLL are also immunosuppressive and further increase the risk of infections.5 These include opportunistic micro-organisms such as Candida, Pneumocystis jirovecii, listeria, nocardia and atypical mycobacteria. In addition, patients have increased risk of viral diseases such as herpes simplex, Epstein-Barr and cytomegalovirus (CMV). Additional infectious complications may include hepatitis B reactivation and progressive multifocal leucoencephalopathy. In spite of the immunosuppressive risk, chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the standard risk therapy in fit patients below 65 years of age with CLL, in absence of 17 p deletion, or TP53 mutation, and with immunoglobulin heavy chain V (IGHV)-mutated.6
To reduce risk of infection, immunoglobulin levels should also be routinely monitored, particularly with rituximab, which reduces the number of B-cells expressing CD20. It is postulated that monitoring immunoglobulins while being treated with rituximab may reduce the risk of serious infections.4
Herein, we present a unique case of a woman treated for CLL who experienced severe pancytopenia and immunosuppression at the completion of her chemo-immunotherapy. She subsequently experienced triple concurrent viral infections, which posed a therapeutic challenge due to her pancytopenia.
Case presentation
A previously healthy 58-year-old woman was diagnosed with CLL through a routine blood test in 2015. Her physical examination was unremarkable and her lymphocyte counts were at 12.36×109 cells/L. Bone marrow biopsy with immunohistochemistry was suggestive of CLL and stained positive for BCL2, CD5 (aberrant T-cell marker), CD20, CD23, CD43 and CD79a (B-cell markers) while BCL6 was negative. The PCR amplification study showed immunoglobulin heavy chain gene rearrangement along with IgG kappa light chain gene arrangement. No t(14;18) BCL2/JH or t(11;14) BCL1/JH gene rearrangements were observed. As she was asymptomatic, and positron emission tomography (PET) scan showed low grade metabolic activity in lymph nodes in cervical, axillary and iliac areas, no therapy was initiated (figure 1). She was followed every 6 months.
Figure 1 Positron emission tomography scan (right) and corresponding CT images (left) of multiple low-grade hypermetabolic lymph nodes in 2017, 2 years after diagnosis of chronic lymphocytic leukaemia. (A) Multiple small low-grade hypermetabolic lymph nodes in bilateral neck regions predominantly in the posterior triangles. SUV of 1.9 in the left and right upper posterior triangles. (B) Hypermetabolic lymph nodes in the left axillary regions, SUV 1.8. (C) Left external iliac lymph node SUV of 3. SUV, Standardized uptake value.
In November 2017 the patient had symptom of a rapid bilateral enlargement of the cervical lymph nodes accompanied by persistent fatigue, night sweats and decreased weight. Lyme disease, HIV, hepatitis B and C and syphilis serologies were performed, and all tests yielded negative results. Repeat PET/CT scan, cytogenetics and bone marrow biopsy demonstrated no evidence of Richter’s transformation into a diffuse large cell lymphoma. Due to significant bulky disease and enlarged adenopathy with B constitutional symptoms, chemo-immunotherapy with FCR was considered. This was furthermore rationalised as she was a fit patient younger than 65 years of age with standard risk for CLL due to the absence of 17 p deletion, or TP53 mutation, and with IGHV being mutated.7
She received six cycles of FCR which was completed uneventfully on 11 November 2019. During FCR therapy, she received oral valacyclovir 500 mg two times per day for herpes prophylaxis as well as Septra DS (160 mg trimethoprim and 800 mg sulfamethoxazole) one tablet Mondays, Wednesdays and Fridays for P. jirovecii prophylaxis. On 18 November, she presented to the emergency room of the McGill University Health Centre (MUHC) with haematuria, suprapubic pain and fever. She was admitted and treated for a urine infection and slowly improved after different antibiotics such as ciprofloxacin, trimethoprim-sulfamethoxazole and ceftriaxone and blood and urinary bacterial cultures were negative. A CT urogram showed moderate bilateral hydroureteronephrosis with diffuse urolithelial and bladder thickening (figure 2). As a whole, these findings were suggestive of an inflammatory or infectious process evoking pyleoureteritis and cystitis.
Figure 2 CT urogram on admission in November 2019, demonstrating (A) poorly distended bladder and marked thickening of bladder walls (green arrow) and (B) moderate dilation of both ureters and collection ducts with marked thickening and enhancement of the urothelium associated with moderate periureteric fat stranding.
Investigations
On admission, she was mildly pancytopenic (table 1). As the patient partially improved and had negative urine cultures, a cyclophosphamide-induced haemorrhagic cystitis was considered, and she was placed on continuous bladder irrigation.
Table 1 Summary of the patient’s serological and microbiological test results during the course of her neutropenia and triple viremia
Laboratory results Reference ranges 20 March 2019 11 November 2019 26 November 2019 25 December 2019 01 January 2020 23 January 2020 01 February 2020 07 February 2020 03 March 2020
Time of intervention First dose FCR Last dose FCR Meropenem started Virology investigated Begins cidofovir+GCSF Cidofovir changed to Ganciclovir Ganciclovir transitioned to valganciclovir Discharge Follow-up
WBC (109/L) 4.0–10.0 30.90 5.90 3.00 1.00 0.60 2.40 6.10 2.40 2.00
Neutrophils 2.0–7.0 3.75 4.18 2.46 0.80 0.36 1.19 5.09 1.73 1.35
Lymphocytes 1.5–4.5 26.26 0.87 0.23 0.08 0.11 0.23 0.46 0.33 0.44
Plt (109/L) 150–450 145 158 123 48 19 54 17 12 39
Hb (g/L) 120–150 142 129 99 63 80 70 70 71 99
Creatinine (umol/L) 50–90 71 68 125 128 118 75 74 69 75
CMV (copies/mL) – – – – 7320 3170 1291 153 149 0
Adenovirus (copies/mL) – – – – – 7.44 log10 4.86 log10 3.74 log10 – 3.30 log10
BK virus urine (copies/mL) – – – – – 2.26×107 – 3.20×108 –
BK virus blood (copies/mL) – – – – – – – – – 3.91×103
CMV, cytomegalovirus; FCR, fludarabine, cyclophosphamide and rituximab; Hb, haemoglobin; Plt, platelet; WBC, white blood cell.
On 1 December 2019 she developed a pancytopenia that required platelet and packed red blood cell transfusions. She remained persistently febrile despite repeated negative bacterial blood and urine cultures. Due to her CLL, pancytopenia and the consideration of immunosuppression induced by FCR chemotherapy, viral infections were investigated. PCR for adenovirus showed 22.4 copies/mL in blood, and positive in urine; PCR for polyoma virus showed 8.81 million copies/mL blood; and PCR for CMV showed 358 copies/mL in blood, confirming viral invasive infections (figure 3). To further investigate her pancytopenia, serology for parvovirus B 19 was carried out and was negative for IgM.
Figure 3 Cytomegalovirus (CMV) and BK viremia (A) and adeno-viremia (B) over the course of treatment.
On 18 December 2019 the patient underwent a double J-stent insertion for bilateral hydronephrosis. Pelvic pain persisted and she continued to pass clots in her urine. Repeat CMV PCR testing on 25 December 2019 showed 7320 copies/mL while an ophthalmological assessment revealed no evidence of CMV retinitis or keratitis. Bone marrow biopsy results showed pancytopenia without transformation (figure 4).
Figure 4 Histology and immunochemistry of bone marrow smear (A) and biopsy (B). Bone marrow biopsy demonstrating hypocellularity. Moderate left shift of the myeloid series and mild left shift of the erythroid series. No lymphocytosis or lymphoma, no definite diagnosis of myelodysplastic syndrome (B).
Treatment
On 1 January 2020, cidofovir was administered to treat the three viral infections of BK polyomavirus, adenovirus and CMV. Cidofovir was given at the dose of 1 mg/kg intravenously three times a week instead of a weekly dose given her kidney injury and high creatinine levels. She received probenecid 2 g orally 1 hour before cidofovir, then 2 hours and 8 hours after the end of infusion to increase cidofovir levels in the blood. For renal protection, she was hydrated with 1 L of 0.9% normal saline during cidofovir infusion. Filgrastim (G-CSF) was initiated for her neutropenia, darbepoetin for her anaemia, and intravenous IgG was infused three times at 4-week intervals for her hypogammaglobulinumia.
Neutropenia worsen despite filgrastim, and CMV viral load continued to increase. Due to cidofovir myelotoxicity, a decision was made to focus treatment on CMV infection, while ignoring the BK and adenovirus. To this end, the patient was changed to ganciclovir 250 mg intravenous two times per day on 23 January 2020 and her urinary symptoms improved for the first time. On 1 February 2020, she was transitioned to oral valganciclovir 450 mg daily and was discharged to home 1 week later, after 101 days in hospital.
Outcome and follow-up
A bone marrow biopsy on 27 January 2020 showed a hypocellular marrow with focal area up to 20%–30% haematopoietic tissue. No evidence of lymphocytosis or lymphoma and no dysplastic changes in morphology were observed. Immunohistochemistry showed <5% CD117, and was negative for CD20, CD34 and PAX5. The histological appearance represented haematopoietic regeneration post-chemotherapy. On 3 March 2020 follow-up, CMV load was undetectable, adenovirus load was 5000 copies/mL, BK load was 3.2×108 copies/mL (table 1). She was switched on CMV prophylaxis with resolved haemorrhagic cystitis and received valganciclovir 450 mg p.o. daily for another 3 months and until her absolute lymphocyte count recovers above 109 cells/L. She continued trimethoprim-sulfamethaxole prophylaxis for 6 months post-chemotherapy. Her double-J stents remain in place. While clinically improved, her neutropenia improved on low dose filgrastim until 4 April 2020. Her blood counts normalised 1 month after and she is followed as an outpatient with Haematology, Infectious Diseases, and Urology services at the MUHC.
Discussion
FCR chemo-immunotherapy is considered the treatment for standard risk CLL patients under the age of 65,7 with a high overall response rate. However, the predominant complication is myelosuppression.8 Persistent neutropenia was reported in 19% and late infections in 9% of patients.9 The frequency of cytopenias was 35% at 3 months and 12% at 9 months after completion of therapy, respectively. Another side effect is prolonged lymphoid immunodeficiency.
Human adenovirus infections usually present as a keratoconjunctivitis or respiratory tract infection. In most healthy individuals the infection is usually self-limited. However, in immunosuppressed patients, infection may disseminate and become potentially life-threatening. Disseminated adenovirus infection can result from either de novo infection or a reactivation of clinically silent infection.10
BK virus is a member of the polyomavirus family. BK virus reactivation occurs only in immunosuppressed patients and can lead to nephropathy, ureteral stenosis, tubular interstitial damage and haemorrhagic cystitis. Viremia occurs in 20%–60% of this population. There is no specific treatment for BK virus-associated nephropathy, therefore viral replication can only be controlled through modulating the immunosuppressive condition.11
CMV is a herpes virus with a large double-stranded DNA that remains latent in the host after primary infection. Immunocompromised patients can have reactivation of their latent infection. Diagnosis of viral reactivation is made through CMV PCR in blood, tissue or body fluid. Manifestations of CMV infection occur most often in the gastrointestinal tract, lungs, liver and retina.12 As we did not observe the typical owl’s eye tissue lesion in the second bone marrow biopsy, we considered that CMV reactivation was a contributing factor for the pancytopenia, and treatment may have prevented such tissue lesion to develop. First line treatment of CMV infection includes intravenous ganciclovir or its oral prodrug valganciclovir, which are DNA polymerase inhibitors. The major side effect of these drugs is myelosuppression, including neutropenia.4
In our patient, the prolonged pancytopenias secondary to FCR was associated with haematuria with an ureteral mass. To date, only two observations on the use of cidofovir to simultaneously treat BK-virus associated haemorrhagic cystitis and CMV reactivation have been reported. However, in the case report by Held et al, the patient had received a bone marrow transplant for chronic myeloid leukaemia, whereas our patient had CLL.
Cidofovir has been suggested in some cases for the treatment of BK virus-associated haemorrhagic cystitis.13 Cidofovir and foscarnet are second-line therapies in patients with CMV that are either resistant or refractory to ganciclovir. Cidofovir is a non-cyclic analogue of cytidine monophosphate that terminates CMV DNA synthesis. In vitro studies showed effectiveness against herpes viruses, including CMV, herpes simplex viruses 1 and 2, varicella-zoster, Epstein-Barr virus, human papillomavirus and adenovirus. The main adverse effect is nephrotoxicity, causing proximal tubular injury. Serum creatinine and urine protein measurements are recommended during administration.14 Probenecid decreases intratubular secretion and maintains a sufficient plasma concentration to allow for once weekly dosing at 5 mg/kg to reduce its nephrotoxicity.13 An alternate dosing regimen, initially used in our patient, was three times per week dosing at 3 mg/kg. In the study performed by Philippe et al, intravenous cidofovir achieve remission in 81.5% of the 22 patients.13
The patient reported by Held et al recovered fully with cidofovir15; however, our patient was switched to ganciclovir due to persistent neutropenia. Bone marrow biopsy was consistent with secondary treatment-related myelosuppression syndrome, without evidence of myelodysplasia or lymphoproliferative infiltration. Myelosuppression is a major side effect of ganciclovir. However, the antiviral effects far outweigh these risks and therefore ganciclovir and its oral prodrug valganciclovir should be considered for patients with pancytopenia secondary to CMV reactivation.
In summary, this unique case of triple-viremia induced haemorrhagic cystitis in an immunosuppressed CLL patient posed both a diagnostic and therapeutic challenge as treatments are nephrotoxic and further increase immunosuppression.
The major learning point is to exercise caution when prescribing FCR chemotherapy on its long-term immunosuppressive effects. It is expected that novel immuno-chemotherapy for CLL should control the disease with reduced immunosuppressive effects.16
Patient’s perspective
Translation from French
I was diagnosed with CLL in November 2015. Started the treatments with FCR protocol in April 2019 (six treatments of three consecutive days each). At the end of the fourth treatment, I was not well. I had fever and a large fatigue with no energy. I finished treatments on the 13th of November 2019. On the week of 18 November, the symptoms appeared: fever, incontinent of urine with blood, no appetite, fatigue.
I visited MUHC emergency, 12 hours wait before I had a doctor’s room. I stayed the night and the next day I saw the doctor, but they did not know what I had. On the 22nd of November I returned to emergency with a lot of fever and other symptoms. I passed the night in an emergency room. On Saturday they released me, had fever and falls.
On the 24th I returned to emergency, fever and incontinence, etc. I was placed in the corridor in a stretcher with a commode next to the whole world. There was nowhere else for me, I had to go through the doors to go to the public toilet and I urinated every 5 min. I stayed in emergency 5 days before I was admitted to Internal Medicine.
It was a bad experience the three times I was in emergency. On 29 November, I had my own room. I was there till 07 February 2020.
The staff took charge rapidly. There were many tests during this long period to find out the cause of my problems. Everything came from the chemotherapy. Many departments were involved: urology, otolaryngology, haematology, internal medicine, infectious diseases.
There were several healthcare workers who spoke on behalf of other departments.
Very good service with the nursing staffs and the préposé (aux bénéficiaires). On my part, my immune system was severely damaged.
Learning points
Infections in immunosuppressed patients remain a diagnostic and therapeutic challenge.
In patient treated for chronic lymphocytic leukaemia, haematuria can be related to viral infections like BK virus, adenovirus and cytomegalovirus (CMV).
BK infection is diagnosed with a high index of suspicion, however, combined CMV and adenovirus infections renders the diagnosis more difficult.
Treatment of these viral infections remains difficult as medications are associated with myelotoxicity (ganciclovir) and renal insufficiency (cidofovir).
The authors would like to thank Dr Malek Merdad and Dr Isabelle Malhamé for their inspiration to write this article.
Contributors: MK and J-PR devised the project, main conceptual ideas and proof outlines. MK took the lead in writing the manuscript the supervision of J-PR. MK created all the images and translated the patient’s perspective from French to English. J-PR and JL provided critical feedback and helped shape analysis and manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | CIDOFOVIR, CYCLOPHOSPHAMIDE, FILGRASTIM, FLUDARABINE PHOSPHATE, HUMAN IMMUNOGLOBULIN G, PROBENECID, RITUXIMAB, SODIUM CHLORIDE, SULFAMETHOXAZOLE\TRIMETHOPRIM, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33402369 | 19,066,566 | 2021-01-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cystitis haemorrhagic'. | Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
Background
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder associated with mature B-cell dysfunction, hypogammaglobulinaemia and T-cell abnormalities. In Europe and North America, CLL is the most common leukaemia, with median age of diagnosis of 70 years.1 Treatment is indicated only for symptomatic disease, such as anaemia <100 g/L and/or thrombocytopenia <100×109/L, massive splenomegaly, lymphadenopathy or constitutional symptoms.2
Infection is a frequent cause of morbidity and mortality in CLL. Roughly 30%–50% of all CLL patients suffer infections, with a high subsequent mortality rate.3 While the majority of infections affect more often the respiratory track, or skin and the gastrointestinal tract.4 The most frequent organisms causing infections are bacteria like Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. This increased susceptibility to infection stems from B-cells with impaired immunoglobulin production capability and dysfunctional T-helper cells, which also assist in antibody production. This impaired capability to produce immunoglobulins, termed hypogammaglobulinaemia, affects 85% of CLL patients, particularly in advanced disease.4
Antineoplastic agents recommended for the treatment of CLL are also immunosuppressive and further increase the risk of infections.5 These include opportunistic micro-organisms such as Candida, Pneumocystis jirovecii, listeria, nocardia and atypical mycobacteria. In addition, patients have increased risk of viral diseases such as herpes simplex, Epstein-Barr and cytomegalovirus (CMV). Additional infectious complications may include hepatitis B reactivation and progressive multifocal leucoencephalopathy. In spite of the immunosuppressive risk, chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the standard risk therapy in fit patients below 65 years of age with CLL, in absence of 17 p deletion, or TP53 mutation, and with immunoglobulin heavy chain V (IGHV)-mutated.6
To reduce risk of infection, immunoglobulin levels should also be routinely monitored, particularly with rituximab, which reduces the number of B-cells expressing CD20. It is postulated that monitoring immunoglobulins while being treated with rituximab may reduce the risk of serious infections.4
Herein, we present a unique case of a woman treated for CLL who experienced severe pancytopenia and immunosuppression at the completion of her chemo-immunotherapy. She subsequently experienced triple concurrent viral infections, which posed a therapeutic challenge due to her pancytopenia.
Case presentation
A previously healthy 58-year-old woman was diagnosed with CLL through a routine blood test in 2015. Her physical examination was unremarkable and her lymphocyte counts were at 12.36×109 cells/L. Bone marrow biopsy with immunohistochemistry was suggestive of CLL and stained positive for BCL2, CD5 (aberrant T-cell marker), CD20, CD23, CD43 and CD79a (B-cell markers) while BCL6 was negative. The PCR amplification study showed immunoglobulin heavy chain gene rearrangement along with IgG kappa light chain gene arrangement. No t(14;18) BCL2/JH or t(11;14) BCL1/JH gene rearrangements were observed. As she was asymptomatic, and positron emission tomography (PET) scan showed low grade metabolic activity in lymph nodes in cervical, axillary and iliac areas, no therapy was initiated (figure 1). She was followed every 6 months.
Figure 1 Positron emission tomography scan (right) and corresponding CT images (left) of multiple low-grade hypermetabolic lymph nodes in 2017, 2 years after diagnosis of chronic lymphocytic leukaemia. (A) Multiple small low-grade hypermetabolic lymph nodes in bilateral neck regions predominantly in the posterior triangles. SUV of 1.9 in the left and right upper posterior triangles. (B) Hypermetabolic lymph nodes in the left axillary regions, SUV 1.8. (C) Left external iliac lymph node SUV of 3. SUV, Standardized uptake value.
In November 2017 the patient had symptom of a rapid bilateral enlargement of the cervical lymph nodes accompanied by persistent fatigue, night sweats and decreased weight. Lyme disease, HIV, hepatitis B and C and syphilis serologies were performed, and all tests yielded negative results. Repeat PET/CT scan, cytogenetics and bone marrow biopsy demonstrated no evidence of Richter’s transformation into a diffuse large cell lymphoma. Due to significant bulky disease and enlarged adenopathy with B constitutional symptoms, chemo-immunotherapy with FCR was considered. This was furthermore rationalised as she was a fit patient younger than 65 years of age with standard risk for CLL due to the absence of 17 p deletion, or TP53 mutation, and with IGHV being mutated.7
She received six cycles of FCR which was completed uneventfully on 11 November 2019. During FCR therapy, she received oral valacyclovir 500 mg two times per day for herpes prophylaxis as well as Septra DS (160 mg trimethoprim and 800 mg sulfamethoxazole) one tablet Mondays, Wednesdays and Fridays for P. jirovecii prophylaxis. On 18 November, she presented to the emergency room of the McGill University Health Centre (MUHC) with haematuria, suprapubic pain and fever. She was admitted and treated for a urine infection and slowly improved after different antibiotics such as ciprofloxacin, trimethoprim-sulfamethoxazole and ceftriaxone and blood and urinary bacterial cultures were negative. A CT urogram showed moderate bilateral hydroureteronephrosis with diffuse urolithelial and bladder thickening (figure 2). As a whole, these findings were suggestive of an inflammatory or infectious process evoking pyleoureteritis and cystitis.
Figure 2 CT urogram on admission in November 2019, demonstrating (A) poorly distended bladder and marked thickening of bladder walls (green arrow) and (B) moderate dilation of both ureters and collection ducts with marked thickening and enhancement of the urothelium associated with moderate periureteric fat stranding.
Investigations
On admission, she was mildly pancytopenic (table 1). As the patient partially improved and had negative urine cultures, a cyclophosphamide-induced haemorrhagic cystitis was considered, and she was placed on continuous bladder irrigation.
Table 1 Summary of the patient’s serological and microbiological test results during the course of her neutropenia and triple viremia
Laboratory results Reference ranges 20 March 2019 11 November 2019 26 November 2019 25 December 2019 01 January 2020 23 January 2020 01 February 2020 07 February 2020 03 March 2020
Time of intervention First dose FCR Last dose FCR Meropenem started Virology investigated Begins cidofovir+GCSF Cidofovir changed to Ganciclovir Ganciclovir transitioned to valganciclovir Discharge Follow-up
WBC (109/L) 4.0–10.0 30.90 5.90 3.00 1.00 0.60 2.40 6.10 2.40 2.00
Neutrophils 2.0–7.0 3.75 4.18 2.46 0.80 0.36 1.19 5.09 1.73 1.35
Lymphocytes 1.5–4.5 26.26 0.87 0.23 0.08 0.11 0.23 0.46 0.33 0.44
Plt (109/L) 150–450 145 158 123 48 19 54 17 12 39
Hb (g/L) 120–150 142 129 99 63 80 70 70 71 99
Creatinine (umol/L) 50–90 71 68 125 128 118 75 74 69 75
CMV (copies/mL) – – – – 7320 3170 1291 153 149 0
Adenovirus (copies/mL) – – – – – 7.44 log10 4.86 log10 3.74 log10 – 3.30 log10
BK virus urine (copies/mL) – – – – – 2.26×107 – 3.20×108 –
BK virus blood (copies/mL) – – – – – – – – – 3.91×103
CMV, cytomegalovirus; FCR, fludarabine, cyclophosphamide and rituximab; Hb, haemoglobin; Plt, platelet; WBC, white blood cell.
On 1 December 2019 she developed a pancytopenia that required platelet and packed red blood cell transfusions. She remained persistently febrile despite repeated negative bacterial blood and urine cultures. Due to her CLL, pancytopenia and the consideration of immunosuppression induced by FCR chemotherapy, viral infections were investigated. PCR for adenovirus showed 22.4 copies/mL in blood, and positive in urine; PCR for polyoma virus showed 8.81 million copies/mL blood; and PCR for CMV showed 358 copies/mL in blood, confirming viral invasive infections (figure 3). To further investigate her pancytopenia, serology for parvovirus B 19 was carried out and was negative for IgM.
Figure 3 Cytomegalovirus (CMV) and BK viremia (A) and adeno-viremia (B) over the course of treatment.
On 18 December 2019 the patient underwent a double J-stent insertion for bilateral hydronephrosis. Pelvic pain persisted and she continued to pass clots in her urine. Repeat CMV PCR testing on 25 December 2019 showed 7320 copies/mL while an ophthalmological assessment revealed no evidence of CMV retinitis or keratitis. Bone marrow biopsy results showed pancytopenia without transformation (figure 4).
Figure 4 Histology and immunochemistry of bone marrow smear (A) and biopsy (B). Bone marrow biopsy demonstrating hypocellularity. Moderate left shift of the myeloid series and mild left shift of the erythroid series. No lymphocytosis or lymphoma, no definite diagnosis of myelodysplastic syndrome (B).
Treatment
On 1 January 2020, cidofovir was administered to treat the three viral infections of BK polyomavirus, adenovirus and CMV. Cidofovir was given at the dose of 1 mg/kg intravenously three times a week instead of a weekly dose given her kidney injury and high creatinine levels. She received probenecid 2 g orally 1 hour before cidofovir, then 2 hours and 8 hours after the end of infusion to increase cidofovir levels in the blood. For renal protection, she was hydrated with 1 L of 0.9% normal saline during cidofovir infusion. Filgrastim (G-CSF) was initiated for her neutropenia, darbepoetin for her anaemia, and intravenous IgG was infused three times at 4-week intervals for her hypogammaglobulinumia.
Neutropenia worsen despite filgrastim, and CMV viral load continued to increase. Due to cidofovir myelotoxicity, a decision was made to focus treatment on CMV infection, while ignoring the BK and adenovirus. To this end, the patient was changed to ganciclovir 250 mg intravenous two times per day on 23 January 2020 and her urinary symptoms improved for the first time. On 1 February 2020, she was transitioned to oral valganciclovir 450 mg daily and was discharged to home 1 week later, after 101 days in hospital.
Outcome and follow-up
A bone marrow biopsy on 27 January 2020 showed a hypocellular marrow with focal area up to 20%–30% haematopoietic tissue. No evidence of lymphocytosis or lymphoma and no dysplastic changes in morphology were observed. Immunohistochemistry showed <5% CD117, and was negative for CD20, CD34 and PAX5. The histological appearance represented haematopoietic regeneration post-chemotherapy. On 3 March 2020 follow-up, CMV load was undetectable, adenovirus load was 5000 copies/mL, BK load was 3.2×108 copies/mL (table 1). She was switched on CMV prophylaxis with resolved haemorrhagic cystitis and received valganciclovir 450 mg p.o. daily for another 3 months and until her absolute lymphocyte count recovers above 109 cells/L. She continued trimethoprim-sulfamethaxole prophylaxis for 6 months post-chemotherapy. Her double-J stents remain in place. While clinically improved, her neutropenia improved on low dose filgrastim until 4 April 2020. Her blood counts normalised 1 month after and she is followed as an outpatient with Haematology, Infectious Diseases, and Urology services at the MUHC.
Discussion
FCR chemo-immunotherapy is considered the treatment for standard risk CLL patients under the age of 65,7 with a high overall response rate. However, the predominant complication is myelosuppression.8 Persistent neutropenia was reported in 19% and late infections in 9% of patients.9 The frequency of cytopenias was 35% at 3 months and 12% at 9 months after completion of therapy, respectively. Another side effect is prolonged lymphoid immunodeficiency.
Human adenovirus infections usually present as a keratoconjunctivitis or respiratory tract infection. In most healthy individuals the infection is usually self-limited. However, in immunosuppressed patients, infection may disseminate and become potentially life-threatening. Disseminated adenovirus infection can result from either de novo infection or a reactivation of clinically silent infection.10
BK virus is a member of the polyomavirus family. BK virus reactivation occurs only in immunosuppressed patients and can lead to nephropathy, ureteral stenosis, tubular interstitial damage and haemorrhagic cystitis. Viremia occurs in 20%–60% of this population. There is no specific treatment for BK virus-associated nephropathy, therefore viral replication can only be controlled through modulating the immunosuppressive condition.11
CMV is a herpes virus with a large double-stranded DNA that remains latent in the host after primary infection. Immunocompromised patients can have reactivation of their latent infection. Diagnosis of viral reactivation is made through CMV PCR in blood, tissue or body fluid. Manifestations of CMV infection occur most often in the gastrointestinal tract, lungs, liver and retina.12 As we did not observe the typical owl’s eye tissue lesion in the second bone marrow biopsy, we considered that CMV reactivation was a contributing factor for the pancytopenia, and treatment may have prevented such tissue lesion to develop. First line treatment of CMV infection includes intravenous ganciclovir or its oral prodrug valganciclovir, which are DNA polymerase inhibitors. The major side effect of these drugs is myelosuppression, including neutropenia.4
In our patient, the prolonged pancytopenias secondary to FCR was associated with haematuria with an ureteral mass. To date, only two observations on the use of cidofovir to simultaneously treat BK-virus associated haemorrhagic cystitis and CMV reactivation have been reported. However, in the case report by Held et al, the patient had received a bone marrow transplant for chronic myeloid leukaemia, whereas our patient had CLL.
Cidofovir has been suggested in some cases for the treatment of BK virus-associated haemorrhagic cystitis.13 Cidofovir and foscarnet are second-line therapies in patients with CMV that are either resistant or refractory to ganciclovir. Cidofovir is a non-cyclic analogue of cytidine monophosphate that terminates CMV DNA synthesis. In vitro studies showed effectiveness against herpes viruses, including CMV, herpes simplex viruses 1 and 2, varicella-zoster, Epstein-Barr virus, human papillomavirus and adenovirus. The main adverse effect is nephrotoxicity, causing proximal tubular injury. Serum creatinine and urine protein measurements are recommended during administration.14 Probenecid decreases intratubular secretion and maintains a sufficient plasma concentration to allow for once weekly dosing at 5 mg/kg to reduce its nephrotoxicity.13 An alternate dosing regimen, initially used in our patient, was three times per week dosing at 3 mg/kg. In the study performed by Philippe et al, intravenous cidofovir achieve remission in 81.5% of the 22 patients.13
The patient reported by Held et al recovered fully with cidofovir15; however, our patient was switched to ganciclovir due to persistent neutropenia. Bone marrow biopsy was consistent with secondary treatment-related myelosuppression syndrome, without evidence of myelodysplasia or lymphoproliferative infiltration. Myelosuppression is a major side effect of ganciclovir. However, the antiviral effects far outweigh these risks and therefore ganciclovir and its oral prodrug valganciclovir should be considered for patients with pancytopenia secondary to CMV reactivation.
In summary, this unique case of triple-viremia induced haemorrhagic cystitis in an immunosuppressed CLL patient posed both a diagnostic and therapeutic challenge as treatments are nephrotoxic and further increase immunosuppression.
The major learning point is to exercise caution when prescribing FCR chemotherapy on its long-term immunosuppressive effects. It is expected that novel immuno-chemotherapy for CLL should control the disease with reduced immunosuppressive effects.16
Patient’s perspective
Translation from French
I was diagnosed with CLL in November 2015. Started the treatments with FCR protocol in April 2019 (six treatments of three consecutive days each). At the end of the fourth treatment, I was not well. I had fever and a large fatigue with no energy. I finished treatments on the 13th of November 2019. On the week of 18 November, the symptoms appeared: fever, incontinent of urine with blood, no appetite, fatigue.
I visited MUHC emergency, 12 hours wait before I had a doctor’s room. I stayed the night and the next day I saw the doctor, but they did not know what I had. On the 22nd of November I returned to emergency with a lot of fever and other symptoms. I passed the night in an emergency room. On Saturday they released me, had fever and falls.
On the 24th I returned to emergency, fever and incontinence, etc. I was placed in the corridor in a stretcher with a commode next to the whole world. There was nowhere else for me, I had to go through the doors to go to the public toilet and I urinated every 5 min. I stayed in emergency 5 days before I was admitted to Internal Medicine.
It was a bad experience the three times I was in emergency. On 29 November, I had my own room. I was there till 07 February 2020.
The staff took charge rapidly. There were many tests during this long period to find out the cause of my problems. Everything came from the chemotherapy. Many departments were involved: urology, otolaryngology, haematology, internal medicine, infectious diseases.
There were several healthcare workers who spoke on behalf of other departments.
Very good service with the nursing staffs and the préposé (aux bénéficiaires). On my part, my immune system was severely damaged.
Learning points
Infections in immunosuppressed patients remain a diagnostic and therapeutic challenge.
In patient treated for chronic lymphocytic leukaemia, haematuria can be related to viral infections like BK virus, adenovirus and cytomegalovirus (CMV).
BK infection is diagnosed with a high index of suspicion, however, combined CMV and adenovirus infections renders the diagnosis more difficult.
Treatment of these viral infections remains difficult as medications are associated with myelotoxicity (ganciclovir) and renal insufficiency (cidofovir).
The authors would like to thank Dr Malek Merdad and Dr Isabelle Malhamé for their inspiration to write this article.
Contributors: MK and J-PR devised the project, main conceptual ideas and proof outlines. MK took the lead in writing the manuscript the supervision of J-PR. MK created all the images and translated the patient’s perspective from French to English. J-PR and JL provided critical feedback and helped shape analysis and manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | CIDOFOVIR, CYCLOPHOSPHAMIDE, FILGRASTIM, FLUDARABINE PHOSPHATE, HUMAN IMMUNOGLOBULIN G, PROBENECID, RITUXIMAB, SODIUM CHLORIDE, SULFAMETHOXAZOLE\TRIMETHOPRIM, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33402369 | 19,066,566 | 2021-01-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hydronephrosis'. | Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
Background
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder associated with mature B-cell dysfunction, hypogammaglobulinaemia and T-cell abnormalities. In Europe and North America, CLL is the most common leukaemia, with median age of diagnosis of 70 years.1 Treatment is indicated only for symptomatic disease, such as anaemia <100 g/L and/or thrombocytopenia <100×109/L, massive splenomegaly, lymphadenopathy or constitutional symptoms.2
Infection is a frequent cause of morbidity and mortality in CLL. Roughly 30%–50% of all CLL patients suffer infections, with a high subsequent mortality rate.3 While the majority of infections affect more often the respiratory track, or skin and the gastrointestinal tract.4 The most frequent organisms causing infections are bacteria like Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. This increased susceptibility to infection stems from B-cells with impaired immunoglobulin production capability and dysfunctional T-helper cells, which also assist in antibody production. This impaired capability to produce immunoglobulins, termed hypogammaglobulinaemia, affects 85% of CLL patients, particularly in advanced disease.4
Antineoplastic agents recommended for the treatment of CLL are also immunosuppressive and further increase the risk of infections.5 These include opportunistic micro-organisms such as Candida, Pneumocystis jirovecii, listeria, nocardia and atypical mycobacteria. In addition, patients have increased risk of viral diseases such as herpes simplex, Epstein-Barr and cytomegalovirus (CMV). Additional infectious complications may include hepatitis B reactivation and progressive multifocal leucoencephalopathy. In spite of the immunosuppressive risk, chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the standard risk therapy in fit patients below 65 years of age with CLL, in absence of 17 p deletion, or TP53 mutation, and with immunoglobulin heavy chain V (IGHV)-mutated.6
To reduce risk of infection, immunoglobulin levels should also be routinely monitored, particularly with rituximab, which reduces the number of B-cells expressing CD20. It is postulated that monitoring immunoglobulins while being treated with rituximab may reduce the risk of serious infections.4
Herein, we present a unique case of a woman treated for CLL who experienced severe pancytopenia and immunosuppression at the completion of her chemo-immunotherapy. She subsequently experienced triple concurrent viral infections, which posed a therapeutic challenge due to her pancytopenia.
Case presentation
A previously healthy 58-year-old woman was diagnosed with CLL through a routine blood test in 2015. Her physical examination was unremarkable and her lymphocyte counts were at 12.36×109 cells/L. Bone marrow biopsy with immunohistochemistry was suggestive of CLL and stained positive for BCL2, CD5 (aberrant T-cell marker), CD20, CD23, CD43 and CD79a (B-cell markers) while BCL6 was negative. The PCR amplification study showed immunoglobulin heavy chain gene rearrangement along with IgG kappa light chain gene arrangement. No t(14;18) BCL2/JH or t(11;14) BCL1/JH gene rearrangements were observed. As she was asymptomatic, and positron emission tomography (PET) scan showed low grade metabolic activity in lymph nodes in cervical, axillary and iliac areas, no therapy was initiated (figure 1). She was followed every 6 months.
Figure 1 Positron emission tomography scan (right) and corresponding CT images (left) of multiple low-grade hypermetabolic lymph nodes in 2017, 2 years after diagnosis of chronic lymphocytic leukaemia. (A) Multiple small low-grade hypermetabolic lymph nodes in bilateral neck regions predominantly in the posterior triangles. SUV of 1.9 in the left and right upper posterior triangles. (B) Hypermetabolic lymph nodes in the left axillary regions, SUV 1.8. (C) Left external iliac lymph node SUV of 3. SUV, Standardized uptake value.
In November 2017 the patient had symptom of a rapid bilateral enlargement of the cervical lymph nodes accompanied by persistent fatigue, night sweats and decreased weight. Lyme disease, HIV, hepatitis B and C and syphilis serologies were performed, and all tests yielded negative results. Repeat PET/CT scan, cytogenetics and bone marrow biopsy demonstrated no evidence of Richter’s transformation into a diffuse large cell lymphoma. Due to significant bulky disease and enlarged adenopathy with B constitutional symptoms, chemo-immunotherapy with FCR was considered. This was furthermore rationalised as she was a fit patient younger than 65 years of age with standard risk for CLL due to the absence of 17 p deletion, or TP53 mutation, and with IGHV being mutated.7
She received six cycles of FCR which was completed uneventfully on 11 November 2019. During FCR therapy, she received oral valacyclovir 500 mg two times per day for herpes prophylaxis as well as Septra DS (160 mg trimethoprim and 800 mg sulfamethoxazole) one tablet Mondays, Wednesdays and Fridays for P. jirovecii prophylaxis. On 18 November, she presented to the emergency room of the McGill University Health Centre (MUHC) with haematuria, suprapubic pain and fever. She was admitted and treated for a urine infection and slowly improved after different antibiotics such as ciprofloxacin, trimethoprim-sulfamethoxazole and ceftriaxone and blood and urinary bacterial cultures were negative. A CT urogram showed moderate bilateral hydroureteronephrosis with diffuse urolithelial and bladder thickening (figure 2). As a whole, these findings were suggestive of an inflammatory or infectious process evoking pyleoureteritis and cystitis.
Figure 2 CT urogram on admission in November 2019, demonstrating (A) poorly distended bladder and marked thickening of bladder walls (green arrow) and (B) moderate dilation of both ureters and collection ducts with marked thickening and enhancement of the urothelium associated with moderate periureteric fat stranding.
Investigations
On admission, she was mildly pancytopenic (table 1). As the patient partially improved and had negative urine cultures, a cyclophosphamide-induced haemorrhagic cystitis was considered, and she was placed on continuous bladder irrigation.
Table 1 Summary of the patient’s serological and microbiological test results during the course of her neutropenia and triple viremia
Laboratory results Reference ranges 20 March 2019 11 November 2019 26 November 2019 25 December 2019 01 January 2020 23 January 2020 01 February 2020 07 February 2020 03 March 2020
Time of intervention First dose FCR Last dose FCR Meropenem started Virology investigated Begins cidofovir+GCSF Cidofovir changed to Ganciclovir Ganciclovir transitioned to valganciclovir Discharge Follow-up
WBC (109/L) 4.0–10.0 30.90 5.90 3.00 1.00 0.60 2.40 6.10 2.40 2.00
Neutrophils 2.0–7.0 3.75 4.18 2.46 0.80 0.36 1.19 5.09 1.73 1.35
Lymphocytes 1.5–4.5 26.26 0.87 0.23 0.08 0.11 0.23 0.46 0.33 0.44
Plt (109/L) 150–450 145 158 123 48 19 54 17 12 39
Hb (g/L) 120–150 142 129 99 63 80 70 70 71 99
Creatinine (umol/L) 50–90 71 68 125 128 118 75 74 69 75
CMV (copies/mL) – – – – 7320 3170 1291 153 149 0
Adenovirus (copies/mL) – – – – – 7.44 log10 4.86 log10 3.74 log10 – 3.30 log10
BK virus urine (copies/mL) – – – – – 2.26×107 – 3.20×108 –
BK virus blood (copies/mL) – – – – – – – – – 3.91×103
CMV, cytomegalovirus; FCR, fludarabine, cyclophosphamide and rituximab; Hb, haemoglobin; Plt, platelet; WBC, white blood cell.
On 1 December 2019 she developed a pancytopenia that required platelet and packed red blood cell transfusions. She remained persistently febrile despite repeated negative bacterial blood and urine cultures. Due to her CLL, pancytopenia and the consideration of immunosuppression induced by FCR chemotherapy, viral infections were investigated. PCR for adenovirus showed 22.4 copies/mL in blood, and positive in urine; PCR for polyoma virus showed 8.81 million copies/mL blood; and PCR for CMV showed 358 copies/mL in blood, confirming viral invasive infections (figure 3). To further investigate her pancytopenia, serology for parvovirus B 19 was carried out and was negative for IgM.
Figure 3 Cytomegalovirus (CMV) and BK viremia (A) and adeno-viremia (B) over the course of treatment.
On 18 December 2019 the patient underwent a double J-stent insertion for bilateral hydronephrosis. Pelvic pain persisted and she continued to pass clots in her urine. Repeat CMV PCR testing on 25 December 2019 showed 7320 copies/mL while an ophthalmological assessment revealed no evidence of CMV retinitis or keratitis. Bone marrow biopsy results showed pancytopenia without transformation (figure 4).
Figure 4 Histology and immunochemistry of bone marrow smear (A) and biopsy (B). Bone marrow biopsy demonstrating hypocellularity. Moderate left shift of the myeloid series and mild left shift of the erythroid series. No lymphocytosis or lymphoma, no definite diagnosis of myelodysplastic syndrome (B).
Treatment
On 1 January 2020, cidofovir was administered to treat the three viral infections of BK polyomavirus, adenovirus and CMV. Cidofovir was given at the dose of 1 mg/kg intravenously three times a week instead of a weekly dose given her kidney injury and high creatinine levels. She received probenecid 2 g orally 1 hour before cidofovir, then 2 hours and 8 hours after the end of infusion to increase cidofovir levels in the blood. For renal protection, she was hydrated with 1 L of 0.9% normal saline during cidofovir infusion. Filgrastim (G-CSF) was initiated for her neutropenia, darbepoetin for her anaemia, and intravenous IgG was infused three times at 4-week intervals for her hypogammaglobulinumia.
Neutropenia worsen despite filgrastim, and CMV viral load continued to increase. Due to cidofovir myelotoxicity, a decision was made to focus treatment on CMV infection, while ignoring the BK and adenovirus. To this end, the patient was changed to ganciclovir 250 mg intravenous two times per day on 23 January 2020 and her urinary symptoms improved for the first time. On 1 February 2020, she was transitioned to oral valganciclovir 450 mg daily and was discharged to home 1 week later, after 101 days in hospital.
Outcome and follow-up
A bone marrow biopsy on 27 January 2020 showed a hypocellular marrow with focal area up to 20%–30% haematopoietic tissue. No evidence of lymphocytosis or lymphoma and no dysplastic changes in morphology were observed. Immunohistochemistry showed <5% CD117, and was negative for CD20, CD34 and PAX5. The histological appearance represented haematopoietic regeneration post-chemotherapy. On 3 March 2020 follow-up, CMV load was undetectable, adenovirus load was 5000 copies/mL, BK load was 3.2×108 copies/mL (table 1). She was switched on CMV prophylaxis with resolved haemorrhagic cystitis and received valganciclovir 450 mg p.o. daily for another 3 months and until her absolute lymphocyte count recovers above 109 cells/L. She continued trimethoprim-sulfamethaxole prophylaxis for 6 months post-chemotherapy. Her double-J stents remain in place. While clinically improved, her neutropenia improved on low dose filgrastim until 4 April 2020. Her blood counts normalised 1 month after and she is followed as an outpatient with Haematology, Infectious Diseases, and Urology services at the MUHC.
Discussion
FCR chemo-immunotherapy is considered the treatment for standard risk CLL patients under the age of 65,7 with a high overall response rate. However, the predominant complication is myelosuppression.8 Persistent neutropenia was reported in 19% and late infections in 9% of patients.9 The frequency of cytopenias was 35% at 3 months and 12% at 9 months after completion of therapy, respectively. Another side effect is prolonged lymphoid immunodeficiency.
Human adenovirus infections usually present as a keratoconjunctivitis or respiratory tract infection. In most healthy individuals the infection is usually self-limited. However, in immunosuppressed patients, infection may disseminate and become potentially life-threatening. Disseminated adenovirus infection can result from either de novo infection or a reactivation of clinically silent infection.10
BK virus is a member of the polyomavirus family. BK virus reactivation occurs only in immunosuppressed patients and can lead to nephropathy, ureteral stenosis, tubular interstitial damage and haemorrhagic cystitis. Viremia occurs in 20%–60% of this population. There is no specific treatment for BK virus-associated nephropathy, therefore viral replication can only be controlled through modulating the immunosuppressive condition.11
CMV is a herpes virus with a large double-stranded DNA that remains latent in the host after primary infection. Immunocompromised patients can have reactivation of their latent infection. Diagnosis of viral reactivation is made through CMV PCR in blood, tissue or body fluid. Manifestations of CMV infection occur most often in the gastrointestinal tract, lungs, liver and retina.12 As we did not observe the typical owl’s eye tissue lesion in the second bone marrow biopsy, we considered that CMV reactivation was a contributing factor for the pancytopenia, and treatment may have prevented such tissue lesion to develop. First line treatment of CMV infection includes intravenous ganciclovir or its oral prodrug valganciclovir, which are DNA polymerase inhibitors. The major side effect of these drugs is myelosuppression, including neutropenia.4
In our patient, the prolonged pancytopenias secondary to FCR was associated with haematuria with an ureteral mass. To date, only two observations on the use of cidofovir to simultaneously treat BK-virus associated haemorrhagic cystitis and CMV reactivation have been reported. However, in the case report by Held et al, the patient had received a bone marrow transplant for chronic myeloid leukaemia, whereas our patient had CLL.
Cidofovir has been suggested in some cases for the treatment of BK virus-associated haemorrhagic cystitis.13 Cidofovir and foscarnet are second-line therapies in patients with CMV that are either resistant or refractory to ganciclovir. Cidofovir is a non-cyclic analogue of cytidine monophosphate that terminates CMV DNA synthesis. In vitro studies showed effectiveness against herpes viruses, including CMV, herpes simplex viruses 1 and 2, varicella-zoster, Epstein-Barr virus, human papillomavirus and adenovirus. The main adverse effect is nephrotoxicity, causing proximal tubular injury. Serum creatinine and urine protein measurements are recommended during administration.14 Probenecid decreases intratubular secretion and maintains a sufficient plasma concentration to allow for once weekly dosing at 5 mg/kg to reduce its nephrotoxicity.13 An alternate dosing regimen, initially used in our patient, was three times per week dosing at 3 mg/kg. In the study performed by Philippe et al, intravenous cidofovir achieve remission in 81.5% of the 22 patients.13
The patient reported by Held et al recovered fully with cidofovir15; however, our patient was switched to ganciclovir due to persistent neutropenia. Bone marrow biopsy was consistent with secondary treatment-related myelosuppression syndrome, without evidence of myelodysplasia or lymphoproliferative infiltration. Myelosuppression is a major side effect of ganciclovir. However, the antiviral effects far outweigh these risks and therefore ganciclovir and its oral prodrug valganciclovir should be considered for patients with pancytopenia secondary to CMV reactivation.
In summary, this unique case of triple-viremia induced haemorrhagic cystitis in an immunosuppressed CLL patient posed both a diagnostic and therapeutic challenge as treatments are nephrotoxic and further increase immunosuppression.
The major learning point is to exercise caution when prescribing FCR chemotherapy on its long-term immunosuppressive effects. It is expected that novel immuno-chemotherapy for CLL should control the disease with reduced immunosuppressive effects.16
Patient’s perspective
Translation from French
I was diagnosed with CLL in November 2015. Started the treatments with FCR protocol in April 2019 (six treatments of three consecutive days each). At the end of the fourth treatment, I was not well. I had fever and a large fatigue with no energy. I finished treatments on the 13th of November 2019. On the week of 18 November, the symptoms appeared: fever, incontinent of urine with blood, no appetite, fatigue.
I visited MUHC emergency, 12 hours wait before I had a doctor’s room. I stayed the night and the next day I saw the doctor, but they did not know what I had. On the 22nd of November I returned to emergency with a lot of fever and other symptoms. I passed the night in an emergency room. On Saturday they released me, had fever and falls.
On the 24th I returned to emergency, fever and incontinence, etc. I was placed in the corridor in a stretcher with a commode next to the whole world. There was nowhere else for me, I had to go through the doors to go to the public toilet and I urinated every 5 min. I stayed in emergency 5 days before I was admitted to Internal Medicine.
It was a bad experience the three times I was in emergency. On 29 November, I had my own room. I was there till 07 February 2020.
The staff took charge rapidly. There were many tests during this long period to find out the cause of my problems. Everything came from the chemotherapy. Many departments were involved: urology, otolaryngology, haematology, internal medicine, infectious diseases.
There were several healthcare workers who spoke on behalf of other departments.
Very good service with the nursing staffs and the préposé (aux bénéficiaires). On my part, my immune system was severely damaged.
Learning points
Infections in immunosuppressed patients remain a diagnostic and therapeutic challenge.
In patient treated for chronic lymphocytic leukaemia, haematuria can be related to viral infections like BK virus, adenovirus and cytomegalovirus (CMV).
BK infection is diagnosed with a high index of suspicion, however, combined CMV and adenovirus infections renders the diagnosis more difficult.
Treatment of these viral infections remains difficult as medications are associated with myelotoxicity (ganciclovir) and renal insufficiency (cidofovir).
The authors would like to thank Dr Malek Merdad and Dr Isabelle Malhamé for their inspiration to write this article.
Contributors: MK and J-PR devised the project, main conceptual ideas and proof outlines. MK took the lead in writing the manuscript the supervision of J-PR. MK created all the images and translated the patient’s perspective from French to English. J-PR and JL provided critical feedback and helped shape analysis and manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | CIDOFOVIR, CYCLOPHOSPHAMIDE, FILGRASTIM, FLUDARABINE PHOSPHATE, HUMAN IMMUNOGLOBULIN G, PROBENECID, RITUXIMAB, SODIUM CHLORIDE, SULFAMETHOXAZOLE\TRIMETHOPRIM, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33402369 | 19,066,566 | 2021-01-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypogammaglobulinaemia'. | Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
Background
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder associated with mature B-cell dysfunction, hypogammaglobulinaemia and T-cell abnormalities. In Europe and North America, CLL is the most common leukaemia, with median age of diagnosis of 70 years.1 Treatment is indicated only for symptomatic disease, such as anaemia <100 g/L and/or thrombocytopenia <100×109/L, massive splenomegaly, lymphadenopathy or constitutional symptoms.2
Infection is a frequent cause of morbidity and mortality in CLL. Roughly 30%–50% of all CLL patients suffer infections, with a high subsequent mortality rate.3 While the majority of infections affect more often the respiratory track, or skin and the gastrointestinal tract.4 The most frequent organisms causing infections are bacteria like Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. This increased susceptibility to infection stems from B-cells with impaired immunoglobulin production capability and dysfunctional T-helper cells, which also assist in antibody production. This impaired capability to produce immunoglobulins, termed hypogammaglobulinaemia, affects 85% of CLL patients, particularly in advanced disease.4
Antineoplastic agents recommended for the treatment of CLL are also immunosuppressive and further increase the risk of infections.5 These include opportunistic micro-organisms such as Candida, Pneumocystis jirovecii, listeria, nocardia and atypical mycobacteria. In addition, patients have increased risk of viral diseases such as herpes simplex, Epstein-Barr and cytomegalovirus (CMV). Additional infectious complications may include hepatitis B reactivation and progressive multifocal leucoencephalopathy. In spite of the immunosuppressive risk, chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the standard risk therapy in fit patients below 65 years of age with CLL, in absence of 17 p deletion, or TP53 mutation, and with immunoglobulin heavy chain V (IGHV)-mutated.6
To reduce risk of infection, immunoglobulin levels should also be routinely monitored, particularly with rituximab, which reduces the number of B-cells expressing CD20. It is postulated that monitoring immunoglobulins while being treated with rituximab may reduce the risk of serious infections.4
Herein, we present a unique case of a woman treated for CLL who experienced severe pancytopenia and immunosuppression at the completion of her chemo-immunotherapy. She subsequently experienced triple concurrent viral infections, which posed a therapeutic challenge due to her pancytopenia.
Case presentation
A previously healthy 58-year-old woman was diagnosed with CLL through a routine blood test in 2015. Her physical examination was unremarkable and her lymphocyte counts were at 12.36×109 cells/L. Bone marrow biopsy with immunohistochemistry was suggestive of CLL and stained positive for BCL2, CD5 (aberrant T-cell marker), CD20, CD23, CD43 and CD79a (B-cell markers) while BCL6 was negative. The PCR amplification study showed immunoglobulin heavy chain gene rearrangement along with IgG kappa light chain gene arrangement. No t(14;18) BCL2/JH or t(11;14) BCL1/JH gene rearrangements were observed. As she was asymptomatic, and positron emission tomography (PET) scan showed low grade metabolic activity in lymph nodes in cervical, axillary and iliac areas, no therapy was initiated (figure 1). She was followed every 6 months.
Figure 1 Positron emission tomography scan (right) and corresponding CT images (left) of multiple low-grade hypermetabolic lymph nodes in 2017, 2 years after diagnosis of chronic lymphocytic leukaemia. (A) Multiple small low-grade hypermetabolic lymph nodes in bilateral neck regions predominantly in the posterior triangles. SUV of 1.9 in the left and right upper posterior triangles. (B) Hypermetabolic lymph nodes in the left axillary regions, SUV 1.8. (C) Left external iliac lymph node SUV of 3. SUV, Standardized uptake value.
In November 2017 the patient had symptom of a rapid bilateral enlargement of the cervical lymph nodes accompanied by persistent fatigue, night sweats and decreased weight. Lyme disease, HIV, hepatitis B and C and syphilis serologies were performed, and all tests yielded negative results. Repeat PET/CT scan, cytogenetics and bone marrow biopsy demonstrated no evidence of Richter’s transformation into a diffuse large cell lymphoma. Due to significant bulky disease and enlarged adenopathy with B constitutional symptoms, chemo-immunotherapy with FCR was considered. This was furthermore rationalised as she was a fit patient younger than 65 years of age with standard risk for CLL due to the absence of 17 p deletion, or TP53 mutation, and with IGHV being mutated.7
She received six cycles of FCR which was completed uneventfully on 11 November 2019. During FCR therapy, she received oral valacyclovir 500 mg two times per day for herpes prophylaxis as well as Septra DS (160 mg trimethoprim and 800 mg sulfamethoxazole) one tablet Mondays, Wednesdays and Fridays for P. jirovecii prophylaxis. On 18 November, she presented to the emergency room of the McGill University Health Centre (MUHC) with haematuria, suprapubic pain and fever. She was admitted and treated for a urine infection and slowly improved after different antibiotics such as ciprofloxacin, trimethoprim-sulfamethoxazole and ceftriaxone and blood and urinary bacterial cultures were negative. A CT urogram showed moderate bilateral hydroureteronephrosis with diffuse urolithelial and bladder thickening (figure 2). As a whole, these findings were suggestive of an inflammatory or infectious process evoking pyleoureteritis and cystitis.
Figure 2 CT urogram on admission in November 2019, demonstrating (A) poorly distended bladder and marked thickening of bladder walls (green arrow) and (B) moderate dilation of both ureters and collection ducts with marked thickening and enhancement of the urothelium associated with moderate periureteric fat stranding.
Investigations
On admission, she was mildly pancytopenic (table 1). As the patient partially improved and had negative urine cultures, a cyclophosphamide-induced haemorrhagic cystitis was considered, and she was placed on continuous bladder irrigation.
Table 1 Summary of the patient’s serological and microbiological test results during the course of her neutropenia and triple viremia
Laboratory results Reference ranges 20 March 2019 11 November 2019 26 November 2019 25 December 2019 01 January 2020 23 January 2020 01 February 2020 07 February 2020 03 March 2020
Time of intervention First dose FCR Last dose FCR Meropenem started Virology investigated Begins cidofovir+GCSF Cidofovir changed to Ganciclovir Ganciclovir transitioned to valganciclovir Discharge Follow-up
WBC (109/L) 4.0–10.0 30.90 5.90 3.00 1.00 0.60 2.40 6.10 2.40 2.00
Neutrophils 2.0–7.0 3.75 4.18 2.46 0.80 0.36 1.19 5.09 1.73 1.35
Lymphocytes 1.5–4.5 26.26 0.87 0.23 0.08 0.11 0.23 0.46 0.33 0.44
Plt (109/L) 150–450 145 158 123 48 19 54 17 12 39
Hb (g/L) 120–150 142 129 99 63 80 70 70 71 99
Creatinine (umol/L) 50–90 71 68 125 128 118 75 74 69 75
CMV (copies/mL) – – – – 7320 3170 1291 153 149 0
Adenovirus (copies/mL) – – – – – 7.44 log10 4.86 log10 3.74 log10 – 3.30 log10
BK virus urine (copies/mL) – – – – – 2.26×107 – 3.20×108 –
BK virus blood (copies/mL) – – – – – – – – – 3.91×103
CMV, cytomegalovirus; FCR, fludarabine, cyclophosphamide and rituximab; Hb, haemoglobin; Plt, platelet; WBC, white blood cell.
On 1 December 2019 she developed a pancytopenia that required platelet and packed red blood cell transfusions. She remained persistently febrile despite repeated negative bacterial blood and urine cultures. Due to her CLL, pancytopenia and the consideration of immunosuppression induced by FCR chemotherapy, viral infections were investigated. PCR for adenovirus showed 22.4 copies/mL in blood, and positive in urine; PCR for polyoma virus showed 8.81 million copies/mL blood; and PCR for CMV showed 358 copies/mL in blood, confirming viral invasive infections (figure 3). To further investigate her pancytopenia, serology for parvovirus B 19 was carried out and was negative for IgM.
Figure 3 Cytomegalovirus (CMV) and BK viremia (A) and adeno-viremia (B) over the course of treatment.
On 18 December 2019 the patient underwent a double J-stent insertion for bilateral hydronephrosis. Pelvic pain persisted and she continued to pass clots in her urine. Repeat CMV PCR testing on 25 December 2019 showed 7320 copies/mL while an ophthalmological assessment revealed no evidence of CMV retinitis or keratitis. Bone marrow biopsy results showed pancytopenia without transformation (figure 4).
Figure 4 Histology and immunochemistry of bone marrow smear (A) and biopsy (B). Bone marrow biopsy demonstrating hypocellularity. Moderate left shift of the myeloid series and mild left shift of the erythroid series. No lymphocytosis or lymphoma, no definite diagnosis of myelodysplastic syndrome (B).
Treatment
On 1 January 2020, cidofovir was administered to treat the three viral infections of BK polyomavirus, adenovirus and CMV. Cidofovir was given at the dose of 1 mg/kg intravenously three times a week instead of a weekly dose given her kidney injury and high creatinine levels. She received probenecid 2 g orally 1 hour before cidofovir, then 2 hours and 8 hours after the end of infusion to increase cidofovir levels in the blood. For renal protection, she was hydrated with 1 L of 0.9% normal saline during cidofovir infusion. Filgrastim (G-CSF) was initiated for her neutropenia, darbepoetin for her anaemia, and intravenous IgG was infused three times at 4-week intervals for her hypogammaglobulinumia.
Neutropenia worsen despite filgrastim, and CMV viral load continued to increase. Due to cidofovir myelotoxicity, a decision was made to focus treatment on CMV infection, while ignoring the BK and adenovirus. To this end, the patient was changed to ganciclovir 250 mg intravenous two times per day on 23 January 2020 and her urinary symptoms improved for the first time. On 1 February 2020, she was transitioned to oral valganciclovir 450 mg daily and was discharged to home 1 week later, after 101 days in hospital.
Outcome and follow-up
A bone marrow biopsy on 27 January 2020 showed a hypocellular marrow with focal area up to 20%–30% haematopoietic tissue. No evidence of lymphocytosis or lymphoma and no dysplastic changes in morphology were observed. Immunohistochemistry showed <5% CD117, and was negative for CD20, CD34 and PAX5. The histological appearance represented haematopoietic regeneration post-chemotherapy. On 3 March 2020 follow-up, CMV load was undetectable, adenovirus load was 5000 copies/mL, BK load was 3.2×108 copies/mL (table 1). She was switched on CMV prophylaxis with resolved haemorrhagic cystitis and received valganciclovir 450 mg p.o. daily for another 3 months and until her absolute lymphocyte count recovers above 109 cells/L. She continued trimethoprim-sulfamethaxole prophylaxis for 6 months post-chemotherapy. Her double-J stents remain in place. While clinically improved, her neutropenia improved on low dose filgrastim until 4 April 2020. Her blood counts normalised 1 month after and she is followed as an outpatient with Haematology, Infectious Diseases, and Urology services at the MUHC.
Discussion
FCR chemo-immunotherapy is considered the treatment for standard risk CLL patients under the age of 65,7 with a high overall response rate. However, the predominant complication is myelosuppression.8 Persistent neutropenia was reported in 19% and late infections in 9% of patients.9 The frequency of cytopenias was 35% at 3 months and 12% at 9 months after completion of therapy, respectively. Another side effect is prolonged lymphoid immunodeficiency.
Human adenovirus infections usually present as a keratoconjunctivitis or respiratory tract infection. In most healthy individuals the infection is usually self-limited. However, in immunosuppressed patients, infection may disseminate and become potentially life-threatening. Disseminated adenovirus infection can result from either de novo infection or a reactivation of clinically silent infection.10
BK virus is a member of the polyomavirus family. BK virus reactivation occurs only in immunosuppressed patients and can lead to nephropathy, ureteral stenosis, tubular interstitial damage and haemorrhagic cystitis. Viremia occurs in 20%–60% of this population. There is no specific treatment for BK virus-associated nephropathy, therefore viral replication can only be controlled through modulating the immunosuppressive condition.11
CMV is a herpes virus with a large double-stranded DNA that remains latent in the host after primary infection. Immunocompromised patients can have reactivation of their latent infection. Diagnosis of viral reactivation is made through CMV PCR in blood, tissue or body fluid. Manifestations of CMV infection occur most often in the gastrointestinal tract, lungs, liver and retina.12 As we did not observe the typical owl’s eye tissue lesion in the second bone marrow biopsy, we considered that CMV reactivation was a contributing factor for the pancytopenia, and treatment may have prevented such tissue lesion to develop. First line treatment of CMV infection includes intravenous ganciclovir or its oral prodrug valganciclovir, which are DNA polymerase inhibitors. The major side effect of these drugs is myelosuppression, including neutropenia.4
In our patient, the prolonged pancytopenias secondary to FCR was associated with haematuria with an ureteral mass. To date, only two observations on the use of cidofovir to simultaneously treat BK-virus associated haemorrhagic cystitis and CMV reactivation have been reported. However, in the case report by Held et al, the patient had received a bone marrow transplant for chronic myeloid leukaemia, whereas our patient had CLL.
Cidofovir has been suggested in some cases for the treatment of BK virus-associated haemorrhagic cystitis.13 Cidofovir and foscarnet are second-line therapies in patients with CMV that are either resistant or refractory to ganciclovir. Cidofovir is a non-cyclic analogue of cytidine monophosphate that terminates CMV DNA synthesis. In vitro studies showed effectiveness against herpes viruses, including CMV, herpes simplex viruses 1 and 2, varicella-zoster, Epstein-Barr virus, human papillomavirus and adenovirus. The main adverse effect is nephrotoxicity, causing proximal tubular injury. Serum creatinine and urine protein measurements are recommended during administration.14 Probenecid decreases intratubular secretion and maintains a sufficient plasma concentration to allow for once weekly dosing at 5 mg/kg to reduce its nephrotoxicity.13 An alternate dosing regimen, initially used in our patient, was three times per week dosing at 3 mg/kg. In the study performed by Philippe et al, intravenous cidofovir achieve remission in 81.5% of the 22 patients.13
The patient reported by Held et al recovered fully with cidofovir15; however, our patient was switched to ganciclovir due to persistent neutropenia. Bone marrow biopsy was consistent with secondary treatment-related myelosuppression syndrome, without evidence of myelodysplasia or lymphoproliferative infiltration. Myelosuppression is a major side effect of ganciclovir. However, the antiviral effects far outweigh these risks and therefore ganciclovir and its oral prodrug valganciclovir should be considered for patients with pancytopenia secondary to CMV reactivation.
In summary, this unique case of triple-viremia induced haemorrhagic cystitis in an immunosuppressed CLL patient posed both a diagnostic and therapeutic challenge as treatments are nephrotoxic and further increase immunosuppression.
The major learning point is to exercise caution when prescribing FCR chemotherapy on its long-term immunosuppressive effects. It is expected that novel immuno-chemotherapy for CLL should control the disease with reduced immunosuppressive effects.16
Patient’s perspective
Translation from French
I was diagnosed with CLL in November 2015. Started the treatments with FCR protocol in April 2019 (six treatments of three consecutive days each). At the end of the fourth treatment, I was not well. I had fever and a large fatigue with no energy. I finished treatments on the 13th of November 2019. On the week of 18 November, the symptoms appeared: fever, incontinent of urine with blood, no appetite, fatigue.
I visited MUHC emergency, 12 hours wait before I had a doctor’s room. I stayed the night and the next day I saw the doctor, but they did not know what I had. On the 22nd of November I returned to emergency with a lot of fever and other symptoms. I passed the night in an emergency room. On Saturday they released me, had fever and falls.
On the 24th I returned to emergency, fever and incontinence, etc. I was placed in the corridor in a stretcher with a commode next to the whole world. There was nowhere else for me, I had to go through the doors to go to the public toilet and I urinated every 5 min. I stayed in emergency 5 days before I was admitted to Internal Medicine.
It was a bad experience the three times I was in emergency. On 29 November, I had my own room. I was there till 07 February 2020.
The staff took charge rapidly. There were many tests during this long period to find out the cause of my problems. Everything came from the chemotherapy. Many departments were involved: urology, otolaryngology, haematology, internal medicine, infectious diseases.
There were several healthcare workers who spoke on behalf of other departments.
Very good service with the nursing staffs and the préposé (aux bénéficiaires). On my part, my immune system was severely damaged.
Learning points
Infections in immunosuppressed patients remain a diagnostic and therapeutic challenge.
In patient treated for chronic lymphocytic leukaemia, haematuria can be related to viral infections like BK virus, adenovirus and cytomegalovirus (CMV).
BK infection is diagnosed with a high index of suspicion, however, combined CMV and adenovirus infections renders the diagnosis more difficult.
Treatment of these viral infections remains difficult as medications are associated with myelotoxicity (ganciclovir) and renal insufficiency (cidofovir).
The authors would like to thank Dr Malek Merdad and Dr Isabelle Malhamé for their inspiration to write this article.
Contributors: MK and J-PR devised the project, main conceptual ideas and proof outlines. MK took the lead in writing the manuscript the supervision of J-PR. MK created all the images and translated the patient’s perspective from French to English. J-PR and JL provided critical feedback and helped shape analysis and manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | CIDOFOVIR, CYCLOPHOSPHAMIDE, FILGRASTIM, FLUDARABINE PHOSPHATE, HUMAN IMMUNOGLOBULIN G, PROBENECID, RITUXIMAB, SODIUM CHLORIDE, SULFAMETHOXAZOLE\TRIMETHOPRIM, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33402369 | 19,066,566 | 2021-01-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myelosuppression'. | Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
Background
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder associated with mature B-cell dysfunction, hypogammaglobulinaemia and T-cell abnormalities. In Europe and North America, CLL is the most common leukaemia, with median age of diagnosis of 70 years.1 Treatment is indicated only for symptomatic disease, such as anaemia <100 g/L and/or thrombocytopenia <100×109/L, massive splenomegaly, lymphadenopathy or constitutional symptoms.2
Infection is a frequent cause of morbidity and mortality in CLL. Roughly 30%–50% of all CLL patients suffer infections, with a high subsequent mortality rate.3 While the majority of infections affect more often the respiratory track, or skin and the gastrointestinal tract.4 The most frequent organisms causing infections are bacteria like Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. This increased susceptibility to infection stems from B-cells with impaired immunoglobulin production capability and dysfunctional T-helper cells, which also assist in antibody production. This impaired capability to produce immunoglobulins, termed hypogammaglobulinaemia, affects 85% of CLL patients, particularly in advanced disease.4
Antineoplastic agents recommended for the treatment of CLL are also immunosuppressive and further increase the risk of infections.5 These include opportunistic micro-organisms such as Candida, Pneumocystis jirovecii, listeria, nocardia and atypical mycobacteria. In addition, patients have increased risk of viral diseases such as herpes simplex, Epstein-Barr and cytomegalovirus (CMV). Additional infectious complications may include hepatitis B reactivation and progressive multifocal leucoencephalopathy. In spite of the immunosuppressive risk, chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the standard risk therapy in fit patients below 65 years of age with CLL, in absence of 17 p deletion, or TP53 mutation, and with immunoglobulin heavy chain V (IGHV)-mutated.6
To reduce risk of infection, immunoglobulin levels should also be routinely monitored, particularly with rituximab, which reduces the number of B-cells expressing CD20. It is postulated that monitoring immunoglobulins while being treated with rituximab may reduce the risk of serious infections.4
Herein, we present a unique case of a woman treated for CLL who experienced severe pancytopenia and immunosuppression at the completion of her chemo-immunotherapy. She subsequently experienced triple concurrent viral infections, which posed a therapeutic challenge due to her pancytopenia.
Case presentation
A previously healthy 58-year-old woman was diagnosed with CLL through a routine blood test in 2015. Her physical examination was unremarkable and her lymphocyte counts were at 12.36×109 cells/L. Bone marrow biopsy with immunohistochemistry was suggestive of CLL and stained positive for BCL2, CD5 (aberrant T-cell marker), CD20, CD23, CD43 and CD79a (B-cell markers) while BCL6 was negative. The PCR amplification study showed immunoglobulin heavy chain gene rearrangement along with IgG kappa light chain gene arrangement. No t(14;18) BCL2/JH or t(11;14) BCL1/JH gene rearrangements were observed. As she was asymptomatic, and positron emission tomography (PET) scan showed low grade metabolic activity in lymph nodes in cervical, axillary and iliac areas, no therapy was initiated (figure 1). She was followed every 6 months.
Figure 1 Positron emission tomography scan (right) and corresponding CT images (left) of multiple low-grade hypermetabolic lymph nodes in 2017, 2 years after diagnosis of chronic lymphocytic leukaemia. (A) Multiple small low-grade hypermetabolic lymph nodes in bilateral neck regions predominantly in the posterior triangles. SUV of 1.9 in the left and right upper posterior triangles. (B) Hypermetabolic lymph nodes in the left axillary regions, SUV 1.8. (C) Left external iliac lymph node SUV of 3. SUV, Standardized uptake value.
In November 2017 the patient had symptom of a rapid bilateral enlargement of the cervical lymph nodes accompanied by persistent fatigue, night sweats and decreased weight. Lyme disease, HIV, hepatitis B and C and syphilis serologies were performed, and all tests yielded negative results. Repeat PET/CT scan, cytogenetics and bone marrow biopsy demonstrated no evidence of Richter’s transformation into a diffuse large cell lymphoma. Due to significant bulky disease and enlarged adenopathy with B constitutional symptoms, chemo-immunotherapy with FCR was considered. This was furthermore rationalised as she was a fit patient younger than 65 years of age with standard risk for CLL due to the absence of 17 p deletion, or TP53 mutation, and with IGHV being mutated.7
She received six cycles of FCR which was completed uneventfully on 11 November 2019. During FCR therapy, she received oral valacyclovir 500 mg two times per day for herpes prophylaxis as well as Septra DS (160 mg trimethoprim and 800 mg sulfamethoxazole) one tablet Mondays, Wednesdays and Fridays for P. jirovecii prophylaxis. On 18 November, she presented to the emergency room of the McGill University Health Centre (MUHC) with haematuria, suprapubic pain and fever. She was admitted and treated for a urine infection and slowly improved after different antibiotics such as ciprofloxacin, trimethoprim-sulfamethoxazole and ceftriaxone and blood and urinary bacterial cultures were negative. A CT urogram showed moderate bilateral hydroureteronephrosis with diffuse urolithelial and bladder thickening (figure 2). As a whole, these findings were suggestive of an inflammatory or infectious process evoking pyleoureteritis and cystitis.
Figure 2 CT urogram on admission in November 2019, demonstrating (A) poorly distended bladder and marked thickening of bladder walls (green arrow) and (B) moderate dilation of both ureters and collection ducts with marked thickening and enhancement of the urothelium associated with moderate periureteric fat stranding.
Investigations
On admission, she was mildly pancytopenic (table 1). As the patient partially improved and had negative urine cultures, a cyclophosphamide-induced haemorrhagic cystitis was considered, and she was placed on continuous bladder irrigation.
Table 1 Summary of the patient’s serological and microbiological test results during the course of her neutropenia and triple viremia
Laboratory results Reference ranges 20 March 2019 11 November 2019 26 November 2019 25 December 2019 01 January 2020 23 January 2020 01 February 2020 07 February 2020 03 March 2020
Time of intervention First dose FCR Last dose FCR Meropenem started Virology investigated Begins cidofovir+GCSF Cidofovir changed to Ganciclovir Ganciclovir transitioned to valganciclovir Discharge Follow-up
WBC (109/L) 4.0–10.0 30.90 5.90 3.00 1.00 0.60 2.40 6.10 2.40 2.00
Neutrophils 2.0–7.0 3.75 4.18 2.46 0.80 0.36 1.19 5.09 1.73 1.35
Lymphocytes 1.5–4.5 26.26 0.87 0.23 0.08 0.11 0.23 0.46 0.33 0.44
Plt (109/L) 150–450 145 158 123 48 19 54 17 12 39
Hb (g/L) 120–150 142 129 99 63 80 70 70 71 99
Creatinine (umol/L) 50–90 71 68 125 128 118 75 74 69 75
CMV (copies/mL) – – – – 7320 3170 1291 153 149 0
Adenovirus (copies/mL) – – – – – 7.44 log10 4.86 log10 3.74 log10 – 3.30 log10
BK virus urine (copies/mL) – – – – – 2.26×107 – 3.20×108 –
BK virus blood (copies/mL) – – – – – – – – – 3.91×103
CMV, cytomegalovirus; FCR, fludarabine, cyclophosphamide and rituximab; Hb, haemoglobin; Plt, platelet; WBC, white blood cell.
On 1 December 2019 she developed a pancytopenia that required platelet and packed red blood cell transfusions. She remained persistently febrile despite repeated negative bacterial blood and urine cultures. Due to her CLL, pancytopenia and the consideration of immunosuppression induced by FCR chemotherapy, viral infections were investigated. PCR for adenovirus showed 22.4 copies/mL in blood, and positive in urine; PCR for polyoma virus showed 8.81 million copies/mL blood; and PCR for CMV showed 358 copies/mL in blood, confirming viral invasive infections (figure 3). To further investigate her pancytopenia, serology for parvovirus B 19 was carried out and was negative for IgM.
Figure 3 Cytomegalovirus (CMV) and BK viremia (A) and adeno-viremia (B) over the course of treatment.
On 18 December 2019 the patient underwent a double J-stent insertion for bilateral hydronephrosis. Pelvic pain persisted and she continued to pass clots in her urine. Repeat CMV PCR testing on 25 December 2019 showed 7320 copies/mL while an ophthalmological assessment revealed no evidence of CMV retinitis or keratitis. Bone marrow biopsy results showed pancytopenia without transformation (figure 4).
Figure 4 Histology and immunochemistry of bone marrow smear (A) and biopsy (B). Bone marrow biopsy demonstrating hypocellularity. Moderate left shift of the myeloid series and mild left shift of the erythroid series. No lymphocytosis or lymphoma, no definite diagnosis of myelodysplastic syndrome (B).
Treatment
On 1 January 2020, cidofovir was administered to treat the three viral infections of BK polyomavirus, adenovirus and CMV. Cidofovir was given at the dose of 1 mg/kg intravenously three times a week instead of a weekly dose given her kidney injury and high creatinine levels. She received probenecid 2 g orally 1 hour before cidofovir, then 2 hours and 8 hours after the end of infusion to increase cidofovir levels in the blood. For renal protection, she was hydrated with 1 L of 0.9% normal saline during cidofovir infusion. Filgrastim (G-CSF) was initiated for her neutropenia, darbepoetin for her anaemia, and intravenous IgG was infused three times at 4-week intervals for her hypogammaglobulinumia.
Neutropenia worsen despite filgrastim, and CMV viral load continued to increase. Due to cidofovir myelotoxicity, a decision was made to focus treatment on CMV infection, while ignoring the BK and adenovirus. To this end, the patient was changed to ganciclovir 250 mg intravenous two times per day on 23 January 2020 and her urinary symptoms improved for the first time. On 1 February 2020, she was transitioned to oral valganciclovir 450 mg daily and was discharged to home 1 week later, after 101 days in hospital.
Outcome and follow-up
A bone marrow biopsy on 27 January 2020 showed a hypocellular marrow with focal area up to 20%–30% haematopoietic tissue. No evidence of lymphocytosis or lymphoma and no dysplastic changes in morphology were observed. Immunohistochemistry showed <5% CD117, and was negative for CD20, CD34 and PAX5. The histological appearance represented haematopoietic regeneration post-chemotherapy. On 3 March 2020 follow-up, CMV load was undetectable, adenovirus load was 5000 copies/mL, BK load was 3.2×108 copies/mL (table 1). She was switched on CMV prophylaxis with resolved haemorrhagic cystitis and received valganciclovir 450 mg p.o. daily for another 3 months and until her absolute lymphocyte count recovers above 109 cells/L. She continued trimethoprim-sulfamethaxole prophylaxis for 6 months post-chemotherapy. Her double-J stents remain in place. While clinically improved, her neutropenia improved on low dose filgrastim until 4 April 2020. Her blood counts normalised 1 month after and she is followed as an outpatient with Haematology, Infectious Diseases, and Urology services at the MUHC.
Discussion
FCR chemo-immunotherapy is considered the treatment for standard risk CLL patients under the age of 65,7 with a high overall response rate. However, the predominant complication is myelosuppression.8 Persistent neutropenia was reported in 19% and late infections in 9% of patients.9 The frequency of cytopenias was 35% at 3 months and 12% at 9 months after completion of therapy, respectively. Another side effect is prolonged lymphoid immunodeficiency.
Human adenovirus infections usually present as a keratoconjunctivitis or respiratory tract infection. In most healthy individuals the infection is usually self-limited. However, in immunosuppressed patients, infection may disseminate and become potentially life-threatening. Disseminated adenovirus infection can result from either de novo infection or a reactivation of clinically silent infection.10
BK virus is a member of the polyomavirus family. BK virus reactivation occurs only in immunosuppressed patients and can lead to nephropathy, ureteral stenosis, tubular interstitial damage and haemorrhagic cystitis. Viremia occurs in 20%–60% of this population. There is no specific treatment for BK virus-associated nephropathy, therefore viral replication can only be controlled through modulating the immunosuppressive condition.11
CMV is a herpes virus with a large double-stranded DNA that remains latent in the host after primary infection. Immunocompromised patients can have reactivation of their latent infection. Diagnosis of viral reactivation is made through CMV PCR in blood, tissue or body fluid. Manifestations of CMV infection occur most often in the gastrointestinal tract, lungs, liver and retina.12 As we did not observe the typical owl’s eye tissue lesion in the second bone marrow biopsy, we considered that CMV reactivation was a contributing factor for the pancytopenia, and treatment may have prevented such tissue lesion to develop. First line treatment of CMV infection includes intravenous ganciclovir or its oral prodrug valganciclovir, which are DNA polymerase inhibitors. The major side effect of these drugs is myelosuppression, including neutropenia.4
In our patient, the prolonged pancytopenias secondary to FCR was associated with haematuria with an ureteral mass. To date, only two observations on the use of cidofovir to simultaneously treat BK-virus associated haemorrhagic cystitis and CMV reactivation have been reported. However, in the case report by Held et al, the patient had received a bone marrow transplant for chronic myeloid leukaemia, whereas our patient had CLL.
Cidofovir has been suggested in some cases for the treatment of BK virus-associated haemorrhagic cystitis.13 Cidofovir and foscarnet are second-line therapies in patients with CMV that are either resistant or refractory to ganciclovir. Cidofovir is a non-cyclic analogue of cytidine monophosphate that terminates CMV DNA synthesis. In vitro studies showed effectiveness against herpes viruses, including CMV, herpes simplex viruses 1 and 2, varicella-zoster, Epstein-Barr virus, human papillomavirus and adenovirus. The main adverse effect is nephrotoxicity, causing proximal tubular injury. Serum creatinine and urine protein measurements are recommended during administration.14 Probenecid decreases intratubular secretion and maintains a sufficient plasma concentration to allow for once weekly dosing at 5 mg/kg to reduce its nephrotoxicity.13 An alternate dosing regimen, initially used in our patient, was three times per week dosing at 3 mg/kg. In the study performed by Philippe et al, intravenous cidofovir achieve remission in 81.5% of the 22 patients.13
The patient reported by Held et al recovered fully with cidofovir15; however, our patient was switched to ganciclovir due to persistent neutropenia. Bone marrow biopsy was consistent with secondary treatment-related myelosuppression syndrome, without evidence of myelodysplasia or lymphoproliferative infiltration. Myelosuppression is a major side effect of ganciclovir. However, the antiviral effects far outweigh these risks and therefore ganciclovir and its oral prodrug valganciclovir should be considered for patients with pancytopenia secondary to CMV reactivation.
In summary, this unique case of triple-viremia induced haemorrhagic cystitis in an immunosuppressed CLL patient posed both a diagnostic and therapeutic challenge as treatments are nephrotoxic and further increase immunosuppression.
The major learning point is to exercise caution when prescribing FCR chemotherapy on its long-term immunosuppressive effects. It is expected that novel immuno-chemotherapy for CLL should control the disease with reduced immunosuppressive effects.16
Patient’s perspective
Translation from French
I was diagnosed with CLL in November 2015. Started the treatments with FCR protocol in April 2019 (six treatments of three consecutive days each). At the end of the fourth treatment, I was not well. I had fever and a large fatigue with no energy. I finished treatments on the 13th of November 2019. On the week of 18 November, the symptoms appeared: fever, incontinent of urine with blood, no appetite, fatigue.
I visited MUHC emergency, 12 hours wait before I had a doctor’s room. I stayed the night and the next day I saw the doctor, but they did not know what I had. On the 22nd of November I returned to emergency with a lot of fever and other symptoms. I passed the night in an emergency room. On Saturday they released me, had fever and falls.
On the 24th I returned to emergency, fever and incontinence, etc. I was placed in the corridor in a stretcher with a commode next to the whole world. There was nowhere else for me, I had to go through the doors to go to the public toilet and I urinated every 5 min. I stayed in emergency 5 days before I was admitted to Internal Medicine.
It was a bad experience the three times I was in emergency. On 29 November, I had my own room. I was there till 07 February 2020.
The staff took charge rapidly. There were many tests during this long period to find out the cause of my problems. Everything came from the chemotherapy. Many departments were involved: urology, otolaryngology, haematology, internal medicine, infectious diseases.
There were several healthcare workers who spoke on behalf of other departments.
Very good service with the nursing staffs and the préposé (aux bénéficiaires). On my part, my immune system was severely damaged.
Learning points
Infections in immunosuppressed patients remain a diagnostic and therapeutic challenge.
In patient treated for chronic lymphocytic leukaemia, haematuria can be related to viral infections like BK virus, adenovirus and cytomegalovirus (CMV).
BK infection is diagnosed with a high index of suspicion, however, combined CMV and adenovirus infections renders the diagnosis more difficult.
Treatment of these viral infections remains difficult as medications are associated with myelotoxicity (ganciclovir) and renal insufficiency (cidofovir).
The authors would like to thank Dr Malek Merdad and Dr Isabelle Malhamé for their inspiration to write this article.
Contributors: MK and J-PR devised the project, main conceptual ideas and proof outlines. MK took the lead in writing the manuscript the supervision of J-PR. MK created all the images and translated the patient’s perspective from French to English. J-PR and JL provided critical feedback and helped shape analysis and manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | CIDOFOVIR, CYCLOPHOSPHAMIDE, FILGRASTIM, FLUDARABINE PHOSPHATE, HUMAN IMMUNOGLOBULIN G, PROBENECID, RITUXIMAB, SODIUM CHLORIDE, SULFAMETHOXAZOLE\TRIMETHOPRIM, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33402369 | 19,066,566 | 2021-01-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neutropenia'. | Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
Background
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder associated with mature B-cell dysfunction, hypogammaglobulinaemia and T-cell abnormalities. In Europe and North America, CLL is the most common leukaemia, with median age of diagnosis of 70 years.1 Treatment is indicated only for symptomatic disease, such as anaemia <100 g/L and/or thrombocytopenia <100×109/L, massive splenomegaly, lymphadenopathy or constitutional symptoms.2
Infection is a frequent cause of morbidity and mortality in CLL. Roughly 30%–50% of all CLL patients suffer infections, with a high subsequent mortality rate.3 While the majority of infections affect more often the respiratory track, or skin and the gastrointestinal tract.4 The most frequent organisms causing infections are bacteria like Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. This increased susceptibility to infection stems from B-cells with impaired immunoglobulin production capability and dysfunctional T-helper cells, which also assist in antibody production. This impaired capability to produce immunoglobulins, termed hypogammaglobulinaemia, affects 85% of CLL patients, particularly in advanced disease.4
Antineoplastic agents recommended for the treatment of CLL are also immunosuppressive and further increase the risk of infections.5 These include opportunistic micro-organisms such as Candida, Pneumocystis jirovecii, listeria, nocardia and atypical mycobacteria. In addition, patients have increased risk of viral diseases such as herpes simplex, Epstein-Barr and cytomegalovirus (CMV). Additional infectious complications may include hepatitis B reactivation and progressive multifocal leucoencephalopathy. In spite of the immunosuppressive risk, chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the standard risk therapy in fit patients below 65 years of age with CLL, in absence of 17 p deletion, or TP53 mutation, and with immunoglobulin heavy chain V (IGHV)-mutated.6
To reduce risk of infection, immunoglobulin levels should also be routinely monitored, particularly with rituximab, which reduces the number of B-cells expressing CD20. It is postulated that monitoring immunoglobulins while being treated with rituximab may reduce the risk of serious infections.4
Herein, we present a unique case of a woman treated for CLL who experienced severe pancytopenia and immunosuppression at the completion of her chemo-immunotherapy. She subsequently experienced triple concurrent viral infections, which posed a therapeutic challenge due to her pancytopenia.
Case presentation
A previously healthy 58-year-old woman was diagnosed with CLL through a routine blood test in 2015. Her physical examination was unremarkable and her lymphocyte counts were at 12.36×109 cells/L. Bone marrow biopsy with immunohistochemistry was suggestive of CLL and stained positive for BCL2, CD5 (aberrant T-cell marker), CD20, CD23, CD43 and CD79a (B-cell markers) while BCL6 was negative. The PCR amplification study showed immunoglobulin heavy chain gene rearrangement along with IgG kappa light chain gene arrangement. No t(14;18) BCL2/JH or t(11;14) BCL1/JH gene rearrangements were observed. As she was asymptomatic, and positron emission tomography (PET) scan showed low grade metabolic activity in lymph nodes in cervical, axillary and iliac areas, no therapy was initiated (figure 1). She was followed every 6 months.
Figure 1 Positron emission tomography scan (right) and corresponding CT images (left) of multiple low-grade hypermetabolic lymph nodes in 2017, 2 years after diagnosis of chronic lymphocytic leukaemia. (A) Multiple small low-grade hypermetabolic lymph nodes in bilateral neck regions predominantly in the posterior triangles. SUV of 1.9 in the left and right upper posterior triangles. (B) Hypermetabolic lymph nodes in the left axillary regions, SUV 1.8. (C) Left external iliac lymph node SUV of 3. SUV, Standardized uptake value.
In November 2017 the patient had symptom of a rapid bilateral enlargement of the cervical lymph nodes accompanied by persistent fatigue, night sweats and decreased weight. Lyme disease, HIV, hepatitis B and C and syphilis serologies were performed, and all tests yielded negative results. Repeat PET/CT scan, cytogenetics and bone marrow biopsy demonstrated no evidence of Richter’s transformation into a diffuse large cell lymphoma. Due to significant bulky disease and enlarged adenopathy with B constitutional symptoms, chemo-immunotherapy with FCR was considered. This was furthermore rationalised as she was a fit patient younger than 65 years of age with standard risk for CLL due to the absence of 17 p deletion, or TP53 mutation, and with IGHV being mutated.7
She received six cycles of FCR which was completed uneventfully on 11 November 2019. During FCR therapy, she received oral valacyclovir 500 mg two times per day for herpes prophylaxis as well as Septra DS (160 mg trimethoprim and 800 mg sulfamethoxazole) one tablet Mondays, Wednesdays and Fridays for P. jirovecii prophylaxis. On 18 November, she presented to the emergency room of the McGill University Health Centre (MUHC) with haematuria, suprapubic pain and fever. She was admitted and treated for a urine infection and slowly improved after different antibiotics such as ciprofloxacin, trimethoprim-sulfamethoxazole and ceftriaxone and blood and urinary bacterial cultures were negative. A CT urogram showed moderate bilateral hydroureteronephrosis with diffuse urolithelial and bladder thickening (figure 2). As a whole, these findings were suggestive of an inflammatory or infectious process evoking pyleoureteritis and cystitis.
Figure 2 CT urogram on admission in November 2019, demonstrating (A) poorly distended bladder and marked thickening of bladder walls (green arrow) and (B) moderate dilation of both ureters and collection ducts with marked thickening and enhancement of the urothelium associated with moderate periureteric fat stranding.
Investigations
On admission, she was mildly pancytopenic (table 1). As the patient partially improved and had negative urine cultures, a cyclophosphamide-induced haemorrhagic cystitis was considered, and she was placed on continuous bladder irrigation.
Table 1 Summary of the patient’s serological and microbiological test results during the course of her neutropenia and triple viremia
Laboratory results Reference ranges 20 March 2019 11 November 2019 26 November 2019 25 December 2019 01 January 2020 23 January 2020 01 February 2020 07 February 2020 03 March 2020
Time of intervention First dose FCR Last dose FCR Meropenem started Virology investigated Begins cidofovir+GCSF Cidofovir changed to Ganciclovir Ganciclovir transitioned to valganciclovir Discharge Follow-up
WBC (109/L) 4.0–10.0 30.90 5.90 3.00 1.00 0.60 2.40 6.10 2.40 2.00
Neutrophils 2.0–7.0 3.75 4.18 2.46 0.80 0.36 1.19 5.09 1.73 1.35
Lymphocytes 1.5–4.5 26.26 0.87 0.23 0.08 0.11 0.23 0.46 0.33 0.44
Plt (109/L) 150–450 145 158 123 48 19 54 17 12 39
Hb (g/L) 120–150 142 129 99 63 80 70 70 71 99
Creatinine (umol/L) 50–90 71 68 125 128 118 75 74 69 75
CMV (copies/mL) – – – – 7320 3170 1291 153 149 0
Adenovirus (copies/mL) – – – – – 7.44 log10 4.86 log10 3.74 log10 – 3.30 log10
BK virus urine (copies/mL) – – – – – 2.26×107 – 3.20×108 –
BK virus blood (copies/mL) – – – – – – – – – 3.91×103
CMV, cytomegalovirus; FCR, fludarabine, cyclophosphamide and rituximab; Hb, haemoglobin; Plt, platelet; WBC, white blood cell.
On 1 December 2019 she developed a pancytopenia that required platelet and packed red blood cell transfusions. She remained persistently febrile despite repeated negative bacterial blood and urine cultures. Due to her CLL, pancytopenia and the consideration of immunosuppression induced by FCR chemotherapy, viral infections were investigated. PCR for adenovirus showed 22.4 copies/mL in blood, and positive in urine; PCR for polyoma virus showed 8.81 million copies/mL blood; and PCR for CMV showed 358 copies/mL in blood, confirming viral invasive infections (figure 3). To further investigate her pancytopenia, serology for parvovirus B 19 was carried out and was negative for IgM.
Figure 3 Cytomegalovirus (CMV) and BK viremia (A) and adeno-viremia (B) over the course of treatment.
On 18 December 2019 the patient underwent a double J-stent insertion for bilateral hydronephrosis. Pelvic pain persisted and she continued to pass clots in her urine. Repeat CMV PCR testing on 25 December 2019 showed 7320 copies/mL while an ophthalmological assessment revealed no evidence of CMV retinitis or keratitis. Bone marrow biopsy results showed pancytopenia without transformation (figure 4).
Figure 4 Histology and immunochemistry of bone marrow smear (A) and biopsy (B). Bone marrow biopsy demonstrating hypocellularity. Moderate left shift of the myeloid series and mild left shift of the erythroid series. No lymphocytosis or lymphoma, no definite diagnosis of myelodysplastic syndrome (B).
Treatment
On 1 January 2020, cidofovir was administered to treat the three viral infections of BK polyomavirus, adenovirus and CMV. Cidofovir was given at the dose of 1 mg/kg intravenously three times a week instead of a weekly dose given her kidney injury and high creatinine levels. She received probenecid 2 g orally 1 hour before cidofovir, then 2 hours and 8 hours after the end of infusion to increase cidofovir levels in the blood. For renal protection, she was hydrated with 1 L of 0.9% normal saline during cidofovir infusion. Filgrastim (G-CSF) was initiated for her neutropenia, darbepoetin for her anaemia, and intravenous IgG was infused three times at 4-week intervals for her hypogammaglobulinumia.
Neutropenia worsen despite filgrastim, and CMV viral load continued to increase. Due to cidofovir myelotoxicity, a decision was made to focus treatment on CMV infection, while ignoring the BK and adenovirus. To this end, the patient was changed to ganciclovir 250 mg intravenous two times per day on 23 January 2020 and her urinary symptoms improved for the first time. On 1 February 2020, she was transitioned to oral valganciclovir 450 mg daily and was discharged to home 1 week later, after 101 days in hospital.
Outcome and follow-up
A bone marrow biopsy on 27 January 2020 showed a hypocellular marrow with focal area up to 20%–30% haematopoietic tissue. No evidence of lymphocytosis or lymphoma and no dysplastic changes in morphology were observed. Immunohistochemistry showed <5% CD117, and was negative for CD20, CD34 and PAX5. The histological appearance represented haematopoietic regeneration post-chemotherapy. On 3 March 2020 follow-up, CMV load was undetectable, adenovirus load was 5000 copies/mL, BK load was 3.2×108 copies/mL (table 1). She was switched on CMV prophylaxis with resolved haemorrhagic cystitis and received valganciclovir 450 mg p.o. daily for another 3 months and until her absolute lymphocyte count recovers above 109 cells/L. She continued trimethoprim-sulfamethaxole prophylaxis for 6 months post-chemotherapy. Her double-J stents remain in place. While clinically improved, her neutropenia improved on low dose filgrastim until 4 April 2020. Her blood counts normalised 1 month after and she is followed as an outpatient with Haematology, Infectious Diseases, and Urology services at the MUHC.
Discussion
FCR chemo-immunotherapy is considered the treatment for standard risk CLL patients under the age of 65,7 with a high overall response rate. However, the predominant complication is myelosuppression.8 Persistent neutropenia was reported in 19% and late infections in 9% of patients.9 The frequency of cytopenias was 35% at 3 months and 12% at 9 months after completion of therapy, respectively. Another side effect is prolonged lymphoid immunodeficiency.
Human adenovirus infections usually present as a keratoconjunctivitis or respiratory tract infection. In most healthy individuals the infection is usually self-limited. However, in immunosuppressed patients, infection may disseminate and become potentially life-threatening. Disseminated adenovirus infection can result from either de novo infection or a reactivation of clinically silent infection.10
BK virus is a member of the polyomavirus family. BK virus reactivation occurs only in immunosuppressed patients and can lead to nephropathy, ureteral stenosis, tubular interstitial damage and haemorrhagic cystitis. Viremia occurs in 20%–60% of this population. There is no specific treatment for BK virus-associated nephropathy, therefore viral replication can only be controlled through modulating the immunosuppressive condition.11
CMV is a herpes virus with a large double-stranded DNA that remains latent in the host after primary infection. Immunocompromised patients can have reactivation of their latent infection. Diagnosis of viral reactivation is made through CMV PCR in blood, tissue or body fluid. Manifestations of CMV infection occur most often in the gastrointestinal tract, lungs, liver and retina.12 As we did not observe the typical owl’s eye tissue lesion in the second bone marrow biopsy, we considered that CMV reactivation was a contributing factor for the pancytopenia, and treatment may have prevented such tissue lesion to develop. First line treatment of CMV infection includes intravenous ganciclovir or its oral prodrug valganciclovir, which are DNA polymerase inhibitors. The major side effect of these drugs is myelosuppression, including neutropenia.4
In our patient, the prolonged pancytopenias secondary to FCR was associated with haematuria with an ureteral mass. To date, only two observations on the use of cidofovir to simultaneously treat BK-virus associated haemorrhagic cystitis and CMV reactivation have been reported. However, in the case report by Held et al, the patient had received a bone marrow transplant for chronic myeloid leukaemia, whereas our patient had CLL.
Cidofovir has been suggested in some cases for the treatment of BK virus-associated haemorrhagic cystitis.13 Cidofovir and foscarnet are second-line therapies in patients with CMV that are either resistant or refractory to ganciclovir. Cidofovir is a non-cyclic analogue of cytidine monophosphate that terminates CMV DNA synthesis. In vitro studies showed effectiveness against herpes viruses, including CMV, herpes simplex viruses 1 and 2, varicella-zoster, Epstein-Barr virus, human papillomavirus and adenovirus. The main adverse effect is nephrotoxicity, causing proximal tubular injury. Serum creatinine and urine protein measurements are recommended during administration.14 Probenecid decreases intratubular secretion and maintains a sufficient plasma concentration to allow for once weekly dosing at 5 mg/kg to reduce its nephrotoxicity.13 An alternate dosing regimen, initially used in our patient, was three times per week dosing at 3 mg/kg. In the study performed by Philippe et al, intravenous cidofovir achieve remission in 81.5% of the 22 patients.13
The patient reported by Held et al recovered fully with cidofovir15; however, our patient was switched to ganciclovir due to persistent neutropenia. Bone marrow biopsy was consistent with secondary treatment-related myelosuppression syndrome, without evidence of myelodysplasia or lymphoproliferative infiltration. Myelosuppression is a major side effect of ganciclovir. However, the antiviral effects far outweigh these risks and therefore ganciclovir and its oral prodrug valganciclovir should be considered for patients with pancytopenia secondary to CMV reactivation.
In summary, this unique case of triple-viremia induced haemorrhagic cystitis in an immunosuppressed CLL patient posed both a diagnostic and therapeutic challenge as treatments are nephrotoxic and further increase immunosuppression.
The major learning point is to exercise caution when prescribing FCR chemotherapy on its long-term immunosuppressive effects. It is expected that novel immuno-chemotherapy for CLL should control the disease with reduced immunosuppressive effects.16
Patient’s perspective
Translation from French
I was diagnosed with CLL in November 2015. Started the treatments with FCR protocol in April 2019 (six treatments of three consecutive days each). At the end of the fourth treatment, I was not well. I had fever and a large fatigue with no energy. I finished treatments on the 13th of November 2019. On the week of 18 November, the symptoms appeared: fever, incontinent of urine with blood, no appetite, fatigue.
I visited MUHC emergency, 12 hours wait before I had a doctor’s room. I stayed the night and the next day I saw the doctor, but they did not know what I had. On the 22nd of November I returned to emergency with a lot of fever and other symptoms. I passed the night in an emergency room. On Saturday they released me, had fever and falls.
On the 24th I returned to emergency, fever and incontinence, etc. I was placed in the corridor in a stretcher with a commode next to the whole world. There was nowhere else for me, I had to go through the doors to go to the public toilet and I urinated every 5 min. I stayed in emergency 5 days before I was admitted to Internal Medicine.
It was a bad experience the three times I was in emergency. On 29 November, I had my own room. I was there till 07 February 2020.
The staff took charge rapidly. There were many tests during this long period to find out the cause of my problems. Everything came from the chemotherapy. Many departments were involved: urology, otolaryngology, haematology, internal medicine, infectious diseases.
There were several healthcare workers who spoke on behalf of other departments.
Very good service with the nursing staffs and the préposé (aux bénéficiaires). On my part, my immune system was severely damaged.
Learning points
Infections in immunosuppressed patients remain a diagnostic and therapeutic challenge.
In patient treated for chronic lymphocytic leukaemia, haematuria can be related to viral infections like BK virus, adenovirus and cytomegalovirus (CMV).
BK infection is diagnosed with a high index of suspicion, however, combined CMV and adenovirus infections renders the diagnosis more difficult.
Treatment of these viral infections remains difficult as medications are associated with myelotoxicity (ganciclovir) and renal insufficiency (cidofovir).
The authors would like to thank Dr Malek Merdad and Dr Isabelle Malhamé for their inspiration to write this article.
Contributors: MK and J-PR devised the project, main conceptual ideas and proof outlines. MK took the lead in writing the manuscript the supervision of J-PR. MK created all the images and translated the patient’s perspective from French to English. J-PR and JL provided critical feedback and helped shape analysis and manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | CIDOFOVIR, DARBEPOETIN ALFA, FILGRASTIM, GANCICLOVIR, HUMAN IMMUNOGLOBULIN G, MEROPENEM, PROBENECID, VALGANCICLOVIR | DrugsGivenReaction | CC BY-NC | 33402369 | 18,752,790 | 2021-01-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pancytopenia'. | Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
Background
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder associated with mature B-cell dysfunction, hypogammaglobulinaemia and T-cell abnormalities. In Europe and North America, CLL is the most common leukaemia, with median age of diagnosis of 70 years.1 Treatment is indicated only for symptomatic disease, such as anaemia <100 g/L and/or thrombocytopenia <100×109/L, massive splenomegaly, lymphadenopathy or constitutional symptoms.2
Infection is a frequent cause of morbidity and mortality in CLL. Roughly 30%–50% of all CLL patients suffer infections, with a high subsequent mortality rate.3 While the majority of infections affect more often the respiratory track, or skin and the gastrointestinal tract.4 The most frequent organisms causing infections are bacteria like Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. This increased susceptibility to infection stems from B-cells with impaired immunoglobulin production capability and dysfunctional T-helper cells, which also assist in antibody production. This impaired capability to produce immunoglobulins, termed hypogammaglobulinaemia, affects 85% of CLL patients, particularly in advanced disease.4
Antineoplastic agents recommended for the treatment of CLL are also immunosuppressive and further increase the risk of infections.5 These include opportunistic micro-organisms such as Candida, Pneumocystis jirovecii, listeria, nocardia and atypical mycobacteria. In addition, patients have increased risk of viral diseases such as herpes simplex, Epstein-Barr and cytomegalovirus (CMV). Additional infectious complications may include hepatitis B reactivation and progressive multifocal leucoencephalopathy. In spite of the immunosuppressive risk, chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the standard risk therapy in fit patients below 65 years of age with CLL, in absence of 17 p deletion, or TP53 mutation, and with immunoglobulin heavy chain V (IGHV)-mutated.6
To reduce risk of infection, immunoglobulin levels should also be routinely monitored, particularly with rituximab, which reduces the number of B-cells expressing CD20. It is postulated that monitoring immunoglobulins while being treated with rituximab may reduce the risk of serious infections.4
Herein, we present a unique case of a woman treated for CLL who experienced severe pancytopenia and immunosuppression at the completion of her chemo-immunotherapy. She subsequently experienced triple concurrent viral infections, which posed a therapeutic challenge due to her pancytopenia.
Case presentation
A previously healthy 58-year-old woman was diagnosed with CLL through a routine blood test in 2015. Her physical examination was unremarkable and her lymphocyte counts were at 12.36×109 cells/L. Bone marrow biopsy with immunohistochemistry was suggestive of CLL and stained positive for BCL2, CD5 (aberrant T-cell marker), CD20, CD23, CD43 and CD79a (B-cell markers) while BCL6 was negative. The PCR amplification study showed immunoglobulin heavy chain gene rearrangement along with IgG kappa light chain gene arrangement. No t(14;18) BCL2/JH or t(11;14) BCL1/JH gene rearrangements were observed. As she was asymptomatic, and positron emission tomography (PET) scan showed low grade metabolic activity in lymph nodes in cervical, axillary and iliac areas, no therapy was initiated (figure 1). She was followed every 6 months.
Figure 1 Positron emission tomography scan (right) and corresponding CT images (left) of multiple low-grade hypermetabolic lymph nodes in 2017, 2 years after diagnosis of chronic lymphocytic leukaemia. (A) Multiple small low-grade hypermetabolic lymph nodes in bilateral neck regions predominantly in the posterior triangles. SUV of 1.9 in the left and right upper posterior triangles. (B) Hypermetabolic lymph nodes in the left axillary regions, SUV 1.8. (C) Left external iliac lymph node SUV of 3. SUV, Standardized uptake value.
In November 2017 the patient had symptom of a rapid bilateral enlargement of the cervical lymph nodes accompanied by persistent fatigue, night sweats and decreased weight. Lyme disease, HIV, hepatitis B and C and syphilis serologies were performed, and all tests yielded negative results. Repeat PET/CT scan, cytogenetics and bone marrow biopsy demonstrated no evidence of Richter’s transformation into a diffuse large cell lymphoma. Due to significant bulky disease and enlarged adenopathy with B constitutional symptoms, chemo-immunotherapy with FCR was considered. This was furthermore rationalised as she was a fit patient younger than 65 years of age with standard risk for CLL due to the absence of 17 p deletion, or TP53 mutation, and with IGHV being mutated.7
She received six cycles of FCR which was completed uneventfully on 11 November 2019. During FCR therapy, she received oral valacyclovir 500 mg two times per day for herpes prophylaxis as well as Septra DS (160 mg trimethoprim and 800 mg sulfamethoxazole) one tablet Mondays, Wednesdays and Fridays for P. jirovecii prophylaxis. On 18 November, she presented to the emergency room of the McGill University Health Centre (MUHC) with haematuria, suprapubic pain and fever. She was admitted and treated for a urine infection and slowly improved after different antibiotics such as ciprofloxacin, trimethoprim-sulfamethoxazole and ceftriaxone and blood and urinary bacterial cultures were negative. A CT urogram showed moderate bilateral hydroureteronephrosis with diffuse urolithelial and bladder thickening (figure 2). As a whole, these findings were suggestive of an inflammatory or infectious process evoking pyleoureteritis and cystitis.
Figure 2 CT urogram on admission in November 2019, demonstrating (A) poorly distended bladder and marked thickening of bladder walls (green arrow) and (B) moderate dilation of both ureters and collection ducts with marked thickening and enhancement of the urothelium associated with moderate periureteric fat stranding.
Investigations
On admission, she was mildly pancytopenic (table 1). As the patient partially improved and had negative urine cultures, a cyclophosphamide-induced haemorrhagic cystitis was considered, and she was placed on continuous bladder irrigation.
Table 1 Summary of the patient’s serological and microbiological test results during the course of her neutropenia and triple viremia
Laboratory results Reference ranges 20 March 2019 11 November 2019 26 November 2019 25 December 2019 01 January 2020 23 January 2020 01 February 2020 07 February 2020 03 March 2020
Time of intervention First dose FCR Last dose FCR Meropenem started Virology investigated Begins cidofovir+GCSF Cidofovir changed to Ganciclovir Ganciclovir transitioned to valganciclovir Discharge Follow-up
WBC (109/L) 4.0–10.0 30.90 5.90 3.00 1.00 0.60 2.40 6.10 2.40 2.00
Neutrophils 2.0–7.0 3.75 4.18 2.46 0.80 0.36 1.19 5.09 1.73 1.35
Lymphocytes 1.5–4.5 26.26 0.87 0.23 0.08 0.11 0.23 0.46 0.33 0.44
Plt (109/L) 150–450 145 158 123 48 19 54 17 12 39
Hb (g/L) 120–150 142 129 99 63 80 70 70 71 99
Creatinine (umol/L) 50–90 71 68 125 128 118 75 74 69 75
CMV (copies/mL) – – – – 7320 3170 1291 153 149 0
Adenovirus (copies/mL) – – – – – 7.44 log10 4.86 log10 3.74 log10 – 3.30 log10
BK virus urine (copies/mL) – – – – – 2.26×107 – 3.20×108 –
BK virus blood (copies/mL) – – – – – – – – – 3.91×103
CMV, cytomegalovirus; FCR, fludarabine, cyclophosphamide and rituximab; Hb, haemoglobin; Plt, platelet; WBC, white blood cell.
On 1 December 2019 she developed a pancytopenia that required platelet and packed red blood cell transfusions. She remained persistently febrile despite repeated negative bacterial blood and urine cultures. Due to her CLL, pancytopenia and the consideration of immunosuppression induced by FCR chemotherapy, viral infections were investigated. PCR for adenovirus showed 22.4 copies/mL in blood, and positive in urine; PCR for polyoma virus showed 8.81 million copies/mL blood; and PCR for CMV showed 358 copies/mL in blood, confirming viral invasive infections (figure 3). To further investigate her pancytopenia, serology for parvovirus B 19 was carried out and was negative for IgM.
Figure 3 Cytomegalovirus (CMV) and BK viremia (A) and adeno-viremia (B) over the course of treatment.
On 18 December 2019 the patient underwent a double J-stent insertion for bilateral hydronephrosis. Pelvic pain persisted and she continued to pass clots in her urine. Repeat CMV PCR testing on 25 December 2019 showed 7320 copies/mL while an ophthalmological assessment revealed no evidence of CMV retinitis or keratitis. Bone marrow biopsy results showed pancytopenia without transformation (figure 4).
Figure 4 Histology and immunochemistry of bone marrow smear (A) and biopsy (B). Bone marrow biopsy demonstrating hypocellularity. Moderate left shift of the myeloid series and mild left shift of the erythroid series. No lymphocytosis or lymphoma, no definite diagnosis of myelodysplastic syndrome (B).
Treatment
On 1 January 2020, cidofovir was administered to treat the three viral infections of BK polyomavirus, adenovirus and CMV. Cidofovir was given at the dose of 1 mg/kg intravenously three times a week instead of a weekly dose given her kidney injury and high creatinine levels. She received probenecid 2 g orally 1 hour before cidofovir, then 2 hours and 8 hours after the end of infusion to increase cidofovir levels in the blood. For renal protection, she was hydrated with 1 L of 0.9% normal saline during cidofovir infusion. Filgrastim (G-CSF) was initiated for her neutropenia, darbepoetin for her anaemia, and intravenous IgG was infused three times at 4-week intervals for her hypogammaglobulinumia.
Neutropenia worsen despite filgrastim, and CMV viral load continued to increase. Due to cidofovir myelotoxicity, a decision was made to focus treatment on CMV infection, while ignoring the BK and adenovirus. To this end, the patient was changed to ganciclovir 250 mg intravenous two times per day on 23 January 2020 and her urinary symptoms improved for the first time. On 1 February 2020, she was transitioned to oral valganciclovir 450 mg daily and was discharged to home 1 week later, after 101 days in hospital.
Outcome and follow-up
A bone marrow biopsy on 27 January 2020 showed a hypocellular marrow with focal area up to 20%–30% haematopoietic tissue. No evidence of lymphocytosis or lymphoma and no dysplastic changes in morphology were observed. Immunohistochemistry showed <5% CD117, and was negative for CD20, CD34 and PAX5. The histological appearance represented haematopoietic regeneration post-chemotherapy. On 3 March 2020 follow-up, CMV load was undetectable, adenovirus load was 5000 copies/mL, BK load was 3.2×108 copies/mL (table 1). She was switched on CMV prophylaxis with resolved haemorrhagic cystitis and received valganciclovir 450 mg p.o. daily for another 3 months and until her absolute lymphocyte count recovers above 109 cells/L. She continued trimethoprim-sulfamethaxole prophylaxis for 6 months post-chemotherapy. Her double-J stents remain in place. While clinically improved, her neutropenia improved on low dose filgrastim until 4 April 2020. Her blood counts normalised 1 month after and she is followed as an outpatient with Haematology, Infectious Diseases, and Urology services at the MUHC.
Discussion
FCR chemo-immunotherapy is considered the treatment for standard risk CLL patients under the age of 65,7 with a high overall response rate. However, the predominant complication is myelosuppression.8 Persistent neutropenia was reported in 19% and late infections in 9% of patients.9 The frequency of cytopenias was 35% at 3 months and 12% at 9 months after completion of therapy, respectively. Another side effect is prolonged lymphoid immunodeficiency.
Human adenovirus infections usually present as a keratoconjunctivitis or respiratory tract infection. In most healthy individuals the infection is usually self-limited. However, in immunosuppressed patients, infection may disseminate and become potentially life-threatening. Disseminated adenovirus infection can result from either de novo infection or a reactivation of clinically silent infection.10
BK virus is a member of the polyomavirus family. BK virus reactivation occurs only in immunosuppressed patients and can lead to nephropathy, ureteral stenosis, tubular interstitial damage and haemorrhagic cystitis. Viremia occurs in 20%–60% of this population. There is no specific treatment for BK virus-associated nephropathy, therefore viral replication can only be controlled through modulating the immunosuppressive condition.11
CMV is a herpes virus with a large double-stranded DNA that remains latent in the host after primary infection. Immunocompromised patients can have reactivation of their latent infection. Diagnosis of viral reactivation is made through CMV PCR in blood, tissue or body fluid. Manifestations of CMV infection occur most often in the gastrointestinal tract, lungs, liver and retina.12 As we did not observe the typical owl’s eye tissue lesion in the second bone marrow biopsy, we considered that CMV reactivation was a contributing factor for the pancytopenia, and treatment may have prevented such tissue lesion to develop. First line treatment of CMV infection includes intravenous ganciclovir or its oral prodrug valganciclovir, which are DNA polymerase inhibitors. The major side effect of these drugs is myelosuppression, including neutropenia.4
In our patient, the prolonged pancytopenias secondary to FCR was associated with haematuria with an ureteral mass. To date, only two observations on the use of cidofovir to simultaneously treat BK-virus associated haemorrhagic cystitis and CMV reactivation have been reported. However, in the case report by Held et al, the patient had received a bone marrow transplant for chronic myeloid leukaemia, whereas our patient had CLL.
Cidofovir has been suggested in some cases for the treatment of BK virus-associated haemorrhagic cystitis.13 Cidofovir and foscarnet are second-line therapies in patients with CMV that are either resistant or refractory to ganciclovir. Cidofovir is a non-cyclic analogue of cytidine monophosphate that terminates CMV DNA synthesis. In vitro studies showed effectiveness against herpes viruses, including CMV, herpes simplex viruses 1 and 2, varicella-zoster, Epstein-Barr virus, human papillomavirus and adenovirus. The main adverse effect is nephrotoxicity, causing proximal tubular injury. Serum creatinine and urine protein measurements are recommended during administration.14 Probenecid decreases intratubular secretion and maintains a sufficient plasma concentration to allow for once weekly dosing at 5 mg/kg to reduce its nephrotoxicity.13 An alternate dosing regimen, initially used in our patient, was three times per week dosing at 3 mg/kg. In the study performed by Philippe et al, intravenous cidofovir achieve remission in 81.5% of the 22 patients.13
The patient reported by Held et al recovered fully with cidofovir15; however, our patient was switched to ganciclovir due to persistent neutropenia. Bone marrow biopsy was consistent with secondary treatment-related myelosuppression syndrome, without evidence of myelodysplasia or lymphoproliferative infiltration. Myelosuppression is a major side effect of ganciclovir. However, the antiviral effects far outweigh these risks and therefore ganciclovir and its oral prodrug valganciclovir should be considered for patients with pancytopenia secondary to CMV reactivation.
In summary, this unique case of triple-viremia induced haemorrhagic cystitis in an immunosuppressed CLL patient posed both a diagnostic and therapeutic challenge as treatments are nephrotoxic and further increase immunosuppression.
The major learning point is to exercise caution when prescribing FCR chemotherapy on its long-term immunosuppressive effects. It is expected that novel immuno-chemotherapy for CLL should control the disease with reduced immunosuppressive effects.16
Patient’s perspective
Translation from French
I was diagnosed with CLL in November 2015. Started the treatments with FCR protocol in April 2019 (six treatments of three consecutive days each). At the end of the fourth treatment, I was not well. I had fever and a large fatigue with no energy. I finished treatments on the 13th of November 2019. On the week of 18 November, the symptoms appeared: fever, incontinent of urine with blood, no appetite, fatigue.
I visited MUHC emergency, 12 hours wait before I had a doctor’s room. I stayed the night and the next day I saw the doctor, but they did not know what I had. On the 22nd of November I returned to emergency with a lot of fever and other symptoms. I passed the night in an emergency room. On Saturday they released me, had fever and falls.
On the 24th I returned to emergency, fever and incontinence, etc. I was placed in the corridor in a stretcher with a commode next to the whole world. There was nowhere else for me, I had to go through the doors to go to the public toilet and I urinated every 5 min. I stayed in emergency 5 days before I was admitted to Internal Medicine.
It was a bad experience the three times I was in emergency. On 29 November, I had my own room. I was there till 07 February 2020.
The staff took charge rapidly. There were many tests during this long period to find out the cause of my problems. Everything came from the chemotherapy. Many departments were involved: urology, otolaryngology, haematology, internal medicine, infectious diseases.
There were several healthcare workers who spoke on behalf of other departments.
Very good service with the nursing staffs and the préposé (aux bénéficiaires). On my part, my immune system was severely damaged.
Learning points
Infections in immunosuppressed patients remain a diagnostic and therapeutic challenge.
In patient treated for chronic lymphocytic leukaemia, haematuria can be related to viral infections like BK virus, adenovirus and cytomegalovirus (CMV).
BK infection is diagnosed with a high index of suspicion, however, combined CMV and adenovirus infections renders the diagnosis more difficult.
Treatment of these viral infections remains difficult as medications are associated with myelotoxicity (ganciclovir) and renal insufficiency (cidofovir).
The authors would like to thank Dr Malek Merdad and Dr Isabelle Malhamé for their inspiration to write this article.
Contributors: MK and J-PR devised the project, main conceptual ideas and proof outlines. MK took the lead in writing the manuscript the supervision of J-PR. MK created all the images and translated the patient’s perspective from French to English. J-PR and JL provided critical feedback and helped shape analysis and manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | CIDOFOVIR, CYCLOPHOSPHAMIDE, FILGRASTIM, FLUDARABINE PHOSPHATE, HUMAN IMMUNOGLOBULIN G, PROBENECID, RITUXIMAB, SODIUM CHLORIDE, SULFAMETHOXAZOLE\TRIMETHOPRIM, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33402369 | 19,066,566 | 2021-01-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Polyomavirus viraemia'. | Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
Background
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder associated with mature B-cell dysfunction, hypogammaglobulinaemia and T-cell abnormalities. In Europe and North America, CLL is the most common leukaemia, with median age of diagnosis of 70 years.1 Treatment is indicated only for symptomatic disease, such as anaemia <100 g/L and/or thrombocytopenia <100×109/L, massive splenomegaly, lymphadenopathy or constitutional symptoms.2
Infection is a frequent cause of morbidity and mortality in CLL. Roughly 30%–50% of all CLL patients suffer infections, with a high subsequent mortality rate.3 While the majority of infections affect more often the respiratory track, or skin and the gastrointestinal tract.4 The most frequent organisms causing infections are bacteria like Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. This increased susceptibility to infection stems from B-cells with impaired immunoglobulin production capability and dysfunctional T-helper cells, which also assist in antibody production. This impaired capability to produce immunoglobulins, termed hypogammaglobulinaemia, affects 85% of CLL patients, particularly in advanced disease.4
Antineoplastic agents recommended for the treatment of CLL are also immunosuppressive and further increase the risk of infections.5 These include opportunistic micro-organisms such as Candida, Pneumocystis jirovecii, listeria, nocardia and atypical mycobacteria. In addition, patients have increased risk of viral diseases such as herpes simplex, Epstein-Barr and cytomegalovirus (CMV). Additional infectious complications may include hepatitis B reactivation and progressive multifocal leucoencephalopathy. In spite of the immunosuppressive risk, chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the standard risk therapy in fit patients below 65 years of age with CLL, in absence of 17 p deletion, or TP53 mutation, and with immunoglobulin heavy chain V (IGHV)-mutated.6
To reduce risk of infection, immunoglobulin levels should also be routinely monitored, particularly with rituximab, which reduces the number of B-cells expressing CD20. It is postulated that monitoring immunoglobulins while being treated with rituximab may reduce the risk of serious infections.4
Herein, we present a unique case of a woman treated for CLL who experienced severe pancytopenia and immunosuppression at the completion of her chemo-immunotherapy. She subsequently experienced triple concurrent viral infections, which posed a therapeutic challenge due to her pancytopenia.
Case presentation
A previously healthy 58-year-old woman was diagnosed with CLL through a routine blood test in 2015. Her physical examination was unremarkable and her lymphocyte counts were at 12.36×109 cells/L. Bone marrow biopsy with immunohistochemistry was suggestive of CLL and stained positive for BCL2, CD5 (aberrant T-cell marker), CD20, CD23, CD43 and CD79a (B-cell markers) while BCL6 was negative. The PCR amplification study showed immunoglobulin heavy chain gene rearrangement along with IgG kappa light chain gene arrangement. No t(14;18) BCL2/JH or t(11;14) BCL1/JH gene rearrangements were observed. As she was asymptomatic, and positron emission tomography (PET) scan showed low grade metabolic activity in lymph nodes in cervical, axillary and iliac areas, no therapy was initiated (figure 1). She was followed every 6 months.
Figure 1 Positron emission tomography scan (right) and corresponding CT images (left) of multiple low-grade hypermetabolic lymph nodes in 2017, 2 years after diagnosis of chronic lymphocytic leukaemia. (A) Multiple small low-grade hypermetabolic lymph nodes in bilateral neck regions predominantly in the posterior triangles. SUV of 1.9 in the left and right upper posterior triangles. (B) Hypermetabolic lymph nodes in the left axillary regions, SUV 1.8. (C) Left external iliac lymph node SUV of 3. SUV, Standardized uptake value.
In November 2017 the patient had symptom of a rapid bilateral enlargement of the cervical lymph nodes accompanied by persistent fatigue, night sweats and decreased weight. Lyme disease, HIV, hepatitis B and C and syphilis serologies were performed, and all tests yielded negative results. Repeat PET/CT scan, cytogenetics and bone marrow biopsy demonstrated no evidence of Richter’s transformation into a diffuse large cell lymphoma. Due to significant bulky disease and enlarged adenopathy with B constitutional symptoms, chemo-immunotherapy with FCR was considered. This was furthermore rationalised as she was a fit patient younger than 65 years of age with standard risk for CLL due to the absence of 17 p deletion, or TP53 mutation, and with IGHV being mutated.7
She received six cycles of FCR which was completed uneventfully on 11 November 2019. During FCR therapy, she received oral valacyclovir 500 mg two times per day for herpes prophylaxis as well as Septra DS (160 mg trimethoprim and 800 mg sulfamethoxazole) one tablet Mondays, Wednesdays and Fridays for P. jirovecii prophylaxis. On 18 November, she presented to the emergency room of the McGill University Health Centre (MUHC) with haematuria, suprapubic pain and fever. She was admitted and treated for a urine infection and slowly improved after different antibiotics such as ciprofloxacin, trimethoprim-sulfamethoxazole and ceftriaxone and blood and urinary bacterial cultures were negative. A CT urogram showed moderate bilateral hydroureteronephrosis with diffuse urolithelial and bladder thickening (figure 2). As a whole, these findings were suggestive of an inflammatory or infectious process evoking pyleoureteritis and cystitis.
Figure 2 CT urogram on admission in November 2019, demonstrating (A) poorly distended bladder and marked thickening of bladder walls (green arrow) and (B) moderate dilation of both ureters and collection ducts with marked thickening and enhancement of the urothelium associated with moderate periureteric fat stranding.
Investigations
On admission, she was mildly pancytopenic (table 1). As the patient partially improved and had negative urine cultures, a cyclophosphamide-induced haemorrhagic cystitis was considered, and she was placed on continuous bladder irrigation.
Table 1 Summary of the patient’s serological and microbiological test results during the course of her neutropenia and triple viremia
Laboratory results Reference ranges 20 March 2019 11 November 2019 26 November 2019 25 December 2019 01 January 2020 23 January 2020 01 February 2020 07 February 2020 03 March 2020
Time of intervention First dose FCR Last dose FCR Meropenem started Virology investigated Begins cidofovir+GCSF Cidofovir changed to Ganciclovir Ganciclovir transitioned to valganciclovir Discharge Follow-up
WBC (109/L) 4.0–10.0 30.90 5.90 3.00 1.00 0.60 2.40 6.10 2.40 2.00
Neutrophils 2.0–7.0 3.75 4.18 2.46 0.80 0.36 1.19 5.09 1.73 1.35
Lymphocytes 1.5–4.5 26.26 0.87 0.23 0.08 0.11 0.23 0.46 0.33 0.44
Plt (109/L) 150–450 145 158 123 48 19 54 17 12 39
Hb (g/L) 120–150 142 129 99 63 80 70 70 71 99
Creatinine (umol/L) 50–90 71 68 125 128 118 75 74 69 75
CMV (copies/mL) – – – – 7320 3170 1291 153 149 0
Adenovirus (copies/mL) – – – – – 7.44 log10 4.86 log10 3.74 log10 – 3.30 log10
BK virus urine (copies/mL) – – – – – 2.26×107 – 3.20×108 –
BK virus blood (copies/mL) – – – – – – – – – 3.91×103
CMV, cytomegalovirus; FCR, fludarabine, cyclophosphamide and rituximab; Hb, haemoglobin; Plt, platelet; WBC, white blood cell.
On 1 December 2019 she developed a pancytopenia that required platelet and packed red blood cell transfusions. She remained persistently febrile despite repeated negative bacterial blood and urine cultures. Due to her CLL, pancytopenia and the consideration of immunosuppression induced by FCR chemotherapy, viral infections were investigated. PCR for adenovirus showed 22.4 copies/mL in blood, and positive in urine; PCR for polyoma virus showed 8.81 million copies/mL blood; and PCR for CMV showed 358 copies/mL in blood, confirming viral invasive infections (figure 3). To further investigate her pancytopenia, serology for parvovirus B 19 was carried out and was negative for IgM.
Figure 3 Cytomegalovirus (CMV) and BK viremia (A) and adeno-viremia (B) over the course of treatment.
On 18 December 2019 the patient underwent a double J-stent insertion for bilateral hydronephrosis. Pelvic pain persisted and she continued to pass clots in her urine. Repeat CMV PCR testing on 25 December 2019 showed 7320 copies/mL while an ophthalmological assessment revealed no evidence of CMV retinitis or keratitis. Bone marrow biopsy results showed pancytopenia without transformation (figure 4).
Figure 4 Histology and immunochemistry of bone marrow smear (A) and biopsy (B). Bone marrow biopsy demonstrating hypocellularity. Moderate left shift of the myeloid series and mild left shift of the erythroid series. No lymphocytosis or lymphoma, no definite diagnosis of myelodysplastic syndrome (B).
Treatment
On 1 January 2020, cidofovir was administered to treat the three viral infections of BK polyomavirus, adenovirus and CMV. Cidofovir was given at the dose of 1 mg/kg intravenously three times a week instead of a weekly dose given her kidney injury and high creatinine levels. She received probenecid 2 g orally 1 hour before cidofovir, then 2 hours and 8 hours after the end of infusion to increase cidofovir levels in the blood. For renal protection, she was hydrated with 1 L of 0.9% normal saline during cidofovir infusion. Filgrastim (G-CSF) was initiated for her neutropenia, darbepoetin for her anaemia, and intravenous IgG was infused three times at 4-week intervals for her hypogammaglobulinumia.
Neutropenia worsen despite filgrastim, and CMV viral load continued to increase. Due to cidofovir myelotoxicity, a decision was made to focus treatment on CMV infection, while ignoring the BK and adenovirus. To this end, the patient was changed to ganciclovir 250 mg intravenous two times per day on 23 January 2020 and her urinary symptoms improved for the first time. On 1 February 2020, she was transitioned to oral valganciclovir 450 mg daily and was discharged to home 1 week later, after 101 days in hospital.
Outcome and follow-up
A bone marrow biopsy on 27 January 2020 showed a hypocellular marrow with focal area up to 20%–30% haematopoietic tissue. No evidence of lymphocytosis or lymphoma and no dysplastic changes in morphology were observed. Immunohistochemistry showed <5% CD117, and was negative for CD20, CD34 and PAX5. The histological appearance represented haematopoietic regeneration post-chemotherapy. On 3 March 2020 follow-up, CMV load was undetectable, adenovirus load was 5000 copies/mL, BK load was 3.2×108 copies/mL (table 1). She was switched on CMV prophylaxis with resolved haemorrhagic cystitis and received valganciclovir 450 mg p.o. daily for another 3 months and until her absolute lymphocyte count recovers above 109 cells/L. She continued trimethoprim-sulfamethaxole prophylaxis for 6 months post-chemotherapy. Her double-J stents remain in place. While clinically improved, her neutropenia improved on low dose filgrastim until 4 April 2020. Her blood counts normalised 1 month after and she is followed as an outpatient with Haematology, Infectious Diseases, and Urology services at the MUHC.
Discussion
FCR chemo-immunotherapy is considered the treatment for standard risk CLL patients under the age of 65,7 with a high overall response rate. However, the predominant complication is myelosuppression.8 Persistent neutropenia was reported in 19% and late infections in 9% of patients.9 The frequency of cytopenias was 35% at 3 months and 12% at 9 months after completion of therapy, respectively. Another side effect is prolonged lymphoid immunodeficiency.
Human adenovirus infections usually present as a keratoconjunctivitis or respiratory tract infection. In most healthy individuals the infection is usually self-limited. However, in immunosuppressed patients, infection may disseminate and become potentially life-threatening. Disseminated adenovirus infection can result from either de novo infection or a reactivation of clinically silent infection.10
BK virus is a member of the polyomavirus family. BK virus reactivation occurs only in immunosuppressed patients and can lead to nephropathy, ureteral stenosis, tubular interstitial damage and haemorrhagic cystitis. Viremia occurs in 20%–60% of this population. There is no specific treatment for BK virus-associated nephropathy, therefore viral replication can only be controlled through modulating the immunosuppressive condition.11
CMV is a herpes virus with a large double-stranded DNA that remains latent in the host after primary infection. Immunocompromised patients can have reactivation of their latent infection. Diagnosis of viral reactivation is made through CMV PCR in blood, tissue or body fluid. Manifestations of CMV infection occur most often in the gastrointestinal tract, lungs, liver and retina.12 As we did not observe the typical owl’s eye tissue lesion in the second bone marrow biopsy, we considered that CMV reactivation was a contributing factor for the pancytopenia, and treatment may have prevented such tissue lesion to develop. First line treatment of CMV infection includes intravenous ganciclovir or its oral prodrug valganciclovir, which are DNA polymerase inhibitors. The major side effect of these drugs is myelosuppression, including neutropenia.4
In our patient, the prolonged pancytopenias secondary to FCR was associated with haematuria with an ureteral mass. To date, only two observations on the use of cidofovir to simultaneously treat BK-virus associated haemorrhagic cystitis and CMV reactivation have been reported. However, in the case report by Held et al, the patient had received a bone marrow transplant for chronic myeloid leukaemia, whereas our patient had CLL.
Cidofovir has been suggested in some cases for the treatment of BK virus-associated haemorrhagic cystitis.13 Cidofovir and foscarnet are second-line therapies in patients with CMV that are either resistant or refractory to ganciclovir. Cidofovir is a non-cyclic analogue of cytidine monophosphate that terminates CMV DNA synthesis. In vitro studies showed effectiveness against herpes viruses, including CMV, herpes simplex viruses 1 and 2, varicella-zoster, Epstein-Barr virus, human papillomavirus and adenovirus. The main adverse effect is nephrotoxicity, causing proximal tubular injury. Serum creatinine and urine protein measurements are recommended during administration.14 Probenecid decreases intratubular secretion and maintains a sufficient plasma concentration to allow for once weekly dosing at 5 mg/kg to reduce its nephrotoxicity.13 An alternate dosing regimen, initially used in our patient, was three times per week dosing at 3 mg/kg. In the study performed by Philippe et al, intravenous cidofovir achieve remission in 81.5% of the 22 patients.13
The patient reported by Held et al recovered fully with cidofovir15; however, our patient was switched to ganciclovir due to persistent neutropenia. Bone marrow biopsy was consistent with secondary treatment-related myelosuppression syndrome, without evidence of myelodysplasia or lymphoproliferative infiltration. Myelosuppression is a major side effect of ganciclovir. However, the antiviral effects far outweigh these risks and therefore ganciclovir and its oral prodrug valganciclovir should be considered for patients with pancytopenia secondary to CMV reactivation.
In summary, this unique case of triple-viremia induced haemorrhagic cystitis in an immunosuppressed CLL patient posed both a diagnostic and therapeutic challenge as treatments are nephrotoxic and further increase immunosuppression.
The major learning point is to exercise caution when prescribing FCR chemotherapy on its long-term immunosuppressive effects. It is expected that novel immuno-chemotherapy for CLL should control the disease with reduced immunosuppressive effects.16
Patient’s perspective
Translation from French
I was diagnosed with CLL in November 2015. Started the treatments with FCR protocol in April 2019 (six treatments of three consecutive days each). At the end of the fourth treatment, I was not well. I had fever and a large fatigue with no energy. I finished treatments on the 13th of November 2019. On the week of 18 November, the symptoms appeared: fever, incontinent of urine with blood, no appetite, fatigue.
I visited MUHC emergency, 12 hours wait before I had a doctor’s room. I stayed the night and the next day I saw the doctor, but they did not know what I had. On the 22nd of November I returned to emergency with a lot of fever and other symptoms. I passed the night in an emergency room. On Saturday they released me, had fever and falls.
On the 24th I returned to emergency, fever and incontinence, etc. I was placed in the corridor in a stretcher with a commode next to the whole world. There was nowhere else for me, I had to go through the doors to go to the public toilet and I urinated every 5 min. I stayed in emergency 5 days before I was admitted to Internal Medicine.
It was a bad experience the three times I was in emergency. On 29 November, I had my own room. I was there till 07 February 2020.
The staff took charge rapidly. There were many tests during this long period to find out the cause of my problems. Everything came from the chemotherapy. Many departments were involved: urology, otolaryngology, haematology, internal medicine, infectious diseases.
There were several healthcare workers who spoke on behalf of other departments.
Very good service with the nursing staffs and the préposé (aux bénéficiaires). On my part, my immune system was severely damaged.
Learning points
Infections in immunosuppressed patients remain a diagnostic and therapeutic challenge.
In patient treated for chronic lymphocytic leukaemia, haematuria can be related to viral infections like BK virus, adenovirus and cytomegalovirus (CMV).
BK infection is diagnosed with a high index of suspicion, however, combined CMV and adenovirus infections renders the diagnosis more difficult.
Treatment of these viral infections remains difficult as medications are associated with myelotoxicity (ganciclovir) and renal insufficiency (cidofovir).
The authors would like to thank Dr Malek Merdad and Dr Isabelle Malhamé for their inspiration to write this article.
Contributors: MK and J-PR devised the project, main conceptual ideas and proof outlines. MK took the lead in writing the manuscript the supervision of J-PR. MK created all the images and translated the patient’s perspective from French to English. J-PR and JL provided critical feedback and helped shape analysis and manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | CIDOFOVIR, CYCLOPHOSPHAMIDE, FILGRASTIM, FLUDARABINE PHOSPHATE, HUMAN IMMUNOGLOBULIN G, PROBENECID, RITUXIMAB, SODIUM CHLORIDE, SULFAMETHOXAZOLE\TRIMETHOPRIM, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33402369 | 19,066,566 | 2021-01-05 |
What was the administration route of drug 'GANCICLOVIR'? | Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
Background
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder associated with mature B-cell dysfunction, hypogammaglobulinaemia and T-cell abnormalities. In Europe and North America, CLL is the most common leukaemia, with median age of diagnosis of 70 years.1 Treatment is indicated only for symptomatic disease, such as anaemia <100 g/L and/or thrombocytopenia <100×109/L, massive splenomegaly, lymphadenopathy or constitutional symptoms.2
Infection is a frequent cause of morbidity and mortality in CLL. Roughly 30%–50% of all CLL patients suffer infections, with a high subsequent mortality rate.3 While the majority of infections affect more often the respiratory track, or skin and the gastrointestinal tract.4 The most frequent organisms causing infections are bacteria like Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. This increased susceptibility to infection stems from B-cells with impaired immunoglobulin production capability and dysfunctional T-helper cells, which also assist in antibody production. This impaired capability to produce immunoglobulins, termed hypogammaglobulinaemia, affects 85% of CLL patients, particularly in advanced disease.4
Antineoplastic agents recommended for the treatment of CLL are also immunosuppressive and further increase the risk of infections.5 These include opportunistic micro-organisms such as Candida, Pneumocystis jirovecii, listeria, nocardia and atypical mycobacteria. In addition, patients have increased risk of viral diseases such as herpes simplex, Epstein-Barr and cytomegalovirus (CMV). Additional infectious complications may include hepatitis B reactivation and progressive multifocal leucoencephalopathy. In spite of the immunosuppressive risk, chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the standard risk therapy in fit patients below 65 years of age with CLL, in absence of 17 p deletion, or TP53 mutation, and with immunoglobulin heavy chain V (IGHV)-mutated.6
To reduce risk of infection, immunoglobulin levels should also be routinely monitored, particularly with rituximab, which reduces the number of B-cells expressing CD20. It is postulated that monitoring immunoglobulins while being treated with rituximab may reduce the risk of serious infections.4
Herein, we present a unique case of a woman treated for CLL who experienced severe pancytopenia and immunosuppression at the completion of her chemo-immunotherapy. She subsequently experienced triple concurrent viral infections, which posed a therapeutic challenge due to her pancytopenia.
Case presentation
A previously healthy 58-year-old woman was diagnosed with CLL through a routine blood test in 2015. Her physical examination was unremarkable and her lymphocyte counts were at 12.36×109 cells/L. Bone marrow biopsy with immunohistochemistry was suggestive of CLL and stained positive for BCL2, CD5 (aberrant T-cell marker), CD20, CD23, CD43 and CD79a (B-cell markers) while BCL6 was negative. The PCR amplification study showed immunoglobulin heavy chain gene rearrangement along with IgG kappa light chain gene arrangement. No t(14;18) BCL2/JH or t(11;14) BCL1/JH gene rearrangements were observed. As she was asymptomatic, and positron emission tomography (PET) scan showed low grade metabolic activity in lymph nodes in cervical, axillary and iliac areas, no therapy was initiated (figure 1). She was followed every 6 months.
Figure 1 Positron emission tomography scan (right) and corresponding CT images (left) of multiple low-grade hypermetabolic lymph nodes in 2017, 2 years after diagnosis of chronic lymphocytic leukaemia. (A) Multiple small low-grade hypermetabolic lymph nodes in bilateral neck regions predominantly in the posterior triangles. SUV of 1.9 in the left and right upper posterior triangles. (B) Hypermetabolic lymph nodes in the left axillary regions, SUV 1.8. (C) Left external iliac lymph node SUV of 3. SUV, Standardized uptake value.
In November 2017 the patient had symptom of a rapid bilateral enlargement of the cervical lymph nodes accompanied by persistent fatigue, night sweats and decreased weight. Lyme disease, HIV, hepatitis B and C and syphilis serologies were performed, and all tests yielded negative results. Repeat PET/CT scan, cytogenetics and bone marrow biopsy demonstrated no evidence of Richter’s transformation into a diffuse large cell lymphoma. Due to significant bulky disease and enlarged adenopathy with B constitutional symptoms, chemo-immunotherapy with FCR was considered. This was furthermore rationalised as she was a fit patient younger than 65 years of age with standard risk for CLL due to the absence of 17 p deletion, or TP53 mutation, and with IGHV being mutated.7
She received six cycles of FCR which was completed uneventfully on 11 November 2019. During FCR therapy, she received oral valacyclovir 500 mg two times per day for herpes prophylaxis as well as Septra DS (160 mg trimethoprim and 800 mg sulfamethoxazole) one tablet Mondays, Wednesdays and Fridays for P. jirovecii prophylaxis. On 18 November, she presented to the emergency room of the McGill University Health Centre (MUHC) with haematuria, suprapubic pain and fever. She was admitted and treated for a urine infection and slowly improved after different antibiotics such as ciprofloxacin, trimethoprim-sulfamethoxazole and ceftriaxone and blood and urinary bacterial cultures were negative. A CT urogram showed moderate bilateral hydroureteronephrosis with diffuse urolithelial and bladder thickening (figure 2). As a whole, these findings were suggestive of an inflammatory or infectious process evoking pyleoureteritis and cystitis.
Figure 2 CT urogram on admission in November 2019, demonstrating (A) poorly distended bladder and marked thickening of bladder walls (green arrow) and (B) moderate dilation of both ureters and collection ducts with marked thickening and enhancement of the urothelium associated with moderate periureteric fat stranding.
Investigations
On admission, she was mildly pancytopenic (table 1). As the patient partially improved and had negative urine cultures, a cyclophosphamide-induced haemorrhagic cystitis was considered, and she was placed on continuous bladder irrigation.
Table 1 Summary of the patient’s serological and microbiological test results during the course of her neutropenia and triple viremia
Laboratory results Reference ranges 20 March 2019 11 November 2019 26 November 2019 25 December 2019 01 January 2020 23 January 2020 01 February 2020 07 February 2020 03 March 2020
Time of intervention First dose FCR Last dose FCR Meropenem started Virology investigated Begins cidofovir+GCSF Cidofovir changed to Ganciclovir Ganciclovir transitioned to valganciclovir Discharge Follow-up
WBC (109/L) 4.0–10.0 30.90 5.90 3.00 1.00 0.60 2.40 6.10 2.40 2.00
Neutrophils 2.0–7.0 3.75 4.18 2.46 0.80 0.36 1.19 5.09 1.73 1.35
Lymphocytes 1.5–4.5 26.26 0.87 0.23 0.08 0.11 0.23 0.46 0.33 0.44
Plt (109/L) 150–450 145 158 123 48 19 54 17 12 39
Hb (g/L) 120–150 142 129 99 63 80 70 70 71 99
Creatinine (umol/L) 50–90 71 68 125 128 118 75 74 69 75
CMV (copies/mL) – – – – 7320 3170 1291 153 149 0
Adenovirus (copies/mL) – – – – – 7.44 log10 4.86 log10 3.74 log10 – 3.30 log10
BK virus urine (copies/mL) – – – – – 2.26×107 – 3.20×108 –
BK virus blood (copies/mL) – – – – – – – – – 3.91×103
CMV, cytomegalovirus; FCR, fludarabine, cyclophosphamide and rituximab; Hb, haemoglobin; Plt, platelet; WBC, white blood cell.
On 1 December 2019 she developed a pancytopenia that required platelet and packed red blood cell transfusions. She remained persistently febrile despite repeated negative bacterial blood and urine cultures. Due to her CLL, pancytopenia and the consideration of immunosuppression induced by FCR chemotherapy, viral infections were investigated. PCR for adenovirus showed 22.4 copies/mL in blood, and positive in urine; PCR for polyoma virus showed 8.81 million copies/mL blood; and PCR for CMV showed 358 copies/mL in blood, confirming viral invasive infections (figure 3). To further investigate her pancytopenia, serology for parvovirus B 19 was carried out and was negative for IgM.
Figure 3 Cytomegalovirus (CMV) and BK viremia (A) and adeno-viremia (B) over the course of treatment.
On 18 December 2019 the patient underwent a double J-stent insertion for bilateral hydronephrosis. Pelvic pain persisted and she continued to pass clots in her urine. Repeat CMV PCR testing on 25 December 2019 showed 7320 copies/mL while an ophthalmological assessment revealed no evidence of CMV retinitis or keratitis. Bone marrow biopsy results showed pancytopenia without transformation (figure 4).
Figure 4 Histology and immunochemistry of bone marrow smear (A) and biopsy (B). Bone marrow biopsy demonstrating hypocellularity. Moderate left shift of the myeloid series and mild left shift of the erythroid series. No lymphocytosis or lymphoma, no definite diagnosis of myelodysplastic syndrome (B).
Treatment
On 1 January 2020, cidofovir was administered to treat the three viral infections of BK polyomavirus, adenovirus and CMV. Cidofovir was given at the dose of 1 mg/kg intravenously three times a week instead of a weekly dose given her kidney injury and high creatinine levels. She received probenecid 2 g orally 1 hour before cidofovir, then 2 hours and 8 hours after the end of infusion to increase cidofovir levels in the blood. For renal protection, she was hydrated with 1 L of 0.9% normal saline during cidofovir infusion. Filgrastim (G-CSF) was initiated for her neutropenia, darbepoetin for her anaemia, and intravenous IgG was infused three times at 4-week intervals for her hypogammaglobulinumia.
Neutropenia worsen despite filgrastim, and CMV viral load continued to increase. Due to cidofovir myelotoxicity, a decision was made to focus treatment on CMV infection, while ignoring the BK and adenovirus. To this end, the patient was changed to ganciclovir 250 mg intravenous two times per day on 23 January 2020 and her urinary symptoms improved for the first time. On 1 February 2020, she was transitioned to oral valganciclovir 450 mg daily and was discharged to home 1 week later, after 101 days in hospital.
Outcome and follow-up
A bone marrow biopsy on 27 January 2020 showed a hypocellular marrow with focal area up to 20%–30% haematopoietic tissue. No evidence of lymphocytosis or lymphoma and no dysplastic changes in morphology were observed. Immunohistochemistry showed <5% CD117, and was negative for CD20, CD34 and PAX5. The histological appearance represented haematopoietic regeneration post-chemotherapy. On 3 March 2020 follow-up, CMV load was undetectable, adenovirus load was 5000 copies/mL, BK load was 3.2×108 copies/mL (table 1). She was switched on CMV prophylaxis with resolved haemorrhagic cystitis and received valganciclovir 450 mg p.o. daily for another 3 months and until her absolute lymphocyte count recovers above 109 cells/L. She continued trimethoprim-sulfamethaxole prophylaxis for 6 months post-chemotherapy. Her double-J stents remain in place. While clinically improved, her neutropenia improved on low dose filgrastim until 4 April 2020. Her blood counts normalised 1 month after and she is followed as an outpatient with Haematology, Infectious Diseases, and Urology services at the MUHC.
Discussion
FCR chemo-immunotherapy is considered the treatment for standard risk CLL patients under the age of 65,7 with a high overall response rate. However, the predominant complication is myelosuppression.8 Persistent neutropenia was reported in 19% and late infections in 9% of patients.9 The frequency of cytopenias was 35% at 3 months and 12% at 9 months after completion of therapy, respectively. Another side effect is prolonged lymphoid immunodeficiency.
Human adenovirus infections usually present as a keratoconjunctivitis or respiratory tract infection. In most healthy individuals the infection is usually self-limited. However, in immunosuppressed patients, infection may disseminate and become potentially life-threatening. Disseminated adenovirus infection can result from either de novo infection or a reactivation of clinically silent infection.10
BK virus is a member of the polyomavirus family. BK virus reactivation occurs only in immunosuppressed patients and can lead to nephropathy, ureteral stenosis, tubular interstitial damage and haemorrhagic cystitis. Viremia occurs in 20%–60% of this population. There is no specific treatment for BK virus-associated nephropathy, therefore viral replication can only be controlled through modulating the immunosuppressive condition.11
CMV is a herpes virus with a large double-stranded DNA that remains latent in the host after primary infection. Immunocompromised patients can have reactivation of their latent infection. Diagnosis of viral reactivation is made through CMV PCR in blood, tissue or body fluid. Manifestations of CMV infection occur most often in the gastrointestinal tract, lungs, liver and retina.12 As we did not observe the typical owl’s eye tissue lesion in the second bone marrow biopsy, we considered that CMV reactivation was a contributing factor for the pancytopenia, and treatment may have prevented such tissue lesion to develop. First line treatment of CMV infection includes intravenous ganciclovir or its oral prodrug valganciclovir, which are DNA polymerase inhibitors. The major side effect of these drugs is myelosuppression, including neutropenia.4
In our patient, the prolonged pancytopenias secondary to FCR was associated with haematuria with an ureteral mass. To date, only two observations on the use of cidofovir to simultaneously treat BK-virus associated haemorrhagic cystitis and CMV reactivation have been reported. However, in the case report by Held et al, the patient had received a bone marrow transplant for chronic myeloid leukaemia, whereas our patient had CLL.
Cidofovir has been suggested in some cases for the treatment of BK virus-associated haemorrhagic cystitis.13 Cidofovir and foscarnet are second-line therapies in patients with CMV that are either resistant or refractory to ganciclovir. Cidofovir is a non-cyclic analogue of cytidine monophosphate that terminates CMV DNA synthesis. In vitro studies showed effectiveness against herpes viruses, including CMV, herpes simplex viruses 1 and 2, varicella-zoster, Epstein-Barr virus, human papillomavirus and adenovirus. The main adverse effect is nephrotoxicity, causing proximal tubular injury. Serum creatinine and urine protein measurements are recommended during administration.14 Probenecid decreases intratubular secretion and maintains a sufficient plasma concentration to allow for once weekly dosing at 5 mg/kg to reduce its nephrotoxicity.13 An alternate dosing regimen, initially used in our patient, was three times per week dosing at 3 mg/kg. In the study performed by Philippe et al, intravenous cidofovir achieve remission in 81.5% of the 22 patients.13
The patient reported by Held et al recovered fully with cidofovir15; however, our patient was switched to ganciclovir due to persistent neutropenia. Bone marrow biopsy was consistent with secondary treatment-related myelosuppression syndrome, without evidence of myelodysplasia or lymphoproliferative infiltration. Myelosuppression is a major side effect of ganciclovir. However, the antiviral effects far outweigh these risks and therefore ganciclovir and its oral prodrug valganciclovir should be considered for patients with pancytopenia secondary to CMV reactivation.
In summary, this unique case of triple-viremia induced haemorrhagic cystitis in an immunosuppressed CLL patient posed both a diagnostic and therapeutic challenge as treatments are nephrotoxic and further increase immunosuppression.
The major learning point is to exercise caution when prescribing FCR chemotherapy on its long-term immunosuppressive effects. It is expected that novel immuno-chemotherapy for CLL should control the disease with reduced immunosuppressive effects.16
Patient’s perspective
Translation from French
I was diagnosed with CLL in November 2015. Started the treatments with FCR protocol in April 2019 (six treatments of three consecutive days each). At the end of the fourth treatment, I was not well. I had fever and a large fatigue with no energy. I finished treatments on the 13th of November 2019. On the week of 18 November, the symptoms appeared: fever, incontinent of urine with blood, no appetite, fatigue.
I visited MUHC emergency, 12 hours wait before I had a doctor’s room. I stayed the night and the next day I saw the doctor, but they did not know what I had. On the 22nd of November I returned to emergency with a lot of fever and other symptoms. I passed the night in an emergency room. On Saturday they released me, had fever and falls.
On the 24th I returned to emergency, fever and incontinence, etc. I was placed in the corridor in a stretcher with a commode next to the whole world. There was nowhere else for me, I had to go through the doors to go to the public toilet and I urinated every 5 min. I stayed in emergency 5 days before I was admitted to Internal Medicine.
It was a bad experience the three times I was in emergency. On 29 November, I had my own room. I was there till 07 February 2020.
The staff took charge rapidly. There were many tests during this long period to find out the cause of my problems. Everything came from the chemotherapy. Many departments were involved: urology, otolaryngology, haematology, internal medicine, infectious diseases.
There were several healthcare workers who spoke on behalf of other departments.
Very good service with the nursing staffs and the préposé (aux bénéficiaires). On my part, my immune system was severely damaged.
Learning points
Infections in immunosuppressed patients remain a diagnostic and therapeutic challenge.
In patient treated for chronic lymphocytic leukaemia, haematuria can be related to viral infections like BK virus, adenovirus and cytomegalovirus (CMV).
BK infection is diagnosed with a high index of suspicion, however, combined CMV and adenovirus infections renders the diagnosis more difficult.
Treatment of these viral infections remains difficult as medications are associated with myelotoxicity (ganciclovir) and renal insufficiency (cidofovir).
The authors would like to thank Dr Malek Merdad and Dr Isabelle Malhamé for their inspiration to write this article.
Contributors: MK and J-PR devised the project, main conceptual ideas and proof outlines. MK took the lead in writing the manuscript the supervision of J-PR. MK created all the images and translated the patient’s perspective from French to English. J-PR and JL provided critical feedback and helped shape analysis and manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33402369 | 18,752,790 | 2021-01-05 |
What was the administration route of drug 'HUMAN IMMUNOGLOBULIN G'? | Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
Background
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder associated with mature B-cell dysfunction, hypogammaglobulinaemia and T-cell abnormalities. In Europe and North America, CLL is the most common leukaemia, with median age of diagnosis of 70 years.1 Treatment is indicated only for symptomatic disease, such as anaemia <100 g/L and/or thrombocytopenia <100×109/L, massive splenomegaly, lymphadenopathy or constitutional symptoms.2
Infection is a frequent cause of morbidity and mortality in CLL. Roughly 30%–50% of all CLL patients suffer infections, with a high subsequent mortality rate.3 While the majority of infections affect more often the respiratory track, or skin and the gastrointestinal tract.4 The most frequent organisms causing infections are bacteria like Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. This increased susceptibility to infection stems from B-cells with impaired immunoglobulin production capability and dysfunctional T-helper cells, which also assist in antibody production. This impaired capability to produce immunoglobulins, termed hypogammaglobulinaemia, affects 85% of CLL patients, particularly in advanced disease.4
Antineoplastic agents recommended for the treatment of CLL are also immunosuppressive and further increase the risk of infections.5 These include opportunistic micro-organisms such as Candida, Pneumocystis jirovecii, listeria, nocardia and atypical mycobacteria. In addition, patients have increased risk of viral diseases such as herpes simplex, Epstein-Barr and cytomegalovirus (CMV). Additional infectious complications may include hepatitis B reactivation and progressive multifocal leucoencephalopathy. In spite of the immunosuppressive risk, chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the standard risk therapy in fit patients below 65 years of age with CLL, in absence of 17 p deletion, or TP53 mutation, and with immunoglobulin heavy chain V (IGHV)-mutated.6
To reduce risk of infection, immunoglobulin levels should also be routinely monitored, particularly with rituximab, which reduces the number of B-cells expressing CD20. It is postulated that monitoring immunoglobulins while being treated with rituximab may reduce the risk of serious infections.4
Herein, we present a unique case of a woman treated for CLL who experienced severe pancytopenia and immunosuppression at the completion of her chemo-immunotherapy. She subsequently experienced triple concurrent viral infections, which posed a therapeutic challenge due to her pancytopenia.
Case presentation
A previously healthy 58-year-old woman was diagnosed with CLL through a routine blood test in 2015. Her physical examination was unremarkable and her lymphocyte counts were at 12.36×109 cells/L. Bone marrow biopsy with immunohistochemistry was suggestive of CLL and stained positive for BCL2, CD5 (aberrant T-cell marker), CD20, CD23, CD43 and CD79a (B-cell markers) while BCL6 was negative. The PCR amplification study showed immunoglobulin heavy chain gene rearrangement along with IgG kappa light chain gene arrangement. No t(14;18) BCL2/JH or t(11;14) BCL1/JH gene rearrangements were observed. As she was asymptomatic, and positron emission tomography (PET) scan showed low grade metabolic activity in lymph nodes in cervical, axillary and iliac areas, no therapy was initiated (figure 1). She was followed every 6 months.
Figure 1 Positron emission tomography scan (right) and corresponding CT images (left) of multiple low-grade hypermetabolic lymph nodes in 2017, 2 years after diagnosis of chronic lymphocytic leukaemia. (A) Multiple small low-grade hypermetabolic lymph nodes in bilateral neck regions predominantly in the posterior triangles. SUV of 1.9 in the left and right upper posterior triangles. (B) Hypermetabolic lymph nodes in the left axillary regions, SUV 1.8. (C) Left external iliac lymph node SUV of 3. SUV, Standardized uptake value.
In November 2017 the patient had symptom of a rapid bilateral enlargement of the cervical lymph nodes accompanied by persistent fatigue, night sweats and decreased weight. Lyme disease, HIV, hepatitis B and C and syphilis serologies were performed, and all tests yielded negative results. Repeat PET/CT scan, cytogenetics and bone marrow biopsy demonstrated no evidence of Richter’s transformation into a diffuse large cell lymphoma. Due to significant bulky disease and enlarged adenopathy with B constitutional symptoms, chemo-immunotherapy with FCR was considered. This was furthermore rationalised as she was a fit patient younger than 65 years of age with standard risk for CLL due to the absence of 17 p deletion, or TP53 mutation, and with IGHV being mutated.7
She received six cycles of FCR which was completed uneventfully on 11 November 2019. During FCR therapy, she received oral valacyclovir 500 mg two times per day for herpes prophylaxis as well as Septra DS (160 mg trimethoprim and 800 mg sulfamethoxazole) one tablet Mondays, Wednesdays and Fridays for P. jirovecii prophylaxis. On 18 November, she presented to the emergency room of the McGill University Health Centre (MUHC) with haematuria, suprapubic pain and fever. She was admitted and treated for a urine infection and slowly improved after different antibiotics such as ciprofloxacin, trimethoprim-sulfamethoxazole and ceftriaxone and blood and urinary bacterial cultures were negative. A CT urogram showed moderate bilateral hydroureteronephrosis with diffuse urolithelial and bladder thickening (figure 2). As a whole, these findings were suggestive of an inflammatory or infectious process evoking pyleoureteritis and cystitis.
Figure 2 CT urogram on admission in November 2019, demonstrating (A) poorly distended bladder and marked thickening of bladder walls (green arrow) and (B) moderate dilation of both ureters and collection ducts with marked thickening and enhancement of the urothelium associated with moderate periureteric fat stranding.
Investigations
On admission, she was mildly pancytopenic (table 1). As the patient partially improved and had negative urine cultures, a cyclophosphamide-induced haemorrhagic cystitis was considered, and she was placed on continuous bladder irrigation.
Table 1 Summary of the patient’s serological and microbiological test results during the course of her neutropenia and triple viremia
Laboratory results Reference ranges 20 March 2019 11 November 2019 26 November 2019 25 December 2019 01 January 2020 23 January 2020 01 February 2020 07 February 2020 03 March 2020
Time of intervention First dose FCR Last dose FCR Meropenem started Virology investigated Begins cidofovir+GCSF Cidofovir changed to Ganciclovir Ganciclovir transitioned to valganciclovir Discharge Follow-up
WBC (109/L) 4.0–10.0 30.90 5.90 3.00 1.00 0.60 2.40 6.10 2.40 2.00
Neutrophils 2.0–7.0 3.75 4.18 2.46 0.80 0.36 1.19 5.09 1.73 1.35
Lymphocytes 1.5–4.5 26.26 0.87 0.23 0.08 0.11 0.23 0.46 0.33 0.44
Plt (109/L) 150–450 145 158 123 48 19 54 17 12 39
Hb (g/L) 120–150 142 129 99 63 80 70 70 71 99
Creatinine (umol/L) 50–90 71 68 125 128 118 75 74 69 75
CMV (copies/mL) – – – – 7320 3170 1291 153 149 0
Adenovirus (copies/mL) – – – – – 7.44 log10 4.86 log10 3.74 log10 – 3.30 log10
BK virus urine (copies/mL) – – – – – 2.26×107 – 3.20×108 –
BK virus blood (copies/mL) – – – – – – – – – 3.91×103
CMV, cytomegalovirus; FCR, fludarabine, cyclophosphamide and rituximab; Hb, haemoglobin; Plt, platelet; WBC, white blood cell.
On 1 December 2019 she developed a pancytopenia that required platelet and packed red blood cell transfusions. She remained persistently febrile despite repeated negative bacterial blood and urine cultures. Due to her CLL, pancytopenia and the consideration of immunosuppression induced by FCR chemotherapy, viral infections were investigated. PCR for adenovirus showed 22.4 copies/mL in blood, and positive in urine; PCR for polyoma virus showed 8.81 million copies/mL blood; and PCR for CMV showed 358 copies/mL in blood, confirming viral invasive infections (figure 3). To further investigate her pancytopenia, serology for parvovirus B 19 was carried out and was negative for IgM.
Figure 3 Cytomegalovirus (CMV) and BK viremia (A) and adeno-viremia (B) over the course of treatment.
On 18 December 2019 the patient underwent a double J-stent insertion for bilateral hydronephrosis. Pelvic pain persisted and she continued to pass clots in her urine. Repeat CMV PCR testing on 25 December 2019 showed 7320 copies/mL while an ophthalmological assessment revealed no evidence of CMV retinitis or keratitis. Bone marrow biopsy results showed pancytopenia without transformation (figure 4).
Figure 4 Histology and immunochemistry of bone marrow smear (A) and biopsy (B). Bone marrow biopsy demonstrating hypocellularity. Moderate left shift of the myeloid series and mild left shift of the erythroid series. No lymphocytosis or lymphoma, no definite diagnosis of myelodysplastic syndrome (B).
Treatment
On 1 January 2020, cidofovir was administered to treat the three viral infections of BK polyomavirus, adenovirus and CMV. Cidofovir was given at the dose of 1 mg/kg intravenously three times a week instead of a weekly dose given her kidney injury and high creatinine levels. She received probenecid 2 g orally 1 hour before cidofovir, then 2 hours and 8 hours after the end of infusion to increase cidofovir levels in the blood. For renal protection, she was hydrated with 1 L of 0.9% normal saline during cidofovir infusion. Filgrastim (G-CSF) was initiated for her neutropenia, darbepoetin for her anaemia, and intravenous IgG was infused three times at 4-week intervals for her hypogammaglobulinumia.
Neutropenia worsen despite filgrastim, and CMV viral load continued to increase. Due to cidofovir myelotoxicity, a decision was made to focus treatment on CMV infection, while ignoring the BK and adenovirus. To this end, the patient was changed to ganciclovir 250 mg intravenous two times per day on 23 January 2020 and her urinary symptoms improved for the first time. On 1 February 2020, she was transitioned to oral valganciclovir 450 mg daily and was discharged to home 1 week later, after 101 days in hospital.
Outcome and follow-up
A bone marrow biopsy on 27 January 2020 showed a hypocellular marrow with focal area up to 20%–30% haematopoietic tissue. No evidence of lymphocytosis or lymphoma and no dysplastic changes in morphology were observed. Immunohistochemistry showed <5% CD117, and was negative for CD20, CD34 and PAX5. The histological appearance represented haematopoietic regeneration post-chemotherapy. On 3 March 2020 follow-up, CMV load was undetectable, adenovirus load was 5000 copies/mL, BK load was 3.2×108 copies/mL (table 1). She was switched on CMV prophylaxis with resolved haemorrhagic cystitis and received valganciclovir 450 mg p.o. daily for another 3 months and until her absolute lymphocyte count recovers above 109 cells/L. She continued trimethoprim-sulfamethaxole prophylaxis for 6 months post-chemotherapy. Her double-J stents remain in place. While clinically improved, her neutropenia improved on low dose filgrastim until 4 April 2020. Her blood counts normalised 1 month after and she is followed as an outpatient with Haematology, Infectious Diseases, and Urology services at the MUHC.
Discussion
FCR chemo-immunotherapy is considered the treatment for standard risk CLL patients under the age of 65,7 with a high overall response rate. However, the predominant complication is myelosuppression.8 Persistent neutropenia was reported in 19% and late infections in 9% of patients.9 The frequency of cytopenias was 35% at 3 months and 12% at 9 months after completion of therapy, respectively. Another side effect is prolonged lymphoid immunodeficiency.
Human adenovirus infections usually present as a keratoconjunctivitis or respiratory tract infection. In most healthy individuals the infection is usually self-limited. However, in immunosuppressed patients, infection may disseminate and become potentially life-threatening. Disseminated adenovirus infection can result from either de novo infection or a reactivation of clinically silent infection.10
BK virus is a member of the polyomavirus family. BK virus reactivation occurs only in immunosuppressed patients and can lead to nephropathy, ureteral stenosis, tubular interstitial damage and haemorrhagic cystitis. Viremia occurs in 20%–60% of this population. There is no specific treatment for BK virus-associated nephropathy, therefore viral replication can only be controlled through modulating the immunosuppressive condition.11
CMV is a herpes virus with a large double-stranded DNA that remains latent in the host after primary infection. Immunocompromised patients can have reactivation of their latent infection. Diagnosis of viral reactivation is made through CMV PCR in blood, tissue or body fluid. Manifestations of CMV infection occur most often in the gastrointestinal tract, lungs, liver and retina.12 As we did not observe the typical owl’s eye tissue lesion in the second bone marrow biopsy, we considered that CMV reactivation was a contributing factor for the pancytopenia, and treatment may have prevented such tissue lesion to develop. First line treatment of CMV infection includes intravenous ganciclovir or its oral prodrug valganciclovir, which are DNA polymerase inhibitors. The major side effect of these drugs is myelosuppression, including neutropenia.4
In our patient, the prolonged pancytopenias secondary to FCR was associated with haematuria with an ureteral mass. To date, only two observations on the use of cidofovir to simultaneously treat BK-virus associated haemorrhagic cystitis and CMV reactivation have been reported. However, in the case report by Held et al, the patient had received a bone marrow transplant for chronic myeloid leukaemia, whereas our patient had CLL.
Cidofovir has been suggested in some cases for the treatment of BK virus-associated haemorrhagic cystitis.13 Cidofovir and foscarnet are second-line therapies in patients with CMV that are either resistant or refractory to ganciclovir. Cidofovir is a non-cyclic analogue of cytidine monophosphate that terminates CMV DNA synthesis. In vitro studies showed effectiveness against herpes viruses, including CMV, herpes simplex viruses 1 and 2, varicella-zoster, Epstein-Barr virus, human papillomavirus and adenovirus. The main adverse effect is nephrotoxicity, causing proximal tubular injury. Serum creatinine and urine protein measurements are recommended during administration.14 Probenecid decreases intratubular secretion and maintains a sufficient plasma concentration to allow for once weekly dosing at 5 mg/kg to reduce its nephrotoxicity.13 An alternate dosing regimen, initially used in our patient, was three times per week dosing at 3 mg/kg. In the study performed by Philippe et al, intravenous cidofovir achieve remission in 81.5% of the 22 patients.13
The patient reported by Held et al recovered fully with cidofovir15; however, our patient was switched to ganciclovir due to persistent neutropenia. Bone marrow biopsy was consistent with secondary treatment-related myelosuppression syndrome, without evidence of myelodysplasia or lymphoproliferative infiltration. Myelosuppression is a major side effect of ganciclovir. However, the antiviral effects far outweigh these risks and therefore ganciclovir and its oral prodrug valganciclovir should be considered for patients with pancytopenia secondary to CMV reactivation.
In summary, this unique case of triple-viremia induced haemorrhagic cystitis in an immunosuppressed CLL patient posed both a diagnostic and therapeutic challenge as treatments are nephrotoxic and further increase immunosuppression.
The major learning point is to exercise caution when prescribing FCR chemotherapy on its long-term immunosuppressive effects. It is expected that novel immuno-chemotherapy for CLL should control the disease with reduced immunosuppressive effects.16
Patient’s perspective
Translation from French
I was diagnosed with CLL in November 2015. Started the treatments with FCR protocol in April 2019 (six treatments of three consecutive days each). At the end of the fourth treatment, I was not well. I had fever and a large fatigue with no energy. I finished treatments on the 13th of November 2019. On the week of 18 November, the symptoms appeared: fever, incontinent of urine with blood, no appetite, fatigue.
I visited MUHC emergency, 12 hours wait before I had a doctor’s room. I stayed the night and the next day I saw the doctor, but they did not know what I had. On the 22nd of November I returned to emergency with a lot of fever and other symptoms. I passed the night in an emergency room. On Saturday they released me, had fever and falls.
On the 24th I returned to emergency, fever and incontinence, etc. I was placed in the corridor in a stretcher with a commode next to the whole world. There was nowhere else for me, I had to go through the doors to go to the public toilet and I urinated every 5 min. I stayed in emergency 5 days before I was admitted to Internal Medicine.
It was a bad experience the three times I was in emergency. On 29 November, I had my own room. I was there till 07 February 2020.
The staff took charge rapidly. There were many tests during this long period to find out the cause of my problems. Everything came from the chemotherapy. Many departments were involved: urology, otolaryngology, haematology, internal medicine, infectious diseases.
There were several healthcare workers who spoke on behalf of other departments.
Very good service with the nursing staffs and the préposé (aux bénéficiaires). On my part, my immune system was severely damaged.
Learning points
Infections in immunosuppressed patients remain a diagnostic and therapeutic challenge.
In patient treated for chronic lymphocytic leukaemia, haematuria can be related to viral infections like BK virus, adenovirus and cytomegalovirus (CMV).
BK infection is diagnosed with a high index of suspicion, however, combined CMV and adenovirus infections renders the diagnosis more difficult.
Treatment of these viral infections remains difficult as medications are associated with myelotoxicity (ganciclovir) and renal insufficiency (cidofovir).
The authors would like to thank Dr Malek Merdad and Dr Isabelle Malhamé for their inspiration to write this article.
Contributors: MK and J-PR devised the project, main conceptual ideas and proof outlines. MK took the lead in writing the manuscript the supervision of J-PR. MK created all the images and translated the patient’s perspective from French to English. J-PR and JL provided critical feedback and helped shape analysis and manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33402369 | 19,066,566 | 2021-01-05 |
What was the administration route of drug 'PROBENECID'? | Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
Background
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder associated with mature B-cell dysfunction, hypogammaglobulinaemia and T-cell abnormalities. In Europe and North America, CLL is the most common leukaemia, with median age of diagnosis of 70 years.1 Treatment is indicated only for symptomatic disease, such as anaemia <100 g/L and/or thrombocytopenia <100×109/L, massive splenomegaly, lymphadenopathy or constitutional symptoms.2
Infection is a frequent cause of morbidity and mortality in CLL. Roughly 30%–50% of all CLL patients suffer infections, with a high subsequent mortality rate.3 While the majority of infections affect more often the respiratory track, or skin and the gastrointestinal tract.4 The most frequent organisms causing infections are bacteria like Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. This increased susceptibility to infection stems from B-cells with impaired immunoglobulin production capability and dysfunctional T-helper cells, which also assist in antibody production. This impaired capability to produce immunoglobulins, termed hypogammaglobulinaemia, affects 85% of CLL patients, particularly in advanced disease.4
Antineoplastic agents recommended for the treatment of CLL are also immunosuppressive and further increase the risk of infections.5 These include opportunistic micro-organisms such as Candida, Pneumocystis jirovecii, listeria, nocardia and atypical mycobacteria. In addition, patients have increased risk of viral diseases such as herpes simplex, Epstein-Barr and cytomegalovirus (CMV). Additional infectious complications may include hepatitis B reactivation and progressive multifocal leucoencephalopathy. In spite of the immunosuppressive risk, chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the standard risk therapy in fit patients below 65 years of age with CLL, in absence of 17 p deletion, or TP53 mutation, and with immunoglobulin heavy chain V (IGHV)-mutated.6
To reduce risk of infection, immunoglobulin levels should also be routinely monitored, particularly with rituximab, which reduces the number of B-cells expressing CD20. It is postulated that monitoring immunoglobulins while being treated with rituximab may reduce the risk of serious infections.4
Herein, we present a unique case of a woman treated for CLL who experienced severe pancytopenia and immunosuppression at the completion of her chemo-immunotherapy. She subsequently experienced triple concurrent viral infections, which posed a therapeutic challenge due to her pancytopenia.
Case presentation
A previously healthy 58-year-old woman was diagnosed with CLL through a routine blood test in 2015. Her physical examination was unremarkable and her lymphocyte counts were at 12.36×109 cells/L. Bone marrow biopsy with immunohistochemistry was suggestive of CLL and stained positive for BCL2, CD5 (aberrant T-cell marker), CD20, CD23, CD43 and CD79a (B-cell markers) while BCL6 was negative. The PCR amplification study showed immunoglobulin heavy chain gene rearrangement along with IgG kappa light chain gene arrangement. No t(14;18) BCL2/JH or t(11;14) BCL1/JH gene rearrangements were observed. As she was asymptomatic, and positron emission tomography (PET) scan showed low grade metabolic activity in lymph nodes in cervical, axillary and iliac areas, no therapy was initiated (figure 1). She was followed every 6 months.
Figure 1 Positron emission tomography scan (right) and corresponding CT images (left) of multiple low-grade hypermetabolic lymph nodes in 2017, 2 years after diagnosis of chronic lymphocytic leukaemia. (A) Multiple small low-grade hypermetabolic lymph nodes in bilateral neck regions predominantly in the posterior triangles. SUV of 1.9 in the left and right upper posterior triangles. (B) Hypermetabolic lymph nodes in the left axillary regions, SUV 1.8. (C) Left external iliac lymph node SUV of 3. SUV, Standardized uptake value.
In November 2017 the patient had symptom of a rapid bilateral enlargement of the cervical lymph nodes accompanied by persistent fatigue, night sweats and decreased weight. Lyme disease, HIV, hepatitis B and C and syphilis serologies were performed, and all tests yielded negative results. Repeat PET/CT scan, cytogenetics and bone marrow biopsy demonstrated no evidence of Richter’s transformation into a diffuse large cell lymphoma. Due to significant bulky disease and enlarged adenopathy with B constitutional symptoms, chemo-immunotherapy with FCR was considered. This was furthermore rationalised as she was a fit patient younger than 65 years of age with standard risk for CLL due to the absence of 17 p deletion, or TP53 mutation, and with IGHV being mutated.7
She received six cycles of FCR which was completed uneventfully on 11 November 2019. During FCR therapy, she received oral valacyclovir 500 mg two times per day for herpes prophylaxis as well as Septra DS (160 mg trimethoprim and 800 mg sulfamethoxazole) one tablet Mondays, Wednesdays and Fridays for P. jirovecii prophylaxis. On 18 November, she presented to the emergency room of the McGill University Health Centre (MUHC) with haematuria, suprapubic pain and fever. She was admitted and treated for a urine infection and slowly improved after different antibiotics such as ciprofloxacin, trimethoprim-sulfamethoxazole and ceftriaxone and blood and urinary bacterial cultures were negative. A CT urogram showed moderate bilateral hydroureteronephrosis with diffuse urolithelial and bladder thickening (figure 2). As a whole, these findings were suggestive of an inflammatory or infectious process evoking pyleoureteritis and cystitis.
Figure 2 CT urogram on admission in November 2019, demonstrating (A) poorly distended bladder and marked thickening of bladder walls (green arrow) and (B) moderate dilation of both ureters and collection ducts with marked thickening and enhancement of the urothelium associated with moderate periureteric fat stranding.
Investigations
On admission, she was mildly pancytopenic (table 1). As the patient partially improved and had negative urine cultures, a cyclophosphamide-induced haemorrhagic cystitis was considered, and she was placed on continuous bladder irrigation.
Table 1 Summary of the patient’s serological and microbiological test results during the course of her neutropenia and triple viremia
Laboratory results Reference ranges 20 March 2019 11 November 2019 26 November 2019 25 December 2019 01 January 2020 23 January 2020 01 February 2020 07 February 2020 03 March 2020
Time of intervention First dose FCR Last dose FCR Meropenem started Virology investigated Begins cidofovir+GCSF Cidofovir changed to Ganciclovir Ganciclovir transitioned to valganciclovir Discharge Follow-up
WBC (109/L) 4.0–10.0 30.90 5.90 3.00 1.00 0.60 2.40 6.10 2.40 2.00
Neutrophils 2.0–7.0 3.75 4.18 2.46 0.80 0.36 1.19 5.09 1.73 1.35
Lymphocytes 1.5–4.5 26.26 0.87 0.23 0.08 0.11 0.23 0.46 0.33 0.44
Plt (109/L) 150–450 145 158 123 48 19 54 17 12 39
Hb (g/L) 120–150 142 129 99 63 80 70 70 71 99
Creatinine (umol/L) 50–90 71 68 125 128 118 75 74 69 75
CMV (copies/mL) – – – – 7320 3170 1291 153 149 0
Adenovirus (copies/mL) – – – – – 7.44 log10 4.86 log10 3.74 log10 – 3.30 log10
BK virus urine (copies/mL) – – – – – 2.26×107 – 3.20×108 –
BK virus blood (copies/mL) – – – – – – – – – 3.91×103
CMV, cytomegalovirus; FCR, fludarabine, cyclophosphamide and rituximab; Hb, haemoglobin; Plt, platelet; WBC, white blood cell.
On 1 December 2019 she developed a pancytopenia that required platelet and packed red blood cell transfusions. She remained persistently febrile despite repeated negative bacterial blood and urine cultures. Due to her CLL, pancytopenia and the consideration of immunosuppression induced by FCR chemotherapy, viral infections were investigated. PCR for adenovirus showed 22.4 copies/mL in blood, and positive in urine; PCR for polyoma virus showed 8.81 million copies/mL blood; and PCR for CMV showed 358 copies/mL in blood, confirming viral invasive infections (figure 3). To further investigate her pancytopenia, serology for parvovirus B 19 was carried out and was negative for IgM.
Figure 3 Cytomegalovirus (CMV) and BK viremia (A) and adeno-viremia (B) over the course of treatment.
On 18 December 2019 the patient underwent a double J-stent insertion for bilateral hydronephrosis. Pelvic pain persisted and she continued to pass clots in her urine. Repeat CMV PCR testing on 25 December 2019 showed 7320 copies/mL while an ophthalmological assessment revealed no evidence of CMV retinitis or keratitis. Bone marrow biopsy results showed pancytopenia without transformation (figure 4).
Figure 4 Histology and immunochemistry of bone marrow smear (A) and biopsy (B). Bone marrow biopsy demonstrating hypocellularity. Moderate left shift of the myeloid series and mild left shift of the erythroid series. No lymphocytosis or lymphoma, no definite diagnosis of myelodysplastic syndrome (B).
Treatment
On 1 January 2020, cidofovir was administered to treat the three viral infections of BK polyomavirus, adenovirus and CMV. Cidofovir was given at the dose of 1 mg/kg intravenously three times a week instead of a weekly dose given her kidney injury and high creatinine levels. She received probenecid 2 g orally 1 hour before cidofovir, then 2 hours and 8 hours after the end of infusion to increase cidofovir levels in the blood. For renal protection, she was hydrated with 1 L of 0.9% normal saline during cidofovir infusion. Filgrastim (G-CSF) was initiated for her neutropenia, darbepoetin for her anaemia, and intravenous IgG was infused three times at 4-week intervals for her hypogammaglobulinumia.
Neutropenia worsen despite filgrastim, and CMV viral load continued to increase. Due to cidofovir myelotoxicity, a decision was made to focus treatment on CMV infection, while ignoring the BK and adenovirus. To this end, the patient was changed to ganciclovir 250 mg intravenous two times per day on 23 January 2020 and her urinary symptoms improved for the first time. On 1 February 2020, she was transitioned to oral valganciclovir 450 mg daily and was discharged to home 1 week later, after 101 days in hospital.
Outcome and follow-up
A bone marrow biopsy on 27 January 2020 showed a hypocellular marrow with focal area up to 20%–30% haematopoietic tissue. No evidence of lymphocytosis or lymphoma and no dysplastic changes in morphology were observed. Immunohistochemistry showed <5% CD117, and was negative for CD20, CD34 and PAX5. The histological appearance represented haematopoietic regeneration post-chemotherapy. On 3 March 2020 follow-up, CMV load was undetectable, adenovirus load was 5000 copies/mL, BK load was 3.2×108 copies/mL (table 1). She was switched on CMV prophylaxis with resolved haemorrhagic cystitis and received valganciclovir 450 mg p.o. daily for another 3 months and until her absolute lymphocyte count recovers above 109 cells/L. She continued trimethoprim-sulfamethaxole prophylaxis for 6 months post-chemotherapy. Her double-J stents remain in place. While clinically improved, her neutropenia improved on low dose filgrastim until 4 April 2020. Her blood counts normalised 1 month after and she is followed as an outpatient with Haematology, Infectious Diseases, and Urology services at the MUHC.
Discussion
FCR chemo-immunotherapy is considered the treatment for standard risk CLL patients under the age of 65,7 with a high overall response rate. However, the predominant complication is myelosuppression.8 Persistent neutropenia was reported in 19% and late infections in 9% of patients.9 The frequency of cytopenias was 35% at 3 months and 12% at 9 months after completion of therapy, respectively. Another side effect is prolonged lymphoid immunodeficiency.
Human adenovirus infections usually present as a keratoconjunctivitis or respiratory tract infection. In most healthy individuals the infection is usually self-limited. However, in immunosuppressed patients, infection may disseminate and become potentially life-threatening. Disseminated adenovirus infection can result from either de novo infection or a reactivation of clinically silent infection.10
BK virus is a member of the polyomavirus family. BK virus reactivation occurs only in immunosuppressed patients and can lead to nephropathy, ureteral stenosis, tubular interstitial damage and haemorrhagic cystitis. Viremia occurs in 20%–60% of this population. There is no specific treatment for BK virus-associated nephropathy, therefore viral replication can only be controlled through modulating the immunosuppressive condition.11
CMV is a herpes virus with a large double-stranded DNA that remains latent in the host after primary infection. Immunocompromised patients can have reactivation of their latent infection. Diagnosis of viral reactivation is made through CMV PCR in blood, tissue or body fluid. Manifestations of CMV infection occur most often in the gastrointestinal tract, lungs, liver and retina.12 As we did not observe the typical owl’s eye tissue lesion in the second bone marrow biopsy, we considered that CMV reactivation was a contributing factor for the pancytopenia, and treatment may have prevented such tissue lesion to develop. First line treatment of CMV infection includes intravenous ganciclovir or its oral prodrug valganciclovir, which are DNA polymerase inhibitors. The major side effect of these drugs is myelosuppression, including neutropenia.4
In our patient, the prolonged pancytopenias secondary to FCR was associated with haematuria with an ureteral mass. To date, only two observations on the use of cidofovir to simultaneously treat BK-virus associated haemorrhagic cystitis and CMV reactivation have been reported. However, in the case report by Held et al, the patient had received a bone marrow transplant for chronic myeloid leukaemia, whereas our patient had CLL.
Cidofovir has been suggested in some cases for the treatment of BK virus-associated haemorrhagic cystitis.13 Cidofovir and foscarnet are second-line therapies in patients with CMV that are either resistant or refractory to ganciclovir. Cidofovir is a non-cyclic analogue of cytidine monophosphate that terminates CMV DNA synthesis. In vitro studies showed effectiveness against herpes viruses, including CMV, herpes simplex viruses 1 and 2, varicella-zoster, Epstein-Barr virus, human papillomavirus and adenovirus. The main adverse effect is nephrotoxicity, causing proximal tubular injury. Serum creatinine and urine protein measurements are recommended during administration.14 Probenecid decreases intratubular secretion and maintains a sufficient plasma concentration to allow for once weekly dosing at 5 mg/kg to reduce its nephrotoxicity.13 An alternate dosing regimen, initially used in our patient, was three times per week dosing at 3 mg/kg. In the study performed by Philippe et al, intravenous cidofovir achieve remission in 81.5% of the 22 patients.13
The patient reported by Held et al recovered fully with cidofovir15; however, our patient was switched to ganciclovir due to persistent neutropenia. Bone marrow biopsy was consistent with secondary treatment-related myelosuppression syndrome, without evidence of myelodysplasia or lymphoproliferative infiltration. Myelosuppression is a major side effect of ganciclovir. However, the antiviral effects far outweigh these risks and therefore ganciclovir and its oral prodrug valganciclovir should be considered for patients with pancytopenia secondary to CMV reactivation.
In summary, this unique case of triple-viremia induced haemorrhagic cystitis in an immunosuppressed CLL patient posed both a diagnostic and therapeutic challenge as treatments are nephrotoxic and further increase immunosuppression.
The major learning point is to exercise caution when prescribing FCR chemotherapy on its long-term immunosuppressive effects. It is expected that novel immuno-chemotherapy for CLL should control the disease with reduced immunosuppressive effects.16
Patient’s perspective
Translation from French
I was diagnosed with CLL in November 2015. Started the treatments with FCR protocol in April 2019 (six treatments of three consecutive days each). At the end of the fourth treatment, I was not well. I had fever and a large fatigue with no energy. I finished treatments on the 13th of November 2019. On the week of 18 November, the symptoms appeared: fever, incontinent of urine with blood, no appetite, fatigue.
I visited MUHC emergency, 12 hours wait before I had a doctor’s room. I stayed the night and the next day I saw the doctor, but they did not know what I had. On the 22nd of November I returned to emergency with a lot of fever and other symptoms. I passed the night in an emergency room. On Saturday they released me, had fever and falls.
On the 24th I returned to emergency, fever and incontinence, etc. I was placed in the corridor in a stretcher with a commode next to the whole world. There was nowhere else for me, I had to go through the doors to go to the public toilet and I urinated every 5 min. I stayed in emergency 5 days before I was admitted to Internal Medicine.
It was a bad experience the three times I was in emergency. On 29 November, I had my own room. I was there till 07 February 2020.
The staff took charge rapidly. There were many tests during this long period to find out the cause of my problems. Everything came from the chemotherapy. Many departments were involved: urology, otolaryngology, haematology, internal medicine, infectious diseases.
There were several healthcare workers who spoke on behalf of other departments.
Very good service with the nursing staffs and the préposé (aux bénéficiaires). On my part, my immune system was severely damaged.
Learning points
Infections in immunosuppressed patients remain a diagnostic and therapeutic challenge.
In patient treated for chronic lymphocytic leukaemia, haematuria can be related to viral infections like BK virus, adenovirus and cytomegalovirus (CMV).
BK infection is diagnosed with a high index of suspicion, however, combined CMV and adenovirus infections renders the diagnosis more difficult.
Treatment of these viral infections remains difficult as medications are associated with myelotoxicity (ganciclovir) and renal insufficiency (cidofovir).
The authors would like to thank Dr Malek Merdad and Dr Isabelle Malhamé for their inspiration to write this article.
Contributors: MK and J-PR devised the project, main conceptual ideas and proof outlines. MK took the lead in writing the manuscript the supervision of J-PR. MK created all the images and translated the patient’s perspective from French to English. J-PR and JL provided critical feedback and helped shape analysis and manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Oral | DrugAdministrationRoute | CC BY-NC | 33402369 | 19,066,566 | 2021-01-05 |
What was the administration route of drug 'VALACYCLOVIR HYDROCHLORIDE'? | Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
Background
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder associated with mature B-cell dysfunction, hypogammaglobulinaemia and T-cell abnormalities. In Europe and North America, CLL is the most common leukaemia, with median age of diagnosis of 70 years.1 Treatment is indicated only for symptomatic disease, such as anaemia <100 g/L and/or thrombocytopenia <100×109/L, massive splenomegaly, lymphadenopathy or constitutional symptoms.2
Infection is a frequent cause of morbidity and mortality in CLL. Roughly 30%–50% of all CLL patients suffer infections, with a high subsequent mortality rate.3 While the majority of infections affect more often the respiratory track, or skin and the gastrointestinal tract.4 The most frequent organisms causing infections are bacteria like Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. This increased susceptibility to infection stems from B-cells with impaired immunoglobulin production capability and dysfunctional T-helper cells, which also assist in antibody production. This impaired capability to produce immunoglobulins, termed hypogammaglobulinaemia, affects 85% of CLL patients, particularly in advanced disease.4
Antineoplastic agents recommended for the treatment of CLL are also immunosuppressive and further increase the risk of infections.5 These include opportunistic micro-organisms such as Candida, Pneumocystis jirovecii, listeria, nocardia and atypical mycobacteria. In addition, patients have increased risk of viral diseases such as herpes simplex, Epstein-Barr and cytomegalovirus (CMV). Additional infectious complications may include hepatitis B reactivation and progressive multifocal leucoencephalopathy. In spite of the immunosuppressive risk, chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the standard risk therapy in fit patients below 65 years of age with CLL, in absence of 17 p deletion, or TP53 mutation, and with immunoglobulin heavy chain V (IGHV)-mutated.6
To reduce risk of infection, immunoglobulin levels should also be routinely monitored, particularly with rituximab, which reduces the number of B-cells expressing CD20. It is postulated that monitoring immunoglobulins while being treated with rituximab may reduce the risk of serious infections.4
Herein, we present a unique case of a woman treated for CLL who experienced severe pancytopenia and immunosuppression at the completion of her chemo-immunotherapy. She subsequently experienced triple concurrent viral infections, which posed a therapeutic challenge due to her pancytopenia.
Case presentation
A previously healthy 58-year-old woman was diagnosed with CLL through a routine blood test in 2015. Her physical examination was unremarkable and her lymphocyte counts were at 12.36×109 cells/L. Bone marrow biopsy with immunohistochemistry was suggestive of CLL and stained positive for BCL2, CD5 (aberrant T-cell marker), CD20, CD23, CD43 and CD79a (B-cell markers) while BCL6 was negative. The PCR amplification study showed immunoglobulin heavy chain gene rearrangement along with IgG kappa light chain gene arrangement. No t(14;18) BCL2/JH or t(11;14) BCL1/JH gene rearrangements were observed. As she was asymptomatic, and positron emission tomography (PET) scan showed low grade metabolic activity in lymph nodes in cervical, axillary and iliac areas, no therapy was initiated (figure 1). She was followed every 6 months.
Figure 1 Positron emission tomography scan (right) and corresponding CT images (left) of multiple low-grade hypermetabolic lymph nodes in 2017, 2 years after diagnosis of chronic lymphocytic leukaemia. (A) Multiple small low-grade hypermetabolic lymph nodes in bilateral neck regions predominantly in the posterior triangles. SUV of 1.9 in the left and right upper posterior triangles. (B) Hypermetabolic lymph nodes in the left axillary regions, SUV 1.8. (C) Left external iliac lymph node SUV of 3. SUV, Standardized uptake value.
In November 2017 the patient had symptom of a rapid bilateral enlargement of the cervical lymph nodes accompanied by persistent fatigue, night sweats and decreased weight. Lyme disease, HIV, hepatitis B and C and syphilis serologies were performed, and all tests yielded negative results. Repeat PET/CT scan, cytogenetics and bone marrow biopsy demonstrated no evidence of Richter’s transformation into a diffuse large cell lymphoma. Due to significant bulky disease and enlarged adenopathy with B constitutional symptoms, chemo-immunotherapy with FCR was considered. This was furthermore rationalised as she was a fit patient younger than 65 years of age with standard risk for CLL due to the absence of 17 p deletion, or TP53 mutation, and with IGHV being mutated.7
She received six cycles of FCR which was completed uneventfully on 11 November 2019. During FCR therapy, she received oral valacyclovir 500 mg two times per day for herpes prophylaxis as well as Septra DS (160 mg trimethoprim and 800 mg sulfamethoxazole) one tablet Mondays, Wednesdays and Fridays for P. jirovecii prophylaxis. On 18 November, she presented to the emergency room of the McGill University Health Centre (MUHC) with haematuria, suprapubic pain and fever. She was admitted and treated for a urine infection and slowly improved after different antibiotics such as ciprofloxacin, trimethoprim-sulfamethoxazole and ceftriaxone and blood and urinary bacterial cultures were negative. A CT urogram showed moderate bilateral hydroureteronephrosis with diffuse urolithelial and bladder thickening (figure 2). As a whole, these findings were suggestive of an inflammatory or infectious process evoking pyleoureteritis and cystitis.
Figure 2 CT urogram on admission in November 2019, demonstrating (A) poorly distended bladder and marked thickening of bladder walls (green arrow) and (B) moderate dilation of both ureters and collection ducts with marked thickening and enhancement of the urothelium associated with moderate periureteric fat stranding.
Investigations
On admission, she was mildly pancytopenic (table 1). As the patient partially improved and had negative urine cultures, a cyclophosphamide-induced haemorrhagic cystitis was considered, and she was placed on continuous bladder irrigation.
Table 1 Summary of the patient’s serological and microbiological test results during the course of her neutropenia and triple viremia
Laboratory results Reference ranges 20 March 2019 11 November 2019 26 November 2019 25 December 2019 01 January 2020 23 January 2020 01 February 2020 07 February 2020 03 March 2020
Time of intervention First dose FCR Last dose FCR Meropenem started Virology investigated Begins cidofovir+GCSF Cidofovir changed to Ganciclovir Ganciclovir transitioned to valganciclovir Discharge Follow-up
WBC (109/L) 4.0–10.0 30.90 5.90 3.00 1.00 0.60 2.40 6.10 2.40 2.00
Neutrophils 2.0–7.0 3.75 4.18 2.46 0.80 0.36 1.19 5.09 1.73 1.35
Lymphocytes 1.5–4.5 26.26 0.87 0.23 0.08 0.11 0.23 0.46 0.33 0.44
Plt (109/L) 150–450 145 158 123 48 19 54 17 12 39
Hb (g/L) 120–150 142 129 99 63 80 70 70 71 99
Creatinine (umol/L) 50–90 71 68 125 128 118 75 74 69 75
CMV (copies/mL) – – – – 7320 3170 1291 153 149 0
Adenovirus (copies/mL) – – – – – 7.44 log10 4.86 log10 3.74 log10 – 3.30 log10
BK virus urine (copies/mL) – – – – – 2.26×107 – 3.20×108 –
BK virus blood (copies/mL) – – – – – – – – – 3.91×103
CMV, cytomegalovirus; FCR, fludarabine, cyclophosphamide and rituximab; Hb, haemoglobin; Plt, platelet; WBC, white blood cell.
On 1 December 2019 she developed a pancytopenia that required platelet and packed red blood cell transfusions. She remained persistently febrile despite repeated negative bacterial blood and urine cultures. Due to her CLL, pancytopenia and the consideration of immunosuppression induced by FCR chemotherapy, viral infections were investigated. PCR for adenovirus showed 22.4 copies/mL in blood, and positive in urine; PCR for polyoma virus showed 8.81 million copies/mL blood; and PCR for CMV showed 358 copies/mL in blood, confirming viral invasive infections (figure 3). To further investigate her pancytopenia, serology for parvovirus B 19 was carried out and was negative for IgM.
Figure 3 Cytomegalovirus (CMV) and BK viremia (A) and adeno-viremia (B) over the course of treatment.
On 18 December 2019 the patient underwent a double J-stent insertion for bilateral hydronephrosis. Pelvic pain persisted and she continued to pass clots in her urine. Repeat CMV PCR testing on 25 December 2019 showed 7320 copies/mL while an ophthalmological assessment revealed no evidence of CMV retinitis or keratitis. Bone marrow biopsy results showed pancytopenia without transformation (figure 4).
Figure 4 Histology and immunochemistry of bone marrow smear (A) and biopsy (B). Bone marrow biopsy demonstrating hypocellularity. Moderate left shift of the myeloid series and mild left shift of the erythroid series. No lymphocytosis or lymphoma, no definite diagnosis of myelodysplastic syndrome (B).
Treatment
On 1 January 2020, cidofovir was administered to treat the three viral infections of BK polyomavirus, adenovirus and CMV. Cidofovir was given at the dose of 1 mg/kg intravenously three times a week instead of a weekly dose given her kidney injury and high creatinine levels. She received probenecid 2 g orally 1 hour before cidofovir, then 2 hours and 8 hours after the end of infusion to increase cidofovir levels in the blood. For renal protection, she was hydrated with 1 L of 0.9% normal saline during cidofovir infusion. Filgrastim (G-CSF) was initiated for her neutropenia, darbepoetin for her anaemia, and intravenous IgG was infused three times at 4-week intervals for her hypogammaglobulinumia.
Neutropenia worsen despite filgrastim, and CMV viral load continued to increase. Due to cidofovir myelotoxicity, a decision was made to focus treatment on CMV infection, while ignoring the BK and adenovirus. To this end, the patient was changed to ganciclovir 250 mg intravenous two times per day on 23 January 2020 and her urinary symptoms improved for the first time. On 1 February 2020, she was transitioned to oral valganciclovir 450 mg daily and was discharged to home 1 week later, after 101 days in hospital.
Outcome and follow-up
A bone marrow biopsy on 27 January 2020 showed a hypocellular marrow with focal area up to 20%–30% haematopoietic tissue. No evidence of lymphocytosis or lymphoma and no dysplastic changes in morphology were observed. Immunohistochemistry showed <5% CD117, and was negative for CD20, CD34 and PAX5. The histological appearance represented haematopoietic regeneration post-chemotherapy. On 3 March 2020 follow-up, CMV load was undetectable, adenovirus load was 5000 copies/mL, BK load was 3.2×108 copies/mL (table 1). She was switched on CMV prophylaxis with resolved haemorrhagic cystitis and received valganciclovir 450 mg p.o. daily for another 3 months and until her absolute lymphocyte count recovers above 109 cells/L. She continued trimethoprim-sulfamethaxole prophylaxis for 6 months post-chemotherapy. Her double-J stents remain in place. While clinically improved, her neutropenia improved on low dose filgrastim until 4 April 2020. Her blood counts normalised 1 month after and she is followed as an outpatient with Haematology, Infectious Diseases, and Urology services at the MUHC.
Discussion
FCR chemo-immunotherapy is considered the treatment for standard risk CLL patients under the age of 65,7 with a high overall response rate. However, the predominant complication is myelosuppression.8 Persistent neutropenia was reported in 19% and late infections in 9% of patients.9 The frequency of cytopenias was 35% at 3 months and 12% at 9 months after completion of therapy, respectively. Another side effect is prolonged lymphoid immunodeficiency.
Human adenovirus infections usually present as a keratoconjunctivitis or respiratory tract infection. In most healthy individuals the infection is usually self-limited. However, in immunosuppressed patients, infection may disseminate and become potentially life-threatening. Disseminated adenovirus infection can result from either de novo infection or a reactivation of clinically silent infection.10
BK virus is a member of the polyomavirus family. BK virus reactivation occurs only in immunosuppressed patients and can lead to nephropathy, ureteral stenosis, tubular interstitial damage and haemorrhagic cystitis. Viremia occurs in 20%–60% of this population. There is no specific treatment for BK virus-associated nephropathy, therefore viral replication can only be controlled through modulating the immunosuppressive condition.11
CMV is a herpes virus with a large double-stranded DNA that remains latent in the host after primary infection. Immunocompromised patients can have reactivation of their latent infection. Diagnosis of viral reactivation is made through CMV PCR in blood, tissue or body fluid. Manifestations of CMV infection occur most often in the gastrointestinal tract, lungs, liver and retina.12 As we did not observe the typical owl’s eye tissue lesion in the second bone marrow biopsy, we considered that CMV reactivation was a contributing factor for the pancytopenia, and treatment may have prevented such tissue lesion to develop. First line treatment of CMV infection includes intravenous ganciclovir or its oral prodrug valganciclovir, which are DNA polymerase inhibitors. The major side effect of these drugs is myelosuppression, including neutropenia.4
In our patient, the prolonged pancytopenias secondary to FCR was associated with haematuria with an ureteral mass. To date, only two observations on the use of cidofovir to simultaneously treat BK-virus associated haemorrhagic cystitis and CMV reactivation have been reported. However, in the case report by Held et al, the patient had received a bone marrow transplant for chronic myeloid leukaemia, whereas our patient had CLL.
Cidofovir has been suggested in some cases for the treatment of BK virus-associated haemorrhagic cystitis.13 Cidofovir and foscarnet are second-line therapies in patients with CMV that are either resistant or refractory to ganciclovir. Cidofovir is a non-cyclic analogue of cytidine monophosphate that terminates CMV DNA synthesis. In vitro studies showed effectiveness against herpes viruses, including CMV, herpes simplex viruses 1 and 2, varicella-zoster, Epstein-Barr virus, human papillomavirus and adenovirus. The main adverse effect is nephrotoxicity, causing proximal tubular injury. Serum creatinine and urine protein measurements are recommended during administration.14 Probenecid decreases intratubular secretion and maintains a sufficient plasma concentration to allow for once weekly dosing at 5 mg/kg to reduce its nephrotoxicity.13 An alternate dosing regimen, initially used in our patient, was three times per week dosing at 3 mg/kg. In the study performed by Philippe et al, intravenous cidofovir achieve remission in 81.5% of the 22 patients.13
The patient reported by Held et al recovered fully with cidofovir15; however, our patient was switched to ganciclovir due to persistent neutropenia. Bone marrow biopsy was consistent with secondary treatment-related myelosuppression syndrome, without evidence of myelodysplasia or lymphoproliferative infiltration. Myelosuppression is a major side effect of ganciclovir. However, the antiviral effects far outweigh these risks and therefore ganciclovir and its oral prodrug valganciclovir should be considered for patients with pancytopenia secondary to CMV reactivation.
In summary, this unique case of triple-viremia induced haemorrhagic cystitis in an immunosuppressed CLL patient posed both a diagnostic and therapeutic challenge as treatments are nephrotoxic and further increase immunosuppression.
The major learning point is to exercise caution when prescribing FCR chemotherapy on its long-term immunosuppressive effects. It is expected that novel immuno-chemotherapy for CLL should control the disease with reduced immunosuppressive effects.16
Patient’s perspective
Translation from French
I was diagnosed with CLL in November 2015. Started the treatments with FCR protocol in April 2019 (six treatments of three consecutive days each). At the end of the fourth treatment, I was not well. I had fever and a large fatigue with no energy. I finished treatments on the 13th of November 2019. On the week of 18 November, the symptoms appeared: fever, incontinent of urine with blood, no appetite, fatigue.
I visited MUHC emergency, 12 hours wait before I had a doctor’s room. I stayed the night and the next day I saw the doctor, but they did not know what I had. On the 22nd of November I returned to emergency with a lot of fever and other symptoms. I passed the night in an emergency room. On Saturday they released me, had fever and falls.
On the 24th I returned to emergency, fever and incontinence, etc. I was placed in the corridor in a stretcher with a commode next to the whole world. There was nowhere else for me, I had to go through the doors to go to the public toilet and I urinated every 5 min. I stayed in emergency 5 days before I was admitted to Internal Medicine.
It was a bad experience the three times I was in emergency. On 29 November, I had my own room. I was there till 07 February 2020.
The staff took charge rapidly. There were many tests during this long period to find out the cause of my problems. Everything came from the chemotherapy. Many departments were involved: urology, otolaryngology, haematology, internal medicine, infectious diseases.
There were several healthcare workers who spoke on behalf of other departments.
Very good service with the nursing staffs and the préposé (aux bénéficiaires). On my part, my immune system was severely damaged.
Learning points
Infections in immunosuppressed patients remain a diagnostic and therapeutic challenge.
In patient treated for chronic lymphocytic leukaemia, haematuria can be related to viral infections like BK virus, adenovirus and cytomegalovirus (CMV).
BK infection is diagnosed with a high index of suspicion, however, combined CMV and adenovirus infections renders the diagnosis more difficult.
Treatment of these viral infections remains difficult as medications are associated with myelotoxicity (ganciclovir) and renal insufficiency (cidofovir).
The authors would like to thank Dr Malek Merdad and Dr Isabelle Malhamé for their inspiration to write this article.
Contributors: MK and J-PR devised the project, main conceptual ideas and proof outlines. MK took the lead in writing the manuscript the supervision of J-PR. MK created all the images and translated the patient’s perspective from French to English. J-PR and JL provided critical feedback and helped shape analysis and manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Oral | DrugAdministrationRoute | CC BY-NC | 33402369 | 19,066,566 | 2021-01-05 |
What was the administration route of drug 'VALGANCICLOVIR'? | Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
Background
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder associated with mature B-cell dysfunction, hypogammaglobulinaemia and T-cell abnormalities. In Europe and North America, CLL is the most common leukaemia, with median age of diagnosis of 70 years.1 Treatment is indicated only for symptomatic disease, such as anaemia <100 g/L and/or thrombocytopenia <100×109/L, massive splenomegaly, lymphadenopathy or constitutional symptoms.2
Infection is a frequent cause of morbidity and mortality in CLL. Roughly 30%–50% of all CLL patients suffer infections, with a high subsequent mortality rate.3 While the majority of infections affect more often the respiratory track, or skin and the gastrointestinal tract.4 The most frequent organisms causing infections are bacteria like Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. This increased susceptibility to infection stems from B-cells with impaired immunoglobulin production capability and dysfunctional T-helper cells, which also assist in antibody production. This impaired capability to produce immunoglobulins, termed hypogammaglobulinaemia, affects 85% of CLL patients, particularly in advanced disease.4
Antineoplastic agents recommended for the treatment of CLL are also immunosuppressive and further increase the risk of infections.5 These include opportunistic micro-organisms such as Candida, Pneumocystis jirovecii, listeria, nocardia and atypical mycobacteria. In addition, patients have increased risk of viral diseases such as herpes simplex, Epstein-Barr and cytomegalovirus (CMV). Additional infectious complications may include hepatitis B reactivation and progressive multifocal leucoencephalopathy. In spite of the immunosuppressive risk, chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the standard risk therapy in fit patients below 65 years of age with CLL, in absence of 17 p deletion, or TP53 mutation, and with immunoglobulin heavy chain V (IGHV)-mutated.6
To reduce risk of infection, immunoglobulin levels should also be routinely monitored, particularly with rituximab, which reduces the number of B-cells expressing CD20. It is postulated that monitoring immunoglobulins while being treated with rituximab may reduce the risk of serious infections.4
Herein, we present a unique case of a woman treated for CLL who experienced severe pancytopenia and immunosuppression at the completion of her chemo-immunotherapy. She subsequently experienced triple concurrent viral infections, which posed a therapeutic challenge due to her pancytopenia.
Case presentation
A previously healthy 58-year-old woman was diagnosed with CLL through a routine blood test in 2015. Her physical examination was unremarkable and her lymphocyte counts were at 12.36×109 cells/L. Bone marrow biopsy with immunohistochemistry was suggestive of CLL and stained positive for BCL2, CD5 (aberrant T-cell marker), CD20, CD23, CD43 and CD79a (B-cell markers) while BCL6 was negative. The PCR amplification study showed immunoglobulin heavy chain gene rearrangement along with IgG kappa light chain gene arrangement. No t(14;18) BCL2/JH or t(11;14) BCL1/JH gene rearrangements were observed. As she was asymptomatic, and positron emission tomography (PET) scan showed low grade metabolic activity in lymph nodes in cervical, axillary and iliac areas, no therapy was initiated (figure 1). She was followed every 6 months.
Figure 1 Positron emission tomography scan (right) and corresponding CT images (left) of multiple low-grade hypermetabolic lymph nodes in 2017, 2 years after diagnosis of chronic lymphocytic leukaemia. (A) Multiple small low-grade hypermetabolic lymph nodes in bilateral neck regions predominantly in the posterior triangles. SUV of 1.9 in the left and right upper posterior triangles. (B) Hypermetabolic lymph nodes in the left axillary regions, SUV 1.8. (C) Left external iliac lymph node SUV of 3. SUV, Standardized uptake value.
In November 2017 the patient had symptom of a rapid bilateral enlargement of the cervical lymph nodes accompanied by persistent fatigue, night sweats and decreased weight. Lyme disease, HIV, hepatitis B and C and syphilis serologies were performed, and all tests yielded negative results. Repeat PET/CT scan, cytogenetics and bone marrow biopsy demonstrated no evidence of Richter’s transformation into a diffuse large cell lymphoma. Due to significant bulky disease and enlarged adenopathy with B constitutional symptoms, chemo-immunotherapy with FCR was considered. This was furthermore rationalised as she was a fit patient younger than 65 years of age with standard risk for CLL due to the absence of 17 p deletion, or TP53 mutation, and with IGHV being mutated.7
She received six cycles of FCR which was completed uneventfully on 11 November 2019. During FCR therapy, she received oral valacyclovir 500 mg two times per day for herpes prophylaxis as well as Septra DS (160 mg trimethoprim and 800 mg sulfamethoxazole) one tablet Mondays, Wednesdays and Fridays for P. jirovecii prophylaxis. On 18 November, she presented to the emergency room of the McGill University Health Centre (MUHC) with haematuria, suprapubic pain and fever. She was admitted and treated for a urine infection and slowly improved after different antibiotics such as ciprofloxacin, trimethoprim-sulfamethoxazole and ceftriaxone and blood and urinary bacterial cultures were negative. A CT urogram showed moderate bilateral hydroureteronephrosis with diffuse urolithelial and bladder thickening (figure 2). As a whole, these findings were suggestive of an inflammatory or infectious process evoking pyleoureteritis and cystitis.
Figure 2 CT urogram on admission in November 2019, demonstrating (A) poorly distended bladder and marked thickening of bladder walls (green arrow) and (B) moderate dilation of both ureters and collection ducts with marked thickening and enhancement of the urothelium associated with moderate periureteric fat stranding.
Investigations
On admission, she was mildly pancytopenic (table 1). As the patient partially improved and had negative urine cultures, a cyclophosphamide-induced haemorrhagic cystitis was considered, and she was placed on continuous bladder irrigation.
Table 1 Summary of the patient’s serological and microbiological test results during the course of her neutropenia and triple viremia
Laboratory results Reference ranges 20 March 2019 11 November 2019 26 November 2019 25 December 2019 01 January 2020 23 January 2020 01 February 2020 07 February 2020 03 March 2020
Time of intervention First dose FCR Last dose FCR Meropenem started Virology investigated Begins cidofovir+GCSF Cidofovir changed to Ganciclovir Ganciclovir transitioned to valganciclovir Discharge Follow-up
WBC (109/L) 4.0–10.0 30.90 5.90 3.00 1.00 0.60 2.40 6.10 2.40 2.00
Neutrophils 2.0–7.0 3.75 4.18 2.46 0.80 0.36 1.19 5.09 1.73 1.35
Lymphocytes 1.5–4.5 26.26 0.87 0.23 0.08 0.11 0.23 0.46 0.33 0.44
Plt (109/L) 150–450 145 158 123 48 19 54 17 12 39
Hb (g/L) 120–150 142 129 99 63 80 70 70 71 99
Creatinine (umol/L) 50–90 71 68 125 128 118 75 74 69 75
CMV (copies/mL) – – – – 7320 3170 1291 153 149 0
Adenovirus (copies/mL) – – – – – 7.44 log10 4.86 log10 3.74 log10 – 3.30 log10
BK virus urine (copies/mL) – – – – – 2.26×107 – 3.20×108 –
BK virus blood (copies/mL) – – – – – – – – – 3.91×103
CMV, cytomegalovirus; FCR, fludarabine, cyclophosphamide and rituximab; Hb, haemoglobin; Plt, platelet; WBC, white blood cell.
On 1 December 2019 she developed a pancytopenia that required platelet and packed red blood cell transfusions. She remained persistently febrile despite repeated negative bacterial blood and urine cultures. Due to her CLL, pancytopenia and the consideration of immunosuppression induced by FCR chemotherapy, viral infections were investigated. PCR for adenovirus showed 22.4 copies/mL in blood, and positive in urine; PCR for polyoma virus showed 8.81 million copies/mL blood; and PCR for CMV showed 358 copies/mL in blood, confirming viral invasive infections (figure 3). To further investigate her pancytopenia, serology for parvovirus B 19 was carried out and was negative for IgM.
Figure 3 Cytomegalovirus (CMV) and BK viremia (A) and adeno-viremia (B) over the course of treatment.
On 18 December 2019 the patient underwent a double J-stent insertion for bilateral hydronephrosis. Pelvic pain persisted and she continued to pass clots in her urine. Repeat CMV PCR testing on 25 December 2019 showed 7320 copies/mL while an ophthalmological assessment revealed no evidence of CMV retinitis or keratitis. Bone marrow biopsy results showed pancytopenia without transformation (figure 4).
Figure 4 Histology and immunochemistry of bone marrow smear (A) and biopsy (B). Bone marrow biopsy demonstrating hypocellularity. Moderate left shift of the myeloid series and mild left shift of the erythroid series. No lymphocytosis or lymphoma, no definite diagnosis of myelodysplastic syndrome (B).
Treatment
On 1 January 2020, cidofovir was administered to treat the three viral infections of BK polyomavirus, adenovirus and CMV. Cidofovir was given at the dose of 1 mg/kg intravenously three times a week instead of a weekly dose given her kidney injury and high creatinine levels. She received probenecid 2 g orally 1 hour before cidofovir, then 2 hours and 8 hours after the end of infusion to increase cidofovir levels in the blood. For renal protection, she was hydrated with 1 L of 0.9% normal saline during cidofovir infusion. Filgrastim (G-CSF) was initiated for her neutropenia, darbepoetin for her anaemia, and intravenous IgG was infused three times at 4-week intervals for her hypogammaglobulinumia.
Neutropenia worsen despite filgrastim, and CMV viral load continued to increase. Due to cidofovir myelotoxicity, a decision was made to focus treatment on CMV infection, while ignoring the BK and adenovirus. To this end, the patient was changed to ganciclovir 250 mg intravenous two times per day on 23 January 2020 and her urinary symptoms improved for the first time. On 1 February 2020, she was transitioned to oral valganciclovir 450 mg daily and was discharged to home 1 week later, after 101 days in hospital.
Outcome and follow-up
A bone marrow biopsy on 27 January 2020 showed a hypocellular marrow with focal area up to 20%–30% haematopoietic tissue. No evidence of lymphocytosis or lymphoma and no dysplastic changes in morphology were observed. Immunohistochemistry showed <5% CD117, and was negative for CD20, CD34 and PAX5. The histological appearance represented haematopoietic regeneration post-chemotherapy. On 3 March 2020 follow-up, CMV load was undetectable, adenovirus load was 5000 copies/mL, BK load was 3.2×108 copies/mL (table 1). She was switched on CMV prophylaxis with resolved haemorrhagic cystitis and received valganciclovir 450 mg p.o. daily for another 3 months and until her absolute lymphocyte count recovers above 109 cells/L. She continued trimethoprim-sulfamethaxole prophylaxis for 6 months post-chemotherapy. Her double-J stents remain in place. While clinically improved, her neutropenia improved on low dose filgrastim until 4 April 2020. Her blood counts normalised 1 month after and she is followed as an outpatient with Haematology, Infectious Diseases, and Urology services at the MUHC.
Discussion
FCR chemo-immunotherapy is considered the treatment for standard risk CLL patients under the age of 65,7 with a high overall response rate. However, the predominant complication is myelosuppression.8 Persistent neutropenia was reported in 19% and late infections in 9% of patients.9 The frequency of cytopenias was 35% at 3 months and 12% at 9 months after completion of therapy, respectively. Another side effect is prolonged lymphoid immunodeficiency.
Human adenovirus infections usually present as a keratoconjunctivitis or respiratory tract infection. In most healthy individuals the infection is usually self-limited. However, in immunosuppressed patients, infection may disseminate and become potentially life-threatening. Disseminated adenovirus infection can result from either de novo infection or a reactivation of clinically silent infection.10
BK virus is a member of the polyomavirus family. BK virus reactivation occurs only in immunosuppressed patients and can lead to nephropathy, ureteral stenosis, tubular interstitial damage and haemorrhagic cystitis. Viremia occurs in 20%–60% of this population. There is no specific treatment for BK virus-associated nephropathy, therefore viral replication can only be controlled through modulating the immunosuppressive condition.11
CMV is a herpes virus with a large double-stranded DNA that remains latent in the host after primary infection. Immunocompromised patients can have reactivation of their latent infection. Diagnosis of viral reactivation is made through CMV PCR in blood, tissue or body fluid. Manifestations of CMV infection occur most often in the gastrointestinal tract, lungs, liver and retina.12 As we did not observe the typical owl’s eye tissue lesion in the second bone marrow biopsy, we considered that CMV reactivation was a contributing factor for the pancytopenia, and treatment may have prevented such tissue lesion to develop. First line treatment of CMV infection includes intravenous ganciclovir or its oral prodrug valganciclovir, which are DNA polymerase inhibitors. The major side effect of these drugs is myelosuppression, including neutropenia.4
In our patient, the prolonged pancytopenias secondary to FCR was associated with haematuria with an ureteral mass. To date, only two observations on the use of cidofovir to simultaneously treat BK-virus associated haemorrhagic cystitis and CMV reactivation have been reported. However, in the case report by Held et al, the patient had received a bone marrow transplant for chronic myeloid leukaemia, whereas our patient had CLL.
Cidofovir has been suggested in some cases for the treatment of BK virus-associated haemorrhagic cystitis.13 Cidofovir and foscarnet are second-line therapies in patients with CMV that are either resistant or refractory to ganciclovir. Cidofovir is a non-cyclic analogue of cytidine monophosphate that terminates CMV DNA synthesis. In vitro studies showed effectiveness against herpes viruses, including CMV, herpes simplex viruses 1 and 2, varicella-zoster, Epstein-Barr virus, human papillomavirus and adenovirus. The main adverse effect is nephrotoxicity, causing proximal tubular injury. Serum creatinine and urine protein measurements are recommended during administration.14 Probenecid decreases intratubular secretion and maintains a sufficient plasma concentration to allow for once weekly dosing at 5 mg/kg to reduce its nephrotoxicity.13 An alternate dosing regimen, initially used in our patient, was three times per week dosing at 3 mg/kg. In the study performed by Philippe et al, intravenous cidofovir achieve remission in 81.5% of the 22 patients.13
The patient reported by Held et al recovered fully with cidofovir15; however, our patient was switched to ganciclovir due to persistent neutropenia. Bone marrow biopsy was consistent with secondary treatment-related myelosuppression syndrome, without evidence of myelodysplasia or lymphoproliferative infiltration. Myelosuppression is a major side effect of ganciclovir. However, the antiviral effects far outweigh these risks and therefore ganciclovir and its oral prodrug valganciclovir should be considered for patients with pancytopenia secondary to CMV reactivation.
In summary, this unique case of triple-viremia induced haemorrhagic cystitis in an immunosuppressed CLL patient posed both a diagnostic and therapeutic challenge as treatments are nephrotoxic and further increase immunosuppression.
The major learning point is to exercise caution when prescribing FCR chemotherapy on its long-term immunosuppressive effects. It is expected that novel immuno-chemotherapy for CLL should control the disease with reduced immunosuppressive effects.16
Patient’s perspective
Translation from French
I was diagnosed with CLL in November 2015. Started the treatments with FCR protocol in April 2019 (six treatments of three consecutive days each). At the end of the fourth treatment, I was not well. I had fever and a large fatigue with no energy. I finished treatments on the 13th of November 2019. On the week of 18 November, the symptoms appeared: fever, incontinent of urine with blood, no appetite, fatigue.
I visited MUHC emergency, 12 hours wait before I had a doctor’s room. I stayed the night and the next day I saw the doctor, but they did not know what I had. On the 22nd of November I returned to emergency with a lot of fever and other symptoms. I passed the night in an emergency room. On Saturday they released me, had fever and falls.
On the 24th I returned to emergency, fever and incontinence, etc. I was placed in the corridor in a stretcher with a commode next to the whole world. There was nowhere else for me, I had to go through the doors to go to the public toilet and I urinated every 5 min. I stayed in emergency 5 days before I was admitted to Internal Medicine.
It was a bad experience the three times I was in emergency. On 29 November, I had my own room. I was there till 07 February 2020.
The staff took charge rapidly. There were many tests during this long period to find out the cause of my problems. Everything came from the chemotherapy. Many departments were involved: urology, otolaryngology, haematology, internal medicine, infectious diseases.
There were several healthcare workers who spoke on behalf of other departments.
Very good service with the nursing staffs and the préposé (aux bénéficiaires). On my part, my immune system was severely damaged.
Learning points
Infections in immunosuppressed patients remain a diagnostic and therapeutic challenge.
In patient treated for chronic lymphocytic leukaemia, haematuria can be related to viral infections like BK virus, adenovirus and cytomegalovirus (CMV).
BK infection is diagnosed with a high index of suspicion, however, combined CMV and adenovirus infections renders the diagnosis more difficult.
Treatment of these viral infections remains difficult as medications are associated with myelotoxicity (ganciclovir) and renal insufficiency (cidofovir).
The authors would like to thank Dr Malek Merdad and Dr Isabelle Malhamé for their inspiration to write this article.
Contributors: MK and J-PR devised the project, main conceptual ideas and proof outlines. MK took the lead in writing the manuscript the supervision of J-PR. MK created all the images and translated the patient’s perspective from French to English. J-PR and JL provided critical feedback and helped shape analysis and manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Oral | DrugAdministrationRoute | CC BY-NC | 33402369 | 18,752,790 | 2021-01-05 |
What was the dosage of drug 'GANCICLOVIR'? | Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
Background
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder associated with mature B-cell dysfunction, hypogammaglobulinaemia and T-cell abnormalities. In Europe and North America, CLL is the most common leukaemia, with median age of diagnosis of 70 years.1 Treatment is indicated only for symptomatic disease, such as anaemia <100 g/L and/or thrombocytopenia <100×109/L, massive splenomegaly, lymphadenopathy or constitutional symptoms.2
Infection is a frequent cause of morbidity and mortality in CLL. Roughly 30%–50% of all CLL patients suffer infections, with a high subsequent mortality rate.3 While the majority of infections affect more often the respiratory track, or skin and the gastrointestinal tract.4 The most frequent organisms causing infections are bacteria like Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. This increased susceptibility to infection stems from B-cells with impaired immunoglobulin production capability and dysfunctional T-helper cells, which also assist in antibody production. This impaired capability to produce immunoglobulins, termed hypogammaglobulinaemia, affects 85% of CLL patients, particularly in advanced disease.4
Antineoplastic agents recommended for the treatment of CLL are also immunosuppressive and further increase the risk of infections.5 These include opportunistic micro-organisms such as Candida, Pneumocystis jirovecii, listeria, nocardia and atypical mycobacteria. In addition, patients have increased risk of viral diseases such as herpes simplex, Epstein-Barr and cytomegalovirus (CMV). Additional infectious complications may include hepatitis B reactivation and progressive multifocal leucoencephalopathy. In spite of the immunosuppressive risk, chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the standard risk therapy in fit patients below 65 years of age with CLL, in absence of 17 p deletion, or TP53 mutation, and with immunoglobulin heavy chain V (IGHV)-mutated.6
To reduce risk of infection, immunoglobulin levels should also be routinely monitored, particularly with rituximab, which reduces the number of B-cells expressing CD20. It is postulated that monitoring immunoglobulins while being treated with rituximab may reduce the risk of serious infections.4
Herein, we present a unique case of a woman treated for CLL who experienced severe pancytopenia and immunosuppression at the completion of her chemo-immunotherapy. She subsequently experienced triple concurrent viral infections, which posed a therapeutic challenge due to her pancytopenia.
Case presentation
A previously healthy 58-year-old woman was diagnosed with CLL through a routine blood test in 2015. Her physical examination was unremarkable and her lymphocyte counts were at 12.36×109 cells/L. Bone marrow biopsy with immunohistochemistry was suggestive of CLL and stained positive for BCL2, CD5 (aberrant T-cell marker), CD20, CD23, CD43 and CD79a (B-cell markers) while BCL6 was negative. The PCR amplification study showed immunoglobulin heavy chain gene rearrangement along with IgG kappa light chain gene arrangement. No t(14;18) BCL2/JH or t(11;14) BCL1/JH gene rearrangements were observed. As she was asymptomatic, and positron emission tomography (PET) scan showed low grade metabolic activity in lymph nodes in cervical, axillary and iliac areas, no therapy was initiated (figure 1). She was followed every 6 months.
Figure 1 Positron emission tomography scan (right) and corresponding CT images (left) of multiple low-grade hypermetabolic lymph nodes in 2017, 2 years after diagnosis of chronic lymphocytic leukaemia. (A) Multiple small low-grade hypermetabolic lymph nodes in bilateral neck regions predominantly in the posterior triangles. SUV of 1.9 in the left and right upper posterior triangles. (B) Hypermetabolic lymph nodes in the left axillary regions, SUV 1.8. (C) Left external iliac lymph node SUV of 3. SUV, Standardized uptake value.
In November 2017 the patient had symptom of a rapid bilateral enlargement of the cervical lymph nodes accompanied by persistent fatigue, night sweats and decreased weight. Lyme disease, HIV, hepatitis B and C and syphilis serologies were performed, and all tests yielded negative results. Repeat PET/CT scan, cytogenetics and bone marrow biopsy demonstrated no evidence of Richter’s transformation into a diffuse large cell lymphoma. Due to significant bulky disease and enlarged adenopathy with B constitutional symptoms, chemo-immunotherapy with FCR was considered. This was furthermore rationalised as she was a fit patient younger than 65 years of age with standard risk for CLL due to the absence of 17 p deletion, or TP53 mutation, and with IGHV being mutated.7
She received six cycles of FCR which was completed uneventfully on 11 November 2019. During FCR therapy, she received oral valacyclovir 500 mg two times per day for herpes prophylaxis as well as Septra DS (160 mg trimethoprim and 800 mg sulfamethoxazole) one tablet Mondays, Wednesdays and Fridays for P. jirovecii prophylaxis. On 18 November, she presented to the emergency room of the McGill University Health Centre (MUHC) with haematuria, suprapubic pain and fever. She was admitted and treated for a urine infection and slowly improved after different antibiotics such as ciprofloxacin, trimethoprim-sulfamethoxazole and ceftriaxone and blood and urinary bacterial cultures were negative. A CT urogram showed moderate bilateral hydroureteronephrosis with diffuse urolithelial and bladder thickening (figure 2). As a whole, these findings were suggestive of an inflammatory or infectious process evoking pyleoureteritis and cystitis.
Figure 2 CT urogram on admission in November 2019, demonstrating (A) poorly distended bladder and marked thickening of bladder walls (green arrow) and (B) moderate dilation of both ureters and collection ducts with marked thickening and enhancement of the urothelium associated with moderate periureteric fat stranding.
Investigations
On admission, she was mildly pancytopenic (table 1). As the patient partially improved and had negative urine cultures, a cyclophosphamide-induced haemorrhagic cystitis was considered, and she was placed on continuous bladder irrigation.
Table 1 Summary of the patient’s serological and microbiological test results during the course of her neutropenia and triple viremia
Laboratory results Reference ranges 20 March 2019 11 November 2019 26 November 2019 25 December 2019 01 January 2020 23 January 2020 01 February 2020 07 February 2020 03 March 2020
Time of intervention First dose FCR Last dose FCR Meropenem started Virology investigated Begins cidofovir+GCSF Cidofovir changed to Ganciclovir Ganciclovir transitioned to valganciclovir Discharge Follow-up
WBC (109/L) 4.0–10.0 30.90 5.90 3.00 1.00 0.60 2.40 6.10 2.40 2.00
Neutrophils 2.0–7.0 3.75 4.18 2.46 0.80 0.36 1.19 5.09 1.73 1.35
Lymphocytes 1.5–4.5 26.26 0.87 0.23 0.08 0.11 0.23 0.46 0.33 0.44
Plt (109/L) 150–450 145 158 123 48 19 54 17 12 39
Hb (g/L) 120–150 142 129 99 63 80 70 70 71 99
Creatinine (umol/L) 50–90 71 68 125 128 118 75 74 69 75
CMV (copies/mL) – – – – 7320 3170 1291 153 149 0
Adenovirus (copies/mL) – – – – – 7.44 log10 4.86 log10 3.74 log10 – 3.30 log10
BK virus urine (copies/mL) – – – – – 2.26×107 – 3.20×108 –
BK virus blood (copies/mL) – – – – – – – – – 3.91×103
CMV, cytomegalovirus; FCR, fludarabine, cyclophosphamide and rituximab; Hb, haemoglobin; Plt, platelet; WBC, white blood cell.
On 1 December 2019 she developed a pancytopenia that required platelet and packed red blood cell transfusions. She remained persistently febrile despite repeated negative bacterial blood and urine cultures. Due to her CLL, pancytopenia and the consideration of immunosuppression induced by FCR chemotherapy, viral infections were investigated. PCR for adenovirus showed 22.4 copies/mL in blood, and positive in urine; PCR for polyoma virus showed 8.81 million copies/mL blood; and PCR for CMV showed 358 copies/mL in blood, confirming viral invasive infections (figure 3). To further investigate her pancytopenia, serology for parvovirus B 19 was carried out and was negative for IgM.
Figure 3 Cytomegalovirus (CMV) and BK viremia (A) and adeno-viremia (B) over the course of treatment.
On 18 December 2019 the patient underwent a double J-stent insertion for bilateral hydronephrosis. Pelvic pain persisted and she continued to pass clots in her urine. Repeat CMV PCR testing on 25 December 2019 showed 7320 copies/mL while an ophthalmological assessment revealed no evidence of CMV retinitis or keratitis. Bone marrow biopsy results showed pancytopenia without transformation (figure 4).
Figure 4 Histology and immunochemistry of bone marrow smear (A) and biopsy (B). Bone marrow biopsy demonstrating hypocellularity. Moderate left shift of the myeloid series and mild left shift of the erythroid series. No lymphocytosis or lymphoma, no definite diagnosis of myelodysplastic syndrome (B).
Treatment
On 1 January 2020, cidofovir was administered to treat the three viral infections of BK polyomavirus, adenovirus and CMV. Cidofovir was given at the dose of 1 mg/kg intravenously three times a week instead of a weekly dose given her kidney injury and high creatinine levels. She received probenecid 2 g orally 1 hour before cidofovir, then 2 hours and 8 hours after the end of infusion to increase cidofovir levels in the blood. For renal protection, she was hydrated with 1 L of 0.9% normal saline during cidofovir infusion. Filgrastim (G-CSF) was initiated for her neutropenia, darbepoetin for her anaemia, and intravenous IgG was infused three times at 4-week intervals for her hypogammaglobulinumia.
Neutropenia worsen despite filgrastim, and CMV viral load continued to increase. Due to cidofovir myelotoxicity, a decision was made to focus treatment on CMV infection, while ignoring the BK and adenovirus. To this end, the patient was changed to ganciclovir 250 mg intravenous two times per day on 23 January 2020 and her urinary symptoms improved for the first time. On 1 February 2020, she was transitioned to oral valganciclovir 450 mg daily and was discharged to home 1 week later, after 101 days in hospital.
Outcome and follow-up
A bone marrow biopsy on 27 January 2020 showed a hypocellular marrow with focal area up to 20%–30% haematopoietic tissue. No evidence of lymphocytosis or lymphoma and no dysplastic changes in morphology were observed. Immunohistochemistry showed <5% CD117, and was negative for CD20, CD34 and PAX5. The histological appearance represented haematopoietic regeneration post-chemotherapy. On 3 March 2020 follow-up, CMV load was undetectable, adenovirus load was 5000 copies/mL, BK load was 3.2×108 copies/mL (table 1). She was switched on CMV prophylaxis with resolved haemorrhagic cystitis and received valganciclovir 450 mg p.o. daily for another 3 months and until her absolute lymphocyte count recovers above 109 cells/L. She continued trimethoprim-sulfamethaxole prophylaxis for 6 months post-chemotherapy. Her double-J stents remain in place. While clinically improved, her neutropenia improved on low dose filgrastim until 4 April 2020. Her blood counts normalised 1 month after and she is followed as an outpatient with Haematology, Infectious Diseases, and Urology services at the MUHC.
Discussion
FCR chemo-immunotherapy is considered the treatment for standard risk CLL patients under the age of 65,7 with a high overall response rate. However, the predominant complication is myelosuppression.8 Persistent neutropenia was reported in 19% and late infections in 9% of patients.9 The frequency of cytopenias was 35% at 3 months and 12% at 9 months after completion of therapy, respectively. Another side effect is prolonged lymphoid immunodeficiency.
Human adenovirus infections usually present as a keratoconjunctivitis or respiratory tract infection. In most healthy individuals the infection is usually self-limited. However, in immunosuppressed patients, infection may disseminate and become potentially life-threatening. Disseminated adenovirus infection can result from either de novo infection or a reactivation of clinically silent infection.10
BK virus is a member of the polyomavirus family. BK virus reactivation occurs only in immunosuppressed patients and can lead to nephropathy, ureteral stenosis, tubular interstitial damage and haemorrhagic cystitis. Viremia occurs in 20%–60% of this population. There is no specific treatment for BK virus-associated nephropathy, therefore viral replication can only be controlled through modulating the immunosuppressive condition.11
CMV is a herpes virus with a large double-stranded DNA that remains latent in the host after primary infection. Immunocompromised patients can have reactivation of their latent infection. Diagnosis of viral reactivation is made through CMV PCR in blood, tissue or body fluid. Manifestations of CMV infection occur most often in the gastrointestinal tract, lungs, liver and retina.12 As we did not observe the typical owl’s eye tissue lesion in the second bone marrow biopsy, we considered that CMV reactivation was a contributing factor for the pancytopenia, and treatment may have prevented such tissue lesion to develop. First line treatment of CMV infection includes intravenous ganciclovir or its oral prodrug valganciclovir, which are DNA polymerase inhibitors. The major side effect of these drugs is myelosuppression, including neutropenia.4
In our patient, the prolonged pancytopenias secondary to FCR was associated with haematuria with an ureteral mass. To date, only two observations on the use of cidofovir to simultaneously treat BK-virus associated haemorrhagic cystitis and CMV reactivation have been reported. However, in the case report by Held et al, the patient had received a bone marrow transplant for chronic myeloid leukaemia, whereas our patient had CLL.
Cidofovir has been suggested in some cases for the treatment of BK virus-associated haemorrhagic cystitis.13 Cidofovir and foscarnet are second-line therapies in patients with CMV that are either resistant or refractory to ganciclovir. Cidofovir is a non-cyclic analogue of cytidine monophosphate that terminates CMV DNA synthesis. In vitro studies showed effectiveness against herpes viruses, including CMV, herpes simplex viruses 1 and 2, varicella-zoster, Epstein-Barr virus, human papillomavirus and adenovirus. The main adverse effect is nephrotoxicity, causing proximal tubular injury. Serum creatinine and urine protein measurements are recommended during administration.14 Probenecid decreases intratubular secretion and maintains a sufficient plasma concentration to allow for once weekly dosing at 5 mg/kg to reduce its nephrotoxicity.13 An alternate dosing regimen, initially used in our patient, was three times per week dosing at 3 mg/kg. In the study performed by Philippe et al, intravenous cidofovir achieve remission in 81.5% of the 22 patients.13
The patient reported by Held et al recovered fully with cidofovir15; however, our patient was switched to ganciclovir due to persistent neutropenia. Bone marrow biopsy was consistent with secondary treatment-related myelosuppression syndrome, without evidence of myelodysplasia or lymphoproliferative infiltration. Myelosuppression is a major side effect of ganciclovir. However, the antiviral effects far outweigh these risks and therefore ganciclovir and its oral prodrug valganciclovir should be considered for patients with pancytopenia secondary to CMV reactivation.
In summary, this unique case of triple-viremia induced haemorrhagic cystitis in an immunosuppressed CLL patient posed both a diagnostic and therapeutic challenge as treatments are nephrotoxic and further increase immunosuppression.
The major learning point is to exercise caution when prescribing FCR chemotherapy on its long-term immunosuppressive effects. It is expected that novel immuno-chemotherapy for CLL should control the disease with reduced immunosuppressive effects.16
Patient’s perspective
Translation from French
I was diagnosed with CLL in November 2015. Started the treatments with FCR protocol in April 2019 (six treatments of three consecutive days each). At the end of the fourth treatment, I was not well. I had fever and a large fatigue with no energy. I finished treatments on the 13th of November 2019. On the week of 18 November, the symptoms appeared: fever, incontinent of urine with blood, no appetite, fatigue.
I visited MUHC emergency, 12 hours wait before I had a doctor’s room. I stayed the night and the next day I saw the doctor, but they did not know what I had. On the 22nd of November I returned to emergency with a lot of fever and other symptoms. I passed the night in an emergency room. On Saturday they released me, had fever and falls.
On the 24th I returned to emergency, fever and incontinence, etc. I was placed in the corridor in a stretcher with a commode next to the whole world. There was nowhere else for me, I had to go through the doors to go to the public toilet and I urinated every 5 min. I stayed in emergency 5 days before I was admitted to Internal Medicine.
It was a bad experience the three times I was in emergency. On 29 November, I had my own room. I was there till 07 February 2020.
The staff took charge rapidly. There were many tests during this long period to find out the cause of my problems. Everything came from the chemotherapy. Many departments were involved: urology, otolaryngology, haematology, internal medicine, infectious diseases.
There were several healthcare workers who spoke on behalf of other departments.
Very good service with the nursing staffs and the préposé (aux bénéficiaires). On my part, my immune system was severely damaged.
Learning points
Infections in immunosuppressed patients remain a diagnostic and therapeutic challenge.
In patient treated for chronic lymphocytic leukaemia, haematuria can be related to viral infections like BK virus, adenovirus and cytomegalovirus (CMV).
BK infection is diagnosed with a high index of suspicion, however, combined CMV and adenovirus infections renders the diagnosis more difficult.
Treatment of these viral infections remains difficult as medications are associated with myelotoxicity (ganciclovir) and renal insufficiency (cidofovir).
The authors would like to thank Dr Malek Merdad and Dr Isabelle Malhamé for their inspiration to write this article.
Contributors: MK and J-PR devised the project, main conceptual ideas and proof outlines. MK took the lead in writing the manuscript the supervision of J-PR. MK created all the images and translated the patient’s perspective from French to English. J-PR and JL provided critical feedback and helped shape analysis and manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | 250 MILLIGRAM, BID | DrugDosageText | CC BY-NC | 33402369 | 18,752,790 | 2021-01-05 |
What was the dosage of drug 'HUMAN IMMUNOGLOBULIN G'? | Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
Background
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder associated with mature B-cell dysfunction, hypogammaglobulinaemia and T-cell abnormalities. In Europe and North America, CLL is the most common leukaemia, with median age of diagnosis of 70 years.1 Treatment is indicated only for symptomatic disease, such as anaemia <100 g/L and/or thrombocytopenia <100×109/L, massive splenomegaly, lymphadenopathy or constitutional symptoms.2
Infection is a frequent cause of morbidity and mortality in CLL. Roughly 30%–50% of all CLL patients suffer infections, with a high subsequent mortality rate.3 While the majority of infections affect more often the respiratory track, or skin and the gastrointestinal tract.4 The most frequent organisms causing infections are bacteria like Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. This increased susceptibility to infection stems from B-cells with impaired immunoglobulin production capability and dysfunctional T-helper cells, which also assist in antibody production. This impaired capability to produce immunoglobulins, termed hypogammaglobulinaemia, affects 85% of CLL patients, particularly in advanced disease.4
Antineoplastic agents recommended for the treatment of CLL are also immunosuppressive and further increase the risk of infections.5 These include opportunistic micro-organisms such as Candida, Pneumocystis jirovecii, listeria, nocardia and atypical mycobacteria. In addition, patients have increased risk of viral diseases such as herpes simplex, Epstein-Barr and cytomegalovirus (CMV). Additional infectious complications may include hepatitis B reactivation and progressive multifocal leucoencephalopathy. In spite of the immunosuppressive risk, chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the standard risk therapy in fit patients below 65 years of age with CLL, in absence of 17 p deletion, or TP53 mutation, and with immunoglobulin heavy chain V (IGHV)-mutated.6
To reduce risk of infection, immunoglobulin levels should also be routinely monitored, particularly with rituximab, which reduces the number of B-cells expressing CD20. It is postulated that monitoring immunoglobulins while being treated with rituximab may reduce the risk of serious infections.4
Herein, we present a unique case of a woman treated for CLL who experienced severe pancytopenia and immunosuppression at the completion of her chemo-immunotherapy. She subsequently experienced triple concurrent viral infections, which posed a therapeutic challenge due to her pancytopenia.
Case presentation
A previously healthy 58-year-old woman was diagnosed with CLL through a routine blood test in 2015. Her physical examination was unremarkable and her lymphocyte counts were at 12.36×109 cells/L. Bone marrow biopsy with immunohistochemistry was suggestive of CLL and stained positive for BCL2, CD5 (aberrant T-cell marker), CD20, CD23, CD43 and CD79a (B-cell markers) while BCL6 was negative. The PCR amplification study showed immunoglobulin heavy chain gene rearrangement along with IgG kappa light chain gene arrangement. No t(14;18) BCL2/JH or t(11;14) BCL1/JH gene rearrangements were observed. As she was asymptomatic, and positron emission tomography (PET) scan showed low grade metabolic activity in lymph nodes in cervical, axillary and iliac areas, no therapy was initiated (figure 1). She was followed every 6 months.
Figure 1 Positron emission tomography scan (right) and corresponding CT images (left) of multiple low-grade hypermetabolic lymph nodes in 2017, 2 years after diagnosis of chronic lymphocytic leukaemia. (A) Multiple small low-grade hypermetabolic lymph nodes in bilateral neck regions predominantly in the posterior triangles. SUV of 1.9 in the left and right upper posterior triangles. (B) Hypermetabolic lymph nodes in the left axillary regions, SUV 1.8. (C) Left external iliac lymph node SUV of 3. SUV, Standardized uptake value.
In November 2017 the patient had symptom of a rapid bilateral enlargement of the cervical lymph nodes accompanied by persistent fatigue, night sweats and decreased weight. Lyme disease, HIV, hepatitis B and C and syphilis serologies were performed, and all tests yielded negative results. Repeat PET/CT scan, cytogenetics and bone marrow biopsy demonstrated no evidence of Richter’s transformation into a diffuse large cell lymphoma. Due to significant bulky disease and enlarged adenopathy with B constitutional symptoms, chemo-immunotherapy with FCR was considered. This was furthermore rationalised as she was a fit patient younger than 65 years of age with standard risk for CLL due to the absence of 17 p deletion, or TP53 mutation, and with IGHV being mutated.7
She received six cycles of FCR which was completed uneventfully on 11 November 2019. During FCR therapy, she received oral valacyclovir 500 mg two times per day for herpes prophylaxis as well as Septra DS (160 mg trimethoprim and 800 mg sulfamethoxazole) one tablet Mondays, Wednesdays and Fridays for P. jirovecii prophylaxis. On 18 November, she presented to the emergency room of the McGill University Health Centre (MUHC) with haematuria, suprapubic pain and fever. She was admitted and treated for a urine infection and slowly improved after different antibiotics such as ciprofloxacin, trimethoprim-sulfamethoxazole and ceftriaxone and blood and urinary bacterial cultures were negative. A CT urogram showed moderate bilateral hydroureteronephrosis with diffuse urolithelial and bladder thickening (figure 2). As a whole, these findings were suggestive of an inflammatory or infectious process evoking pyleoureteritis and cystitis.
Figure 2 CT urogram on admission in November 2019, demonstrating (A) poorly distended bladder and marked thickening of bladder walls (green arrow) and (B) moderate dilation of both ureters and collection ducts with marked thickening and enhancement of the urothelium associated with moderate periureteric fat stranding.
Investigations
On admission, she was mildly pancytopenic (table 1). As the patient partially improved and had negative urine cultures, a cyclophosphamide-induced haemorrhagic cystitis was considered, and she was placed on continuous bladder irrigation.
Table 1 Summary of the patient’s serological and microbiological test results during the course of her neutropenia and triple viremia
Laboratory results Reference ranges 20 March 2019 11 November 2019 26 November 2019 25 December 2019 01 January 2020 23 January 2020 01 February 2020 07 February 2020 03 March 2020
Time of intervention First dose FCR Last dose FCR Meropenem started Virology investigated Begins cidofovir+GCSF Cidofovir changed to Ganciclovir Ganciclovir transitioned to valganciclovir Discharge Follow-up
WBC (109/L) 4.0–10.0 30.90 5.90 3.00 1.00 0.60 2.40 6.10 2.40 2.00
Neutrophils 2.0–7.0 3.75 4.18 2.46 0.80 0.36 1.19 5.09 1.73 1.35
Lymphocytes 1.5–4.5 26.26 0.87 0.23 0.08 0.11 0.23 0.46 0.33 0.44
Plt (109/L) 150–450 145 158 123 48 19 54 17 12 39
Hb (g/L) 120–150 142 129 99 63 80 70 70 71 99
Creatinine (umol/L) 50–90 71 68 125 128 118 75 74 69 75
CMV (copies/mL) – – – – 7320 3170 1291 153 149 0
Adenovirus (copies/mL) – – – – – 7.44 log10 4.86 log10 3.74 log10 – 3.30 log10
BK virus urine (copies/mL) – – – – – 2.26×107 – 3.20×108 –
BK virus blood (copies/mL) – – – – – – – – – 3.91×103
CMV, cytomegalovirus; FCR, fludarabine, cyclophosphamide and rituximab; Hb, haemoglobin; Plt, platelet; WBC, white blood cell.
On 1 December 2019 she developed a pancytopenia that required platelet and packed red blood cell transfusions. She remained persistently febrile despite repeated negative bacterial blood and urine cultures. Due to her CLL, pancytopenia and the consideration of immunosuppression induced by FCR chemotherapy, viral infections were investigated. PCR for adenovirus showed 22.4 copies/mL in blood, and positive in urine; PCR for polyoma virus showed 8.81 million copies/mL blood; and PCR for CMV showed 358 copies/mL in blood, confirming viral invasive infections (figure 3). To further investigate her pancytopenia, serology for parvovirus B 19 was carried out and was negative for IgM.
Figure 3 Cytomegalovirus (CMV) and BK viremia (A) and adeno-viremia (B) over the course of treatment.
On 18 December 2019 the patient underwent a double J-stent insertion for bilateral hydronephrosis. Pelvic pain persisted and she continued to pass clots in her urine. Repeat CMV PCR testing on 25 December 2019 showed 7320 copies/mL while an ophthalmological assessment revealed no evidence of CMV retinitis or keratitis. Bone marrow biopsy results showed pancytopenia without transformation (figure 4).
Figure 4 Histology and immunochemistry of bone marrow smear (A) and biopsy (B). Bone marrow biopsy demonstrating hypocellularity. Moderate left shift of the myeloid series and mild left shift of the erythroid series. No lymphocytosis or lymphoma, no definite diagnosis of myelodysplastic syndrome (B).
Treatment
On 1 January 2020, cidofovir was administered to treat the three viral infections of BK polyomavirus, adenovirus and CMV. Cidofovir was given at the dose of 1 mg/kg intravenously three times a week instead of a weekly dose given her kidney injury and high creatinine levels. She received probenecid 2 g orally 1 hour before cidofovir, then 2 hours and 8 hours after the end of infusion to increase cidofovir levels in the blood. For renal protection, she was hydrated with 1 L of 0.9% normal saline during cidofovir infusion. Filgrastim (G-CSF) was initiated for her neutropenia, darbepoetin for her anaemia, and intravenous IgG was infused three times at 4-week intervals for her hypogammaglobulinumia.
Neutropenia worsen despite filgrastim, and CMV viral load continued to increase. Due to cidofovir myelotoxicity, a decision was made to focus treatment on CMV infection, while ignoring the BK and adenovirus. To this end, the patient was changed to ganciclovir 250 mg intravenous two times per day on 23 January 2020 and her urinary symptoms improved for the first time. On 1 February 2020, she was transitioned to oral valganciclovir 450 mg daily and was discharged to home 1 week later, after 101 days in hospital.
Outcome and follow-up
A bone marrow biopsy on 27 January 2020 showed a hypocellular marrow with focal area up to 20%–30% haematopoietic tissue. No evidence of lymphocytosis or lymphoma and no dysplastic changes in morphology were observed. Immunohistochemistry showed <5% CD117, and was negative for CD20, CD34 and PAX5. The histological appearance represented haematopoietic regeneration post-chemotherapy. On 3 March 2020 follow-up, CMV load was undetectable, adenovirus load was 5000 copies/mL, BK load was 3.2×108 copies/mL (table 1). She was switched on CMV prophylaxis with resolved haemorrhagic cystitis and received valganciclovir 450 mg p.o. daily for another 3 months and until her absolute lymphocyte count recovers above 109 cells/L. She continued trimethoprim-sulfamethaxole prophylaxis for 6 months post-chemotherapy. Her double-J stents remain in place. While clinically improved, her neutropenia improved on low dose filgrastim until 4 April 2020. Her blood counts normalised 1 month after and she is followed as an outpatient with Haematology, Infectious Diseases, and Urology services at the MUHC.
Discussion
FCR chemo-immunotherapy is considered the treatment for standard risk CLL patients under the age of 65,7 with a high overall response rate. However, the predominant complication is myelosuppression.8 Persistent neutropenia was reported in 19% and late infections in 9% of patients.9 The frequency of cytopenias was 35% at 3 months and 12% at 9 months after completion of therapy, respectively. Another side effect is prolonged lymphoid immunodeficiency.
Human adenovirus infections usually present as a keratoconjunctivitis or respiratory tract infection. In most healthy individuals the infection is usually self-limited. However, in immunosuppressed patients, infection may disseminate and become potentially life-threatening. Disseminated adenovirus infection can result from either de novo infection or a reactivation of clinically silent infection.10
BK virus is a member of the polyomavirus family. BK virus reactivation occurs only in immunosuppressed patients and can lead to nephropathy, ureteral stenosis, tubular interstitial damage and haemorrhagic cystitis. Viremia occurs in 20%–60% of this population. There is no specific treatment for BK virus-associated nephropathy, therefore viral replication can only be controlled through modulating the immunosuppressive condition.11
CMV is a herpes virus with a large double-stranded DNA that remains latent in the host after primary infection. Immunocompromised patients can have reactivation of their latent infection. Diagnosis of viral reactivation is made through CMV PCR in blood, tissue or body fluid. Manifestations of CMV infection occur most often in the gastrointestinal tract, lungs, liver and retina.12 As we did not observe the typical owl’s eye tissue lesion in the second bone marrow biopsy, we considered that CMV reactivation was a contributing factor for the pancytopenia, and treatment may have prevented such tissue lesion to develop. First line treatment of CMV infection includes intravenous ganciclovir or its oral prodrug valganciclovir, which are DNA polymerase inhibitors. The major side effect of these drugs is myelosuppression, including neutropenia.4
In our patient, the prolonged pancytopenias secondary to FCR was associated with haematuria with an ureteral mass. To date, only two observations on the use of cidofovir to simultaneously treat BK-virus associated haemorrhagic cystitis and CMV reactivation have been reported. However, in the case report by Held et al, the patient had received a bone marrow transplant for chronic myeloid leukaemia, whereas our patient had CLL.
Cidofovir has been suggested in some cases for the treatment of BK virus-associated haemorrhagic cystitis.13 Cidofovir and foscarnet are second-line therapies in patients with CMV that are either resistant or refractory to ganciclovir. Cidofovir is a non-cyclic analogue of cytidine monophosphate that terminates CMV DNA synthesis. In vitro studies showed effectiveness against herpes viruses, including CMV, herpes simplex viruses 1 and 2, varicella-zoster, Epstein-Barr virus, human papillomavirus and adenovirus. The main adverse effect is nephrotoxicity, causing proximal tubular injury. Serum creatinine and urine protein measurements are recommended during administration.14 Probenecid decreases intratubular secretion and maintains a sufficient plasma concentration to allow for once weekly dosing at 5 mg/kg to reduce its nephrotoxicity.13 An alternate dosing regimen, initially used in our patient, was three times per week dosing at 3 mg/kg. In the study performed by Philippe et al, intravenous cidofovir achieve remission in 81.5% of the 22 patients.13
The patient reported by Held et al recovered fully with cidofovir15; however, our patient was switched to ganciclovir due to persistent neutropenia. Bone marrow biopsy was consistent with secondary treatment-related myelosuppression syndrome, without evidence of myelodysplasia or lymphoproliferative infiltration. Myelosuppression is a major side effect of ganciclovir. However, the antiviral effects far outweigh these risks and therefore ganciclovir and its oral prodrug valganciclovir should be considered for patients with pancytopenia secondary to CMV reactivation.
In summary, this unique case of triple-viremia induced haemorrhagic cystitis in an immunosuppressed CLL patient posed both a diagnostic and therapeutic challenge as treatments are nephrotoxic and further increase immunosuppression.
The major learning point is to exercise caution when prescribing FCR chemotherapy on its long-term immunosuppressive effects. It is expected that novel immuno-chemotherapy for CLL should control the disease with reduced immunosuppressive effects.16
Patient’s perspective
Translation from French
I was diagnosed with CLL in November 2015. Started the treatments with FCR protocol in April 2019 (six treatments of three consecutive days each). At the end of the fourth treatment, I was not well. I had fever and a large fatigue with no energy. I finished treatments on the 13th of November 2019. On the week of 18 November, the symptoms appeared: fever, incontinent of urine with blood, no appetite, fatigue.
I visited MUHC emergency, 12 hours wait before I had a doctor’s room. I stayed the night and the next day I saw the doctor, but they did not know what I had. On the 22nd of November I returned to emergency with a lot of fever and other symptoms. I passed the night in an emergency room. On Saturday they released me, had fever and falls.
On the 24th I returned to emergency, fever and incontinence, etc. I was placed in the corridor in a stretcher with a commode next to the whole world. There was nowhere else for me, I had to go through the doors to go to the public toilet and I urinated every 5 min. I stayed in emergency 5 days before I was admitted to Internal Medicine.
It was a bad experience the three times I was in emergency. On 29 November, I had my own room. I was there till 07 February 2020.
The staff took charge rapidly. There were many tests during this long period to find out the cause of my problems. Everything came from the chemotherapy. Many departments were involved: urology, otolaryngology, haematology, internal medicine, infectious diseases.
There were several healthcare workers who spoke on behalf of other departments.
Very good service with the nursing staffs and the préposé (aux bénéficiaires). On my part, my immune system was severely damaged.
Learning points
Infections in immunosuppressed patients remain a diagnostic and therapeutic challenge.
In patient treated for chronic lymphocytic leukaemia, haematuria can be related to viral infections like BK virus, adenovirus and cytomegalovirus (CMV).
BK infection is diagnosed with a high index of suspicion, however, combined CMV and adenovirus infections renders the diagnosis more difficult.
Treatment of these viral infections remains difficult as medications are associated with myelotoxicity (ganciclovir) and renal insufficiency (cidofovir).
The authors would like to thank Dr Malek Merdad and Dr Isabelle Malhamé for their inspiration to write this article.
Contributors: MK and J-PR devised the project, main conceptual ideas and proof outlines. MK took the lead in writing the manuscript the supervision of J-PR. MK created all the images and translated the patient’s perspective from French to English. J-PR and JL provided critical feedback and helped shape analysis and manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | THREE TIMES AT 4 WEEK INTERVALS | DrugDosageText | CC BY-NC | 33402369 | 18,752,790 | 2021-01-05 |
What was the dosage of drug 'SODIUM CHLORIDE'? | Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
Background
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder associated with mature B-cell dysfunction, hypogammaglobulinaemia and T-cell abnormalities. In Europe and North America, CLL is the most common leukaemia, with median age of diagnosis of 70 years.1 Treatment is indicated only for symptomatic disease, such as anaemia <100 g/L and/or thrombocytopenia <100×109/L, massive splenomegaly, lymphadenopathy or constitutional symptoms.2
Infection is a frequent cause of morbidity and mortality in CLL. Roughly 30%–50% of all CLL patients suffer infections, with a high subsequent mortality rate.3 While the majority of infections affect more often the respiratory track, or skin and the gastrointestinal tract.4 The most frequent organisms causing infections are bacteria like Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. This increased susceptibility to infection stems from B-cells with impaired immunoglobulin production capability and dysfunctional T-helper cells, which also assist in antibody production. This impaired capability to produce immunoglobulins, termed hypogammaglobulinaemia, affects 85% of CLL patients, particularly in advanced disease.4
Antineoplastic agents recommended for the treatment of CLL are also immunosuppressive and further increase the risk of infections.5 These include opportunistic micro-organisms such as Candida, Pneumocystis jirovecii, listeria, nocardia and atypical mycobacteria. In addition, patients have increased risk of viral diseases such as herpes simplex, Epstein-Barr and cytomegalovirus (CMV). Additional infectious complications may include hepatitis B reactivation and progressive multifocal leucoencephalopathy. In spite of the immunosuppressive risk, chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the standard risk therapy in fit patients below 65 years of age with CLL, in absence of 17 p deletion, or TP53 mutation, and with immunoglobulin heavy chain V (IGHV)-mutated.6
To reduce risk of infection, immunoglobulin levels should also be routinely monitored, particularly with rituximab, which reduces the number of B-cells expressing CD20. It is postulated that monitoring immunoglobulins while being treated with rituximab may reduce the risk of serious infections.4
Herein, we present a unique case of a woman treated for CLL who experienced severe pancytopenia and immunosuppression at the completion of her chemo-immunotherapy. She subsequently experienced triple concurrent viral infections, which posed a therapeutic challenge due to her pancytopenia.
Case presentation
A previously healthy 58-year-old woman was diagnosed with CLL through a routine blood test in 2015. Her physical examination was unremarkable and her lymphocyte counts were at 12.36×109 cells/L. Bone marrow biopsy with immunohistochemistry was suggestive of CLL and stained positive for BCL2, CD5 (aberrant T-cell marker), CD20, CD23, CD43 and CD79a (B-cell markers) while BCL6 was negative. The PCR amplification study showed immunoglobulin heavy chain gene rearrangement along with IgG kappa light chain gene arrangement. No t(14;18) BCL2/JH or t(11;14) BCL1/JH gene rearrangements were observed. As she was asymptomatic, and positron emission tomography (PET) scan showed low grade metabolic activity in lymph nodes in cervical, axillary and iliac areas, no therapy was initiated (figure 1). She was followed every 6 months.
Figure 1 Positron emission tomography scan (right) and corresponding CT images (left) of multiple low-grade hypermetabolic lymph nodes in 2017, 2 years after diagnosis of chronic lymphocytic leukaemia. (A) Multiple small low-grade hypermetabolic lymph nodes in bilateral neck regions predominantly in the posterior triangles. SUV of 1.9 in the left and right upper posterior triangles. (B) Hypermetabolic lymph nodes in the left axillary regions, SUV 1.8. (C) Left external iliac lymph node SUV of 3. SUV, Standardized uptake value.
In November 2017 the patient had symptom of a rapid bilateral enlargement of the cervical lymph nodes accompanied by persistent fatigue, night sweats and decreased weight. Lyme disease, HIV, hepatitis B and C and syphilis serologies were performed, and all tests yielded negative results. Repeat PET/CT scan, cytogenetics and bone marrow biopsy demonstrated no evidence of Richter’s transformation into a diffuse large cell lymphoma. Due to significant bulky disease and enlarged adenopathy with B constitutional symptoms, chemo-immunotherapy with FCR was considered. This was furthermore rationalised as she was a fit patient younger than 65 years of age with standard risk for CLL due to the absence of 17 p deletion, or TP53 mutation, and with IGHV being mutated.7
She received six cycles of FCR which was completed uneventfully on 11 November 2019. During FCR therapy, she received oral valacyclovir 500 mg two times per day for herpes prophylaxis as well as Septra DS (160 mg trimethoprim and 800 mg sulfamethoxazole) one tablet Mondays, Wednesdays and Fridays for P. jirovecii prophylaxis. On 18 November, she presented to the emergency room of the McGill University Health Centre (MUHC) with haematuria, suprapubic pain and fever. She was admitted and treated for a urine infection and slowly improved after different antibiotics such as ciprofloxacin, trimethoprim-sulfamethoxazole and ceftriaxone and blood and urinary bacterial cultures were negative. A CT urogram showed moderate bilateral hydroureteronephrosis with diffuse urolithelial and bladder thickening (figure 2). As a whole, these findings were suggestive of an inflammatory or infectious process evoking pyleoureteritis and cystitis.
Figure 2 CT urogram on admission in November 2019, demonstrating (A) poorly distended bladder and marked thickening of bladder walls (green arrow) and (B) moderate dilation of both ureters and collection ducts with marked thickening and enhancement of the urothelium associated with moderate periureteric fat stranding.
Investigations
On admission, she was mildly pancytopenic (table 1). As the patient partially improved and had negative urine cultures, a cyclophosphamide-induced haemorrhagic cystitis was considered, and she was placed on continuous bladder irrigation.
Table 1 Summary of the patient’s serological and microbiological test results during the course of her neutropenia and triple viremia
Laboratory results Reference ranges 20 March 2019 11 November 2019 26 November 2019 25 December 2019 01 January 2020 23 January 2020 01 February 2020 07 February 2020 03 March 2020
Time of intervention First dose FCR Last dose FCR Meropenem started Virology investigated Begins cidofovir+GCSF Cidofovir changed to Ganciclovir Ganciclovir transitioned to valganciclovir Discharge Follow-up
WBC (109/L) 4.0–10.0 30.90 5.90 3.00 1.00 0.60 2.40 6.10 2.40 2.00
Neutrophils 2.0–7.0 3.75 4.18 2.46 0.80 0.36 1.19 5.09 1.73 1.35
Lymphocytes 1.5–4.5 26.26 0.87 0.23 0.08 0.11 0.23 0.46 0.33 0.44
Plt (109/L) 150–450 145 158 123 48 19 54 17 12 39
Hb (g/L) 120–150 142 129 99 63 80 70 70 71 99
Creatinine (umol/L) 50–90 71 68 125 128 118 75 74 69 75
CMV (copies/mL) – – – – 7320 3170 1291 153 149 0
Adenovirus (copies/mL) – – – – – 7.44 log10 4.86 log10 3.74 log10 – 3.30 log10
BK virus urine (copies/mL) – – – – – 2.26×107 – 3.20×108 –
BK virus blood (copies/mL) – – – – – – – – – 3.91×103
CMV, cytomegalovirus; FCR, fludarabine, cyclophosphamide and rituximab; Hb, haemoglobin; Plt, platelet; WBC, white blood cell.
On 1 December 2019 she developed a pancytopenia that required platelet and packed red blood cell transfusions. She remained persistently febrile despite repeated negative bacterial blood and urine cultures. Due to her CLL, pancytopenia and the consideration of immunosuppression induced by FCR chemotherapy, viral infections were investigated. PCR for adenovirus showed 22.4 copies/mL in blood, and positive in urine; PCR for polyoma virus showed 8.81 million copies/mL blood; and PCR for CMV showed 358 copies/mL in blood, confirming viral invasive infections (figure 3). To further investigate her pancytopenia, serology for parvovirus B 19 was carried out and was negative for IgM.
Figure 3 Cytomegalovirus (CMV) and BK viremia (A) and adeno-viremia (B) over the course of treatment.
On 18 December 2019 the patient underwent a double J-stent insertion for bilateral hydronephrosis. Pelvic pain persisted and she continued to pass clots in her urine. Repeat CMV PCR testing on 25 December 2019 showed 7320 copies/mL while an ophthalmological assessment revealed no evidence of CMV retinitis or keratitis. Bone marrow biopsy results showed pancytopenia without transformation (figure 4).
Figure 4 Histology and immunochemistry of bone marrow smear (A) and biopsy (B). Bone marrow biopsy demonstrating hypocellularity. Moderate left shift of the myeloid series and mild left shift of the erythroid series. No lymphocytosis or lymphoma, no definite diagnosis of myelodysplastic syndrome (B).
Treatment
On 1 January 2020, cidofovir was administered to treat the three viral infections of BK polyomavirus, adenovirus and CMV. Cidofovir was given at the dose of 1 mg/kg intravenously three times a week instead of a weekly dose given her kidney injury and high creatinine levels. She received probenecid 2 g orally 1 hour before cidofovir, then 2 hours and 8 hours after the end of infusion to increase cidofovir levels in the blood. For renal protection, she was hydrated with 1 L of 0.9% normal saline during cidofovir infusion. Filgrastim (G-CSF) was initiated for her neutropenia, darbepoetin for her anaemia, and intravenous IgG was infused three times at 4-week intervals for her hypogammaglobulinumia.
Neutropenia worsen despite filgrastim, and CMV viral load continued to increase. Due to cidofovir myelotoxicity, a decision was made to focus treatment on CMV infection, while ignoring the BK and adenovirus. To this end, the patient was changed to ganciclovir 250 mg intravenous two times per day on 23 January 2020 and her urinary symptoms improved for the first time. On 1 February 2020, she was transitioned to oral valganciclovir 450 mg daily and was discharged to home 1 week later, after 101 days in hospital.
Outcome and follow-up
A bone marrow biopsy on 27 January 2020 showed a hypocellular marrow with focal area up to 20%–30% haematopoietic tissue. No evidence of lymphocytosis or lymphoma and no dysplastic changes in morphology were observed. Immunohistochemistry showed <5% CD117, and was negative for CD20, CD34 and PAX5. The histological appearance represented haematopoietic regeneration post-chemotherapy. On 3 March 2020 follow-up, CMV load was undetectable, adenovirus load was 5000 copies/mL, BK load was 3.2×108 copies/mL (table 1). She was switched on CMV prophylaxis with resolved haemorrhagic cystitis and received valganciclovir 450 mg p.o. daily for another 3 months and until her absolute lymphocyte count recovers above 109 cells/L. She continued trimethoprim-sulfamethaxole prophylaxis for 6 months post-chemotherapy. Her double-J stents remain in place. While clinically improved, her neutropenia improved on low dose filgrastim until 4 April 2020. Her blood counts normalised 1 month after and she is followed as an outpatient with Haematology, Infectious Diseases, and Urology services at the MUHC.
Discussion
FCR chemo-immunotherapy is considered the treatment for standard risk CLL patients under the age of 65,7 with a high overall response rate. However, the predominant complication is myelosuppression.8 Persistent neutropenia was reported in 19% and late infections in 9% of patients.9 The frequency of cytopenias was 35% at 3 months and 12% at 9 months after completion of therapy, respectively. Another side effect is prolonged lymphoid immunodeficiency.
Human adenovirus infections usually present as a keratoconjunctivitis or respiratory tract infection. In most healthy individuals the infection is usually self-limited. However, in immunosuppressed patients, infection may disseminate and become potentially life-threatening. Disseminated adenovirus infection can result from either de novo infection or a reactivation of clinically silent infection.10
BK virus is a member of the polyomavirus family. BK virus reactivation occurs only in immunosuppressed patients and can lead to nephropathy, ureteral stenosis, tubular interstitial damage and haemorrhagic cystitis. Viremia occurs in 20%–60% of this population. There is no specific treatment for BK virus-associated nephropathy, therefore viral replication can only be controlled through modulating the immunosuppressive condition.11
CMV is a herpes virus with a large double-stranded DNA that remains latent in the host after primary infection. Immunocompromised patients can have reactivation of their latent infection. Diagnosis of viral reactivation is made through CMV PCR in blood, tissue or body fluid. Manifestations of CMV infection occur most often in the gastrointestinal tract, lungs, liver and retina.12 As we did not observe the typical owl’s eye tissue lesion in the second bone marrow biopsy, we considered that CMV reactivation was a contributing factor for the pancytopenia, and treatment may have prevented such tissue lesion to develop. First line treatment of CMV infection includes intravenous ganciclovir or its oral prodrug valganciclovir, which are DNA polymerase inhibitors. The major side effect of these drugs is myelosuppression, including neutropenia.4
In our patient, the prolonged pancytopenias secondary to FCR was associated with haematuria with an ureteral mass. To date, only two observations on the use of cidofovir to simultaneously treat BK-virus associated haemorrhagic cystitis and CMV reactivation have been reported. However, in the case report by Held et al, the patient had received a bone marrow transplant for chronic myeloid leukaemia, whereas our patient had CLL.
Cidofovir has been suggested in some cases for the treatment of BK virus-associated haemorrhagic cystitis.13 Cidofovir and foscarnet are second-line therapies in patients with CMV that are either resistant or refractory to ganciclovir. Cidofovir is a non-cyclic analogue of cytidine monophosphate that terminates CMV DNA synthesis. In vitro studies showed effectiveness against herpes viruses, including CMV, herpes simplex viruses 1 and 2, varicella-zoster, Epstein-Barr virus, human papillomavirus and adenovirus. The main adverse effect is nephrotoxicity, causing proximal tubular injury. Serum creatinine and urine protein measurements are recommended during administration.14 Probenecid decreases intratubular secretion and maintains a sufficient plasma concentration to allow for once weekly dosing at 5 mg/kg to reduce its nephrotoxicity.13 An alternate dosing regimen, initially used in our patient, was three times per week dosing at 3 mg/kg. In the study performed by Philippe et al, intravenous cidofovir achieve remission in 81.5% of the 22 patients.13
The patient reported by Held et al recovered fully with cidofovir15; however, our patient was switched to ganciclovir due to persistent neutropenia. Bone marrow biopsy was consistent with secondary treatment-related myelosuppression syndrome, without evidence of myelodysplasia or lymphoproliferative infiltration. Myelosuppression is a major side effect of ganciclovir. However, the antiviral effects far outweigh these risks and therefore ganciclovir and its oral prodrug valganciclovir should be considered for patients with pancytopenia secondary to CMV reactivation.
In summary, this unique case of triple-viremia induced haemorrhagic cystitis in an immunosuppressed CLL patient posed both a diagnostic and therapeutic challenge as treatments are nephrotoxic and further increase immunosuppression.
The major learning point is to exercise caution when prescribing FCR chemotherapy on its long-term immunosuppressive effects. It is expected that novel immuno-chemotherapy for CLL should control the disease with reduced immunosuppressive effects.16
Patient’s perspective
Translation from French
I was diagnosed with CLL in November 2015. Started the treatments with FCR protocol in April 2019 (six treatments of three consecutive days each). At the end of the fourth treatment, I was not well. I had fever and a large fatigue with no energy. I finished treatments on the 13th of November 2019. On the week of 18 November, the symptoms appeared: fever, incontinent of urine with blood, no appetite, fatigue.
I visited MUHC emergency, 12 hours wait before I had a doctor’s room. I stayed the night and the next day I saw the doctor, but they did not know what I had. On the 22nd of November I returned to emergency with a lot of fever and other symptoms. I passed the night in an emergency room. On Saturday they released me, had fever and falls.
On the 24th I returned to emergency, fever and incontinence, etc. I was placed in the corridor in a stretcher with a commode next to the whole world. There was nowhere else for me, I had to go through the doors to go to the public toilet and I urinated every 5 min. I stayed in emergency 5 days before I was admitted to Internal Medicine.
It was a bad experience the three times I was in emergency. On 29 November, I had my own room. I was there till 07 February 2020.
The staff took charge rapidly. There were many tests during this long period to find out the cause of my problems. Everything came from the chemotherapy. Many departments were involved: urology, otolaryngology, haematology, internal medicine, infectious diseases.
There were several healthcare workers who spoke on behalf of other departments.
Very good service with the nursing staffs and the préposé (aux bénéficiaires). On my part, my immune system was severely damaged.
Learning points
Infections in immunosuppressed patients remain a diagnostic and therapeutic challenge.
In patient treated for chronic lymphocytic leukaemia, haematuria can be related to viral infections like BK virus, adenovirus and cytomegalovirus (CMV).
BK infection is diagnosed with a high index of suspicion, however, combined CMV and adenovirus infections renders the diagnosis more difficult.
Treatment of these viral infections remains difficult as medications are associated with myelotoxicity (ganciclovir) and renal insufficiency (cidofovir).
The authors would like to thank Dr Malek Merdad and Dr Isabelle Malhamé for their inspiration to write this article.
Contributors: MK and J-PR devised the project, main conceptual ideas and proof outlines. MK took the lead in writing the manuscript the supervision of J-PR. MK created all the images and translated the patient’s perspective from French to English. J-PR and JL provided critical feedback and helped shape analysis and manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | 1 LT | DrugDosageText | CC BY-NC | 33402369 | 19,066,566 | 2021-01-05 |
What was the dosage of drug 'SULFAMETHOXAZOLE\TRIMETHOPRIM'? | Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
Background
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder associated with mature B-cell dysfunction, hypogammaglobulinaemia and T-cell abnormalities. In Europe and North America, CLL is the most common leukaemia, with median age of diagnosis of 70 years.1 Treatment is indicated only for symptomatic disease, such as anaemia <100 g/L and/or thrombocytopenia <100×109/L, massive splenomegaly, lymphadenopathy or constitutional symptoms.2
Infection is a frequent cause of morbidity and mortality in CLL. Roughly 30%–50% of all CLL patients suffer infections, with a high subsequent mortality rate.3 While the majority of infections affect more often the respiratory track, or skin and the gastrointestinal tract.4 The most frequent organisms causing infections are bacteria like Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. This increased susceptibility to infection stems from B-cells with impaired immunoglobulin production capability and dysfunctional T-helper cells, which also assist in antibody production. This impaired capability to produce immunoglobulins, termed hypogammaglobulinaemia, affects 85% of CLL patients, particularly in advanced disease.4
Antineoplastic agents recommended for the treatment of CLL are also immunosuppressive and further increase the risk of infections.5 These include opportunistic micro-organisms such as Candida, Pneumocystis jirovecii, listeria, nocardia and atypical mycobacteria. In addition, patients have increased risk of viral diseases such as herpes simplex, Epstein-Barr and cytomegalovirus (CMV). Additional infectious complications may include hepatitis B reactivation and progressive multifocal leucoencephalopathy. In spite of the immunosuppressive risk, chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the standard risk therapy in fit patients below 65 years of age with CLL, in absence of 17 p deletion, or TP53 mutation, and with immunoglobulin heavy chain V (IGHV)-mutated.6
To reduce risk of infection, immunoglobulin levels should also be routinely monitored, particularly with rituximab, which reduces the number of B-cells expressing CD20. It is postulated that monitoring immunoglobulins while being treated with rituximab may reduce the risk of serious infections.4
Herein, we present a unique case of a woman treated for CLL who experienced severe pancytopenia and immunosuppression at the completion of her chemo-immunotherapy. She subsequently experienced triple concurrent viral infections, which posed a therapeutic challenge due to her pancytopenia.
Case presentation
A previously healthy 58-year-old woman was diagnosed with CLL through a routine blood test in 2015. Her physical examination was unremarkable and her lymphocyte counts were at 12.36×109 cells/L. Bone marrow biopsy with immunohistochemistry was suggestive of CLL and stained positive for BCL2, CD5 (aberrant T-cell marker), CD20, CD23, CD43 and CD79a (B-cell markers) while BCL6 was negative. The PCR amplification study showed immunoglobulin heavy chain gene rearrangement along with IgG kappa light chain gene arrangement. No t(14;18) BCL2/JH or t(11;14) BCL1/JH gene rearrangements were observed. As she was asymptomatic, and positron emission tomography (PET) scan showed low grade metabolic activity in lymph nodes in cervical, axillary and iliac areas, no therapy was initiated (figure 1). She was followed every 6 months.
Figure 1 Positron emission tomography scan (right) and corresponding CT images (left) of multiple low-grade hypermetabolic lymph nodes in 2017, 2 years after diagnosis of chronic lymphocytic leukaemia. (A) Multiple small low-grade hypermetabolic lymph nodes in bilateral neck regions predominantly in the posterior triangles. SUV of 1.9 in the left and right upper posterior triangles. (B) Hypermetabolic lymph nodes in the left axillary regions, SUV 1.8. (C) Left external iliac lymph node SUV of 3. SUV, Standardized uptake value.
In November 2017 the patient had symptom of a rapid bilateral enlargement of the cervical lymph nodes accompanied by persistent fatigue, night sweats and decreased weight. Lyme disease, HIV, hepatitis B and C and syphilis serologies were performed, and all tests yielded negative results. Repeat PET/CT scan, cytogenetics and bone marrow biopsy demonstrated no evidence of Richter’s transformation into a diffuse large cell lymphoma. Due to significant bulky disease and enlarged adenopathy with B constitutional symptoms, chemo-immunotherapy with FCR was considered. This was furthermore rationalised as she was a fit patient younger than 65 years of age with standard risk for CLL due to the absence of 17 p deletion, or TP53 mutation, and with IGHV being mutated.7
She received six cycles of FCR which was completed uneventfully on 11 November 2019. During FCR therapy, she received oral valacyclovir 500 mg two times per day for herpes prophylaxis as well as Septra DS (160 mg trimethoprim and 800 mg sulfamethoxazole) one tablet Mondays, Wednesdays and Fridays for P. jirovecii prophylaxis. On 18 November, she presented to the emergency room of the McGill University Health Centre (MUHC) with haematuria, suprapubic pain and fever. She was admitted and treated for a urine infection and slowly improved after different antibiotics such as ciprofloxacin, trimethoprim-sulfamethoxazole and ceftriaxone and blood and urinary bacterial cultures were negative. A CT urogram showed moderate bilateral hydroureteronephrosis with diffuse urolithelial and bladder thickening (figure 2). As a whole, these findings were suggestive of an inflammatory or infectious process evoking pyleoureteritis and cystitis.
Figure 2 CT urogram on admission in November 2019, demonstrating (A) poorly distended bladder and marked thickening of bladder walls (green arrow) and (B) moderate dilation of both ureters and collection ducts with marked thickening and enhancement of the urothelium associated with moderate periureteric fat stranding.
Investigations
On admission, she was mildly pancytopenic (table 1). As the patient partially improved and had negative urine cultures, a cyclophosphamide-induced haemorrhagic cystitis was considered, and she was placed on continuous bladder irrigation.
Table 1 Summary of the patient’s serological and microbiological test results during the course of her neutropenia and triple viremia
Laboratory results Reference ranges 20 March 2019 11 November 2019 26 November 2019 25 December 2019 01 January 2020 23 January 2020 01 February 2020 07 February 2020 03 March 2020
Time of intervention First dose FCR Last dose FCR Meropenem started Virology investigated Begins cidofovir+GCSF Cidofovir changed to Ganciclovir Ganciclovir transitioned to valganciclovir Discharge Follow-up
WBC (109/L) 4.0–10.0 30.90 5.90 3.00 1.00 0.60 2.40 6.10 2.40 2.00
Neutrophils 2.0–7.0 3.75 4.18 2.46 0.80 0.36 1.19 5.09 1.73 1.35
Lymphocytes 1.5–4.5 26.26 0.87 0.23 0.08 0.11 0.23 0.46 0.33 0.44
Plt (109/L) 150–450 145 158 123 48 19 54 17 12 39
Hb (g/L) 120–150 142 129 99 63 80 70 70 71 99
Creatinine (umol/L) 50–90 71 68 125 128 118 75 74 69 75
CMV (copies/mL) – – – – 7320 3170 1291 153 149 0
Adenovirus (copies/mL) – – – – – 7.44 log10 4.86 log10 3.74 log10 – 3.30 log10
BK virus urine (copies/mL) – – – – – 2.26×107 – 3.20×108 –
BK virus blood (copies/mL) – – – – – – – – – 3.91×103
CMV, cytomegalovirus; FCR, fludarabine, cyclophosphamide and rituximab; Hb, haemoglobin; Plt, platelet; WBC, white blood cell.
On 1 December 2019 she developed a pancytopenia that required platelet and packed red blood cell transfusions. She remained persistently febrile despite repeated negative bacterial blood and urine cultures. Due to her CLL, pancytopenia and the consideration of immunosuppression induced by FCR chemotherapy, viral infections were investigated. PCR for adenovirus showed 22.4 copies/mL in blood, and positive in urine; PCR for polyoma virus showed 8.81 million copies/mL blood; and PCR for CMV showed 358 copies/mL in blood, confirming viral invasive infections (figure 3). To further investigate her pancytopenia, serology for parvovirus B 19 was carried out and was negative for IgM.
Figure 3 Cytomegalovirus (CMV) and BK viremia (A) and adeno-viremia (B) over the course of treatment.
On 18 December 2019 the patient underwent a double J-stent insertion for bilateral hydronephrosis. Pelvic pain persisted and she continued to pass clots in her urine. Repeat CMV PCR testing on 25 December 2019 showed 7320 copies/mL while an ophthalmological assessment revealed no evidence of CMV retinitis or keratitis. Bone marrow biopsy results showed pancytopenia without transformation (figure 4).
Figure 4 Histology and immunochemistry of bone marrow smear (A) and biopsy (B). Bone marrow biopsy demonstrating hypocellularity. Moderate left shift of the myeloid series and mild left shift of the erythroid series. No lymphocytosis or lymphoma, no definite diagnosis of myelodysplastic syndrome (B).
Treatment
On 1 January 2020, cidofovir was administered to treat the three viral infections of BK polyomavirus, adenovirus and CMV. Cidofovir was given at the dose of 1 mg/kg intravenously three times a week instead of a weekly dose given her kidney injury and high creatinine levels. She received probenecid 2 g orally 1 hour before cidofovir, then 2 hours and 8 hours after the end of infusion to increase cidofovir levels in the blood. For renal protection, she was hydrated with 1 L of 0.9% normal saline during cidofovir infusion. Filgrastim (G-CSF) was initiated for her neutropenia, darbepoetin for her anaemia, and intravenous IgG was infused three times at 4-week intervals for her hypogammaglobulinumia.
Neutropenia worsen despite filgrastim, and CMV viral load continued to increase. Due to cidofovir myelotoxicity, a decision was made to focus treatment on CMV infection, while ignoring the BK and adenovirus. To this end, the patient was changed to ganciclovir 250 mg intravenous two times per day on 23 January 2020 and her urinary symptoms improved for the first time. On 1 February 2020, she was transitioned to oral valganciclovir 450 mg daily and was discharged to home 1 week later, after 101 days in hospital.
Outcome and follow-up
A bone marrow biopsy on 27 January 2020 showed a hypocellular marrow with focal area up to 20%–30% haematopoietic tissue. No evidence of lymphocytosis or lymphoma and no dysplastic changes in morphology were observed. Immunohistochemistry showed <5% CD117, and was negative for CD20, CD34 and PAX5. The histological appearance represented haematopoietic regeneration post-chemotherapy. On 3 March 2020 follow-up, CMV load was undetectable, adenovirus load was 5000 copies/mL, BK load was 3.2×108 copies/mL (table 1). She was switched on CMV prophylaxis with resolved haemorrhagic cystitis and received valganciclovir 450 mg p.o. daily for another 3 months and until her absolute lymphocyte count recovers above 109 cells/L. She continued trimethoprim-sulfamethaxole prophylaxis for 6 months post-chemotherapy. Her double-J stents remain in place. While clinically improved, her neutropenia improved on low dose filgrastim until 4 April 2020. Her blood counts normalised 1 month after and she is followed as an outpatient with Haematology, Infectious Diseases, and Urology services at the MUHC.
Discussion
FCR chemo-immunotherapy is considered the treatment for standard risk CLL patients under the age of 65,7 with a high overall response rate. However, the predominant complication is myelosuppression.8 Persistent neutropenia was reported in 19% and late infections in 9% of patients.9 The frequency of cytopenias was 35% at 3 months and 12% at 9 months after completion of therapy, respectively. Another side effect is prolonged lymphoid immunodeficiency.
Human adenovirus infections usually present as a keratoconjunctivitis or respiratory tract infection. In most healthy individuals the infection is usually self-limited. However, in immunosuppressed patients, infection may disseminate and become potentially life-threatening. Disseminated adenovirus infection can result from either de novo infection or a reactivation of clinically silent infection.10
BK virus is a member of the polyomavirus family. BK virus reactivation occurs only in immunosuppressed patients and can lead to nephropathy, ureteral stenosis, tubular interstitial damage and haemorrhagic cystitis. Viremia occurs in 20%–60% of this population. There is no specific treatment for BK virus-associated nephropathy, therefore viral replication can only be controlled through modulating the immunosuppressive condition.11
CMV is a herpes virus with a large double-stranded DNA that remains latent in the host after primary infection. Immunocompromised patients can have reactivation of their latent infection. Diagnosis of viral reactivation is made through CMV PCR in blood, tissue or body fluid. Manifestations of CMV infection occur most often in the gastrointestinal tract, lungs, liver and retina.12 As we did not observe the typical owl’s eye tissue lesion in the second bone marrow biopsy, we considered that CMV reactivation was a contributing factor for the pancytopenia, and treatment may have prevented such tissue lesion to develop. First line treatment of CMV infection includes intravenous ganciclovir or its oral prodrug valganciclovir, which are DNA polymerase inhibitors. The major side effect of these drugs is myelosuppression, including neutropenia.4
In our patient, the prolonged pancytopenias secondary to FCR was associated with haematuria with an ureteral mass. To date, only two observations on the use of cidofovir to simultaneously treat BK-virus associated haemorrhagic cystitis and CMV reactivation have been reported. However, in the case report by Held et al, the patient had received a bone marrow transplant for chronic myeloid leukaemia, whereas our patient had CLL.
Cidofovir has been suggested in some cases for the treatment of BK virus-associated haemorrhagic cystitis.13 Cidofovir and foscarnet are second-line therapies in patients with CMV that are either resistant or refractory to ganciclovir. Cidofovir is a non-cyclic analogue of cytidine monophosphate that terminates CMV DNA synthesis. In vitro studies showed effectiveness against herpes viruses, including CMV, herpes simplex viruses 1 and 2, varicella-zoster, Epstein-Barr virus, human papillomavirus and adenovirus. The main adverse effect is nephrotoxicity, causing proximal tubular injury. Serum creatinine and urine protein measurements are recommended during administration.14 Probenecid decreases intratubular secretion and maintains a sufficient plasma concentration to allow for once weekly dosing at 5 mg/kg to reduce its nephrotoxicity.13 An alternate dosing regimen, initially used in our patient, was three times per week dosing at 3 mg/kg. In the study performed by Philippe et al, intravenous cidofovir achieve remission in 81.5% of the 22 patients.13
The patient reported by Held et al recovered fully with cidofovir15; however, our patient was switched to ganciclovir due to persistent neutropenia. Bone marrow biopsy was consistent with secondary treatment-related myelosuppression syndrome, without evidence of myelodysplasia or lymphoproliferative infiltration. Myelosuppression is a major side effect of ganciclovir. However, the antiviral effects far outweigh these risks and therefore ganciclovir and its oral prodrug valganciclovir should be considered for patients with pancytopenia secondary to CMV reactivation.
In summary, this unique case of triple-viremia induced haemorrhagic cystitis in an immunosuppressed CLL patient posed both a diagnostic and therapeutic challenge as treatments are nephrotoxic and further increase immunosuppression.
The major learning point is to exercise caution when prescribing FCR chemotherapy on its long-term immunosuppressive effects. It is expected that novel immuno-chemotherapy for CLL should control the disease with reduced immunosuppressive effects.16
Patient’s perspective
Translation from French
I was diagnosed with CLL in November 2015. Started the treatments with FCR protocol in April 2019 (six treatments of three consecutive days each). At the end of the fourth treatment, I was not well. I had fever and a large fatigue with no energy. I finished treatments on the 13th of November 2019. On the week of 18 November, the symptoms appeared: fever, incontinent of urine with blood, no appetite, fatigue.
I visited MUHC emergency, 12 hours wait before I had a doctor’s room. I stayed the night and the next day I saw the doctor, but they did not know what I had. On the 22nd of November I returned to emergency with a lot of fever and other symptoms. I passed the night in an emergency room. On Saturday they released me, had fever and falls.
On the 24th I returned to emergency, fever and incontinence, etc. I was placed in the corridor in a stretcher with a commode next to the whole world. There was nowhere else for me, I had to go through the doors to go to the public toilet and I urinated every 5 min. I stayed in emergency 5 days before I was admitted to Internal Medicine.
It was a bad experience the three times I was in emergency. On 29 November, I had my own room. I was there till 07 February 2020.
The staff took charge rapidly. There were many tests during this long period to find out the cause of my problems. Everything came from the chemotherapy. Many departments were involved: urology, otolaryngology, haematology, internal medicine, infectious diseases.
There were several healthcare workers who spoke on behalf of other departments.
Very good service with the nursing staffs and the préposé (aux bénéficiaires). On my part, my immune system was severely damaged.
Learning points
Infections in immunosuppressed patients remain a diagnostic and therapeutic challenge.
In patient treated for chronic lymphocytic leukaemia, haematuria can be related to viral infections like BK virus, adenovirus and cytomegalovirus (CMV).
BK infection is diagnosed with a high index of suspicion, however, combined CMV and adenovirus infections renders the diagnosis more difficult.
Treatment of these viral infections remains difficult as medications are associated with myelotoxicity (ganciclovir) and renal insufficiency (cidofovir).
The authors would like to thank Dr Malek Merdad and Dr Isabelle Malhamé for their inspiration to write this article.
Contributors: MK and J-PR devised the project, main conceptual ideas and proof outlines. MK took the lead in writing the manuscript the supervision of J-PR. MK created all the images and translated the patient’s perspective from French to English. J-PR and JL provided critical feedback and helped shape analysis and manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | ON MONDAY, TUESDAY AND WEDNESDAY EVERY WEEK | DrugDosageText | CC BY-NC | 33402369 | 19,066,566 | 2021-01-05 |
What was the dosage of drug 'VALACYCLOVIR HYDROCHLORIDE'? | Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
Background
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder associated with mature B-cell dysfunction, hypogammaglobulinaemia and T-cell abnormalities. In Europe and North America, CLL is the most common leukaemia, with median age of diagnosis of 70 years.1 Treatment is indicated only for symptomatic disease, such as anaemia <100 g/L and/or thrombocytopenia <100×109/L, massive splenomegaly, lymphadenopathy or constitutional symptoms.2
Infection is a frequent cause of morbidity and mortality in CLL. Roughly 30%–50% of all CLL patients suffer infections, with a high subsequent mortality rate.3 While the majority of infections affect more often the respiratory track, or skin and the gastrointestinal tract.4 The most frequent organisms causing infections are bacteria like Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. This increased susceptibility to infection stems from B-cells with impaired immunoglobulin production capability and dysfunctional T-helper cells, which also assist in antibody production. This impaired capability to produce immunoglobulins, termed hypogammaglobulinaemia, affects 85% of CLL patients, particularly in advanced disease.4
Antineoplastic agents recommended for the treatment of CLL are also immunosuppressive and further increase the risk of infections.5 These include opportunistic micro-organisms such as Candida, Pneumocystis jirovecii, listeria, nocardia and atypical mycobacteria. In addition, patients have increased risk of viral diseases such as herpes simplex, Epstein-Barr and cytomegalovirus (CMV). Additional infectious complications may include hepatitis B reactivation and progressive multifocal leucoencephalopathy. In spite of the immunosuppressive risk, chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the standard risk therapy in fit patients below 65 years of age with CLL, in absence of 17 p deletion, or TP53 mutation, and with immunoglobulin heavy chain V (IGHV)-mutated.6
To reduce risk of infection, immunoglobulin levels should also be routinely monitored, particularly with rituximab, which reduces the number of B-cells expressing CD20. It is postulated that monitoring immunoglobulins while being treated with rituximab may reduce the risk of serious infections.4
Herein, we present a unique case of a woman treated for CLL who experienced severe pancytopenia and immunosuppression at the completion of her chemo-immunotherapy. She subsequently experienced triple concurrent viral infections, which posed a therapeutic challenge due to her pancytopenia.
Case presentation
A previously healthy 58-year-old woman was diagnosed with CLL through a routine blood test in 2015. Her physical examination was unremarkable and her lymphocyte counts were at 12.36×109 cells/L. Bone marrow biopsy with immunohistochemistry was suggestive of CLL and stained positive for BCL2, CD5 (aberrant T-cell marker), CD20, CD23, CD43 and CD79a (B-cell markers) while BCL6 was negative. The PCR amplification study showed immunoglobulin heavy chain gene rearrangement along with IgG kappa light chain gene arrangement. No t(14;18) BCL2/JH or t(11;14) BCL1/JH gene rearrangements were observed. As she was asymptomatic, and positron emission tomography (PET) scan showed low grade metabolic activity in lymph nodes in cervical, axillary and iliac areas, no therapy was initiated (figure 1). She was followed every 6 months.
Figure 1 Positron emission tomography scan (right) and corresponding CT images (left) of multiple low-grade hypermetabolic lymph nodes in 2017, 2 years after diagnosis of chronic lymphocytic leukaemia. (A) Multiple small low-grade hypermetabolic lymph nodes in bilateral neck regions predominantly in the posterior triangles. SUV of 1.9 in the left and right upper posterior triangles. (B) Hypermetabolic lymph nodes in the left axillary regions, SUV 1.8. (C) Left external iliac lymph node SUV of 3. SUV, Standardized uptake value.
In November 2017 the patient had symptom of a rapid bilateral enlargement of the cervical lymph nodes accompanied by persistent fatigue, night sweats and decreased weight. Lyme disease, HIV, hepatitis B and C and syphilis serologies were performed, and all tests yielded negative results. Repeat PET/CT scan, cytogenetics and bone marrow biopsy demonstrated no evidence of Richter’s transformation into a diffuse large cell lymphoma. Due to significant bulky disease and enlarged adenopathy with B constitutional symptoms, chemo-immunotherapy with FCR was considered. This was furthermore rationalised as she was a fit patient younger than 65 years of age with standard risk for CLL due to the absence of 17 p deletion, or TP53 mutation, and with IGHV being mutated.7
She received six cycles of FCR which was completed uneventfully on 11 November 2019. During FCR therapy, she received oral valacyclovir 500 mg two times per day for herpes prophylaxis as well as Septra DS (160 mg trimethoprim and 800 mg sulfamethoxazole) one tablet Mondays, Wednesdays and Fridays for P. jirovecii prophylaxis. On 18 November, she presented to the emergency room of the McGill University Health Centre (MUHC) with haematuria, suprapubic pain and fever. She was admitted and treated for a urine infection and slowly improved after different antibiotics such as ciprofloxacin, trimethoprim-sulfamethoxazole and ceftriaxone and blood and urinary bacterial cultures were negative. A CT urogram showed moderate bilateral hydroureteronephrosis with diffuse urolithelial and bladder thickening (figure 2). As a whole, these findings were suggestive of an inflammatory or infectious process evoking pyleoureteritis and cystitis.
Figure 2 CT urogram on admission in November 2019, demonstrating (A) poorly distended bladder and marked thickening of bladder walls (green arrow) and (B) moderate dilation of both ureters and collection ducts with marked thickening and enhancement of the urothelium associated with moderate periureteric fat stranding.
Investigations
On admission, she was mildly pancytopenic (table 1). As the patient partially improved and had negative urine cultures, a cyclophosphamide-induced haemorrhagic cystitis was considered, and she was placed on continuous bladder irrigation.
Table 1 Summary of the patient’s serological and microbiological test results during the course of her neutropenia and triple viremia
Laboratory results Reference ranges 20 March 2019 11 November 2019 26 November 2019 25 December 2019 01 January 2020 23 January 2020 01 February 2020 07 February 2020 03 March 2020
Time of intervention First dose FCR Last dose FCR Meropenem started Virology investigated Begins cidofovir+GCSF Cidofovir changed to Ganciclovir Ganciclovir transitioned to valganciclovir Discharge Follow-up
WBC (109/L) 4.0–10.0 30.90 5.90 3.00 1.00 0.60 2.40 6.10 2.40 2.00
Neutrophils 2.0–7.0 3.75 4.18 2.46 0.80 0.36 1.19 5.09 1.73 1.35
Lymphocytes 1.5–4.5 26.26 0.87 0.23 0.08 0.11 0.23 0.46 0.33 0.44
Plt (109/L) 150–450 145 158 123 48 19 54 17 12 39
Hb (g/L) 120–150 142 129 99 63 80 70 70 71 99
Creatinine (umol/L) 50–90 71 68 125 128 118 75 74 69 75
CMV (copies/mL) – – – – 7320 3170 1291 153 149 0
Adenovirus (copies/mL) – – – – – 7.44 log10 4.86 log10 3.74 log10 – 3.30 log10
BK virus urine (copies/mL) – – – – – 2.26×107 – 3.20×108 –
BK virus blood (copies/mL) – – – – – – – – – 3.91×103
CMV, cytomegalovirus; FCR, fludarabine, cyclophosphamide and rituximab; Hb, haemoglobin; Plt, platelet; WBC, white blood cell.
On 1 December 2019 she developed a pancytopenia that required platelet and packed red blood cell transfusions. She remained persistently febrile despite repeated negative bacterial blood and urine cultures. Due to her CLL, pancytopenia and the consideration of immunosuppression induced by FCR chemotherapy, viral infections were investigated. PCR for adenovirus showed 22.4 copies/mL in blood, and positive in urine; PCR for polyoma virus showed 8.81 million copies/mL blood; and PCR for CMV showed 358 copies/mL in blood, confirming viral invasive infections (figure 3). To further investigate her pancytopenia, serology for parvovirus B 19 was carried out and was negative for IgM.
Figure 3 Cytomegalovirus (CMV) and BK viremia (A) and adeno-viremia (B) over the course of treatment.
On 18 December 2019 the patient underwent a double J-stent insertion for bilateral hydronephrosis. Pelvic pain persisted and she continued to pass clots in her urine. Repeat CMV PCR testing on 25 December 2019 showed 7320 copies/mL while an ophthalmological assessment revealed no evidence of CMV retinitis or keratitis. Bone marrow biopsy results showed pancytopenia without transformation (figure 4).
Figure 4 Histology and immunochemistry of bone marrow smear (A) and biopsy (B). Bone marrow biopsy demonstrating hypocellularity. Moderate left shift of the myeloid series and mild left shift of the erythroid series. No lymphocytosis or lymphoma, no definite diagnosis of myelodysplastic syndrome (B).
Treatment
On 1 January 2020, cidofovir was administered to treat the three viral infections of BK polyomavirus, adenovirus and CMV. Cidofovir was given at the dose of 1 mg/kg intravenously three times a week instead of a weekly dose given her kidney injury and high creatinine levels. She received probenecid 2 g orally 1 hour before cidofovir, then 2 hours and 8 hours after the end of infusion to increase cidofovir levels in the blood. For renal protection, she was hydrated with 1 L of 0.9% normal saline during cidofovir infusion. Filgrastim (G-CSF) was initiated for her neutropenia, darbepoetin for her anaemia, and intravenous IgG was infused three times at 4-week intervals for her hypogammaglobulinumia.
Neutropenia worsen despite filgrastim, and CMV viral load continued to increase. Due to cidofovir myelotoxicity, a decision was made to focus treatment on CMV infection, while ignoring the BK and adenovirus. To this end, the patient was changed to ganciclovir 250 mg intravenous two times per day on 23 January 2020 and her urinary symptoms improved for the first time. On 1 February 2020, she was transitioned to oral valganciclovir 450 mg daily and was discharged to home 1 week later, after 101 days in hospital.
Outcome and follow-up
A bone marrow biopsy on 27 January 2020 showed a hypocellular marrow with focal area up to 20%–30% haematopoietic tissue. No evidence of lymphocytosis or lymphoma and no dysplastic changes in morphology were observed. Immunohistochemistry showed <5% CD117, and was negative for CD20, CD34 and PAX5. The histological appearance represented haematopoietic regeneration post-chemotherapy. On 3 March 2020 follow-up, CMV load was undetectable, adenovirus load was 5000 copies/mL, BK load was 3.2×108 copies/mL (table 1). She was switched on CMV prophylaxis with resolved haemorrhagic cystitis and received valganciclovir 450 mg p.o. daily for another 3 months and until her absolute lymphocyte count recovers above 109 cells/L. She continued trimethoprim-sulfamethaxole prophylaxis for 6 months post-chemotherapy. Her double-J stents remain in place. While clinically improved, her neutropenia improved on low dose filgrastim until 4 April 2020. Her blood counts normalised 1 month after and she is followed as an outpatient with Haematology, Infectious Diseases, and Urology services at the MUHC.
Discussion
FCR chemo-immunotherapy is considered the treatment for standard risk CLL patients under the age of 65,7 with a high overall response rate. However, the predominant complication is myelosuppression.8 Persistent neutropenia was reported in 19% and late infections in 9% of patients.9 The frequency of cytopenias was 35% at 3 months and 12% at 9 months after completion of therapy, respectively. Another side effect is prolonged lymphoid immunodeficiency.
Human adenovirus infections usually present as a keratoconjunctivitis or respiratory tract infection. In most healthy individuals the infection is usually self-limited. However, in immunosuppressed patients, infection may disseminate and become potentially life-threatening. Disseminated adenovirus infection can result from either de novo infection or a reactivation of clinically silent infection.10
BK virus is a member of the polyomavirus family. BK virus reactivation occurs only in immunosuppressed patients and can lead to nephropathy, ureteral stenosis, tubular interstitial damage and haemorrhagic cystitis. Viremia occurs in 20%–60% of this population. There is no specific treatment for BK virus-associated nephropathy, therefore viral replication can only be controlled through modulating the immunosuppressive condition.11
CMV is a herpes virus with a large double-stranded DNA that remains latent in the host after primary infection. Immunocompromised patients can have reactivation of their latent infection. Diagnosis of viral reactivation is made through CMV PCR in blood, tissue or body fluid. Manifestations of CMV infection occur most often in the gastrointestinal tract, lungs, liver and retina.12 As we did not observe the typical owl’s eye tissue lesion in the second bone marrow biopsy, we considered that CMV reactivation was a contributing factor for the pancytopenia, and treatment may have prevented such tissue lesion to develop. First line treatment of CMV infection includes intravenous ganciclovir or its oral prodrug valganciclovir, which are DNA polymerase inhibitors. The major side effect of these drugs is myelosuppression, including neutropenia.4
In our patient, the prolonged pancytopenias secondary to FCR was associated with haematuria with an ureteral mass. To date, only two observations on the use of cidofovir to simultaneously treat BK-virus associated haemorrhagic cystitis and CMV reactivation have been reported. However, in the case report by Held et al, the patient had received a bone marrow transplant for chronic myeloid leukaemia, whereas our patient had CLL.
Cidofovir has been suggested in some cases for the treatment of BK virus-associated haemorrhagic cystitis.13 Cidofovir and foscarnet are second-line therapies in patients with CMV that are either resistant or refractory to ganciclovir. Cidofovir is a non-cyclic analogue of cytidine monophosphate that terminates CMV DNA synthesis. In vitro studies showed effectiveness against herpes viruses, including CMV, herpes simplex viruses 1 and 2, varicella-zoster, Epstein-Barr virus, human papillomavirus and adenovirus. The main adverse effect is nephrotoxicity, causing proximal tubular injury. Serum creatinine and urine protein measurements are recommended during administration.14 Probenecid decreases intratubular secretion and maintains a sufficient plasma concentration to allow for once weekly dosing at 5 mg/kg to reduce its nephrotoxicity.13 An alternate dosing regimen, initially used in our patient, was three times per week dosing at 3 mg/kg. In the study performed by Philippe et al, intravenous cidofovir achieve remission in 81.5% of the 22 patients.13
The patient reported by Held et al recovered fully with cidofovir15; however, our patient was switched to ganciclovir due to persistent neutropenia. Bone marrow biopsy was consistent with secondary treatment-related myelosuppression syndrome, without evidence of myelodysplasia or lymphoproliferative infiltration. Myelosuppression is a major side effect of ganciclovir. However, the antiviral effects far outweigh these risks and therefore ganciclovir and its oral prodrug valganciclovir should be considered for patients with pancytopenia secondary to CMV reactivation.
In summary, this unique case of triple-viremia induced haemorrhagic cystitis in an immunosuppressed CLL patient posed both a diagnostic and therapeutic challenge as treatments are nephrotoxic and further increase immunosuppression.
The major learning point is to exercise caution when prescribing FCR chemotherapy on its long-term immunosuppressive effects. It is expected that novel immuno-chemotherapy for CLL should control the disease with reduced immunosuppressive effects.16
Patient’s perspective
Translation from French
I was diagnosed with CLL in November 2015. Started the treatments with FCR protocol in April 2019 (six treatments of three consecutive days each). At the end of the fourth treatment, I was not well. I had fever and a large fatigue with no energy. I finished treatments on the 13th of November 2019. On the week of 18 November, the symptoms appeared: fever, incontinent of urine with blood, no appetite, fatigue.
I visited MUHC emergency, 12 hours wait before I had a doctor’s room. I stayed the night and the next day I saw the doctor, but they did not know what I had. On the 22nd of November I returned to emergency with a lot of fever and other symptoms. I passed the night in an emergency room. On Saturday they released me, had fever and falls.
On the 24th I returned to emergency, fever and incontinence, etc. I was placed in the corridor in a stretcher with a commode next to the whole world. There was nowhere else for me, I had to go through the doors to go to the public toilet and I urinated every 5 min. I stayed in emergency 5 days before I was admitted to Internal Medicine.
It was a bad experience the three times I was in emergency. On 29 November, I had my own room. I was there till 07 February 2020.
The staff took charge rapidly. There were many tests during this long period to find out the cause of my problems. Everything came from the chemotherapy. Many departments were involved: urology, otolaryngology, haematology, internal medicine, infectious diseases.
There were several healthcare workers who spoke on behalf of other departments.
Very good service with the nursing staffs and the préposé (aux bénéficiaires). On my part, my immune system was severely damaged.
Learning points
Infections in immunosuppressed patients remain a diagnostic and therapeutic challenge.
In patient treated for chronic lymphocytic leukaemia, haematuria can be related to viral infections like BK virus, adenovirus and cytomegalovirus (CMV).
BK infection is diagnosed with a high index of suspicion, however, combined CMV and adenovirus infections renders the diagnosis more difficult.
Treatment of these viral infections remains difficult as medications are associated with myelotoxicity (ganciclovir) and renal insufficiency (cidofovir).
The authors would like to thank Dr Malek Merdad and Dr Isabelle Malhamé for their inspiration to write this article.
Contributors: MK and J-PR devised the project, main conceptual ideas and proof outlines. MK took the lead in writing the manuscript the supervision of J-PR. MK created all the images and translated the patient’s perspective from French to English. J-PR and JL provided critical feedback and helped shape analysis and manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | 1000 MILLIGRAM DAILY; | DrugDosageText | CC BY-NC | 33402369 | 19,066,566 | 2021-01-05 |
What was the dosage of drug 'VALGANCICLOVIR'? | Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
Background
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder associated with mature B-cell dysfunction, hypogammaglobulinaemia and T-cell abnormalities. In Europe and North America, CLL is the most common leukaemia, with median age of diagnosis of 70 years.1 Treatment is indicated only for symptomatic disease, such as anaemia <100 g/L and/or thrombocytopenia <100×109/L, massive splenomegaly, lymphadenopathy or constitutional symptoms.2
Infection is a frequent cause of morbidity and mortality in CLL. Roughly 30%–50% of all CLL patients suffer infections, with a high subsequent mortality rate.3 While the majority of infections affect more often the respiratory track, or skin and the gastrointestinal tract.4 The most frequent organisms causing infections are bacteria like Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. This increased susceptibility to infection stems from B-cells with impaired immunoglobulin production capability and dysfunctional T-helper cells, which also assist in antibody production. This impaired capability to produce immunoglobulins, termed hypogammaglobulinaemia, affects 85% of CLL patients, particularly in advanced disease.4
Antineoplastic agents recommended for the treatment of CLL are also immunosuppressive and further increase the risk of infections.5 These include opportunistic micro-organisms such as Candida, Pneumocystis jirovecii, listeria, nocardia and atypical mycobacteria. In addition, patients have increased risk of viral diseases such as herpes simplex, Epstein-Barr and cytomegalovirus (CMV). Additional infectious complications may include hepatitis B reactivation and progressive multifocal leucoencephalopathy. In spite of the immunosuppressive risk, chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the standard risk therapy in fit patients below 65 years of age with CLL, in absence of 17 p deletion, or TP53 mutation, and with immunoglobulin heavy chain V (IGHV)-mutated.6
To reduce risk of infection, immunoglobulin levels should also be routinely monitored, particularly with rituximab, which reduces the number of B-cells expressing CD20. It is postulated that monitoring immunoglobulins while being treated with rituximab may reduce the risk of serious infections.4
Herein, we present a unique case of a woman treated for CLL who experienced severe pancytopenia and immunosuppression at the completion of her chemo-immunotherapy. She subsequently experienced triple concurrent viral infections, which posed a therapeutic challenge due to her pancytopenia.
Case presentation
A previously healthy 58-year-old woman was diagnosed with CLL through a routine blood test in 2015. Her physical examination was unremarkable and her lymphocyte counts were at 12.36×109 cells/L. Bone marrow biopsy with immunohistochemistry was suggestive of CLL and stained positive for BCL2, CD5 (aberrant T-cell marker), CD20, CD23, CD43 and CD79a (B-cell markers) while BCL6 was negative. The PCR amplification study showed immunoglobulin heavy chain gene rearrangement along with IgG kappa light chain gene arrangement. No t(14;18) BCL2/JH or t(11;14) BCL1/JH gene rearrangements were observed. As she was asymptomatic, and positron emission tomography (PET) scan showed low grade metabolic activity in lymph nodes in cervical, axillary and iliac areas, no therapy was initiated (figure 1). She was followed every 6 months.
Figure 1 Positron emission tomography scan (right) and corresponding CT images (left) of multiple low-grade hypermetabolic lymph nodes in 2017, 2 years after diagnosis of chronic lymphocytic leukaemia. (A) Multiple small low-grade hypermetabolic lymph nodes in bilateral neck regions predominantly in the posterior triangles. SUV of 1.9 in the left and right upper posterior triangles. (B) Hypermetabolic lymph nodes in the left axillary regions, SUV 1.8. (C) Left external iliac lymph node SUV of 3. SUV, Standardized uptake value.
In November 2017 the patient had symptom of a rapid bilateral enlargement of the cervical lymph nodes accompanied by persistent fatigue, night sweats and decreased weight. Lyme disease, HIV, hepatitis B and C and syphilis serologies were performed, and all tests yielded negative results. Repeat PET/CT scan, cytogenetics and bone marrow biopsy demonstrated no evidence of Richter’s transformation into a diffuse large cell lymphoma. Due to significant bulky disease and enlarged adenopathy with B constitutional symptoms, chemo-immunotherapy with FCR was considered. This was furthermore rationalised as she was a fit patient younger than 65 years of age with standard risk for CLL due to the absence of 17 p deletion, or TP53 mutation, and with IGHV being mutated.7
She received six cycles of FCR which was completed uneventfully on 11 November 2019. During FCR therapy, she received oral valacyclovir 500 mg two times per day for herpes prophylaxis as well as Septra DS (160 mg trimethoprim and 800 mg sulfamethoxazole) one tablet Mondays, Wednesdays and Fridays for P. jirovecii prophylaxis. On 18 November, she presented to the emergency room of the McGill University Health Centre (MUHC) with haematuria, suprapubic pain and fever. She was admitted and treated for a urine infection and slowly improved after different antibiotics such as ciprofloxacin, trimethoprim-sulfamethoxazole and ceftriaxone and blood and urinary bacterial cultures were negative. A CT urogram showed moderate bilateral hydroureteronephrosis with diffuse urolithelial and bladder thickening (figure 2). As a whole, these findings were suggestive of an inflammatory or infectious process evoking pyleoureteritis and cystitis.
Figure 2 CT urogram on admission in November 2019, demonstrating (A) poorly distended bladder and marked thickening of bladder walls (green arrow) and (B) moderate dilation of both ureters and collection ducts with marked thickening and enhancement of the urothelium associated with moderate periureteric fat stranding.
Investigations
On admission, she was mildly pancytopenic (table 1). As the patient partially improved and had negative urine cultures, a cyclophosphamide-induced haemorrhagic cystitis was considered, and she was placed on continuous bladder irrigation.
Table 1 Summary of the patient’s serological and microbiological test results during the course of her neutropenia and triple viremia
Laboratory results Reference ranges 20 March 2019 11 November 2019 26 November 2019 25 December 2019 01 January 2020 23 January 2020 01 February 2020 07 February 2020 03 March 2020
Time of intervention First dose FCR Last dose FCR Meropenem started Virology investigated Begins cidofovir+GCSF Cidofovir changed to Ganciclovir Ganciclovir transitioned to valganciclovir Discharge Follow-up
WBC (109/L) 4.0–10.0 30.90 5.90 3.00 1.00 0.60 2.40 6.10 2.40 2.00
Neutrophils 2.0–7.0 3.75 4.18 2.46 0.80 0.36 1.19 5.09 1.73 1.35
Lymphocytes 1.5–4.5 26.26 0.87 0.23 0.08 0.11 0.23 0.46 0.33 0.44
Plt (109/L) 150–450 145 158 123 48 19 54 17 12 39
Hb (g/L) 120–150 142 129 99 63 80 70 70 71 99
Creatinine (umol/L) 50–90 71 68 125 128 118 75 74 69 75
CMV (copies/mL) – – – – 7320 3170 1291 153 149 0
Adenovirus (copies/mL) – – – – – 7.44 log10 4.86 log10 3.74 log10 – 3.30 log10
BK virus urine (copies/mL) – – – – – 2.26×107 – 3.20×108 –
BK virus blood (copies/mL) – – – – – – – – – 3.91×103
CMV, cytomegalovirus; FCR, fludarabine, cyclophosphamide and rituximab; Hb, haemoglobin; Plt, platelet; WBC, white blood cell.
On 1 December 2019 she developed a pancytopenia that required platelet and packed red blood cell transfusions. She remained persistently febrile despite repeated negative bacterial blood and urine cultures. Due to her CLL, pancytopenia and the consideration of immunosuppression induced by FCR chemotherapy, viral infections were investigated. PCR for adenovirus showed 22.4 copies/mL in blood, and positive in urine; PCR for polyoma virus showed 8.81 million copies/mL blood; and PCR for CMV showed 358 copies/mL in blood, confirming viral invasive infections (figure 3). To further investigate her pancytopenia, serology for parvovirus B 19 was carried out and was negative for IgM.
Figure 3 Cytomegalovirus (CMV) and BK viremia (A) and adeno-viremia (B) over the course of treatment.
On 18 December 2019 the patient underwent a double J-stent insertion for bilateral hydronephrosis. Pelvic pain persisted and she continued to pass clots in her urine. Repeat CMV PCR testing on 25 December 2019 showed 7320 copies/mL while an ophthalmological assessment revealed no evidence of CMV retinitis or keratitis. Bone marrow biopsy results showed pancytopenia without transformation (figure 4).
Figure 4 Histology and immunochemistry of bone marrow smear (A) and biopsy (B). Bone marrow biopsy demonstrating hypocellularity. Moderate left shift of the myeloid series and mild left shift of the erythroid series. No lymphocytosis or lymphoma, no definite diagnosis of myelodysplastic syndrome (B).
Treatment
On 1 January 2020, cidofovir was administered to treat the three viral infections of BK polyomavirus, adenovirus and CMV. Cidofovir was given at the dose of 1 mg/kg intravenously three times a week instead of a weekly dose given her kidney injury and high creatinine levels. She received probenecid 2 g orally 1 hour before cidofovir, then 2 hours and 8 hours after the end of infusion to increase cidofovir levels in the blood. For renal protection, she was hydrated with 1 L of 0.9% normal saline during cidofovir infusion. Filgrastim (G-CSF) was initiated for her neutropenia, darbepoetin for her anaemia, and intravenous IgG was infused three times at 4-week intervals for her hypogammaglobulinumia.
Neutropenia worsen despite filgrastim, and CMV viral load continued to increase. Due to cidofovir myelotoxicity, a decision was made to focus treatment on CMV infection, while ignoring the BK and adenovirus. To this end, the patient was changed to ganciclovir 250 mg intravenous two times per day on 23 January 2020 and her urinary symptoms improved for the first time. On 1 February 2020, she was transitioned to oral valganciclovir 450 mg daily and was discharged to home 1 week later, after 101 days in hospital.
Outcome and follow-up
A bone marrow biopsy on 27 January 2020 showed a hypocellular marrow with focal area up to 20%–30% haematopoietic tissue. No evidence of lymphocytosis or lymphoma and no dysplastic changes in morphology were observed. Immunohistochemistry showed <5% CD117, and was negative for CD20, CD34 and PAX5. The histological appearance represented haematopoietic regeneration post-chemotherapy. On 3 March 2020 follow-up, CMV load was undetectable, adenovirus load was 5000 copies/mL, BK load was 3.2×108 copies/mL (table 1). She was switched on CMV prophylaxis with resolved haemorrhagic cystitis and received valganciclovir 450 mg p.o. daily for another 3 months and until her absolute lymphocyte count recovers above 109 cells/L. She continued trimethoprim-sulfamethaxole prophylaxis for 6 months post-chemotherapy. Her double-J stents remain in place. While clinically improved, her neutropenia improved on low dose filgrastim until 4 April 2020. Her blood counts normalised 1 month after and she is followed as an outpatient with Haematology, Infectious Diseases, and Urology services at the MUHC.
Discussion
FCR chemo-immunotherapy is considered the treatment for standard risk CLL patients under the age of 65,7 with a high overall response rate. However, the predominant complication is myelosuppression.8 Persistent neutropenia was reported in 19% and late infections in 9% of patients.9 The frequency of cytopenias was 35% at 3 months and 12% at 9 months after completion of therapy, respectively. Another side effect is prolonged lymphoid immunodeficiency.
Human adenovirus infections usually present as a keratoconjunctivitis or respiratory tract infection. In most healthy individuals the infection is usually self-limited. However, in immunosuppressed patients, infection may disseminate and become potentially life-threatening. Disseminated adenovirus infection can result from either de novo infection or a reactivation of clinically silent infection.10
BK virus is a member of the polyomavirus family. BK virus reactivation occurs only in immunosuppressed patients and can lead to nephropathy, ureteral stenosis, tubular interstitial damage and haemorrhagic cystitis. Viremia occurs in 20%–60% of this population. There is no specific treatment for BK virus-associated nephropathy, therefore viral replication can only be controlled through modulating the immunosuppressive condition.11
CMV is a herpes virus with a large double-stranded DNA that remains latent in the host after primary infection. Immunocompromised patients can have reactivation of their latent infection. Diagnosis of viral reactivation is made through CMV PCR in blood, tissue or body fluid. Manifestations of CMV infection occur most often in the gastrointestinal tract, lungs, liver and retina.12 As we did not observe the typical owl’s eye tissue lesion in the second bone marrow biopsy, we considered that CMV reactivation was a contributing factor for the pancytopenia, and treatment may have prevented such tissue lesion to develop. First line treatment of CMV infection includes intravenous ganciclovir or its oral prodrug valganciclovir, which are DNA polymerase inhibitors. The major side effect of these drugs is myelosuppression, including neutropenia.4
In our patient, the prolonged pancytopenias secondary to FCR was associated with haematuria with an ureteral mass. To date, only two observations on the use of cidofovir to simultaneously treat BK-virus associated haemorrhagic cystitis and CMV reactivation have been reported. However, in the case report by Held et al, the patient had received a bone marrow transplant for chronic myeloid leukaemia, whereas our patient had CLL.
Cidofovir has been suggested in some cases for the treatment of BK virus-associated haemorrhagic cystitis.13 Cidofovir and foscarnet are second-line therapies in patients with CMV that are either resistant or refractory to ganciclovir. Cidofovir is a non-cyclic analogue of cytidine monophosphate that terminates CMV DNA synthesis. In vitro studies showed effectiveness against herpes viruses, including CMV, herpes simplex viruses 1 and 2, varicella-zoster, Epstein-Barr virus, human papillomavirus and adenovirus. The main adverse effect is nephrotoxicity, causing proximal tubular injury. Serum creatinine and urine protein measurements are recommended during administration.14 Probenecid decreases intratubular secretion and maintains a sufficient plasma concentration to allow for once weekly dosing at 5 mg/kg to reduce its nephrotoxicity.13 An alternate dosing regimen, initially used in our patient, was three times per week dosing at 3 mg/kg. In the study performed by Philippe et al, intravenous cidofovir achieve remission in 81.5% of the 22 patients.13
The patient reported by Held et al recovered fully with cidofovir15; however, our patient was switched to ganciclovir due to persistent neutropenia. Bone marrow biopsy was consistent with secondary treatment-related myelosuppression syndrome, without evidence of myelodysplasia or lymphoproliferative infiltration. Myelosuppression is a major side effect of ganciclovir. However, the antiviral effects far outweigh these risks and therefore ganciclovir and its oral prodrug valganciclovir should be considered for patients with pancytopenia secondary to CMV reactivation.
In summary, this unique case of triple-viremia induced haemorrhagic cystitis in an immunosuppressed CLL patient posed both a diagnostic and therapeutic challenge as treatments are nephrotoxic and further increase immunosuppression.
The major learning point is to exercise caution when prescribing FCR chemotherapy on its long-term immunosuppressive effects. It is expected that novel immuno-chemotherapy for CLL should control the disease with reduced immunosuppressive effects.16
Patient’s perspective
Translation from French
I was diagnosed with CLL in November 2015. Started the treatments with FCR protocol in April 2019 (six treatments of three consecutive days each). At the end of the fourth treatment, I was not well. I had fever and a large fatigue with no energy. I finished treatments on the 13th of November 2019. On the week of 18 November, the symptoms appeared: fever, incontinent of urine with blood, no appetite, fatigue.
I visited MUHC emergency, 12 hours wait before I had a doctor’s room. I stayed the night and the next day I saw the doctor, but they did not know what I had. On the 22nd of November I returned to emergency with a lot of fever and other symptoms. I passed the night in an emergency room. On Saturday they released me, had fever and falls.
On the 24th I returned to emergency, fever and incontinence, etc. I was placed in the corridor in a stretcher with a commode next to the whole world. There was nowhere else for me, I had to go through the doors to go to the public toilet and I urinated every 5 min. I stayed in emergency 5 days before I was admitted to Internal Medicine.
It was a bad experience the three times I was in emergency. On 29 November, I had my own room. I was there till 07 February 2020.
The staff took charge rapidly. There were many tests during this long period to find out the cause of my problems. Everything came from the chemotherapy. Many departments were involved: urology, otolaryngology, haematology, internal medicine, infectious diseases.
There were several healthcare workers who spoke on behalf of other departments.
Very good service with the nursing staffs and the préposé (aux bénéficiaires). On my part, my immune system was severely damaged.
Learning points
Infections in immunosuppressed patients remain a diagnostic and therapeutic challenge.
In patient treated for chronic lymphocytic leukaemia, haematuria can be related to viral infections like BK virus, adenovirus and cytomegalovirus (CMV).
BK infection is diagnosed with a high index of suspicion, however, combined CMV and adenovirus infections renders the diagnosis more difficult.
Treatment of these viral infections remains difficult as medications are associated with myelotoxicity (ganciclovir) and renal insufficiency (cidofovir).
The authors would like to thank Dr Malek Merdad and Dr Isabelle Malhamé for their inspiration to write this article.
Contributors: MK and J-PR devised the project, main conceptual ideas and proof outlines. MK took the lead in writing the manuscript the supervision of J-PR. MK created all the images and translated the patient’s perspective from French to English. J-PR and JL provided critical feedback and helped shape analysis and manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | 450 MILLIGRAM, QD | DrugDosageText | CC BY-NC | 33402369 | 18,752,790 | 2021-01-05 |
What was the outcome of reaction 'Cystitis haemorrhagic'? | Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
Background
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder associated with mature B-cell dysfunction, hypogammaglobulinaemia and T-cell abnormalities. In Europe and North America, CLL is the most common leukaemia, with median age of diagnosis of 70 years.1 Treatment is indicated only for symptomatic disease, such as anaemia <100 g/L and/or thrombocytopenia <100×109/L, massive splenomegaly, lymphadenopathy or constitutional symptoms.2
Infection is a frequent cause of morbidity and mortality in CLL. Roughly 30%–50% of all CLL patients suffer infections, with a high subsequent mortality rate.3 While the majority of infections affect more often the respiratory track, or skin and the gastrointestinal tract.4 The most frequent organisms causing infections are bacteria like Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. This increased susceptibility to infection stems from B-cells with impaired immunoglobulin production capability and dysfunctional T-helper cells, which also assist in antibody production. This impaired capability to produce immunoglobulins, termed hypogammaglobulinaemia, affects 85% of CLL patients, particularly in advanced disease.4
Antineoplastic agents recommended for the treatment of CLL are also immunosuppressive and further increase the risk of infections.5 These include opportunistic micro-organisms such as Candida, Pneumocystis jirovecii, listeria, nocardia and atypical mycobacteria. In addition, patients have increased risk of viral diseases such as herpes simplex, Epstein-Barr and cytomegalovirus (CMV). Additional infectious complications may include hepatitis B reactivation and progressive multifocal leucoencephalopathy. In spite of the immunosuppressive risk, chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the standard risk therapy in fit patients below 65 years of age with CLL, in absence of 17 p deletion, or TP53 mutation, and with immunoglobulin heavy chain V (IGHV)-mutated.6
To reduce risk of infection, immunoglobulin levels should also be routinely monitored, particularly with rituximab, which reduces the number of B-cells expressing CD20. It is postulated that monitoring immunoglobulins while being treated with rituximab may reduce the risk of serious infections.4
Herein, we present a unique case of a woman treated for CLL who experienced severe pancytopenia and immunosuppression at the completion of her chemo-immunotherapy. She subsequently experienced triple concurrent viral infections, which posed a therapeutic challenge due to her pancytopenia.
Case presentation
A previously healthy 58-year-old woman was diagnosed with CLL through a routine blood test in 2015. Her physical examination was unremarkable and her lymphocyte counts were at 12.36×109 cells/L. Bone marrow biopsy with immunohistochemistry was suggestive of CLL and stained positive for BCL2, CD5 (aberrant T-cell marker), CD20, CD23, CD43 and CD79a (B-cell markers) while BCL6 was negative. The PCR amplification study showed immunoglobulin heavy chain gene rearrangement along with IgG kappa light chain gene arrangement. No t(14;18) BCL2/JH or t(11;14) BCL1/JH gene rearrangements were observed. As she was asymptomatic, and positron emission tomography (PET) scan showed low grade metabolic activity in lymph nodes in cervical, axillary and iliac areas, no therapy was initiated (figure 1). She was followed every 6 months.
Figure 1 Positron emission tomography scan (right) and corresponding CT images (left) of multiple low-grade hypermetabolic lymph nodes in 2017, 2 years after diagnosis of chronic lymphocytic leukaemia. (A) Multiple small low-grade hypermetabolic lymph nodes in bilateral neck regions predominantly in the posterior triangles. SUV of 1.9 in the left and right upper posterior triangles. (B) Hypermetabolic lymph nodes in the left axillary regions, SUV 1.8. (C) Left external iliac lymph node SUV of 3. SUV, Standardized uptake value.
In November 2017 the patient had symptom of a rapid bilateral enlargement of the cervical lymph nodes accompanied by persistent fatigue, night sweats and decreased weight. Lyme disease, HIV, hepatitis B and C and syphilis serologies were performed, and all tests yielded negative results. Repeat PET/CT scan, cytogenetics and bone marrow biopsy demonstrated no evidence of Richter’s transformation into a diffuse large cell lymphoma. Due to significant bulky disease and enlarged adenopathy with B constitutional symptoms, chemo-immunotherapy with FCR was considered. This was furthermore rationalised as she was a fit patient younger than 65 years of age with standard risk for CLL due to the absence of 17 p deletion, or TP53 mutation, and with IGHV being mutated.7
She received six cycles of FCR which was completed uneventfully on 11 November 2019. During FCR therapy, she received oral valacyclovir 500 mg two times per day for herpes prophylaxis as well as Septra DS (160 mg trimethoprim and 800 mg sulfamethoxazole) one tablet Mondays, Wednesdays and Fridays for P. jirovecii prophylaxis. On 18 November, she presented to the emergency room of the McGill University Health Centre (MUHC) with haematuria, suprapubic pain and fever. She was admitted and treated for a urine infection and slowly improved after different antibiotics such as ciprofloxacin, trimethoprim-sulfamethoxazole and ceftriaxone and blood and urinary bacterial cultures were negative. A CT urogram showed moderate bilateral hydroureteronephrosis with diffuse urolithelial and bladder thickening (figure 2). As a whole, these findings were suggestive of an inflammatory or infectious process evoking pyleoureteritis and cystitis.
Figure 2 CT urogram on admission in November 2019, demonstrating (A) poorly distended bladder and marked thickening of bladder walls (green arrow) and (B) moderate dilation of both ureters and collection ducts with marked thickening and enhancement of the urothelium associated with moderate periureteric fat stranding.
Investigations
On admission, she was mildly pancytopenic (table 1). As the patient partially improved and had negative urine cultures, a cyclophosphamide-induced haemorrhagic cystitis was considered, and she was placed on continuous bladder irrigation.
Table 1 Summary of the patient’s serological and microbiological test results during the course of her neutropenia and triple viremia
Laboratory results Reference ranges 20 March 2019 11 November 2019 26 November 2019 25 December 2019 01 January 2020 23 January 2020 01 February 2020 07 February 2020 03 March 2020
Time of intervention First dose FCR Last dose FCR Meropenem started Virology investigated Begins cidofovir+GCSF Cidofovir changed to Ganciclovir Ganciclovir transitioned to valganciclovir Discharge Follow-up
WBC (109/L) 4.0–10.0 30.90 5.90 3.00 1.00 0.60 2.40 6.10 2.40 2.00
Neutrophils 2.0–7.0 3.75 4.18 2.46 0.80 0.36 1.19 5.09 1.73 1.35
Lymphocytes 1.5–4.5 26.26 0.87 0.23 0.08 0.11 0.23 0.46 0.33 0.44
Plt (109/L) 150–450 145 158 123 48 19 54 17 12 39
Hb (g/L) 120–150 142 129 99 63 80 70 70 71 99
Creatinine (umol/L) 50–90 71 68 125 128 118 75 74 69 75
CMV (copies/mL) – – – – 7320 3170 1291 153 149 0
Adenovirus (copies/mL) – – – – – 7.44 log10 4.86 log10 3.74 log10 – 3.30 log10
BK virus urine (copies/mL) – – – – – 2.26×107 – 3.20×108 –
BK virus blood (copies/mL) – – – – – – – – – 3.91×103
CMV, cytomegalovirus; FCR, fludarabine, cyclophosphamide and rituximab; Hb, haemoglobin; Plt, platelet; WBC, white blood cell.
On 1 December 2019 she developed a pancytopenia that required platelet and packed red blood cell transfusions. She remained persistently febrile despite repeated negative bacterial blood and urine cultures. Due to her CLL, pancytopenia and the consideration of immunosuppression induced by FCR chemotherapy, viral infections were investigated. PCR for adenovirus showed 22.4 copies/mL in blood, and positive in urine; PCR for polyoma virus showed 8.81 million copies/mL blood; and PCR for CMV showed 358 copies/mL in blood, confirming viral invasive infections (figure 3). To further investigate her pancytopenia, serology for parvovirus B 19 was carried out and was negative for IgM.
Figure 3 Cytomegalovirus (CMV) and BK viremia (A) and adeno-viremia (B) over the course of treatment.
On 18 December 2019 the patient underwent a double J-stent insertion for bilateral hydronephrosis. Pelvic pain persisted and she continued to pass clots in her urine. Repeat CMV PCR testing on 25 December 2019 showed 7320 copies/mL while an ophthalmological assessment revealed no evidence of CMV retinitis or keratitis. Bone marrow biopsy results showed pancytopenia without transformation (figure 4).
Figure 4 Histology and immunochemistry of bone marrow smear (A) and biopsy (B). Bone marrow biopsy demonstrating hypocellularity. Moderate left shift of the myeloid series and mild left shift of the erythroid series. No lymphocytosis or lymphoma, no definite diagnosis of myelodysplastic syndrome (B).
Treatment
On 1 January 2020, cidofovir was administered to treat the three viral infections of BK polyomavirus, adenovirus and CMV. Cidofovir was given at the dose of 1 mg/kg intravenously three times a week instead of a weekly dose given her kidney injury and high creatinine levels. She received probenecid 2 g orally 1 hour before cidofovir, then 2 hours and 8 hours after the end of infusion to increase cidofovir levels in the blood. For renal protection, she was hydrated with 1 L of 0.9% normal saline during cidofovir infusion. Filgrastim (G-CSF) was initiated for her neutropenia, darbepoetin for her anaemia, and intravenous IgG was infused three times at 4-week intervals for her hypogammaglobulinumia.
Neutropenia worsen despite filgrastim, and CMV viral load continued to increase. Due to cidofovir myelotoxicity, a decision was made to focus treatment on CMV infection, while ignoring the BK and adenovirus. To this end, the patient was changed to ganciclovir 250 mg intravenous two times per day on 23 January 2020 and her urinary symptoms improved for the first time. On 1 February 2020, she was transitioned to oral valganciclovir 450 mg daily and was discharged to home 1 week later, after 101 days in hospital.
Outcome and follow-up
A bone marrow biopsy on 27 January 2020 showed a hypocellular marrow with focal area up to 20%–30% haematopoietic tissue. No evidence of lymphocytosis or lymphoma and no dysplastic changes in morphology were observed. Immunohistochemistry showed <5% CD117, and was negative for CD20, CD34 and PAX5. The histological appearance represented haematopoietic regeneration post-chemotherapy. On 3 March 2020 follow-up, CMV load was undetectable, adenovirus load was 5000 copies/mL, BK load was 3.2×108 copies/mL (table 1). She was switched on CMV prophylaxis with resolved haemorrhagic cystitis and received valganciclovir 450 mg p.o. daily for another 3 months and until her absolute lymphocyte count recovers above 109 cells/L. She continued trimethoprim-sulfamethaxole prophylaxis for 6 months post-chemotherapy. Her double-J stents remain in place. While clinically improved, her neutropenia improved on low dose filgrastim until 4 April 2020. Her blood counts normalised 1 month after and she is followed as an outpatient with Haematology, Infectious Diseases, and Urology services at the MUHC.
Discussion
FCR chemo-immunotherapy is considered the treatment for standard risk CLL patients under the age of 65,7 with a high overall response rate. However, the predominant complication is myelosuppression.8 Persistent neutropenia was reported in 19% and late infections in 9% of patients.9 The frequency of cytopenias was 35% at 3 months and 12% at 9 months after completion of therapy, respectively. Another side effect is prolonged lymphoid immunodeficiency.
Human adenovirus infections usually present as a keratoconjunctivitis or respiratory tract infection. In most healthy individuals the infection is usually self-limited. However, in immunosuppressed patients, infection may disseminate and become potentially life-threatening. Disseminated adenovirus infection can result from either de novo infection or a reactivation of clinically silent infection.10
BK virus is a member of the polyomavirus family. BK virus reactivation occurs only in immunosuppressed patients and can lead to nephropathy, ureteral stenosis, tubular interstitial damage and haemorrhagic cystitis. Viremia occurs in 20%–60% of this population. There is no specific treatment for BK virus-associated nephropathy, therefore viral replication can only be controlled through modulating the immunosuppressive condition.11
CMV is a herpes virus with a large double-stranded DNA that remains latent in the host after primary infection. Immunocompromised patients can have reactivation of their latent infection. Diagnosis of viral reactivation is made through CMV PCR in blood, tissue or body fluid. Manifestations of CMV infection occur most often in the gastrointestinal tract, lungs, liver and retina.12 As we did not observe the typical owl’s eye tissue lesion in the second bone marrow biopsy, we considered that CMV reactivation was a contributing factor for the pancytopenia, and treatment may have prevented such tissue lesion to develop. First line treatment of CMV infection includes intravenous ganciclovir or its oral prodrug valganciclovir, which are DNA polymerase inhibitors. The major side effect of these drugs is myelosuppression, including neutropenia.4
In our patient, the prolonged pancytopenias secondary to FCR was associated with haematuria with an ureteral mass. To date, only two observations on the use of cidofovir to simultaneously treat BK-virus associated haemorrhagic cystitis and CMV reactivation have been reported. However, in the case report by Held et al, the patient had received a bone marrow transplant for chronic myeloid leukaemia, whereas our patient had CLL.
Cidofovir has been suggested in some cases for the treatment of BK virus-associated haemorrhagic cystitis.13 Cidofovir and foscarnet are second-line therapies in patients with CMV that are either resistant or refractory to ganciclovir. Cidofovir is a non-cyclic analogue of cytidine monophosphate that terminates CMV DNA synthesis. In vitro studies showed effectiveness against herpes viruses, including CMV, herpes simplex viruses 1 and 2, varicella-zoster, Epstein-Barr virus, human papillomavirus and adenovirus. The main adverse effect is nephrotoxicity, causing proximal tubular injury. Serum creatinine and urine protein measurements are recommended during administration.14 Probenecid decreases intratubular secretion and maintains a sufficient plasma concentration to allow for once weekly dosing at 5 mg/kg to reduce its nephrotoxicity.13 An alternate dosing regimen, initially used in our patient, was three times per week dosing at 3 mg/kg. In the study performed by Philippe et al, intravenous cidofovir achieve remission in 81.5% of the 22 patients.13
The patient reported by Held et al recovered fully with cidofovir15; however, our patient was switched to ganciclovir due to persistent neutropenia. Bone marrow biopsy was consistent with secondary treatment-related myelosuppression syndrome, without evidence of myelodysplasia or lymphoproliferative infiltration. Myelosuppression is a major side effect of ganciclovir. However, the antiviral effects far outweigh these risks and therefore ganciclovir and its oral prodrug valganciclovir should be considered for patients with pancytopenia secondary to CMV reactivation.
In summary, this unique case of triple-viremia induced haemorrhagic cystitis in an immunosuppressed CLL patient posed both a diagnostic and therapeutic challenge as treatments are nephrotoxic and further increase immunosuppression.
The major learning point is to exercise caution when prescribing FCR chemotherapy on its long-term immunosuppressive effects. It is expected that novel immuno-chemotherapy for CLL should control the disease with reduced immunosuppressive effects.16
Patient’s perspective
Translation from French
I was diagnosed with CLL in November 2015. Started the treatments with FCR protocol in April 2019 (six treatments of three consecutive days each). At the end of the fourth treatment, I was not well. I had fever and a large fatigue with no energy. I finished treatments on the 13th of November 2019. On the week of 18 November, the symptoms appeared: fever, incontinent of urine with blood, no appetite, fatigue.
I visited MUHC emergency, 12 hours wait before I had a doctor’s room. I stayed the night and the next day I saw the doctor, but they did not know what I had. On the 22nd of November I returned to emergency with a lot of fever and other symptoms. I passed the night in an emergency room. On Saturday they released me, had fever and falls.
On the 24th I returned to emergency, fever and incontinence, etc. I was placed in the corridor in a stretcher with a commode next to the whole world. There was nowhere else for me, I had to go through the doors to go to the public toilet and I urinated every 5 min. I stayed in emergency 5 days before I was admitted to Internal Medicine.
It was a bad experience the three times I was in emergency. On 29 November, I had my own room. I was there till 07 February 2020.
The staff took charge rapidly. There were many tests during this long period to find out the cause of my problems. Everything came from the chemotherapy. Many departments were involved: urology, otolaryngology, haematology, internal medicine, infectious diseases.
There were several healthcare workers who spoke on behalf of other departments.
Very good service with the nursing staffs and the préposé (aux bénéficiaires). On my part, my immune system was severely damaged.
Learning points
Infections in immunosuppressed patients remain a diagnostic and therapeutic challenge.
In patient treated for chronic lymphocytic leukaemia, haematuria can be related to viral infections like BK virus, adenovirus and cytomegalovirus (CMV).
BK infection is diagnosed with a high index of suspicion, however, combined CMV and adenovirus infections renders the diagnosis more difficult.
Treatment of these viral infections remains difficult as medications are associated with myelotoxicity (ganciclovir) and renal insufficiency (cidofovir).
The authors would like to thank Dr Malek Merdad and Dr Isabelle Malhamé for their inspiration to write this article.
Contributors: MK and J-PR devised the project, main conceptual ideas and proof outlines. MK took the lead in writing the manuscript the supervision of J-PR. MK created all the images and translated the patient’s perspective from French to English. J-PR and JL provided critical feedback and helped shape analysis and manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33402369 | 19,066,566 | 2021-01-05 |
What was the outcome of reaction 'Cytomegalovirus infection'? | Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
Background
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder associated with mature B-cell dysfunction, hypogammaglobulinaemia and T-cell abnormalities. In Europe and North America, CLL is the most common leukaemia, with median age of diagnosis of 70 years.1 Treatment is indicated only for symptomatic disease, such as anaemia <100 g/L and/or thrombocytopenia <100×109/L, massive splenomegaly, lymphadenopathy or constitutional symptoms.2
Infection is a frequent cause of morbidity and mortality in CLL. Roughly 30%–50% of all CLL patients suffer infections, with a high subsequent mortality rate.3 While the majority of infections affect more often the respiratory track, or skin and the gastrointestinal tract.4 The most frequent organisms causing infections are bacteria like Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. This increased susceptibility to infection stems from B-cells with impaired immunoglobulin production capability and dysfunctional T-helper cells, which also assist in antibody production. This impaired capability to produce immunoglobulins, termed hypogammaglobulinaemia, affects 85% of CLL patients, particularly in advanced disease.4
Antineoplastic agents recommended for the treatment of CLL are also immunosuppressive and further increase the risk of infections.5 These include opportunistic micro-organisms such as Candida, Pneumocystis jirovecii, listeria, nocardia and atypical mycobacteria. In addition, patients have increased risk of viral diseases such as herpes simplex, Epstein-Barr and cytomegalovirus (CMV). Additional infectious complications may include hepatitis B reactivation and progressive multifocal leucoencephalopathy. In spite of the immunosuppressive risk, chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the standard risk therapy in fit patients below 65 years of age with CLL, in absence of 17 p deletion, or TP53 mutation, and with immunoglobulin heavy chain V (IGHV)-mutated.6
To reduce risk of infection, immunoglobulin levels should also be routinely monitored, particularly with rituximab, which reduces the number of B-cells expressing CD20. It is postulated that monitoring immunoglobulins while being treated with rituximab may reduce the risk of serious infections.4
Herein, we present a unique case of a woman treated for CLL who experienced severe pancytopenia and immunosuppression at the completion of her chemo-immunotherapy. She subsequently experienced triple concurrent viral infections, which posed a therapeutic challenge due to her pancytopenia.
Case presentation
A previously healthy 58-year-old woman was diagnosed with CLL through a routine blood test in 2015. Her physical examination was unremarkable and her lymphocyte counts were at 12.36×109 cells/L. Bone marrow biopsy with immunohistochemistry was suggestive of CLL and stained positive for BCL2, CD5 (aberrant T-cell marker), CD20, CD23, CD43 and CD79a (B-cell markers) while BCL6 was negative. The PCR amplification study showed immunoglobulin heavy chain gene rearrangement along with IgG kappa light chain gene arrangement. No t(14;18) BCL2/JH or t(11;14) BCL1/JH gene rearrangements were observed. As she was asymptomatic, and positron emission tomography (PET) scan showed low grade metabolic activity in lymph nodes in cervical, axillary and iliac areas, no therapy was initiated (figure 1). She was followed every 6 months.
Figure 1 Positron emission tomography scan (right) and corresponding CT images (left) of multiple low-grade hypermetabolic lymph nodes in 2017, 2 years after diagnosis of chronic lymphocytic leukaemia. (A) Multiple small low-grade hypermetabolic lymph nodes in bilateral neck regions predominantly in the posterior triangles. SUV of 1.9 in the left and right upper posterior triangles. (B) Hypermetabolic lymph nodes in the left axillary regions, SUV 1.8. (C) Left external iliac lymph node SUV of 3. SUV, Standardized uptake value.
In November 2017 the patient had symptom of a rapid bilateral enlargement of the cervical lymph nodes accompanied by persistent fatigue, night sweats and decreased weight. Lyme disease, HIV, hepatitis B and C and syphilis serologies were performed, and all tests yielded negative results. Repeat PET/CT scan, cytogenetics and bone marrow biopsy demonstrated no evidence of Richter’s transformation into a diffuse large cell lymphoma. Due to significant bulky disease and enlarged adenopathy with B constitutional symptoms, chemo-immunotherapy with FCR was considered. This was furthermore rationalised as she was a fit patient younger than 65 years of age with standard risk for CLL due to the absence of 17 p deletion, or TP53 mutation, and with IGHV being mutated.7
She received six cycles of FCR which was completed uneventfully on 11 November 2019. During FCR therapy, she received oral valacyclovir 500 mg two times per day for herpes prophylaxis as well as Septra DS (160 mg trimethoprim and 800 mg sulfamethoxazole) one tablet Mondays, Wednesdays and Fridays for P. jirovecii prophylaxis. On 18 November, she presented to the emergency room of the McGill University Health Centre (MUHC) with haematuria, suprapubic pain and fever. She was admitted and treated for a urine infection and slowly improved after different antibiotics such as ciprofloxacin, trimethoprim-sulfamethoxazole and ceftriaxone and blood and urinary bacterial cultures were negative. A CT urogram showed moderate bilateral hydroureteronephrosis with diffuse urolithelial and bladder thickening (figure 2). As a whole, these findings were suggestive of an inflammatory or infectious process evoking pyleoureteritis and cystitis.
Figure 2 CT urogram on admission in November 2019, demonstrating (A) poorly distended bladder and marked thickening of bladder walls (green arrow) and (B) moderate dilation of both ureters and collection ducts with marked thickening and enhancement of the urothelium associated with moderate periureteric fat stranding.
Investigations
On admission, she was mildly pancytopenic (table 1). As the patient partially improved and had negative urine cultures, a cyclophosphamide-induced haemorrhagic cystitis was considered, and she was placed on continuous bladder irrigation.
Table 1 Summary of the patient’s serological and microbiological test results during the course of her neutropenia and triple viremia
Laboratory results Reference ranges 20 March 2019 11 November 2019 26 November 2019 25 December 2019 01 January 2020 23 January 2020 01 February 2020 07 February 2020 03 March 2020
Time of intervention First dose FCR Last dose FCR Meropenem started Virology investigated Begins cidofovir+GCSF Cidofovir changed to Ganciclovir Ganciclovir transitioned to valganciclovir Discharge Follow-up
WBC (109/L) 4.0–10.0 30.90 5.90 3.00 1.00 0.60 2.40 6.10 2.40 2.00
Neutrophils 2.0–7.0 3.75 4.18 2.46 0.80 0.36 1.19 5.09 1.73 1.35
Lymphocytes 1.5–4.5 26.26 0.87 0.23 0.08 0.11 0.23 0.46 0.33 0.44
Plt (109/L) 150–450 145 158 123 48 19 54 17 12 39
Hb (g/L) 120–150 142 129 99 63 80 70 70 71 99
Creatinine (umol/L) 50–90 71 68 125 128 118 75 74 69 75
CMV (copies/mL) – – – – 7320 3170 1291 153 149 0
Adenovirus (copies/mL) – – – – – 7.44 log10 4.86 log10 3.74 log10 – 3.30 log10
BK virus urine (copies/mL) – – – – – 2.26×107 – 3.20×108 –
BK virus blood (copies/mL) – – – – – – – – – 3.91×103
CMV, cytomegalovirus; FCR, fludarabine, cyclophosphamide and rituximab; Hb, haemoglobin; Plt, platelet; WBC, white blood cell.
On 1 December 2019 she developed a pancytopenia that required platelet and packed red blood cell transfusions. She remained persistently febrile despite repeated negative bacterial blood and urine cultures. Due to her CLL, pancytopenia and the consideration of immunosuppression induced by FCR chemotherapy, viral infections were investigated. PCR for adenovirus showed 22.4 copies/mL in blood, and positive in urine; PCR for polyoma virus showed 8.81 million copies/mL blood; and PCR for CMV showed 358 copies/mL in blood, confirming viral invasive infections (figure 3). To further investigate her pancytopenia, serology for parvovirus B 19 was carried out and was negative for IgM.
Figure 3 Cytomegalovirus (CMV) and BK viremia (A) and adeno-viremia (B) over the course of treatment.
On 18 December 2019 the patient underwent a double J-stent insertion for bilateral hydronephrosis. Pelvic pain persisted and she continued to pass clots in her urine. Repeat CMV PCR testing on 25 December 2019 showed 7320 copies/mL while an ophthalmological assessment revealed no evidence of CMV retinitis or keratitis. Bone marrow biopsy results showed pancytopenia without transformation (figure 4).
Figure 4 Histology and immunochemistry of bone marrow smear (A) and biopsy (B). Bone marrow biopsy demonstrating hypocellularity. Moderate left shift of the myeloid series and mild left shift of the erythroid series. No lymphocytosis or lymphoma, no definite diagnosis of myelodysplastic syndrome (B).
Treatment
On 1 January 2020, cidofovir was administered to treat the three viral infections of BK polyomavirus, adenovirus and CMV. Cidofovir was given at the dose of 1 mg/kg intravenously three times a week instead of a weekly dose given her kidney injury and high creatinine levels. She received probenecid 2 g orally 1 hour before cidofovir, then 2 hours and 8 hours after the end of infusion to increase cidofovir levels in the blood. For renal protection, she was hydrated with 1 L of 0.9% normal saline during cidofovir infusion. Filgrastim (G-CSF) was initiated for her neutropenia, darbepoetin for her anaemia, and intravenous IgG was infused three times at 4-week intervals for her hypogammaglobulinumia.
Neutropenia worsen despite filgrastim, and CMV viral load continued to increase. Due to cidofovir myelotoxicity, a decision was made to focus treatment on CMV infection, while ignoring the BK and adenovirus. To this end, the patient was changed to ganciclovir 250 mg intravenous two times per day on 23 January 2020 and her urinary symptoms improved for the first time. On 1 February 2020, she was transitioned to oral valganciclovir 450 mg daily and was discharged to home 1 week later, after 101 days in hospital.
Outcome and follow-up
A bone marrow biopsy on 27 January 2020 showed a hypocellular marrow with focal area up to 20%–30% haematopoietic tissue. No evidence of lymphocytosis or lymphoma and no dysplastic changes in morphology were observed. Immunohistochemistry showed <5% CD117, and was negative for CD20, CD34 and PAX5. The histological appearance represented haematopoietic regeneration post-chemotherapy. On 3 March 2020 follow-up, CMV load was undetectable, adenovirus load was 5000 copies/mL, BK load was 3.2×108 copies/mL (table 1). She was switched on CMV prophylaxis with resolved haemorrhagic cystitis and received valganciclovir 450 mg p.o. daily for another 3 months and until her absolute lymphocyte count recovers above 109 cells/L. She continued trimethoprim-sulfamethaxole prophylaxis for 6 months post-chemotherapy. Her double-J stents remain in place. While clinically improved, her neutropenia improved on low dose filgrastim until 4 April 2020. Her blood counts normalised 1 month after and she is followed as an outpatient with Haematology, Infectious Diseases, and Urology services at the MUHC.
Discussion
FCR chemo-immunotherapy is considered the treatment for standard risk CLL patients under the age of 65,7 with a high overall response rate. However, the predominant complication is myelosuppression.8 Persistent neutropenia was reported in 19% and late infections in 9% of patients.9 The frequency of cytopenias was 35% at 3 months and 12% at 9 months after completion of therapy, respectively. Another side effect is prolonged lymphoid immunodeficiency.
Human adenovirus infections usually present as a keratoconjunctivitis or respiratory tract infection. In most healthy individuals the infection is usually self-limited. However, in immunosuppressed patients, infection may disseminate and become potentially life-threatening. Disseminated adenovirus infection can result from either de novo infection or a reactivation of clinically silent infection.10
BK virus is a member of the polyomavirus family. BK virus reactivation occurs only in immunosuppressed patients and can lead to nephropathy, ureteral stenosis, tubular interstitial damage and haemorrhagic cystitis. Viremia occurs in 20%–60% of this population. There is no specific treatment for BK virus-associated nephropathy, therefore viral replication can only be controlled through modulating the immunosuppressive condition.11
CMV is a herpes virus with a large double-stranded DNA that remains latent in the host after primary infection. Immunocompromised patients can have reactivation of their latent infection. Diagnosis of viral reactivation is made through CMV PCR in blood, tissue or body fluid. Manifestations of CMV infection occur most often in the gastrointestinal tract, lungs, liver and retina.12 As we did not observe the typical owl’s eye tissue lesion in the second bone marrow biopsy, we considered that CMV reactivation was a contributing factor for the pancytopenia, and treatment may have prevented such tissue lesion to develop. First line treatment of CMV infection includes intravenous ganciclovir or its oral prodrug valganciclovir, which are DNA polymerase inhibitors. The major side effect of these drugs is myelosuppression, including neutropenia.4
In our patient, the prolonged pancytopenias secondary to FCR was associated with haematuria with an ureteral mass. To date, only two observations on the use of cidofovir to simultaneously treat BK-virus associated haemorrhagic cystitis and CMV reactivation have been reported. However, in the case report by Held et al, the patient had received a bone marrow transplant for chronic myeloid leukaemia, whereas our patient had CLL.
Cidofovir has been suggested in some cases for the treatment of BK virus-associated haemorrhagic cystitis.13 Cidofovir and foscarnet are second-line therapies in patients with CMV that are either resistant or refractory to ganciclovir. Cidofovir is a non-cyclic analogue of cytidine monophosphate that terminates CMV DNA synthesis. In vitro studies showed effectiveness against herpes viruses, including CMV, herpes simplex viruses 1 and 2, varicella-zoster, Epstein-Barr virus, human papillomavirus and adenovirus. The main adverse effect is nephrotoxicity, causing proximal tubular injury. Serum creatinine and urine protein measurements are recommended during administration.14 Probenecid decreases intratubular secretion and maintains a sufficient plasma concentration to allow for once weekly dosing at 5 mg/kg to reduce its nephrotoxicity.13 An alternate dosing regimen, initially used in our patient, was three times per week dosing at 3 mg/kg. In the study performed by Philippe et al, intravenous cidofovir achieve remission in 81.5% of the 22 patients.13
The patient reported by Held et al recovered fully with cidofovir15; however, our patient was switched to ganciclovir due to persistent neutropenia. Bone marrow biopsy was consistent with secondary treatment-related myelosuppression syndrome, without evidence of myelodysplasia or lymphoproliferative infiltration. Myelosuppression is a major side effect of ganciclovir. However, the antiviral effects far outweigh these risks and therefore ganciclovir and its oral prodrug valganciclovir should be considered for patients with pancytopenia secondary to CMV reactivation.
In summary, this unique case of triple-viremia induced haemorrhagic cystitis in an immunosuppressed CLL patient posed both a diagnostic and therapeutic challenge as treatments are nephrotoxic and further increase immunosuppression.
The major learning point is to exercise caution when prescribing FCR chemotherapy on its long-term immunosuppressive effects. It is expected that novel immuno-chemotherapy for CLL should control the disease with reduced immunosuppressive effects.16
Patient’s perspective
Translation from French
I was diagnosed with CLL in November 2015. Started the treatments with FCR protocol in April 2019 (six treatments of three consecutive days each). At the end of the fourth treatment, I was not well. I had fever and a large fatigue with no energy. I finished treatments on the 13th of November 2019. On the week of 18 November, the symptoms appeared: fever, incontinent of urine with blood, no appetite, fatigue.
I visited MUHC emergency, 12 hours wait before I had a doctor’s room. I stayed the night and the next day I saw the doctor, but they did not know what I had. On the 22nd of November I returned to emergency with a lot of fever and other symptoms. I passed the night in an emergency room. On Saturday they released me, had fever and falls.
On the 24th I returned to emergency, fever and incontinence, etc. I was placed in the corridor in a stretcher with a commode next to the whole world. There was nowhere else for me, I had to go through the doors to go to the public toilet and I urinated every 5 min. I stayed in emergency 5 days before I was admitted to Internal Medicine.
It was a bad experience the three times I was in emergency. On 29 November, I had my own room. I was there till 07 February 2020.
The staff took charge rapidly. There were many tests during this long period to find out the cause of my problems. Everything came from the chemotherapy. Many departments were involved: urology, otolaryngology, haematology, internal medicine, infectious diseases.
There were several healthcare workers who spoke on behalf of other departments.
Very good service with the nursing staffs and the préposé (aux bénéficiaires). On my part, my immune system was severely damaged.
Learning points
Infections in immunosuppressed patients remain a diagnostic and therapeutic challenge.
In patient treated for chronic lymphocytic leukaemia, haematuria can be related to viral infections like BK virus, adenovirus and cytomegalovirus (CMV).
BK infection is diagnosed with a high index of suspicion, however, combined CMV and adenovirus infections renders the diagnosis more difficult.
Treatment of these viral infections remains difficult as medications are associated with myelotoxicity (ganciclovir) and renal insufficiency (cidofovir).
The authors would like to thank Dr Malek Merdad and Dr Isabelle Malhamé for their inspiration to write this article.
Contributors: MK and J-PR devised the project, main conceptual ideas and proof outlines. MK took the lead in writing the manuscript the supervision of J-PR. MK created all the images and translated the patient’s perspective from French to English. J-PR and JL provided critical feedback and helped shape analysis and manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33402369 | 19,066,566 | 2021-01-05 |
What was the outcome of reaction 'Hydronephrosis'? | Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
Background
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder associated with mature B-cell dysfunction, hypogammaglobulinaemia and T-cell abnormalities. In Europe and North America, CLL is the most common leukaemia, with median age of diagnosis of 70 years.1 Treatment is indicated only for symptomatic disease, such as anaemia <100 g/L and/or thrombocytopenia <100×109/L, massive splenomegaly, lymphadenopathy or constitutional symptoms.2
Infection is a frequent cause of morbidity and mortality in CLL. Roughly 30%–50% of all CLL patients suffer infections, with a high subsequent mortality rate.3 While the majority of infections affect more often the respiratory track, or skin and the gastrointestinal tract.4 The most frequent organisms causing infections are bacteria like Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. This increased susceptibility to infection stems from B-cells with impaired immunoglobulin production capability and dysfunctional T-helper cells, which also assist in antibody production. This impaired capability to produce immunoglobulins, termed hypogammaglobulinaemia, affects 85% of CLL patients, particularly in advanced disease.4
Antineoplastic agents recommended for the treatment of CLL are also immunosuppressive and further increase the risk of infections.5 These include opportunistic micro-organisms such as Candida, Pneumocystis jirovecii, listeria, nocardia and atypical mycobacteria. In addition, patients have increased risk of viral diseases such as herpes simplex, Epstein-Barr and cytomegalovirus (CMV). Additional infectious complications may include hepatitis B reactivation and progressive multifocal leucoencephalopathy. In spite of the immunosuppressive risk, chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the standard risk therapy in fit patients below 65 years of age with CLL, in absence of 17 p deletion, or TP53 mutation, and with immunoglobulin heavy chain V (IGHV)-mutated.6
To reduce risk of infection, immunoglobulin levels should also be routinely monitored, particularly with rituximab, which reduces the number of B-cells expressing CD20. It is postulated that monitoring immunoglobulins while being treated with rituximab may reduce the risk of serious infections.4
Herein, we present a unique case of a woman treated for CLL who experienced severe pancytopenia and immunosuppression at the completion of her chemo-immunotherapy. She subsequently experienced triple concurrent viral infections, which posed a therapeutic challenge due to her pancytopenia.
Case presentation
A previously healthy 58-year-old woman was diagnosed with CLL through a routine blood test in 2015. Her physical examination was unremarkable and her lymphocyte counts were at 12.36×109 cells/L. Bone marrow biopsy with immunohistochemistry was suggestive of CLL and stained positive for BCL2, CD5 (aberrant T-cell marker), CD20, CD23, CD43 and CD79a (B-cell markers) while BCL6 was negative. The PCR amplification study showed immunoglobulin heavy chain gene rearrangement along with IgG kappa light chain gene arrangement. No t(14;18) BCL2/JH or t(11;14) BCL1/JH gene rearrangements were observed. As she was asymptomatic, and positron emission tomography (PET) scan showed low grade metabolic activity in lymph nodes in cervical, axillary and iliac areas, no therapy was initiated (figure 1). She was followed every 6 months.
Figure 1 Positron emission tomography scan (right) and corresponding CT images (left) of multiple low-grade hypermetabolic lymph nodes in 2017, 2 years after diagnosis of chronic lymphocytic leukaemia. (A) Multiple small low-grade hypermetabolic lymph nodes in bilateral neck regions predominantly in the posterior triangles. SUV of 1.9 in the left and right upper posterior triangles. (B) Hypermetabolic lymph nodes in the left axillary regions, SUV 1.8. (C) Left external iliac lymph node SUV of 3. SUV, Standardized uptake value.
In November 2017 the patient had symptom of a rapid bilateral enlargement of the cervical lymph nodes accompanied by persistent fatigue, night sweats and decreased weight. Lyme disease, HIV, hepatitis B and C and syphilis serologies were performed, and all tests yielded negative results. Repeat PET/CT scan, cytogenetics and bone marrow biopsy demonstrated no evidence of Richter’s transformation into a diffuse large cell lymphoma. Due to significant bulky disease and enlarged adenopathy with B constitutional symptoms, chemo-immunotherapy with FCR was considered. This was furthermore rationalised as she was a fit patient younger than 65 years of age with standard risk for CLL due to the absence of 17 p deletion, or TP53 mutation, and with IGHV being mutated.7
She received six cycles of FCR which was completed uneventfully on 11 November 2019. During FCR therapy, she received oral valacyclovir 500 mg two times per day for herpes prophylaxis as well as Septra DS (160 mg trimethoprim and 800 mg sulfamethoxazole) one tablet Mondays, Wednesdays and Fridays for P. jirovecii prophylaxis. On 18 November, she presented to the emergency room of the McGill University Health Centre (MUHC) with haematuria, suprapubic pain and fever. She was admitted and treated for a urine infection and slowly improved after different antibiotics such as ciprofloxacin, trimethoprim-sulfamethoxazole and ceftriaxone and blood and urinary bacterial cultures were negative. A CT urogram showed moderate bilateral hydroureteronephrosis with diffuse urolithelial and bladder thickening (figure 2). As a whole, these findings were suggestive of an inflammatory or infectious process evoking pyleoureteritis and cystitis.
Figure 2 CT urogram on admission in November 2019, demonstrating (A) poorly distended bladder and marked thickening of bladder walls (green arrow) and (B) moderate dilation of both ureters and collection ducts with marked thickening and enhancement of the urothelium associated with moderate periureteric fat stranding.
Investigations
On admission, she was mildly pancytopenic (table 1). As the patient partially improved and had negative urine cultures, a cyclophosphamide-induced haemorrhagic cystitis was considered, and she was placed on continuous bladder irrigation.
Table 1 Summary of the patient’s serological and microbiological test results during the course of her neutropenia and triple viremia
Laboratory results Reference ranges 20 March 2019 11 November 2019 26 November 2019 25 December 2019 01 January 2020 23 January 2020 01 February 2020 07 February 2020 03 March 2020
Time of intervention First dose FCR Last dose FCR Meropenem started Virology investigated Begins cidofovir+GCSF Cidofovir changed to Ganciclovir Ganciclovir transitioned to valganciclovir Discharge Follow-up
WBC (109/L) 4.0–10.0 30.90 5.90 3.00 1.00 0.60 2.40 6.10 2.40 2.00
Neutrophils 2.0–7.0 3.75 4.18 2.46 0.80 0.36 1.19 5.09 1.73 1.35
Lymphocytes 1.5–4.5 26.26 0.87 0.23 0.08 0.11 0.23 0.46 0.33 0.44
Plt (109/L) 150–450 145 158 123 48 19 54 17 12 39
Hb (g/L) 120–150 142 129 99 63 80 70 70 71 99
Creatinine (umol/L) 50–90 71 68 125 128 118 75 74 69 75
CMV (copies/mL) – – – – 7320 3170 1291 153 149 0
Adenovirus (copies/mL) – – – – – 7.44 log10 4.86 log10 3.74 log10 – 3.30 log10
BK virus urine (copies/mL) – – – – – 2.26×107 – 3.20×108 –
BK virus blood (copies/mL) – – – – – – – – – 3.91×103
CMV, cytomegalovirus; FCR, fludarabine, cyclophosphamide and rituximab; Hb, haemoglobin; Plt, platelet; WBC, white blood cell.
On 1 December 2019 she developed a pancytopenia that required platelet and packed red blood cell transfusions. She remained persistently febrile despite repeated negative bacterial blood and urine cultures. Due to her CLL, pancytopenia and the consideration of immunosuppression induced by FCR chemotherapy, viral infections were investigated. PCR for adenovirus showed 22.4 copies/mL in blood, and positive in urine; PCR for polyoma virus showed 8.81 million copies/mL blood; and PCR for CMV showed 358 copies/mL in blood, confirming viral invasive infections (figure 3). To further investigate her pancytopenia, serology for parvovirus B 19 was carried out and was negative for IgM.
Figure 3 Cytomegalovirus (CMV) and BK viremia (A) and adeno-viremia (B) over the course of treatment.
On 18 December 2019 the patient underwent a double J-stent insertion for bilateral hydronephrosis. Pelvic pain persisted and she continued to pass clots in her urine. Repeat CMV PCR testing on 25 December 2019 showed 7320 copies/mL while an ophthalmological assessment revealed no evidence of CMV retinitis or keratitis. Bone marrow biopsy results showed pancytopenia without transformation (figure 4).
Figure 4 Histology and immunochemistry of bone marrow smear (A) and biopsy (B). Bone marrow biopsy demonstrating hypocellularity. Moderate left shift of the myeloid series and mild left shift of the erythroid series. No lymphocytosis or lymphoma, no definite diagnosis of myelodysplastic syndrome (B).
Treatment
On 1 January 2020, cidofovir was administered to treat the three viral infections of BK polyomavirus, adenovirus and CMV. Cidofovir was given at the dose of 1 mg/kg intravenously three times a week instead of a weekly dose given her kidney injury and high creatinine levels. She received probenecid 2 g orally 1 hour before cidofovir, then 2 hours and 8 hours after the end of infusion to increase cidofovir levels in the blood. For renal protection, she was hydrated with 1 L of 0.9% normal saline during cidofovir infusion. Filgrastim (G-CSF) was initiated for her neutropenia, darbepoetin for her anaemia, and intravenous IgG was infused three times at 4-week intervals for her hypogammaglobulinumia.
Neutropenia worsen despite filgrastim, and CMV viral load continued to increase. Due to cidofovir myelotoxicity, a decision was made to focus treatment on CMV infection, while ignoring the BK and adenovirus. To this end, the patient was changed to ganciclovir 250 mg intravenous two times per day on 23 January 2020 and her urinary symptoms improved for the first time. On 1 February 2020, she was transitioned to oral valganciclovir 450 mg daily and was discharged to home 1 week later, after 101 days in hospital.
Outcome and follow-up
A bone marrow biopsy on 27 January 2020 showed a hypocellular marrow with focal area up to 20%–30% haematopoietic tissue. No evidence of lymphocytosis or lymphoma and no dysplastic changes in morphology were observed. Immunohistochemistry showed <5% CD117, and was negative for CD20, CD34 and PAX5. The histological appearance represented haematopoietic regeneration post-chemotherapy. On 3 March 2020 follow-up, CMV load was undetectable, adenovirus load was 5000 copies/mL, BK load was 3.2×108 copies/mL (table 1). She was switched on CMV prophylaxis with resolved haemorrhagic cystitis and received valganciclovir 450 mg p.o. daily for another 3 months and until her absolute lymphocyte count recovers above 109 cells/L. She continued trimethoprim-sulfamethaxole prophylaxis for 6 months post-chemotherapy. Her double-J stents remain in place. While clinically improved, her neutropenia improved on low dose filgrastim until 4 April 2020. Her blood counts normalised 1 month after and she is followed as an outpatient with Haematology, Infectious Diseases, and Urology services at the MUHC.
Discussion
FCR chemo-immunotherapy is considered the treatment for standard risk CLL patients under the age of 65,7 with a high overall response rate. However, the predominant complication is myelosuppression.8 Persistent neutropenia was reported in 19% and late infections in 9% of patients.9 The frequency of cytopenias was 35% at 3 months and 12% at 9 months after completion of therapy, respectively. Another side effect is prolonged lymphoid immunodeficiency.
Human adenovirus infections usually present as a keratoconjunctivitis or respiratory tract infection. In most healthy individuals the infection is usually self-limited. However, in immunosuppressed patients, infection may disseminate and become potentially life-threatening. Disseminated adenovirus infection can result from either de novo infection or a reactivation of clinically silent infection.10
BK virus is a member of the polyomavirus family. BK virus reactivation occurs only in immunosuppressed patients and can lead to nephropathy, ureteral stenosis, tubular interstitial damage and haemorrhagic cystitis. Viremia occurs in 20%–60% of this population. There is no specific treatment for BK virus-associated nephropathy, therefore viral replication can only be controlled through modulating the immunosuppressive condition.11
CMV is a herpes virus with a large double-stranded DNA that remains latent in the host after primary infection. Immunocompromised patients can have reactivation of their latent infection. Diagnosis of viral reactivation is made through CMV PCR in blood, tissue or body fluid. Manifestations of CMV infection occur most often in the gastrointestinal tract, lungs, liver and retina.12 As we did not observe the typical owl’s eye tissue lesion in the second bone marrow biopsy, we considered that CMV reactivation was a contributing factor for the pancytopenia, and treatment may have prevented such tissue lesion to develop. First line treatment of CMV infection includes intravenous ganciclovir or its oral prodrug valganciclovir, which are DNA polymerase inhibitors. The major side effect of these drugs is myelosuppression, including neutropenia.4
In our patient, the prolonged pancytopenias secondary to FCR was associated with haematuria with an ureteral mass. To date, only two observations on the use of cidofovir to simultaneously treat BK-virus associated haemorrhagic cystitis and CMV reactivation have been reported. However, in the case report by Held et al, the patient had received a bone marrow transplant for chronic myeloid leukaemia, whereas our patient had CLL.
Cidofovir has been suggested in some cases for the treatment of BK virus-associated haemorrhagic cystitis.13 Cidofovir and foscarnet are second-line therapies in patients with CMV that are either resistant or refractory to ganciclovir. Cidofovir is a non-cyclic analogue of cytidine monophosphate that terminates CMV DNA synthesis. In vitro studies showed effectiveness against herpes viruses, including CMV, herpes simplex viruses 1 and 2, varicella-zoster, Epstein-Barr virus, human papillomavirus and adenovirus. The main adverse effect is nephrotoxicity, causing proximal tubular injury. Serum creatinine and urine protein measurements are recommended during administration.14 Probenecid decreases intratubular secretion and maintains a sufficient plasma concentration to allow for once weekly dosing at 5 mg/kg to reduce its nephrotoxicity.13 An alternate dosing regimen, initially used in our patient, was three times per week dosing at 3 mg/kg. In the study performed by Philippe et al, intravenous cidofovir achieve remission in 81.5% of the 22 patients.13
The patient reported by Held et al recovered fully with cidofovir15; however, our patient was switched to ganciclovir due to persistent neutropenia. Bone marrow biopsy was consistent with secondary treatment-related myelosuppression syndrome, without evidence of myelodysplasia or lymphoproliferative infiltration. Myelosuppression is a major side effect of ganciclovir. However, the antiviral effects far outweigh these risks and therefore ganciclovir and its oral prodrug valganciclovir should be considered for patients with pancytopenia secondary to CMV reactivation.
In summary, this unique case of triple-viremia induced haemorrhagic cystitis in an immunosuppressed CLL patient posed both a diagnostic and therapeutic challenge as treatments are nephrotoxic and further increase immunosuppression.
The major learning point is to exercise caution when prescribing FCR chemotherapy on its long-term immunosuppressive effects. It is expected that novel immuno-chemotherapy for CLL should control the disease with reduced immunosuppressive effects.16
Patient’s perspective
Translation from French
I was diagnosed with CLL in November 2015. Started the treatments with FCR protocol in April 2019 (six treatments of three consecutive days each). At the end of the fourth treatment, I was not well. I had fever and a large fatigue with no energy. I finished treatments on the 13th of November 2019. On the week of 18 November, the symptoms appeared: fever, incontinent of urine with blood, no appetite, fatigue.
I visited MUHC emergency, 12 hours wait before I had a doctor’s room. I stayed the night and the next day I saw the doctor, but they did not know what I had. On the 22nd of November I returned to emergency with a lot of fever and other symptoms. I passed the night in an emergency room. On Saturday they released me, had fever and falls.
On the 24th I returned to emergency, fever and incontinence, etc. I was placed in the corridor in a stretcher with a commode next to the whole world. There was nowhere else for me, I had to go through the doors to go to the public toilet and I urinated every 5 min. I stayed in emergency 5 days before I was admitted to Internal Medicine.
It was a bad experience the three times I was in emergency. On 29 November, I had my own room. I was there till 07 February 2020.
The staff took charge rapidly. There were many tests during this long period to find out the cause of my problems. Everything came from the chemotherapy. Many departments were involved: urology, otolaryngology, haematology, internal medicine, infectious diseases.
There were several healthcare workers who spoke on behalf of other departments.
Very good service with the nursing staffs and the préposé (aux bénéficiaires). On my part, my immune system was severely damaged.
Learning points
Infections in immunosuppressed patients remain a diagnostic and therapeutic challenge.
In patient treated for chronic lymphocytic leukaemia, haematuria can be related to viral infections like BK virus, adenovirus and cytomegalovirus (CMV).
BK infection is diagnosed with a high index of suspicion, however, combined CMV and adenovirus infections renders the diagnosis more difficult.
Treatment of these viral infections remains difficult as medications are associated with myelotoxicity (ganciclovir) and renal insufficiency (cidofovir).
The authors would like to thank Dr Malek Merdad and Dr Isabelle Malhamé for their inspiration to write this article.
Contributors: MK and J-PR devised the project, main conceptual ideas and proof outlines. MK took the lead in writing the manuscript the supervision of J-PR. MK created all the images and translated the patient’s perspective from French to English. J-PR and JL provided critical feedback and helped shape analysis and manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovering | ReactionOutcome | CC BY-NC | 33402369 | 19,066,566 | 2021-01-05 |
What was the outcome of reaction 'Myelosuppression'? | Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
Background
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder associated with mature B-cell dysfunction, hypogammaglobulinaemia and T-cell abnormalities. In Europe and North America, CLL is the most common leukaemia, with median age of diagnosis of 70 years.1 Treatment is indicated only for symptomatic disease, such as anaemia <100 g/L and/or thrombocytopenia <100×109/L, massive splenomegaly, lymphadenopathy or constitutional symptoms.2
Infection is a frequent cause of morbidity and mortality in CLL. Roughly 30%–50% of all CLL patients suffer infections, with a high subsequent mortality rate.3 While the majority of infections affect more often the respiratory track, or skin and the gastrointestinal tract.4 The most frequent organisms causing infections are bacteria like Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. This increased susceptibility to infection stems from B-cells with impaired immunoglobulin production capability and dysfunctional T-helper cells, which also assist in antibody production. This impaired capability to produce immunoglobulins, termed hypogammaglobulinaemia, affects 85% of CLL patients, particularly in advanced disease.4
Antineoplastic agents recommended for the treatment of CLL are also immunosuppressive and further increase the risk of infections.5 These include opportunistic micro-organisms such as Candida, Pneumocystis jirovecii, listeria, nocardia and atypical mycobacteria. In addition, patients have increased risk of viral diseases such as herpes simplex, Epstein-Barr and cytomegalovirus (CMV). Additional infectious complications may include hepatitis B reactivation and progressive multifocal leucoencephalopathy. In spite of the immunosuppressive risk, chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the standard risk therapy in fit patients below 65 years of age with CLL, in absence of 17 p deletion, or TP53 mutation, and with immunoglobulin heavy chain V (IGHV)-mutated.6
To reduce risk of infection, immunoglobulin levels should also be routinely monitored, particularly with rituximab, which reduces the number of B-cells expressing CD20. It is postulated that monitoring immunoglobulins while being treated with rituximab may reduce the risk of serious infections.4
Herein, we present a unique case of a woman treated for CLL who experienced severe pancytopenia and immunosuppression at the completion of her chemo-immunotherapy. She subsequently experienced triple concurrent viral infections, which posed a therapeutic challenge due to her pancytopenia.
Case presentation
A previously healthy 58-year-old woman was diagnosed with CLL through a routine blood test in 2015. Her physical examination was unremarkable and her lymphocyte counts were at 12.36×109 cells/L. Bone marrow biopsy with immunohistochemistry was suggestive of CLL and stained positive for BCL2, CD5 (aberrant T-cell marker), CD20, CD23, CD43 and CD79a (B-cell markers) while BCL6 was negative. The PCR amplification study showed immunoglobulin heavy chain gene rearrangement along with IgG kappa light chain gene arrangement. No t(14;18) BCL2/JH or t(11;14) BCL1/JH gene rearrangements were observed. As she was asymptomatic, and positron emission tomography (PET) scan showed low grade metabolic activity in lymph nodes in cervical, axillary and iliac areas, no therapy was initiated (figure 1). She was followed every 6 months.
Figure 1 Positron emission tomography scan (right) and corresponding CT images (left) of multiple low-grade hypermetabolic lymph nodes in 2017, 2 years after diagnosis of chronic lymphocytic leukaemia. (A) Multiple small low-grade hypermetabolic lymph nodes in bilateral neck regions predominantly in the posterior triangles. SUV of 1.9 in the left and right upper posterior triangles. (B) Hypermetabolic lymph nodes in the left axillary regions, SUV 1.8. (C) Left external iliac lymph node SUV of 3. SUV, Standardized uptake value.
In November 2017 the patient had symptom of a rapid bilateral enlargement of the cervical lymph nodes accompanied by persistent fatigue, night sweats and decreased weight. Lyme disease, HIV, hepatitis B and C and syphilis serologies were performed, and all tests yielded negative results. Repeat PET/CT scan, cytogenetics and bone marrow biopsy demonstrated no evidence of Richter’s transformation into a diffuse large cell lymphoma. Due to significant bulky disease and enlarged adenopathy with B constitutional symptoms, chemo-immunotherapy with FCR was considered. This was furthermore rationalised as she was a fit patient younger than 65 years of age with standard risk for CLL due to the absence of 17 p deletion, or TP53 mutation, and with IGHV being mutated.7
She received six cycles of FCR which was completed uneventfully on 11 November 2019. During FCR therapy, she received oral valacyclovir 500 mg two times per day for herpes prophylaxis as well as Septra DS (160 mg trimethoprim and 800 mg sulfamethoxazole) one tablet Mondays, Wednesdays and Fridays for P. jirovecii prophylaxis. On 18 November, she presented to the emergency room of the McGill University Health Centre (MUHC) with haematuria, suprapubic pain and fever. She was admitted and treated for a urine infection and slowly improved after different antibiotics such as ciprofloxacin, trimethoprim-sulfamethoxazole and ceftriaxone and blood and urinary bacterial cultures were negative. A CT urogram showed moderate bilateral hydroureteronephrosis with diffuse urolithelial and bladder thickening (figure 2). As a whole, these findings were suggestive of an inflammatory or infectious process evoking pyleoureteritis and cystitis.
Figure 2 CT urogram on admission in November 2019, demonstrating (A) poorly distended bladder and marked thickening of bladder walls (green arrow) and (B) moderate dilation of both ureters and collection ducts with marked thickening and enhancement of the urothelium associated with moderate periureteric fat stranding.
Investigations
On admission, she was mildly pancytopenic (table 1). As the patient partially improved and had negative urine cultures, a cyclophosphamide-induced haemorrhagic cystitis was considered, and she was placed on continuous bladder irrigation.
Table 1 Summary of the patient’s serological and microbiological test results during the course of her neutropenia and triple viremia
Laboratory results Reference ranges 20 March 2019 11 November 2019 26 November 2019 25 December 2019 01 January 2020 23 January 2020 01 February 2020 07 February 2020 03 March 2020
Time of intervention First dose FCR Last dose FCR Meropenem started Virology investigated Begins cidofovir+GCSF Cidofovir changed to Ganciclovir Ganciclovir transitioned to valganciclovir Discharge Follow-up
WBC (109/L) 4.0–10.0 30.90 5.90 3.00 1.00 0.60 2.40 6.10 2.40 2.00
Neutrophils 2.0–7.0 3.75 4.18 2.46 0.80 0.36 1.19 5.09 1.73 1.35
Lymphocytes 1.5–4.5 26.26 0.87 0.23 0.08 0.11 0.23 0.46 0.33 0.44
Plt (109/L) 150–450 145 158 123 48 19 54 17 12 39
Hb (g/L) 120–150 142 129 99 63 80 70 70 71 99
Creatinine (umol/L) 50–90 71 68 125 128 118 75 74 69 75
CMV (copies/mL) – – – – 7320 3170 1291 153 149 0
Adenovirus (copies/mL) – – – – – 7.44 log10 4.86 log10 3.74 log10 – 3.30 log10
BK virus urine (copies/mL) – – – – – 2.26×107 – 3.20×108 –
BK virus blood (copies/mL) – – – – – – – – – 3.91×103
CMV, cytomegalovirus; FCR, fludarabine, cyclophosphamide and rituximab; Hb, haemoglobin; Plt, platelet; WBC, white blood cell.
On 1 December 2019 she developed a pancytopenia that required platelet and packed red blood cell transfusions. She remained persistently febrile despite repeated negative bacterial blood and urine cultures. Due to her CLL, pancytopenia and the consideration of immunosuppression induced by FCR chemotherapy, viral infections were investigated. PCR for adenovirus showed 22.4 copies/mL in blood, and positive in urine; PCR for polyoma virus showed 8.81 million copies/mL blood; and PCR for CMV showed 358 copies/mL in blood, confirming viral invasive infections (figure 3). To further investigate her pancytopenia, serology for parvovirus B 19 was carried out and was negative for IgM.
Figure 3 Cytomegalovirus (CMV) and BK viremia (A) and adeno-viremia (B) over the course of treatment.
On 18 December 2019 the patient underwent a double J-stent insertion for bilateral hydronephrosis. Pelvic pain persisted and she continued to pass clots in her urine. Repeat CMV PCR testing on 25 December 2019 showed 7320 copies/mL while an ophthalmological assessment revealed no evidence of CMV retinitis or keratitis. Bone marrow biopsy results showed pancytopenia without transformation (figure 4).
Figure 4 Histology and immunochemistry of bone marrow smear (A) and biopsy (B). Bone marrow biopsy demonstrating hypocellularity. Moderate left shift of the myeloid series and mild left shift of the erythroid series. No lymphocytosis or lymphoma, no definite diagnosis of myelodysplastic syndrome (B).
Treatment
On 1 January 2020, cidofovir was administered to treat the three viral infections of BK polyomavirus, adenovirus and CMV. Cidofovir was given at the dose of 1 mg/kg intravenously three times a week instead of a weekly dose given her kidney injury and high creatinine levels. She received probenecid 2 g orally 1 hour before cidofovir, then 2 hours and 8 hours after the end of infusion to increase cidofovir levels in the blood. For renal protection, she was hydrated with 1 L of 0.9% normal saline during cidofovir infusion. Filgrastim (G-CSF) was initiated for her neutropenia, darbepoetin for her anaemia, and intravenous IgG was infused three times at 4-week intervals for her hypogammaglobulinumia.
Neutropenia worsen despite filgrastim, and CMV viral load continued to increase. Due to cidofovir myelotoxicity, a decision was made to focus treatment on CMV infection, while ignoring the BK and adenovirus. To this end, the patient was changed to ganciclovir 250 mg intravenous two times per day on 23 January 2020 and her urinary symptoms improved for the first time. On 1 February 2020, she was transitioned to oral valganciclovir 450 mg daily and was discharged to home 1 week later, after 101 days in hospital.
Outcome and follow-up
A bone marrow biopsy on 27 January 2020 showed a hypocellular marrow with focal area up to 20%–30% haematopoietic tissue. No evidence of lymphocytosis or lymphoma and no dysplastic changes in morphology were observed. Immunohistochemistry showed <5% CD117, and was negative for CD20, CD34 and PAX5. The histological appearance represented haematopoietic regeneration post-chemotherapy. On 3 March 2020 follow-up, CMV load was undetectable, adenovirus load was 5000 copies/mL, BK load was 3.2×108 copies/mL (table 1). She was switched on CMV prophylaxis with resolved haemorrhagic cystitis and received valganciclovir 450 mg p.o. daily for another 3 months and until her absolute lymphocyte count recovers above 109 cells/L. She continued trimethoprim-sulfamethaxole prophylaxis for 6 months post-chemotherapy. Her double-J stents remain in place. While clinically improved, her neutropenia improved on low dose filgrastim until 4 April 2020. Her blood counts normalised 1 month after and she is followed as an outpatient with Haematology, Infectious Diseases, and Urology services at the MUHC.
Discussion
FCR chemo-immunotherapy is considered the treatment for standard risk CLL patients under the age of 65,7 with a high overall response rate. However, the predominant complication is myelosuppression.8 Persistent neutropenia was reported in 19% and late infections in 9% of patients.9 The frequency of cytopenias was 35% at 3 months and 12% at 9 months after completion of therapy, respectively. Another side effect is prolonged lymphoid immunodeficiency.
Human adenovirus infections usually present as a keratoconjunctivitis or respiratory tract infection. In most healthy individuals the infection is usually self-limited. However, in immunosuppressed patients, infection may disseminate and become potentially life-threatening. Disseminated adenovirus infection can result from either de novo infection or a reactivation of clinically silent infection.10
BK virus is a member of the polyomavirus family. BK virus reactivation occurs only in immunosuppressed patients and can lead to nephropathy, ureteral stenosis, tubular interstitial damage and haemorrhagic cystitis. Viremia occurs in 20%–60% of this population. There is no specific treatment for BK virus-associated nephropathy, therefore viral replication can only be controlled through modulating the immunosuppressive condition.11
CMV is a herpes virus with a large double-stranded DNA that remains latent in the host after primary infection. Immunocompromised patients can have reactivation of their latent infection. Diagnosis of viral reactivation is made through CMV PCR in blood, tissue or body fluid. Manifestations of CMV infection occur most often in the gastrointestinal tract, lungs, liver and retina.12 As we did not observe the typical owl’s eye tissue lesion in the second bone marrow biopsy, we considered that CMV reactivation was a contributing factor for the pancytopenia, and treatment may have prevented such tissue lesion to develop. First line treatment of CMV infection includes intravenous ganciclovir or its oral prodrug valganciclovir, which are DNA polymerase inhibitors. The major side effect of these drugs is myelosuppression, including neutropenia.4
In our patient, the prolonged pancytopenias secondary to FCR was associated with haematuria with an ureteral mass. To date, only two observations on the use of cidofovir to simultaneously treat BK-virus associated haemorrhagic cystitis and CMV reactivation have been reported. However, in the case report by Held et al, the patient had received a bone marrow transplant for chronic myeloid leukaemia, whereas our patient had CLL.
Cidofovir has been suggested in some cases for the treatment of BK virus-associated haemorrhagic cystitis.13 Cidofovir and foscarnet are second-line therapies in patients with CMV that are either resistant or refractory to ganciclovir. Cidofovir is a non-cyclic analogue of cytidine monophosphate that terminates CMV DNA synthesis. In vitro studies showed effectiveness against herpes viruses, including CMV, herpes simplex viruses 1 and 2, varicella-zoster, Epstein-Barr virus, human papillomavirus and adenovirus. The main adverse effect is nephrotoxicity, causing proximal tubular injury. Serum creatinine and urine protein measurements are recommended during administration.14 Probenecid decreases intratubular secretion and maintains a sufficient plasma concentration to allow for once weekly dosing at 5 mg/kg to reduce its nephrotoxicity.13 An alternate dosing regimen, initially used in our patient, was three times per week dosing at 3 mg/kg. In the study performed by Philippe et al, intravenous cidofovir achieve remission in 81.5% of the 22 patients.13
The patient reported by Held et al recovered fully with cidofovir15; however, our patient was switched to ganciclovir due to persistent neutropenia. Bone marrow biopsy was consistent with secondary treatment-related myelosuppression syndrome, without evidence of myelodysplasia or lymphoproliferative infiltration. Myelosuppression is a major side effect of ganciclovir. However, the antiviral effects far outweigh these risks and therefore ganciclovir and its oral prodrug valganciclovir should be considered for patients with pancytopenia secondary to CMV reactivation.
In summary, this unique case of triple-viremia induced haemorrhagic cystitis in an immunosuppressed CLL patient posed both a diagnostic and therapeutic challenge as treatments are nephrotoxic and further increase immunosuppression.
The major learning point is to exercise caution when prescribing FCR chemotherapy on its long-term immunosuppressive effects. It is expected that novel immuno-chemotherapy for CLL should control the disease with reduced immunosuppressive effects.16
Patient’s perspective
Translation from French
I was diagnosed with CLL in November 2015. Started the treatments with FCR protocol in April 2019 (six treatments of three consecutive days each). At the end of the fourth treatment, I was not well. I had fever and a large fatigue with no energy. I finished treatments on the 13th of November 2019. On the week of 18 November, the symptoms appeared: fever, incontinent of urine with blood, no appetite, fatigue.
I visited MUHC emergency, 12 hours wait before I had a doctor’s room. I stayed the night and the next day I saw the doctor, but they did not know what I had. On the 22nd of November I returned to emergency with a lot of fever and other symptoms. I passed the night in an emergency room. On Saturday they released me, had fever and falls.
On the 24th I returned to emergency, fever and incontinence, etc. I was placed in the corridor in a stretcher with a commode next to the whole world. There was nowhere else for me, I had to go through the doors to go to the public toilet and I urinated every 5 min. I stayed in emergency 5 days before I was admitted to Internal Medicine.
It was a bad experience the three times I was in emergency. On 29 November, I had my own room. I was there till 07 February 2020.
The staff took charge rapidly. There were many tests during this long period to find out the cause of my problems. Everything came from the chemotherapy. Many departments were involved: urology, otolaryngology, haematology, internal medicine, infectious diseases.
There were several healthcare workers who spoke on behalf of other departments.
Very good service with the nursing staffs and the préposé (aux bénéficiaires). On my part, my immune system was severely damaged.
Learning points
Infections in immunosuppressed patients remain a diagnostic and therapeutic challenge.
In patient treated for chronic lymphocytic leukaemia, haematuria can be related to viral infections like BK virus, adenovirus and cytomegalovirus (CMV).
BK infection is diagnosed with a high index of suspicion, however, combined CMV and adenovirus infections renders the diagnosis more difficult.
Treatment of these viral infections remains difficult as medications are associated with myelotoxicity (ganciclovir) and renal insufficiency (cidofovir).
The authors would like to thank Dr Malek Merdad and Dr Isabelle Malhamé for their inspiration to write this article.
Contributors: MK and J-PR devised the project, main conceptual ideas and proof outlines. MK took the lead in writing the manuscript the supervision of J-PR. MK created all the images and translated the patient’s perspective from French to English. J-PR and JL provided critical feedback and helped shape analysis and manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33402369 | 19,066,566 | 2021-01-05 |
What was the outcome of reaction 'Neutropenia'? | Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
Background
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder associated with mature B-cell dysfunction, hypogammaglobulinaemia and T-cell abnormalities. In Europe and North America, CLL is the most common leukaemia, with median age of diagnosis of 70 years.1 Treatment is indicated only for symptomatic disease, such as anaemia <100 g/L and/or thrombocytopenia <100×109/L, massive splenomegaly, lymphadenopathy or constitutional symptoms.2
Infection is a frequent cause of morbidity and mortality in CLL. Roughly 30%–50% of all CLL patients suffer infections, with a high subsequent mortality rate.3 While the majority of infections affect more often the respiratory track, or skin and the gastrointestinal tract.4 The most frequent organisms causing infections are bacteria like Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. This increased susceptibility to infection stems from B-cells with impaired immunoglobulin production capability and dysfunctional T-helper cells, which also assist in antibody production. This impaired capability to produce immunoglobulins, termed hypogammaglobulinaemia, affects 85% of CLL patients, particularly in advanced disease.4
Antineoplastic agents recommended for the treatment of CLL are also immunosuppressive and further increase the risk of infections.5 These include opportunistic micro-organisms such as Candida, Pneumocystis jirovecii, listeria, nocardia and atypical mycobacteria. In addition, patients have increased risk of viral diseases such as herpes simplex, Epstein-Barr and cytomegalovirus (CMV). Additional infectious complications may include hepatitis B reactivation and progressive multifocal leucoencephalopathy. In spite of the immunosuppressive risk, chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the standard risk therapy in fit patients below 65 years of age with CLL, in absence of 17 p deletion, or TP53 mutation, and with immunoglobulin heavy chain V (IGHV)-mutated.6
To reduce risk of infection, immunoglobulin levels should also be routinely monitored, particularly with rituximab, which reduces the number of B-cells expressing CD20. It is postulated that monitoring immunoglobulins while being treated with rituximab may reduce the risk of serious infections.4
Herein, we present a unique case of a woman treated for CLL who experienced severe pancytopenia and immunosuppression at the completion of her chemo-immunotherapy. She subsequently experienced triple concurrent viral infections, which posed a therapeutic challenge due to her pancytopenia.
Case presentation
A previously healthy 58-year-old woman was diagnosed with CLL through a routine blood test in 2015. Her physical examination was unremarkable and her lymphocyte counts were at 12.36×109 cells/L. Bone marrow biopsy with immunohistochemistry was suggestive of CLL and stained positive for BCL2, CD5 (aberrant T-cell marker), CD20, CD23, CD43 and CD79a (B-cell markers) while BCL6 was negative. The PCR amplification study showed immunoglobulin heavy chain gene rearrangement along with IgG kappa light chain gene arrangement. No t(14;18) BCL2/JH or t(11;14) BCL1/JH gene rearrangements were observed. As she was asymptomatic, and positron emission tomography (PET) scan showed low grade metabolic activity in lymph nodes in cervical, axillary and iliac areas, no therapy was initiated (figure 1). She was followed every 6 months.
Figure 1 Positron emission tomography scan (right) and corresponding CT images (left) of multiple low-grade hypermetabolic lymph nodes in 2017, 2 years after diagnosis of chronic lymphocytic leukaemia. (A) Multiple small low-grade hypermetabolic lymph nodes in bilateral neck regions predominantly in the posterior triangles. SUV of 1.9 in the left and right upper posterior triangles. (B) Hypermetabolic lymph nodes in the left axillary regions, SUV 1.8. (C) Left external iliac lymph node SUV of 3. SUV, Standardized uptake value.
In November 2017 the patient had symptom of a rapid bilateral enlargement of the cervical lymph nodes accompanied by persistent fatigue, night sweats and decreased weight. Lyme disease, HIV, hepatitis B and C and syphilis serologies were performed, and all tests yielded negative results. Repeat PET/CT scan, cytogenetics and bone marrow biopsy demonstrated no evidence of Richter’s transformation into a diffuse large cell lymphoma. Due to significant bulky disease and enlarged adenopathy with B constitutional symptoms, chemo-immunotherapy with FCR was considered. This was furthermore rationalised as she was a fit patient younger than 65 years of age with standard risk for CLL due to the absence of 17 p deletion, or TP53 mutation, and with IGHV being mutated.7
She received six cycles of FCR which was completed uneventfully on 11 November 2019. During FCR therapy, she received oral valacyclovir 500 mg two times per day for herpes prophylaxis as well as Septra DS (160 mg trimethoprim and 800 mg sulfamethoxazole) one tablet Mondays, Wednesdays and Fridays for P. jirovecii prophylaxis. On 18 November, she presented to the emergency room of the McGill University Health Centre (MUHC) with haematuria, suprapubic pain and fever. She was admitted and treated for a urine infection and slowly improved after different antibiotics such as ciprofloxacin, trimethoprim-sulfamethoxazole and ceftriaxone and blood and urinary bacterial cultures were negative. A CT urogram showed moderate bilateral hydroureteronephrosis with diffuse urolithelial and bladder thickening (figure 2). As a whole, these findings were suggestive of an inflammatory or infectious process evoking pyleoureteritis and cystitis.
Figure 2 CT urogram on admission in November 2019, demonstrating (A) poorly distended bladder and marked thickening of bladder walls (green arrow) and (B) moderate dilation of both ureters and collection ducts with marked thickening and enhancement of the urothelium associated with moderate periureteric fat stranding.
Investigations
On admission, she was mildly pancytopenic (table 1). As the patient partially improved and had negative urine cultures, a cyclophosphamide-induced haemorrhagic cystitis was considered, and she was placed on continuous bladder irrigation.
Table 1 Summary of the patient’s serological and microbiological test results during the course of her neutropenia and triple viremia
Laboratory results Reference ranges 20 March 2019 11 November 2019 26 November 2019 25 December 2019 01 January 2020 23 January 2020 01 February 2020 07 February 2020 03 March 2020
Time of intervention First dose FCR Last dose FCR Meropenem started Virology investigated Begins cidofovir+GCSF Cidofovir changed to Ganciclovir Ganciclovir transitioned to valganciclovir Discharge Follow-up
WBC (109/L) 4.0–10.0 30.90 5.90 3.00 1.00 0.60 2.40 6.10 2.40 2.00
Neutrophils 2.0–7.0 3.75 4.18 2.46 0.80 0.36 1.19 5.09 1.73 1.35
Lymphocytes 1.5–4.5 26.26 0.87 0.23 0.08 0.11 0.23 0.46 0.33 0.44
Plt (109/L) 150–450 145 158 123 48 19 54 17 12 39
Hb (g/L) 120–150 142 129 99 63 80 70 70 71 99
Creatinine (umol/L) 50–90 71 68 125 128 118 75 74 69 75
CMV (copies/mL) – – – – 7320 3170 1291 153 149 0
Adenovirus (copies/mL) – – – – – 7.44 log10 4.86 log10 3.74 log10 – 3.30 log10
BK virus urine (copies/mL) – – – – – 2.26×107 – 3.20×108 –
BK virus blood (copies/mL) – – – – – – – – – 3.91×103
CMV, cytomegalovirus; FCR, fludarabine, cyclophosphamide and rituximab; Hb, haemoglobin; Plt, platelet; WBC, white blood cell.
On 1 December 2019 she developed a pancytopenia that required platelet and packed red blood cell transfusions. She remained persistently febrile despite repeated negative bacterial blood and urine cultures. Due to her CLL, pancytopenia and the consideration of immunosuppression induced by FCR chemotherapy, viral infections were investigated. PCR for adenovirus showed 22.4 copies/mL in blood, and positive in urine; PCR for polyoma virus showed 8.81 million copies/mL blood; and PCR for CMV showed 358 copies/mL in blood, confirming viral invasive infections (figure 3). To further investigate her pancytopenia, serology for parvovirus B 19 was carried out and was negative for IgM.
Figure 3 Cytomegalovirus (CMV) and BK viremia (A) and adeno-viremia (B) over the course of treatment.
On 18 December 2019 the patient underwent a double J-stent insertion for bilateral hydronephrosis. Pelvic pain persisted and she continued to pass clots in her urine. Repeat CMV PCR testing on 25 December 2019 showed 7320 copies/mL while an ophthalmological assessment revealed no evidence of CMV retinitis or keratitis. Bone marrow biopsy results showed pancytopenia without transformation (figure 4).
Figure 4 Histology and immunochemistry of bone marrow smear (A) and biopsy (B). Bone marrow biopsy demonstrating hypocellularity. Moderate left shift of the myeloid series and mild left shift of the erythroid series. No lymphocytosis or lymphoma, no definite diagnosis of myelodysplastic syndrome (B).
Treatment
On 1 January 2020, cidofovir was administered to treat the three viral infections of BK polyomavirus, adenovirus and CMV. Cidofovir was given at the dose of 1 mg/kg intravenously three times a week instead of a weekly dose given her kidney injury and high creatinine levels. She received probenecid 2 g orally 1 hour before cidofovir, then 2 hours and 8 hours after the end of infusion to increase cidofovir levels in the blood. For renal protection, she was hydrated with 1 L of 0.9% normal saline during cidofovir infusion. Filgrastim (G-CSF) was initiated for her neutropenia, darbepoetin for her anaemia, and intravenous IgG was infused three times at 4-week intervals for her hypogammaglobulinumia.
Neutropenia worsen despite filgrastim, and CMV viral load continued to increase. Due to cidofovir myelotoxicity, a decision was made to focus treatment on CMV infection, while ignoring the BK and adenovirus. To this end, the patient was changed to ganciclovir 250 mg intravenous two times per day on 23 January 2020 and her urinary symptoms improved for the first time. On 1 February 2020, she was transitioned to oral valganciclovir 450 mg daily and was discharged to home 1 week later, after 101 days in hospital.
Outcome and follow-up
A bone marrow biopsy on 27 January 2020 showed a hypocellular marrow with focal area up to 20%–30% haematopoietic tissue. No evidence of lymphocytosis or lymphoma and no dysplastic changes in morphology were observed. Immunohistochemistry showed <5% CD117, and was negative for CD20, CD34 and PAX5. The histological appearance represented haematopoietic regeneration post-chemotherapy. On 3 March 2020 follow-up, CMV load was undetectable, adenovirus load was 5000 copies/mL, BK load was 3.2×108 copies/mL (table 1). She was switched on CMV prophylaxis with resolved haemorrhagic cystitis and received valganciclovir 450 mg p.o. daily for another 3 months and until her absolute lymphocyte count recovers above 109 cells/L. She continued trimethoprim-sulfamethaxole prophylaxis for 6 months post-chemotherapy. Her double-J stents remain in place. While clinically improved, her neutropenia improved on low dose filgrastim until 4 April 2020. Her blood counts normalised 1 month after and she is followed as an outpatient with Haematology, Infectious Diseases, and Urology services at the MUHC.
Discussion
FCR chemo-immunotherapy is considered the treatment for standard risk CLL patients under the age of 65,7 with a high overall response rate. However, the predominant complication is myelosuppression.8 Persistent neutropenia was reported in 19% and late infections in 9% of patients.9 The frequency of cytopenias was 35% at 3 months and 12% at 9 months after completion of therapy, respectively. Another side effect is prolonged lymphoid immunodeficiency.
Human adenovirus infections usually present as a keratoconjunctivitis or respiratory tract infection. In most healthy individuals the infection is usually self-limited. However, in immunosuppressed patients, infection may disseminate and become potentially life-threatening. Disseminated adenovirus infection can result from either de novo infection or a reactivation of clinically silent infection.10
BK virus is a member of the polyomavirus family. BK virus reactivation occurs only in immunosuppressed patients and can lead to nephropathy, ureteral stenosis, tubular interstitial damage and haemorrhagic cystitis. Viremia occurs in 20%–60% of this population. There is no specific treatment for BK virus-associated nephropathy, therefore viral replication can only be controlled through modulating the immunosuppressive condition.11
CMV is a herpes virus with a large double-stranded DNA that remains latent in the host after primary infection. Immunocompromised patients can have reactivation of their latent infection. Diagnosis of viral reactivation is made through CMV PCR in blood, tissue or body fluid. Manifestations of CMV infection occur most often in the gastrointestinal tract, lungs, liver and retina.12 As we did not observe the typical owl’s eye tissue lesion in the second bone marrow biopsy, we considered that CMV reactivation was a contributing factor for the pancytopenia, and treatment may have prevented such tissue lesion to develop. First line treatment of CMV infection includes intravenous ganciclovir or its oral prodrug valganciclovir, which are DNA polymerase inhibitors. The major side effect of these drugs is myelosuppression, including neutropenia.4
In our patient, the prolonged pancytopenias secondary to FCR was associated with haematuria with an ureteral mass. To date, only two observations on the use of cidofovir to simultaneously treat BK-virus associated haemorrhagic cystitis and CMV reactivation have been reported. However, in the case report by Held et al, the patient had received a bone marrow transplant for chronic myeloid leukaemia, whereas our patient had CLL.
Cidofovir has been suggested in some cases for the treatment of BK virus-associated haemorrhagic cystitis.13 Cidofovir and foscarnet are second-line therapies in patients with CMV that are either resistant or refractory to ganciclovir. Cidofovir is a non-cyclic analogue of cytidine monophosphate that terminates CMV DNA synthesis. In vitro studies showed effectiveness against herpes viruses, including CMV, herpes simplex viruses 1 and 2, varicella-zoster, Epstein-Barr virus, human papillomavirus and adenovirus. The main adverse effect is nephrotoxicity, causing proximal tubular injury. Serum creatinine and urine protein measurements are recommended during administration.14 Probenecid decreases intratubular secretion and maintains a sufficient plasma concentration to allow for once weekly dosing at 5 mg/kg to reduce its nephrotoxicity.13 An alternate dosing regimen, initially used in our patient, was three times per week dosing at 3 mg/kg. In the study performed by Philippe et al, intravenous cidofovir achieve remission in 81.5% of the 22 patients.13
The patient reported by Held et al recovered fully with cidofovir15; however, our patient was switched to ganciclovir due to persistent neutropenia. Bone marrow biopsy was consistent with secondary treatment-related myelosuppression syndrome, without evidence of myelodysplasia or lymphoproliferative infiltration. Myelosuppression is a major side effect of ganciclovir. However, the antiviral effects far outweigh these risks and therefore ganciclovir and its oral prodrug valganciclovir should be considered for patients with pancytopenia secondary to CMV reactivation.
In summary, this unique case of triple-viremia induced haemorrhagic cystitis in an immunosuppressed CLL patient posed both a diagnostic and therapeutic challenge as treatments are nephrotoxic and further increase immunosuppression.
The major learning point is to exercise caution when prescribing FCR chemotherapy on its long-term immunosuppressive effects. It is expected that novel immuno-chemotherapy for CLL should control the disease with reduced immunosuppressive effects.16
Patient’s perspective
Translation from French
I was diagnosed with CLL in November 2015. Started the treatments with FCR protocol in April 2019 (six treatments of three consecutive days each). At the end of the fourth treatment, I was not well. I had fever and a large fatigue with no energy. I finished treatments on the 13th of November 2019. On the week of 18 November, the symptoms appeared: fever, incontinent of urine with blood, no appetite, fatigue.
I visited MUHC emergency, 12 hours wait before I had a doctor’s room. I stayed the night and the next day I saw the doctor, but they did not know what I had. On the 22nd of November I returned to emergency with a lot of fever and other symptoms. I passed the night in an emergency room. On Saturday they released me, had fever and falls.
On the 24th I returned to emergency, fever and incontinence, etc. I was placed in the corridor in a stretcher with a commode next to the whole world. There was nowhere else for me, I had to go through the doors to go to the public toilet and I urinated every 5 min. I stayed in emergency 5 days before I was admitted to Internal Medicine.
It was a bad experience the three times I was in emergency. On 29 November, I had my own room. I was there till 07 February 2020.
The staff took charge rapidly. There were many tests during this long period to find out the cause of my problems. Everything came from the chemotherapy. Many departments were involved: urology, otolaryngology, haematology, internal medicine, infectious diseases.
There were several healthcare workers who spoke on behalf of other departments.
Very good service with the nursing staffs and the préposé (aux bénéficiaires). On my part, my immune system was severely damaged.
Learning points
Infections in immunosuppressed patients remain a diagnostic and therapeutic challenge.
In patient treated for chronic lymphocytic leukaemia, haematuria can be related to viral infections like BK virus, adenovirus and cytomegalovirus (CMV).
BK infection is diagnosed with a high index of suspicion, however, combined CMV and adenovirus infections renders the diagnosis more difficult.
Treatment of these viral infections remains difficult as medications are associated with myelotoxicity (ganciclovir) and renal insufficiency (cidofovir).
The authors would like to thank Dr Malek Merdad and Dr Isabelle Malhamé for their inspiration to write this article.
Contributors: MK and J-PR devised the project, main conceptual ideas and proof outlines. MK took the lead in writing the manuscript the supervision of J-PR. MK created all the images and translated the patient’s perspective from French to English. J-PR and JL provided critical feedback and helped shape analysis and manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33402369 | 18,752,790 | 2021-01-05 |
What was the outcome of reaction 'Pancytopenia'? | Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
Background
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder associated with mature B-cell dysfunction, hypogammaglobulinaemia and T-cell abnormalities. In Europe and North America, CLL is the most common leukaemia, with median age of diagnosis of 70 years.1 Treatment is indicated only for symptomatic disease, such as anaemia <100 g/L and/or thrombocytopenia <100×109/L, massive splenomegaly, lymphadenopathy or constitutional symptoms.2
Infection is a frequent cause of morbidity and mortality in CLL. Roughly 30%–50% of all CLL patients suffer infections, with a high subsequent mortality rate.3 While the majority of infections affect more often the respiratory track, or skin and the gastrointestinal tract.4 The most frequent organisms causing infections are bacteria like Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. This increased susceptibility to infection stems from B-cells with impaired immunoglobulin production capability and dysfunctional T-helper cells, which also assist in antibody production. This impaired capability to produce immunoglobulins, termed hypogammaglobulinaemia, affects 85% of CLL patients, particularly in advanced disease.4
Antineoplastic agents recommended for the treatment of CLL are also immunosuppressive and further increase the risk of infections.5 These include opportunistic micro-organisms such as Candida, Pneumocystis jirovecii, listeria, nocardia and atypical mycobacteria. In addition, patients have increased risk of viral diseases such as herpes simplex, Epstein-Barr and cytomegalovirus (CMV). Additional infectious complications may include hepatitis B reactivation and progressive multifocal leucoencephalopathy. In spite of the immunosuppressive risk, chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the standard risk therapy in fit patients below 65 years of age with CLL, in absence of 17 p deletion, or TP53 mutation, and with immunoglobulin heavy chain V (IGHV)-mutated.6
To reduce risk of infection, immunoglobulin levels should also be routinely monitored, particularly with rituximab, which reduces the number of B-cells expressing CD20. It is postulated that monitoring immunoglobulins while being treated with rituximab may reduce the risk of serious infections.4
Herein, we present a unique case of a woman treated for CLL who experienced severe pancytopenia and immunosuppression at the completion of her chemo-immunotherapy. She subsequently experienced triple concurrent viral infections, which posed a therapeutic challenge due to her pancytopenia.
Case presentation
A previously healthy 58-year-old woman was diagnosed with CLL through a routine blood test in 2015. Her physical examination was unremarkable and her lymphocyte counts were at 12.36×109 cells/L. Bone marrow biopsy with immunohistochemistry was suggestive of CLL and stained positive for BCL2, CD5 (aberrant T-cell marker), CD20, CD23, CD43 and CD79a (B-cell markers) while BCL6 was negative. The PCR amplification study showed immunoglobulin heavy chain gene rearrangement along with IgG kappa light chain gene arrangement. No t(14;18) BCL2/JH or t(11;14) BCL1/JH gene rearrangements were observed. As she was asymptomatic, and positron emission tomography (PET) scan showed low grade metabolic activity in lymph nodes in cervical, axillary and iliac areas, no therapy was initiated (figure 1). She was followed every 6 months.
Figure 1 Positron emission tomography scan (right) and corresponding CT images (left) of multiple low-grade hypermetabolic lymph nodes in 2017, 2 years after diagnosis of chronic lymphocytic leukaemia. (A) Multiple small low-grade hypermetabolic lymph nodes in bilateral neck regions predominantly in the posterior triangles. SUV of 1.9 in the left and right upper posterior triangles. (B) Hypermetabolic lymph nodes in the left axillary regions, SUV 1.8. (C) Left external iliac lymph node SUV of 3. SUV, Standardized uptake value.
In November 2017 the patient had symptom of a rapid bilateral enlargement of the cervical lymph nodes accompanied by persistent fatigue, night sweats and decreased weight. Lyme disease, HIV, hepatitis B and C and syphilis serologies were performed, and all tests yielded negative results. Repeat PET/CT scan, cytogenetics and bone marrow biopsy demonstrated no evidence of Richter’s transformation into a diffuse large cell lymphoma. Due to significant bulky disease and enlarged adenopathy with B constitutional symptoms, chemo-immunotherapy with FCR was considered. This was furthermore rationalised as she was a fit patient younger than 65 years of age with standard risk for CLL due to the absence of 17 p deletion, or TP53 mutation, and with IGHV being mutated.7
She received six cycles of FCR which was completed uneventfully on 11 November 2019. During FCR therapy, she received oral valacyclovir 500 mg two times per day for herpes prophylaxis as well as Septra DS (160 mg trimethoprim and 800 mg sulfamethoxazole) one tablet Mondays, Wednesdays and Fridays for P. jirovecii prophylaxis. On 18 November, she presented to the emergency room of the McGill University Health Centre (MUHC) with haematuria, suprapubic pain and fever. She was admitted and treated for a urine infection and slowly improved after different antibiotics such as ciprofloxacin, trimethoprim-sulfamethoxazole and ceftriaxone and blood and urinary bacterial cultures were negative. A CT urogram showed moderate bilateral hydroureteronephrosis with diffuse urolithelial and bladder thickening (figure 2). As a whole, these findings were suggestive of an inflammatory or infectious process evoking pyleoureteritis and cystitis.
Figure 2 CT urogram on admission in November 2019, demonstrating (A) poorly distended bladder and marked thickening of bladder walls (green arrow) and (B) moderate dilation of both ureters and collection ducts with marked thickening and enhancement of the urothelium associated with moderate periureteric fat stranding.
Investigations
On admission, she was mildly pancytopenic (table 1). As the patient partially improved and had negative urine cultures, a cyclophosphamide-induced haemorrhagic cystitis was considered, and she was placed on continuous bladder irrigation.
Table 1 Summary of the patient’s serological and microbiological test results during the course of her neutropenia and triple viremia
Laboratory results Reference ranges 20 March 2019 11 November 2019 26 November 2019 25 December 2019 01 January 2020 23 January 2020 01 February 2020 07 February 2020 03 March 2020
Time of intervention First dose FCR Last dose FCR Meropenem started Virology investigated Begins cidofovir+GCSF Cidofovir changed to Ganciclovir Ganciclovir transitioned to valganciclovir Discharge Follow-up
WBC (109/L) 4.0–10.0 30.90 5.90 3.00 1.00 0.60 2.40 6.10 2.40 2.00
Neutrophils 2.0–7.0 3.75 4.18 2.46 0.80 0.36 1.19 5.09 1.73 1.35
Lymphocytes 1.5–4.5 26.26 0.87 0.23 0.08 0.11 0.23 0.46 0.33 0.44
Plt (109/L) 150–450 145 158 123 48 19 54 17 12 39
Hb (g/L) 120–150 142 129 99 63 80 70 70 71 99
Creatinine (umol/L) 50–90 71 68 125 128 118 75 74 69 75
CMV (copies/mL) – – – – 7320 3170 1291 153 149 0
Adenovirus (copies/mL) – – – – – 7.44 log10 4.86 log10 3.74 log10 – 3.30 log10
BK virus urine (copies/mL) – – – – – 2.26×107 – 3.20×108 –
BK virus blood (copies/mL) – – – – – – – – – 3.91×103
CMV, cytomegalovirus; FCR, fludarabine, cyclophosphamide and rituximab; Hb, haemoglobin; Plt, platelet; WBC, white blood cell.
On 1 December 2019 she developed a pancytopenia that required platelet and packed red blood cell transfusions. She remained persistently febrile despite repeated negative bacterial blood and urine cultures. Due to her CLL, pancytopenia and the consideration of immunosuppression induced by FCR chemotherapy, viral infections were investigated. PCR for adenovirus showed 22.4 copies/mL in blood, and positive in urine; PCR for polyoma virus showed 8.81 million copies/mL blood; and PCR for CMV showed 358 copies/mL in blood, confirming viral invasive infections (figure 3). To further investigate her pancytopenia, serology for parvovirus B 19 was carried out and was negative for IgM.
Figure 3 Cytomegalovirus (CMV) and BK viremia (A) and adeno-viremia (B) over the course of treatment.
On 18 December 2019 the patient underwent a double J-stent insertion for bilateral hydronephrosis. Pelvic pain persisted and she continued to pass clots in her urine. Repeat CMV PCR testing on 25 December 2019 showed 7320 copies/mL while an ophthalmological assessment revealed no evidence of CMV retinitis or keratitis. Bone marrow biopsy results showed pancytopenia without transformation (figure 4).
Figure 4 Histology and immunochemistry of bone marrow smear (A) and biopsy (B). Bone marrow biopsy demonstrating hypocellularity. Moderate left shift of the myeloid series and mild left shift of the erythroid series. No lymphocytosis or lymphoma, no definite diagnosis of myelodysplastic syndrome (B).
Treatment
On 1 January 2020, cidofovir was administered to treat the three viral infections of BK polyomavirus, adenovirus and CMV. Cidofovir was given at the dose of 1 mg/kg intravenously three times a week instead of a weekly dose given her kidney injury and high creatinine levels. She received probenecid 2 g orally 1 hour before cidofovir, then 2 hours and 8 hours after the end of infusion to increase cidofovir levels in the blood. For renal protection, she was hydrated with 1 L of 0.9% normal saline during cidofovir infusion. Filgrastim (G-CSF) was initiated for her neutropenia, darbepoetin for her anaemia, and intravenous IgG was infused three times at 4-week intervals for her hypogammaglobulinumia.
Neutropenia worsen despite filgrastim, and CMV viral load continued to increase. Due to cidofovir myelotoxicity, a decision was made to focus treatment on CMV infection, while ignoring the BK and adenovirus. To this end, the patient was changed to ganciclovir 250 mg intravenous two times per day on 23 January 2020 and her urinary symptoms improved for the first time. On 1 February 2020, she was transitioned to oral valganciclovir 450 mg daily and was discharged to home 1 week later, after 101 days in hospital.
Outcome and follow-up
A bone marrow biopsy on 27 January 2020 showed a hypocellular marrow with focal area up to 20%–30% haematopoietic tissue. No evidence of lymphocytosis or lymphoma and no dysplastic changes in morphology were observed. Immunohistochemistry showed <5% CD117, and was negative for CD20, CD34 and PAX5. The histological appearance represented haematopoietic regeneration post-chemotherapy. On 3 March 2020 follow-up, CMV load was undetectable, adenovirus load was 5000 copies/mL, BK load was 3.2×108 copies/mL (table 1). She was switched on CMV prophylaxis with resolved haemorrhagic cystitis and received valganciclovir 450 mg p.o. daily for another 3 months and until her absolute lymphocyte count recovers above 109 cells/L. She continued trimethoprim-sulfamethaxole prophylaxis for 6 months post-chemotherapy. Her double-J stents remain in place. While clinically improved, her neutropenia improved on low dose filgrastim until 4 April 2020. Her blood counts normalised 1 month after and she is followed as an outpatient with Haematology, Infectious Diseases, and Urology services at the MUHC.
Discussion
FCR chemo-immunotherapy is considered the treatment for standard risk CLL patients under the age of 65,7 with a high overall response rate. However, the predominant complication is myelosuppression.8 Persistent neutropenia was reported in 19% and late infections in 9% of patients.9 The frequency of cytopenias was 35% at 3 months and 12% at 9 months after completion of therapy, respectively. Another side effect is prolonged lymphoid immunodeficiency.
Human adenovirus infections usually present as a keratoconjunctivitis or respiratory tract infection. In most healthy individuals the infection is usually self-limited. However, in immunosuppressed patients, infection may disseminate and become potentially life-threatening. Disseminated adenovirus infection can result from either de novo infection or a reactivation of clinically silent infection.10
BK virus is a member of the polyomavirus family. BK virus reactivation occurs only in immunosuppressed patients and can lead to nephropathy, ureteral stenosis, tubular interstitial damage and haemorrhagic cystitis. Viremia occurs in 20%–60% of this population. There is no specific treatment for BK virus-associated nephropathy, therefore viral replication can only be controlled through modulating the immunosuppressive condition.11
CMV is a herpes virus with a large double-stranded DNA that remains latent in the host after primary infection. Immunocompromised patients can have reactivation of their latent infection. Diagnosis of viral reactivation is made through CMV PCR in blood, tissue or body fluid. Manifestations of CMV infection occur most often in the gastrointestinal tract, lungs, liver and retina.12 As we did not observe the typical owl’s eye tissue lesion in the second bone marrow biopsy, we considered that CMV reactivation was a contributing factor for the pancytopenia, and treatment may have prevented such tissue lesion to develop. First line treatment of CMV infection includes intravenous ganciclovir or its oral prodrug valganciclovir, which are DNA polymerase inhibitors. The major side effect of these drugs is myelosuppression, including neutropenia.4
In our patient, the prolonged pancytopenias secondary to FCR was associated with haematuria with an ureteral mass. To date, only two observations on the use of cidofovir to simultaneously treat BK-virus associated haemorrhagic cystitis and CMV reactivation have been reported. However, in the case report by Held et al, the patient had received a bone marrow transplant for chronic myeloid leukaemia, whereas our patient had CLL.
Cidofovir has been suggested in some cases for the treatment of BK virus-associated haemorrhagic cystitis.13 Cidofovir and foscarnet are second-line therapies in patients with CMV that are either resistant or refractory to ganciclovir. Cidofovir is a non-cyclic analogue of cytidine monophosphate that terminates CMV DNA synthesis. In vitro studies showed effectiveness against herpes viruses, including CMV, herpes simplex viruses 1 and 2, varicella-zoster, Epstein-Barr virus, human papillomavirus and adenovirus. The main adverse effect is nephrotoxicity, causing proximal tubular injury. Serum creatinine and urine protein measurements are recommended during administration.14 Probenecid decreases intratubular secretion and maintains a sufficient plasma concentration to allow for once weekly dosing at 5 mg/kg to reduce its nephrotoxicity.13 An alternate dosing regimen, initially used in our patient, was three times per week dosing at 3 mg/kg. In the study performed by Philippe et al, intravenous cidofovir achieve remission in 81.5% of the 22 patients.13
The patient reported by Held et al recovered fully with cidofovir15; however, our patient was switched to ganciclovir due to persistent neutropenia. Bone marrow biopsy was consistent with secondary treatment-related myelosuppression syndrome, without evidence of myelodysplasia or lymphoproliferative infiltration. Myelosuppression is a major side effect of ganciclovir. However, the antiviral effects far outweigh these risks and therefore ganciclovir and its oral prodrug valganciclovir should be considered for patients with pancytopenia secondary to CMV reactivation.
In summary, this unique case of triple-viremia induced haemorrhagic cystitis in an immunosuppressed CLL patient posed both a diagnostic and therapeutic challenge as treatments are nephrotoxic and further increase immunosuppression.
The major learning point is to exercise caution when prescribing FCR chemotherapy on its long-term immunosuppressive effects. It is expected that novel immuno-chemotherapy for CLL should control the disease with reduced immunosuppressive effects.16
Patient’s perspective
Translation from French
I was diagnosed with CLL in November 2015. Started the treatments with FCR protocol in April 2019 (six treatments of three consecutive days each). At the end of the fourth treatment, I was not well. I had fever and a large fatigue with no energy. I finished treatments on the 13th of November 2019. On the week of 18 November, the symptoms appeared: fever, incontinent of urine with blood, no appetite, fatigue.
I visited MUHC emergency, 12 hours wait before I had a doctor’s room. I stayed the night and the next day I saw the doctor, but they did not know what I had. On the 22nd of November I returned to emergency with a lot of fever and other symptoms. I passed the night in an emergency room. On Saturday they released me, had fever and falls.
On the 24th I returned to emergency, fever and incontinence, etc. I was placed in the corridor in a stretcher with a commode next to the whole world. There was nowhere else for me, I had to go through the doors to go to the public toilet and I urinated every 5 min. I stayed in emergency 5 days before I was admitted to Internal Medicine.
It was a bad experience the three times I was in emergency. On 29 November, I had my own room. I was there till 07 February 2020.
The staff took charge rapidly. There were many tests during this long period to find out the cause of my problems. Everything came from the chemotherapy. Many departments were involved: urology, otolaryngology, haematology, internal medicine, infectious diseases.
There were several healthcare workers who spoke on behalf of other departments.
Very good service with the nursing staffs and the préposé (aux bénéficiaires). On my part, my immune system was severely damaged.
Learning points
Infections in immunosuppressed patients remain a diagnostic and therapeutic challenge.
In patient treated for chronic lymphocytic leukaemia, haematuria can be related to viral infections like BK virus, adenovirus and cytomegalovirus (CMV).
BK infection is diagnosed with a high index of suspicion, however, combined CMV and adenovirus infections renders the diagnosis more difficult.
Treatment of these viral infections remains difficult as medications are associated with myelotoxicity (ganciclovir) and renal insufficiency (cidofovir).
The authors would like to thank Dr Malek Merdad and Dr Isabelle Malhamé for their inspiration to write this article.
Contributors: MK and J-PR devised the project, main conceptual ideas and proof outlines. MK took the lead in writing the manuscript the supervision of J-PR. MK created all the images and translated the patient’s perspective from French to English. J-PR and JL provided critical feedback and helped shape analysis and manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33402369 | 19,066,566 | 2021-01-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Intra-abdominal haemorrhage'. | A phase II study of gemcitabine, erlotinib and S-1 in patients with advanced pancreatic cancer.
Background: We evaluated the efficacy and safety of gemcitabine in combination with erlotinib and S-1 for the treatment of advanced pancreatic cancer. Methods: Chemotherapy-naïve patients with pathologically-proven locally advanced, recurrent, or metastatic pancreatic adenocarcinoma were assessed for eligibility. Gemcitabine was administered at 1,000 mg/m2 intravenously on days 1 and 8, erlotinib was administered at 100 mg/day on days 1-21, and S-1 was administered at 60 mg/m2 on days 1-14 every 21 days and continued to a maximum of 8 cycles of treatment. Dose escalation of S-1 to 80 mg/m2 was permitted from the second cycle for pre-defined tolerable patients. Results: Thirty-seven patients (median age 61.5 years) were enrolled. A total of 140 cycles of chemotherapy were administered (median of 3.8; range 1-8 cycles). Toxicities were evaluated in 36 patients, and the responses were evaluated in 32 patients. Major grade 3/4 toxicities included neutropenia (25%), febrile neutropenia (2.8%), fatigue (22.2%), infection (8.3%), vomiting (5.6%), and mucositis (5.6%). The confirmed overall response rate was 12.5% [95% confidence interval (CI), 5.1-28.9%] and the disease control rate was 71.9% (95% CI, 56.8-86.3%). The median progression-free survival and overall survival were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively. Conclusion: The combination of gemcitabine, erlotinib, and S-1 provided an acceptable toxicity profile and modest clinical benefits in patients with advanced pancreatic cancer.
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is an intractable disease and is the 7th leading cause of global cancer deaths in industrialized countries 1. Because more than 80% of PDAC is locally advanced unresectable or metastatic at the time of diagnosis 2, the prognosis of PDAC patients is dismal with a 5-year relative survival rate of 11.4% 3. Although various types of targeted agents and immunotherapeutic agents are actively used in other cancers, cytotoxic chemotherapy remains the mainstream treatment for unresectable PDAC.
Following the approval of gemcitabine by the US Food and Drug Administration in 1997 4, gemcitabine-based chemotherapy was considered the standard of care for patients with advanced PDAC for a decade. In the era of gemcitabine, various attempts were made simultaneously to find an optimal drug combination that could function synergistically with gemcitabine. A number of drugs, including cytotoxic agents 5-10 and targeted agents 11, 12, in combination with gemcitabine, were tested in large randomized clinical trials, but they failed to improve the efficacy.
Among the various drugs investigated, erlotinib, a small-molecule inhibitor of epidermal growth factor receptor, improved the efficacy of gemcitabine in a randomized phase III trial 13. In this study, erlotinib in combination with gemcitabine showed a small but statistically significant improvement in overall survival when compared to gemcitabine monotherapy (6.2 months vs. 5.9 months, p=0.038). S-1, an oral fluoropyrimidine derivative, was also studied as a combination partner of gemcitabine and has consistently shown promising results in terms of efficacy and safety in a series of phase II studies 14-18.
At the time this study was proposed and designed, gemcitabine plus erlotinib combination chemotherapy was approved as front-line chemotherapy for unresectable PDAC and was widely used globally. However, since the benefit of gemcitabine plus erlotinib in survival prolongation was too small, there has been a continuing need for new drugs or combination regimens for patients with PDAC. In this background, combination therapy with gemcitabine, erlotinib, and S-1 (GTS regimen) has been proposed as a novel front-line treatment for unresectable PDAC, and this study was conducted to demonstrate the efficacy and safety of this regimen.
With two combination regimens of FOLFIRINOX (a combination of oxaliplatin, folinic acid, irinotecan, and fluorouracil [5-FU]) 19 and albumin-bound paclitaxel/gemcitabine 20 currently accepted as front-line treatments and actively used in fit patients, the clinician's interest and possible range of application for our combination regimen will be limited. However, since GTS combination therapy has never been investigated in PDAC, it would be valuable to report and share efficacy and safety data.
Methods
Patient eligibility
Patients were eligible for this study if they fulfilled all of the following criteria: (1) pathologically confirmed unresectable locally advanced, recurrent, or metastatic adenocarcinoma of the pancreas; (2) measurable disease, as defined using version 1.1 of the Response Evaluation Criteria In Solid Tumors (RECIST); (3) age ≥18 years; (4) Eastern Cooperative Oncology Group (ECOG) performance status of 0-1; (5) prior adjuvant chemotherapy without gemcitabine, erlotinib, or S-1 that had been completed >4 weeks before enrollment; (6) more than 4 weeks since completion of prior radiotherapy (measurable lesions are outside the radiation field); (7) adequate hematological, renal, and hepatic functions, as defined using an absolute neutrophil count of ≥1.5 × 109/L, a platelet count of ≥100 × 109/L, serum creatinine levels of ≤1.5 × upper limit of normal or creatinine clearance ≥50 mL/min, serum bilirubin ≤2× UNL, aspartate aminotransferase and alanine aminotransferase levels of ≤2.5×; and, (8) willingness to provide informed consent to participate in this study.
Patients were excluded based on the following criteria: (1) a history of treatment with gemcitabine, erlotinib, or S-1 as adjuvant chemotherapy; (2) contraindication for any drug contained in the chemotherapy regimen; (3) central nervous system metastasis; (4) serious GI bleeding or obvious bowel obstruction; (5) other previous or concurrent malignancies within the last 5 years, with the exception of cured basal cell carcinoma of the skin or carcinoma in situ of the uterine cervix; (6) pregnant or lactating female patients; (7) sexually active and the partner is unwilling to practice contraception during the study; and (8) other clinically significant comorbid conditions, such as an active infection or severe cardiopulmonary dysfunction.
Treatment and study design
The treatment consisted of intravenous administration of gemcitabine at 1,000 mg/m2 on days 1 and 8 every 3 weeks, continuously orally administered erlotinib at 100 mg/day, and orally administered S-1 at 30 mg/m2 twice daily on days 1-14 of each cycle. Patients with a body surface area of <1.25 m2 received 80 mg of S-1 daily, those with a body surface area of 1.25-1.5 m2 received 100 mg of S-1 daily, and those with a body surface area of ≥1.5 m2 received 120 mg of S-1 daily. Treatment was delivered as a 3-week cycle and repeated up to a maximum of 8 cycles of chemotherapy, or until disease progression, unacceptable toxicity, or the patient's refusal.
This trial was a prospective, single-arm phase II study evaluating combination chemotherapy with gemcitabine, erlotinib, and S-1 in previously untreated patients with unresectable locally advanced or metastatic pancreatic cancer. The primary endpoint was the confirmed objective response rate (ORR), and the secondary endpoints were median progression-free survival (PFS), median overall survival (OS), disease control rate (DCR), and toxicity profiles. The investigation was performed in accordance with the Declaration of Helsinki, and the protocol was approved by the institutional review boards of Hallym University Medical Center, Anyang-si, South Korea, and Asan Medical Center, Seoul, South Korea (protocol number: HMC-HO-GI-1201).
Dose modifications and dose intensity
Dose modifications were performed according to the study protocol. The next treatment cycle was initiated only when the neutrophil count was 1.5 × 109/L or greater and the platelet count was 100 × 109/L or greater. Treatment was delayed in the event of grade 3/4 nonhematologic toxicities until the toxicities were resolved to grade 1 or lower. The doses of gemcitabine and S-1 were reduced by 25% of the initial doses for related grade 3/4 neutropenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, or for the second occurrence of the same grade 2 neutropenia and thrombocytopenia. The doses of gemcitabine were reduced by 50% of the initial doses for grade 4 thrombocytopenia, or for the second occurrence of the grade 3/4 neutropenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, or for the third occurrence of grade 3 neutropenia and thrombocytopenia. In the case of the second occurrence of grade 2 thrombocytopenia, grade 3/4 neutropenia, grade 3 febrile neutropenia, or the third occurrence of grade 2 neutropenia, erlotinib was omitted until recovery and then re-challenged. Treatment was discontinued if, despite the dose reduction, the same toxicity occurred for a fourth time at grade 2, a third time at grade 3, or a second time at grade 4 or any occurrence of life-threatening sepsis during treatment. In addition, if the toxicity had not improved to grade 0 or 1 after 3 weeks, the patient was withdrawn from the study. The dose reduction was maintained in subsequent cycles.
To evaluate a function of the drug and the frequency of administration, we calculated the relative dose intensity (RDI), which is expressed as the ratio of the administered amount of dose per time unit (mg/m2/week) to that of the originally planned dose.
Toxicity and response evaluation
A physical examination with vital signs, complete blood cell counts with differentials, and blood chemistry tests were performed before every administration of gemcitabine in each subsequent cycle. Toxicity was evaluated and graded according to version 4.0 of the Common Terminology Criteria for Adverse Events of the National Cancer Institute. All of the patients who received at least one dose of treatment were included in the toxicity assessment. For the toxicity analysis, the data indicating the worst toxicity for each patient from all of the chemotherapy cycles were used. The proportion of patients who experienced adverse events was calculated by dividing the number of patients who experienced adverse events during the treatment period by the number of patients evaluable for safety analysis. Response to treatment according to RECIST version 1.1 was evaluated every 2 cycles. Patients with CR or PR required a confirmatory disease assessment at least 4 weeks later. PFS was defined as the interval from the date of treatment initiation to the first date of documented disease progression or death due to any cause. OS was defined as the interval from the date of treatment initiation to the date of death.
Statistical analysis
According to Simon's optimal two-stage design, 25 patients were required for enrollment to test the null hypothesis that the true ORR is 10% versus the alternative hypothesis that the true ORR is at least 30%, at a significance level of p<0.05 with a power of 80%. If two or more responses were observed among 15 patients in the first stage, the study was continued with 10 additional patients included. As the drop-out rate was assumed to be 10%, the number of patients necessary for recruitment into the study was calculated to be 28.
Descriptive statistics were used to summarize the patients' characteristics, tumor responses, and safety events. The Kaplan-Meier method was used to estimate the median PFS and OS. All enrolled patients were included in an intent-to-treat analysis.
Results
Patient characteristics
From October 2012 to May 2016, 37 patients who met the inclusion criteria were enrolled in this study. We exceeded the planned number of patients because several unexpected dropouts occurred early in the study and we allowed simultaneous registration of excess patients before the end of the study from multiple institutions. The reasons for dropout are explained below. The demographic and pathologic characteristics of the patients are described in Table 1. The median age was 61.5 years (range 35-88 years). Sixteen patients (43.2%) were male, and the majority of patients (73.0%) had an ECOG PS of 1. Twenty-six patients (70.3%) had metastatic disease, eight patients (21.6%) had recurrent pancreatic cancer after curative surgery, and three patients (8.1%) had locally advanced disease at the time of screening. The most common metastatic sites were distant lymph nodes (43.2%), the liver (43.2%), the lung (29.7%), and the peritoneum (27.0%).
Treatment administration
In total, 140 treatment cycles were administered to 37 patients, with a median of 3.8 cycles (range 1-10 cycles) per patient. Five patients did not complete the first cycle of chemotherapy: two patients died (one patient died of cerebral infarction and one patient died of hepatic tumor rupture), two patients withdrew their informed consent, and one patient was lost to follow-up. Seven patients (18.9%) completed eight or more cycles of chemotherapy. Eleven patients (29.7%) required dose reductions or delays. The mean relative dose intensities (ratio of the dose received to the dose planned) of gemcitabine, S-1 for all of the cycles administered were 0.87 [95% confidence interval (CI) 0.81-0.93], and 0.92 (95% CI 0.87-0.96), respectively (Table 2).
Efficacy
Of the 37 patients, 32 were eligible for response evaluation. Five patients were not available for response evaluation: the detailed reasons for 5 patients who did not complete the first cycle are described in the 'Treatment administration' section. The tumor responses are summarized in Table 3. There were 4 partial responses, 19 cases of stable disease, and 9 cases of disease progression. All partial responses are confirmed in the following CT scan. The confirmed ORR was 12.5% (95% CI 5.1-28.9%) and the disease control rate was 71.9% (95% CI 56.8-86.3%). The median time to response was 1.4 months (95% CI 1.3-1.5 months) and the median duration of response was 7.4 months (95% CI 3.8-11.0 months).
At the time of analysis, 13 patients (35.1%) were still alive with a median follow-up duration of 12.9 months (95% CI 9.6-16.3 months). The median PFS was 3.7 months (95% CI 2.8-4.6 months) and the median OS was 6.7 months (95% CI 3.4-9.9 months; Figures 1 & 2).
Toxicities
Safety was assessed in 36 patients on the basis of 139 cycles. One patient was lost to follow-up after receiving gemcitabine on day 1 of the first cycle, was excluded. One patient died suddenly of abdominal hemorrhage due to hepatic tumor rupture on day 3 of the first cycle. The adverse events are listed in Table 4. The most common grade 3/4 hematologic toxicity was neutropenia (25.0%). Febrile neutropenia developed in one patient (2.8%), who recovered without complications. Nonhematologic toxicities were usually mild and manageable. Grade 3 toxicities with a frequency of 5% or more included fatigue, infection, vomiting, and mucositis.
Discussion
In this study, the confirmed ORR of patients was 12.5%, which is slightly better than that of gemcitabine plus erlotinib 13 and is lower than the results of phase III studies of gemcitabine plus S-1 (GS) 21. The DCR was 71.9% (95% CI, 56.8-86.3%) and the median PFS and OS were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively. The GTS regimen showed an acceptable toxicity profile in the safety analysis. Since, at this point, FOLFIRINOX and albumin-bound paclitaxel/gemcitabine are actively used as standard treatments; the implications of this result are thought to be limited.
5-FU showed a marked synergistic cytotoxic effect with gemcitabine in pancreatic cancer cells in vitro 22 and S-1, which has an equivalent efficacy with a continuous 5-FU infusion in solid cancer, showed promising results in several phase II studies with an ORR of 28-48% 14-18. This study aimed to improve the efficacy of the existing treatment and to investigate a novel triple-combination regimen by adding S-1, which exhibits a synergistic effect with efficacy-proven gemcitabine plus erlotinib.
While this study was in progress, the results of a phase III study (GEST study) comparing GS with gemcitabine alone were published 21. In this trial, despite the improvement in PFS and ORR, GS showed numerically longer OS compared to gemcitabine alone, but it was not statistically significant (10.1 months vs. 8.8 months, p=0.15). In the subgroup analysis of GEST study, GS was associated with significantly improved OS in locally advanced disease compared to metastatic disease. Furthermore, a pooled analysis of subsequent randomized studies comparing GS to gemcitabine alone also re-confirmed that GS showed better OS in locally advanced disease than metastatic disease (16.4 months vs. 11.8 months, HR 0.708, p=0.02) and supported the result of the subgroup analysis from the GEST study. Since most of the participants in this study had recurrent or metastatic disease rather than locally advanced disease, it is assumed that the differences in characteristics of the study population may lead to unsatisfactory results. In our study, the best response of all three patients with locally advanced disease was stable disease but it is difficult to determine statistical significance because the number of patients was too small.
Recently, it was recommended that patients with locally advanced disease should be studied separately from those with metastatic disease because locally advanced and metastatic disease are considered to be two different clinical entities, each with distinctive clinical characteristics 23. Therefore, a study design with an appropriately selected population will be required to further clarify the efficacy of the GTS regimen.
In this study, the median age of the patients was >60 years, and 75% of the patients were symptomatic at the beginning of the study. More than half of the patients had two or more metastatic sites, and 45% and 13% of patients presented with liver metastasis and peritoneal metastasis, respectively. The patients' demographics in our study are relatively inferior to the conditions of other studies, and these differences may have influenced the outcome.
Regarding the safety analysis, GTS showed a modest toxicity profile. Except for neutropenia (25%) and fatigue (22%), the incidence of all other G3 or 4 toxicity profiles did not exceed 10%, which was similar or relatively lower than that of gemcitabine plus erlotinib 13 and GS 21.
Conclusion
In conclusion, GTS did not show the expected efficacy outcome with a confirmed ORR of 12.5%. However, considering the meaningful effect that GS showed in locally advanced disease in a subsequent study and the modest safety profile that our study showed, there may be room to further investigate the GTS regimen depending on the profile of the patient.
S-1 is sponsored by Jeil Pharmaceutical Co.,Ltd, Seoul, Korea.
Funding
This research was supported by the Hallym University Research Fund (Protocol No. HMC-HO-GI-1201).
Figure 1 Progression-free survival.
Figure 2 Overall survival.
Table 1 Patient characteristics (n=37)
Characteristics No. of patients (%)
Age, median (range) 61.5 (35-88)
Gender
Male 16 (43.2%)
Female 21 (56.8%)
Performance status (ECOG)
0 10 (27.0%)
1 27 (73.0%)
Location of primary tumor site
Head 9 (24.3%)
Body 7 (18.9%)
Tail 9 (24.3%)
Diffuse 4 (10.8%)
Unknown 8 (21.6%)
Histology
Well differentiated 5 (13.5%)
Moderately differentiated 9 (24.3%)
Poorly differentiated 4 (10.8%)
Undifferentiated 1 (2.7%)
Unknown 18 (48.6%)
Disease status at the time of screening
Locally advanced 3 (8.1%)
Metastatic 26 (70.3%)
Recurrence after curative surgery 8 (21.6%)
Metastatic sites
Lymph node 16 (43.2%)
Liver 16 (43.2%)
Lung 11 (29.7%)
Peritoneum 10 (27.0%)
Others 8 (21.6%)
No. of metastatic sites
1 14 (41.2%)
2 11 (32.4%)
≥3 9 (26.5%)
ECOG: Eastern Cooperative Oncology Group.
Table 2 Duration of drug administration and dose intensity
Criteria
No. of cycles 140
Median cycles 3.8 (1-8)
No. of patients with dose reduction 11
Relative dose intensity for gemcitabine, Mean (range) 0.87 (0.81-0.93)
Relative dose intensity for S-1, Mean (range) 0.92 (0.87-0.96)
Table 3 Treatment efficacy result
Response No. of patients
Complete response 0
Partial response 4
Stable disease 19
Progressive disease 9
Overall response rate (Confirmed) 12.5% (95% CI, 5.1-28.9%)
Disease control rate 71.9% (95% CI, 56.8-86.3%)
Table 4 Incidence of grade 3/4 adverse events
Grade 3/4 adverse events Number of patients (%) (Total N=36)
Hematologic
Neutropenia 9 (25%)
Febrile neutropenia 1 (2.8%)
Thrombocytopenia 1 (2.8%)
Non-hematologic
Fatigue 8 (22.2%)
Infection 3 (8.3%)
Vomiting 2 (5.6%)
Mucositis 2 (5.6%)
Nausea 1 (2.8%)
Diarrhea 1 (2.8%)
Hepatopathy 1 (2.8%)
Others 4 (11.1%) | ERLOTINIB, GEMCITABINE HYDROCHLORIDE, GIMERACIL\OTERACIL\TEGAFUR | DrugsGivenReaction | CC BY | 33403047 | 18,745,930 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Tumour rupture'. | A phase II study of gemcitabine, erlotinib and S-1 in patients with advanced pancreatic cancer.
Background: We evaluated the efficacy and safety of gemcitabine in combination with erlotinib and S-1 for the treatment of advanced pancreatic cancer. Methods: Chemotherapy-naïve patients with pathologically-proven locally advanced, recurrent, or metastatic pancreatic adenocarcinoma were assessed for eligibility. Gemcitabine was administered at 1,000 mg/m2 intravenously on days 1 and 8, erlotinib was administered at 100 mg/day on days 1-21, and S-1 was administered at 60 mg/m2 on days 1-14 every 21 days and continued to a maximum of 8 cycles of treatment. Dose escalation of S-1 to 80 mg/m2 was permitted from the second cycle for pre-defined tolerable patients. Results: Thirty-seven patients (median age 61.5 years) were enrolled. A total of 140 cycles of chemotherapy were administered (median of 3.8; range 1-8 cycles). Toxicities were evaluated in 36 patients, and the responses were evaluated in 32 patients. Major grade 3/4 toxicities included neutropenia (25%), febrile neutropenia (2.8%), fatigue (22.2%), infection (8.3%), vomiting (5.6%), and mucositis (5.6%). The confirmed overall response rate was 12.5% [95% confidence interval (CI), 5.1-28.9%] and the disease control rate was 71.9% (95% CI, 56.8-86.3%). The median progression-free survival and overall survival were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively. Conclusion: The combination of gemcitabine, erlotinib, and S-1 provided an acceptable toxicity profile and modest clinical benefits in patients with advanced pancreatic cancer.
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is an intractable disease and is the 7th leading cause of global cancer deaths in industrialized countries 1. Because more than 80% of PDAC is locally advanced unresectable or metastatic at the time of diagnosis 2, the prognosis of PDAC patients is dismal with a 5-year relative survival rate of 11.4% 3. Although various types of targeted agents and immunotherapeutic agents are actively used in other cancers, cytotoxic chemotherapy remains the mainstream treatment for unresectable PDAC.
Following the approval of gemcitabine by the US Food and Drug Administration in 1997 4, gemcitabine-based chemotherapy was considered the standard of care for patients with advanced PDAC for a decade. In the era of gemcitabine, various attempts were made simultaneously to find an optimal drug combination that could function synergistically with gemcitabine. A number of drugs, including cytotoxic agents 5-10 and targeted agents 11, 12, in combination with gemcitabine, were tested in large randomized clinical trials, but they failed to improve the efficacy.
Among the various drugs investigated, erlotinib, a small-molecule inhibitor of epidermal growth factor receptor, improved the efficacy of gemcitabine in a randomized phase III trial 13. In this study, erlotinib in combination with gemcitabine showed a small but statistically significant improvement in overall survival when compared to gemcitabine monotherapy (6.2 months vs. 5.9 months, p=0.038). S-1, an oral fluoropyrimidine derivative, was also studied as a combination partner of gemcitabine and has consistently shown promising results in terms of efficacy and safety in a series of phase II studies 14-18.
At the time this study was proposed and designed, gemcitabine plus erlotinib combination chemotherapy was approved as front-line chemotherapy for unresectable PDAC and was widely used globally. However, since the benefit of gemcitabine plus erlotinib in survival prolongation was too small, there has been a continuing need for new drugs or combination regimens for patients with PDAC. In this background, combination therapy with gemcitabine, erlotinib, and S-1 (GTS regimen) has been proposed as a novel front-line treatment for unresectable PDAC, and this study was conducted to demonstrate the efficacy and safety of this regimen.
With two combination regimens of FOLFIRINOX (a combination of oxaliplatin, folinic acid, irinotecan, and fluorouracil [5-FU]) 19 and albumin-bound paclitaxel/gemcitabine 20 currently accepted as front-line treatments and actively used in fit patients, the clinician's interest and possible range of application for our combination regimen will be limited. However, since GTS combination therapy has never been investigated in PDAC, it would be valuable to report and share efficacy and safety data.
Methods
Patient eligibility
Patients were eligible for this study if they fulfilled all of the following criteria: (1) pathologically confirmed unresectable locally advanced, recurrent, or metastatic adenocarcinoma of the pancreas; (2) measurable disease, as defined using version 1.1 of the Response Evaluation Criteria In Solid Tumors (RECIST); (3) age ≥18 years; (4) Eastern Cooperative Oncology Group (ECOG) performance status of 0-1; (5) prior adjuvant chemotherapy without gemcitabine, erlotinib, or S-1 that had been completed >4 weeks before enrollment; (6) more than 4 weeks since completion of prior radiotherapy (measurable lesions are outside the radiation field); (7) adequate hematological, renal, and hepatic functions, as defined using an absolute neutrophil count of ≥1.5 × 109/L, a platelet count of ≥100 × 109/L, serum creatinine levels of ≤1.5 × upper limit of normal or creatinine clearance ≥50 mL/min, serum bilirubin ≤2× UNL, aspartate aminotransferase and alanine aminotransferase levels of ≤2.5×; and, (8) willingness to provide informed consent to participate in this study.
Patients were excluded based on the following criteria: (1) a history of treatment with gemcitabine, erlotinib, or S-1 as adjuvant chemotherapy; (2) contraindication for any drug contained in the chemotherapy regimen; (3) central nervous system metastasis; (4) serious GI bleeding or obvious bowel obstruction; (5) other previous or concurrent malignancies within the last 5 years, with the exception of cured basal cell carcinoma of the skin or carcinoma in situ of the uterine cervix; (6) pregnant or lactating female patients; (7) sexually active and the partner is unwilling to practice contraception during the study; and (8) other clinically significant comorbid conditions, such as an active infection or severe cardiopulmonary dysfunction.
Treatment and study design
The treatment consisted of intravenous administration of gemcitabine at 1,000 mg/m2 on days 1 and 8 every 3 weeks, continuously orally administered erlotinib at 100 mg/day, and orally administered S-1 at 30 mg/m2 twice daily on days 1-14 of each cycle. Patients with a body surface area of <1.25 m2 received 80 mg of S-1 daily, those with a body surface area of 1.25-1.5 m2 received 100 mg of S-1 daily, and those with a body surface area of ≥1.5 m2 received 120 mg of S-1 daily. Treatment was delivered as a 3-week cycle and repeated up to a maximum of 8 cycles of chemotherapy, or until disease progression, unacceptable toxicity, or the patient's refusal.
This trial was a prospective, single-arm phase II study evaluating combination chemotherapy with gemcitabine, erlotinib, and S-1 in previously untreated patients with unresectable locally advanced or metastatic pancreatic cancer. The primary endpoint was the confirmed objective response rate (ORR), and the secondary endpoints were median progression-free survival (PFS), median overall survival (OS), disease control rate (DCR), and toxicity profiles. The investigation was performed in accordance with the Declaration of Helsinki, and the protocol was approved by the institutional review boards of Hallym University Medical Center, Anyang-si, South Korea, and Asan Medical Center, Seoul, South Korea (protocol number: HMC-HO-GI-1201).
Dose modifications and dose intensity
Dose modifications were performed according to the study protocol. The next treatment cycle was initiated only when the neutrophil count was 1.5 × 109/L or greater and the platelet count was 100 × 109/L or greater. Treatment was delayed in the event of grade 3/4 nonhematologic toxicities until the toxicities were resolved to grade 1 or lower. The doses of gemcitabine and S-1 were reduced by 25% of the initial doses for related grade 3/4 neutropenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, or for the second occurrence of the same grade 2 neutropenia and thrombocytopenia. The doses of gemcitabine were reduced by 50% of the initial doses for grade 4 thrombocytopenia, or for the second occurrence of the grade 3/4 neutropenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, or for the third occurrence of grade 3 neutropenia and thrombocytopenia. In the case of the second occurrence of grade 2 thrombocytopenia, grade 3/4 neutropenia, grade 3 febrile neutropenia, or the third occurrence of grade 2 neutropenia, erlotinib was omitted until recovery and then re-challenged. Treatment was discontinued if, despite the dose reduction, the same toxicity occurred for a fourth time at grade 2, a third time at grade 3, or a second time at grade 4 or any occurrence of life-threatening sepsis during treatment. In addition, if the toxicity had not improved to grade 0 or 1 after 3 weeks, the patient was withdrawn from the study. The dose reduction was maintained in subsequent cycles.
To evaluate a function of the drug and the frequency of administration, we calculated the relative dose intensity (RDI), which is expressed as the ratio of the administered amount of dose per time unit (mg/m2/week) to that of the originally planned dose.
Toxicity and response evaluation
A physical examination with vital signs, complete blood cell counts with differentials, and blood chemistry tests were performed before every administration of gemcitabine in each subsequent cycle. Toxicity was evaluated and graded according to version 4.0 of the Common Terminology Criteria for Adverse Events of the National Cancer Institute. All of the patients who received at least one dose of treatment were included in the toxicity assessment. For the toxicity analysis, the data indicating the worst toxicity for each patient from all of the chemotherapy cycles were used. The proportion of patients who experienced adverse events was calculated by dividing the number of patients who experienced adverse events during the treatment period by the number of patients evaluable for safety analysis. Response to treatment according to RECIST version 1.1 was evaluated every 2 cycles. Patients with CR or PR required a confirmatory disease assessment at least 4 weeks later. PFS was defined as the interval from the date of treatment initiation to the first date of documented disease progression or death due to any cause. OS was defined as the interval from the date of treatment initiation to the date of death.
Statistical analysis
According to Simon's optimal two-stage design, 25 patients were required for enrollment to test the null hypothesis that the true ORR is 10% versus the alternative hypothesis that the true ORR is at least 30%, at a significance level of p<0.05 with a power of 80%. If two or more responses were observed among 15 patients in the first stage, the study was continued with 10 additional patients included. As the drop-out rate was assumed to be 10%, the number of patients necessary for recruitment into the study was calculated to be 28.
Descriptive statistics were used to summarize the patients' characteristics, tumor responses, and safety events. The Kaplan-Meier method was used to estimate the median PFS and OS. All enrolled patients were included in an intent-to-treat analysis.
Results
Patient characteristics
From October 2012 to May 2016, 37 patients who met the inclusion criteria were enrolled in this study. We exceeded the planned number of patients because several unexpected dropouts occurred early in the study and we allowed simultaneous registration of excess patients before the end of the study from multiple institutions. The reasons for dropout are explained below. The demographic and pathologic characteristics of the patients are described in Table 1. The median age was 61.5 years (range 35-88 years). Sixteen patients (43.2%) were male, and the majority of patients (73.0%) had an ECOG PS of 1. Twenty-six patients (70.3%) had metastatic disease, eight patients (21.6%) had recurrent pancreatic cancer after curative surgery, and three patients (8.1%) had locally advanced disease at the time of screening. The most common metastatic sites were distant lymph nodes (43.2%), the liver (43.2%), the lung (29.7%), and the peritoneum (27.0%).
Treatment administration
In total, 140 treatment cycles were administered to 37 patients, with a median of 3.8 cycles (range 1-10 cycles) per patient. Five patients did not complete the first cycle of chemotherapy: two patients died (one patient died of cerebral infarction and one patient died of hepatic tumor rupture), two patients withdrew their informed consent, and one patient was lost to follow-up. Seven patients (18.9%) completed eight or more cycles of chemotherapy. Eleven patients (29.7%) required dose reductions or delays. The mean relative dose intensities (ratio of the dose received to the dose planned) of gemcitabine, S-1 for all of the cycles administered were 0.87 [95% confidence interval (CI) 0.81-0.93], and 0.92 (95% CI 0.87-0.96), respectively (Table 2).
Efficacy
Of the 37 patients, 32 were eligible for response evaluation. Five patients were not available for response evaluation: the detailed reasons for 5 patients who did not complete the first cycle are described in the 'Treatment administration' section. The tumor responses are summarized in Table 3. There were 4 partial responses, 19 cases of stable disease, and 9 cases of disease progression. All partial responses are confirmed in the following CT scan. The confirmed ORR was 12.5% (95% CI 5.1-28.9%) and the disease control rate was 71.9% (95% CI 56.8-86.3%). The median time to response was 1.4 months (95% CI 1.3-1.5 months) and the median duration of response was 7.4 months (95% CI 3.8-11.0 months).
At the time of analysis, 13 patients (35.1%) were still alive with a median follow-up duration of 12.9 months (95% CI 9.6-16.3 months). The median PFS was 3.7 months (95% CI 2.8-4.6 months) and the median OS was 6.7 months (95% CI 3.4-9.9 months; Figures 1 & 2).
Toxicities
Safety was assessed in 36 patients on the basis of 139 cycles. One patient was lost to follow-up after receiving gemcitabine on day 1 of the first cycle, was excluded. One patient died suddenly of abdominal hemorrhage due to hepatic tumor rupture on day 3 of the first cycle. The adverse events are listed in Table 4. The most common grade 3/4 hematologic toxicity was neutropenia (25.0%). Febrile neutropenia developed in one patient (2.8%), who recovered without complications. Nonhematologic toxicities were usually mild and manageable. Grade 3 toxicities with a frequency of 5% or more included fatigue, infection, vomiting, and mucositis.
Discussion
In this study, the confirmed ORR of patients was 12.5%, which is slightly better than that of gemcitabine plus erlotinib 13 and is lower than the results of phase III studies of gemcitabine plus S-1 (GS) 21. The DCR was 71.9% (95% CI, 56.8-86.3%) and the median PFS and OS were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively. The GTS regimen showed an acceptable toxicity profile in the safety analysis. Since, at this point, FOLFIRINOX and albumin-bound paclitaxel/gemcitabine are actively used as standard treatments; the implications of this result are thought to be limited.
5-FU showed a marked synergistic cytotoxic effect with gemcitabine in pancreatic cancer cells in vitro 22 and S-1, which has an equivalent efficacy with a continuous 5-FU infusion in solid cancer, showed promising results in several phase II studies with an ORR of 28-48% 14-18. This study aimed to improve the efficacy of the existing treatment and to investigate a novel triple-combination regimen by adding S-1, which exhibits a synergistic effect with efficacy-proven gemcitabine plus erlotinib.
While this study was in progress, the results of a phase III study (GEST study) comparing GS with gemcitabine alone were published 21. In this trial, despite the improvement in PFS and ORR, GS showed numerically longer OS compared to gemcitabine alone, but it was not statistically significant (10.1 months vs. 8.8 months, p=0.15). In the subgroup analysis of GEST study, GS was associated with significantly improved OS in locally advanced disease compared to metastatic disease. Furthermore, a pooled analysis of subsequent randomized studies comparing GS to gemcitabine alone also re-confirmed that GS showed better OS in locally advanced disease than metastatic disease (16.4 months vs. 11.8 months, HR 0.708, p=0.02) and supported the result of the subgroup analysis from the GEST study. Since most of the participants in this study had recurrent or metastatic disease rather than locally advanced disease, it is assumed that the differences in characteristics of the study population may lead to unsatisfactory results. In our study, the best response of all three patients with locally advanced disease was stable disease but it is difficult to determine statistical significance because the number of patients was too small.
Recently, it was recommended that patients with locally advanced disease should be studied separately from those with metastatic disease because locally advanced and metastatic disease are considered to be two different clinical entities, each with distinctive clinical characteristics 23. Therefore, a study design with an appropriately selected population will be required to further clarify the efficacy of the GTS regimen.
In this study, the median age of the patients was >60 years, and 75% of the patients were symptomatic at the beginning of the study. More than half of the patients had two or more metastatic sites, and 45% and 13% of patients presented with liver metastasis and peritoneal metastasis, respectively. The patients' demographics in our study are relatively inferior to the conditions of other studies, and these differences may have influenced the outcome.
Regarding the safety analysis, GTS showed a modest toxicity profile. Except for neutropenia (25%) and fatigue (22%), the incidence of all other G3 or 4 toxicity profiles did not exceed 10%, which was similar or relatively lower than that of gemcitabine plus erlotinib 13 and GS 21.
Conclusion
In conclusion, GTS did not show the expected efficacy outcome with a confirmed ORR of 12.5%. However, considering the meaningful effect that GS showed in locally advanced disease in a subsequent study and the modest safety profile that our study showed, there may be room to further investigate the GTS regimen depending on the profile of the patient.
S-1 is sponsored by Jeil Pharmaceutical Co.,Ltd, Seoul, Korea.
Funding
This research was supported by the Hallym University Research Fund (Protocol No. HMC-HO-GI-1201).
Figure 1 Progression-free survival.
Figure 2 Overall survival.
Table 1 Patient characteristics (n=37)
Characteristics No. of patients (%)
Age, median (range) 61.5 (35-88)
Gender
Male 16 (43.2%)
Female 21 (56.8%)
Performance status (ECOG)
0 10 (27.0%)
1 27 (73.0%)
Location of primary tumor site
Head 9 (24.3%)
Body 7 (18.9%)
Tail 9 (24.3%)
Diffuse 4 (10.8%)
Unknown 8 (21.6%)
Histology
Well differentiated 5 (13.5%)
Moderately differentiated 9 (24.3%)
Poorly differentiated 4 (10.8%)
Undifferentiated 1 (2.7%)
Unknown 18 (48.6%)
Disease status at the time of screening
Locally advanced 3 (8.1%)
Metastatic 26 (70.3%)
Recurrence after curative surgery 8 (21.6%)
Metastatic sites
Lymph node 16 (43.2%)
Liver 16 (43.2%)
Lung 11 (29.7%)
Peritoneum 10 (27.0%)
Others 8 (21.6%)
No. of metastatic sites
1 14 (41.2%)
2 11 (32.4%)
≥3 9 (26.5%)
ECOG: Eastern Cooperative Oncology Group.
Table 2 Duration of drug administration and dose intensity
Criteria
No. of cycles 140
Median cycles 3.8 (1-8)
No. of patients with dose reduction 11
Relative dose intensity for gemcitabine, Mean (range) 0.87 (0.81-0.93)
Relative dose intensity for S-1, Mean (range) 0.92 (0.87-0.96)
Table 3 Treatment efficacy result
Response No. of patients
Complete response 0
Partial response 4
Stable disease 19
Progressive disease 9
Overall response rate (Confirmed) 12.5% (95% CI, 5.1-28.9%)
Disease control rate 71.9% (95% CI, 56.8-86.3%)
Table 4 Incidence of grade 3/4 adverse events
Grade 3/4 adverse events Number of patients (%) (Total N=36)
Hematologic
Neutropenia 9 (25%)
Febrile neutropenia 1 (2.8%)
Thrombocytopenia 1 (2.8%)
Non-hematologic
Fatigue 8 (22.2%)
Infection 3 (8.3%)
Vomiting 2 (5.6%)
Mucositis 2 (5.6%)
Nausea 1 (2.8%)
Diarrhea 1 (2.8%)
Hepatopathy 1 (2.8%)
Others 4 (11.1%) | ERLOTINIB, GEMCITABINE HYDROCHLORIDE, GIMERACIL\OTERACIL\TEGAFUR | DrugsGivenReaction | CC BY | 33403047 | 18,745,930 | 2021 |
What was the administration route of drug 'ERLOTINIB'? | A phase II study of gemcitabine, erlotinib and S-1 in patients with advanced pancreatic cancer.
Background: We evaluated the efficacy and safety of gemcitabine in combination with erlotinib and S-1 for the treatment of advanced pancreatic cancer. Methods: Chemotherapy-naïve patients with pathologically-proven locally advanced, recurrent, or metastatic pancreatic adenocarcinoma were assessed for eligibility. Gemcitabine was administered at 1,000 mg/m2 intravenously on days 1 and 8, erlotinib was administered at 100 mg/day on days 1-21, and S-1 was administered at 60 mg/m2 on days 1-14 every 21 days and continued to a maximum of 8 cycles of treatment. Dose escalation of S-1 to 80 mg/m2 was permitted from the second cycle for pre-defined tolerable patients. Results: Thirty-seven patients (median age 61.5 years) were enrolled. A total of 140 cycles of chemotherapy were administered (median of 3.8; range 1-8 cycles). Toxicities were evaluated in 36 patients, and the responses were evaluated in 32 patients. Major grade 3/4 toxicities included neutropenia (25%), febrile neutropenia (2.8%), fatigue (22.2%), infection (8.3%), vomiting (5.6%), and mucositis (5.6%). The confirmed overall response rate was 12.5% [95% confidence interval (CI), 5.1-28.9%] and the disease control rate was 71.9% (95% CI, 56.8-86.3%). The median progression-free survival and overall survival were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively. Conclusion: The combination of gemcitabine, erlotinib, and S-1 provided an acceptable toxicity profile and modest clinical benefits in patients with advanced pancreatic cancer.
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is an intractable disease and is the 7th leading cause of global cancer deaths in industrialized countries 1. Because more than 80% of PDAC is locally advanced unresectable or metastatic at the time of diagnosis 2, the prognosis of PDAC patients is dismal with a 5-year relative survival rate of 11.4% 3. Although various types of targeted agents and immunotherapeutic agents are actively used in other cancers, cytotoxic chemotherapy remains the mainstream treatment for unresectable PDAC.
Following the approval of gemcitabine by the US Food and Drug Administration in 1997 4, gemcitabine-based chemotherapy was considered the standard of care for patients with advanced PDAC for a decade. In the era of gemcitabine, various attempts were made simultaneously to find an optimal drug combination that could function synergistically with gemcitabine. A number of drugs, including cytotoxic agents 5-10 and targeted agents 11, 12, in combination with gemcitabine, were tested in large randomized clinical trials, but they failed to improve the efficacy.
Among the various drugs investigated, erlotinib, a small-molecule inhibitor of epidermal growth factor receptor, improved the efficacy of gemcitabine in a randomized phase III trial 13. In this study, erlotinib in combination with gemcitabine showed a small but statistically significant improvement in overall survival when compared to gemcitabine monotherapy (6.2 months vs. 5.9 months, p=0.038). S-1, an oral fluoropyrimidine derivative, was also studied as a combination partner of gemcitabine and has consistently shown promising results in terms of efficacy and safety in a series of phase II studies 14-18.
At the time this study was proposed and designed, gemcitabine plus erlotinib combination chemotherapy was approved as front-line chemotherapy for unresectable PDAC and was widely used globally. However, since the benefit of gemcitabine plus erlotinib in survival prolongation was too small, there has been a continuing need for new drugs or combination regimens for patients with PDAC. In this background, combination therapy with gemcitabine, erlotinib, and S-1 (GTS regimen) has been proposed as a novel front-line treatment for unresectable PDAC, and this study was conducted to demonstrate the efficacy and safety of this regimen.
With two combination regimens of FOLFIRINOX (a combination of oxaliplatin, folinic acid, irinotecan, and fluorouracil [5-FU]) 19 and albumin-bound paclitaxel/gemcitabine 20 currently accepted as front-line treatments and actively used in fit patients, the clinician's interest and possible range of application for our combination regimen will be limited. However, since GTS combination therapy has never been investigated in PDAC, it would be valuable to report and share efficacy and safety data.
Methods
Patient eligibility
Patients were eligible for this study if they fulfilled all of the following criteria: (1) pathologically confirmed unresectable locally advanced, recurrent, or metastatic adenocarcinoma of the pancreas; (2) measurable disease, as defined using version 1.1 of the Response Evaluation Criteria In Solid Tumors (RECIST); (3) age ≥18 years; (4) Eastern Cooperative Oncology Group (ECOG) performance status of 0-1; (5) prior adjuvant chemotherapy without gemcitabine, erlotinib, or S-1 that had been completed >4 weeks before enrollment; (6) more than 4 weeks since completion of prior radiotherapy (measurable lesions are outside the radiation field); (7) adequate hematological, renal, and hepatic functions, as defined using an absolute neutrophil count of ≥1.5 × 109/L, a platelet count of ≥100 × 109/L, serum creatinine levels of ≤1.5 × upper limit of normal or creatinine clearance ≥50 mL/min, serum bilirubin ≤2× UNL, aspartate aminotransferase and alanine aminotransferase levels of ≤2.5×; and, (8) willingness to provide informed consent to participate in this study.
Patients were excluded based on the following criteria: (1) a history of treatment with gemcitabine, erlotinib, or S-1 as adjuvant chemotherapy; (2) contraindication for any drug contained in the chemotherapy regimen; (3) central nervous system metastasis; (4) serious GI bleeding or obvious bowel obstruction; (5) other previous or concurrent malignancies within the last 5 years, with the exception of cured basal cell carcinoma of the skin or carcinoma in situ of the uterine cervix; (6) pregnant or lactating female patients; (7) sexually active and the partner is unwilling to practice contraception during the study; and (8) other clinically significant comorbid conditions, such as an active infection or severe cardiopulmonary dysfunction.
Treatment and study design
The treatment consisted of intravenous administration of gemcitabine at 1,000 mg/m2 on days 1 and 8 every 3 weeks, continuously orally administered erlotinib at 100 mg/day, and orally administered S-1 at 30 mg/m2 twice daily on days 1-14 of each cycle. Patients with a body surface area of <1.25 m2 received 80 mg of S-1 daily, those with a body surface area of 1.25-1.5 m2 received 100 mg of S-1 daily, and those with a body surface area of ≥1.5 m2 received 120 mg of S-1 daily. Treatment was delivered as a 3-week cycle and repeated up to a maximum of 8 cycles of chemotherapy, or until disease progression, unacceptable toxicity, or the patient's refusal.
This trial was a prospective, single-arm phase II study evaluating combination chemotherapy with gemcitabine, erlotinib, and S-1 in previously untreated patients with unresectable locally advanced or metastatic pancreatic cancer. The primary endpoint was the confirmed objective response rate (ORR), and the secondary endpoints were median progression-free survival (PFS), median overall survival (OS), disease control rate (DCR), and toxicity profiles. The investigation was performed in accordance with the Declaration of Helsinki, and the protocol was approved by the institutional review boards of Hallym University Medical Center, Anyang-si, South Korea, and Asan Medical Center, Seoul, South Korea (protocol number: HMC-HO-GI-1201).
Dose modifications and dose intensity
Dose modifications were performed according to the study protocol. The next treatment cycle was initiated only when the neutrophil count was 1.5 × 109/L or greater and the platelet count was 100 × 109/L or greater. Treatment was delayed in the event of grade 3/4 nonhematologic toxicities until the toxicities were resolved to grade 1 or lower. The doses of gemcitabine and S-1 were reduced by 25% of the initial doses for related grade 3/4 neutropenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, or for the second occurrence of the same grade 2 neutropenia and thrombocytopenia. The doses of gemcitabine were reduced by 50% of the initial doses for grade 4 thrombocytopenia, or for the second occurrence of the grade 3/4 neutropenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, or for the third occurrence of grade 3 neutropenia and thrombocytopenia. In the case of the second occurrence of grade 2 thrombocytopenia, grade 3/4 neutropenia, grade 3 febrile neutropenia, or the third occurrence of grade 2 neutropenia, erlotinib was omitted until recovery and then re-challenged. Treatment was discontinued if, despite the dose reduction, the same toxicity occurred for a fourth time at grade 2, a third time at grade 3, or a second time at grade 4 or any occurrence of life-threatening sepsis during treatment. In addition, if the toxicity had not improved to grade 0 or 1 after 3 weeks, the patient was withdrawn from the study. The dose reduction was maintained in subsequent cycles.
To evaluate a function of the drug and the frequency of administration, we calculated the relative dose intensity (RDI), which is expressed as the ratio of the administered amount of dose per time unit (mg/m2/week) to that of the originally planned dose.
Toxicity and response evaluation
A physical examination with vital signs, complete blood cell counts with differentials, and blood chemistry tests were performed before every administration of gemcitabine in each subsequent cycle. Toxicity was evaluated and graded according to version 4.0 of the Common Terminology Criteria for Adverse Events of the National Cancer Institute. All of the patients who received at least one dose of treatment were included in the toxicity assessment. For the toxicity analysis, the data indicating the worst toxicity for each patient from all of the chemotherapy cycles were used. The proportion of patients who experienced adverse events was calculated by dividing the number of patients who experienced adverse events during the treatment period by the number of patients evaluable for safety analysis. Response to treatment according to RECIST version 1.1 was evaluated every 2 cycles. Patients with CR or PR required a confirmatory disease assessment at least 4 weeks later. PFS was defined as the interval from the date of treatment initiation to the first date of documented disease progression or death due to any cause. OS was defined as the interval from the date of treatment initiation to the date of death.
Statistical analysis
According to Simon's optimal two-stage design, 25 patients were required for enrollment to test the null hypothesis that the true ORR is 10% versus the alternative hypothesis that the true ORR is at least 30%, at a significance level of p<0.05 with a power of 80%. If two or more responses were observed among 15 patients in the first stage, the study was continued with 10 additional patients included. As the drop-out rate was assumed to be 10%, the number of patients necessary for recruitment into the study was calculated to be 28.
Descriptive statistics were used to summarize the patients' characteristics, tumor responses, and safety events. The Kaplan-Meier method was used to estimate the median PFS and OS. All enrolled patients were included in an intent-to-treat analysis.
Results
Patient characteristics
From October 2012 to May 2016, 37 patients who met the inclusion criteria were enrolled in this study. We exceeded the planned number of patients because several unexpected dropouts occurred early in the study and we allowed simultaneous registration of excess patients before the end of the study from multiple institutions. The reasons for dropout are explained below. The demographic and pathologic characteristics of the patients are described in Table 1. The median age was 61.5 years (range 35-88 years). Sixteen patients (43.2%) were male, and the majority of patients (73.0%) had an ECOG PS of 1. Twenty-six patients (70.3%) had metastatic disease, eight patients (21.6%) had recurrent pancreatic cancer after curative surgery, and three patients (8.1%) had locally advanced disease at the time of screening. The most common metastatic sites were distant lymph nodes (43.2%), the liver (43.2%), the lung (29.7%), and the peritoneum (27.0%).
Treatment administration
In total, 140 treatment cycles were administered to 37 patients, with a median of 3.8 cycles (range 1-10 cycles) per patient. Five patients did not complete the first cycle of chemotherapy: two patients died (one patient died of cerebral infarction and one patient died of hepatic tumor rupture), two patients withdrew their informed consent, and one patient was lost to follow-up. Seven patients (18.9%) completed eight or more cycles of chemotherapy. Eleven patients (29.7%) required dose reductions or delays. The mean relative dose intensities (ratio of the dose received to the dose planned) of gemcitabine, S-1 for all of the cycles administered were 0.87 [95% confidence interval (CI) 0.81-0.93], and 0.92 (95% CI 0.87-0.96), respectively (Table 2).
Efficacy
Of the 37 patients, 32 were eligible for response evaluation. Five patients were not available for response evaluation: the detailed reasons for 5 patients who did not complete the first cycle are described in the 'Treatment administration' section. The tumor responses are summarized in Table 3. There were 4 partial responses, 19 cases of stable disease, and 9 cases of disease progression. All partial responses are confirmed in the following CT scan. The confirmed ORR was 12.5% (95% CI 5.1-28.9%) and the disease control rate was 71.9% (95% CI 56.8-86.3%). The median time to response was 1.4 months (95% CI 1.3-1.5 months) and the median duration of response was 7.4 months (95% CI 3.8-11.0 months).
At the time of analysis, 13 patients (35.1%) were still alive with a median follow-up duration of 12.9 months (95% CI 9.6-16.3 months). The median PFS was 3.7 months (95% CI 2.8-4.6 months) and the median OS was 6.7 months (95% CI 3.4-9.9 months; Figures 1 & 2).
Toxicities
Safety was assessed in 36 patients on the basis of 139 cycles. One patient was lost to follow-up after receiving gemcitabine on day 1 of the first cycle, was excluded. One patient died suddenly of abdominal hemorrhage due to hepatic tumor rupture on day 3 of the first cycle. The adverse events are listed in Table 4. The most common grade 3/4 hematologic toxicity was neutropenia (25.0%). Febrile neutropenia developed in one patient (2.8%), who recovered without complications. Nonhematologic toxicities were usually mild and manageable. Grade 3 toxicities with a frequency of 5% or more included fatigue, infection, vomiting, and mucositis.
Discussion
In this study, the confirmed ORR of patients was 12.5%, which is slightly better than that of gemcitabine plus erlotinib 13 and is lower than the results of phase III studies of gemcitabine plus S-1 (GS) 21. The DCR was 71.9% (95% CI, 56.8-86.3%) and the median PFS and OS were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively. The GTS regimen showed an acceptable toxicity profile in the safety analysis. Since, at this point, FOLFIRINOX and albumin-bound paclitaxel/gemcitabine are actively used as standard treatments; the implications of this result are thought to be limited.
5-FU showed a marked synergistic cytotoxic effect with gemcitabine in pancreatic cancer cells in vitro 22 and S-1, which has an equivalent efficacy with a continuous 5-FU infusion in solid cancer, showed promising results in several phase II studies with an ORR of 28-48% 14-18. This study aimed to improve the efficacy of the existing treatment and to investigate a novel triple-combination regimen by adding S-1, which exhibits a synergistic effect with efficacy-proven gemcitabine plus erlotinib.
While this study was in progress, the results of a phase III study (GEST study) comparing GS with gemcitabine alone were published 21. In this trial, despite the improvement in PFS and ORR, GS showed numerically longer OS compared to gemcitabine alone, but it was not statistically significant (10.1 months vs. 8.8 months, p=0.15). In the subgroup analysis of GEST study, GS was associated with significantly improved OS in locally advanced disease compared to metastatic disease. Furthermore, a pooled analysis of subsequent randomized studies comparing GS to gemcitabine alone also re-confirmed that GS showed better OS in locally advanced disease than metastatic disease (16.4 months vs. 11.8 months, HR 0.708, p=0.02) and supported the result of the subgroup analysis from the GEST study. Since most of the participants in this study had recurrent or metastatic disease rather than locally advanced disease, it is assumed that the differences in characteristics of the study population may lead to unsatisfactory results. In our study, the best response of all three patients with locally advanced disease was stable disease but it is difficult to determine statistical significance because the number of patients was too small.
Recently, it was recommended that patients with locally advanced disease should be studied separately from those with metastatic disease because locally advanced and metastatic disease are considered to be two different clinical entities, each with distinctive clinical characteristics 23. Therefore, a study design with an appropriately selected population will be required to further clarify the efficacy of the GTS regimen.
In this study, the median age of the patients was >60 years, and 75% of the patients were symptomatic at the beginning of the study. More than half of the patients had two or more metastatic sites, and 45% and 13% of patients presented with liver metastasis and peritoneal metastasis, respectively. The patients' demographics in our study are relatively inferior to the conditions of other studies, and these differences may have influenced the outcome.
Regarding the safety analysis, GTS showed a modest toxicity profile. Except for neutropenia (25%) and fatigue (22%), the incidence of all other G3 or 4 toxicity profiles did not exceed 10%, which was similar or relatively lower than that of gemcitabine plus erlotinib 13 and GS 21.
Conclusion
In conclusion, GTS did not show the expected efficacy outcome with a confirmed ORR of 12.5%. However, considering the meaningful effect that GS showed in locally advanced disease in a subsequent study and the modest safety profile that our study showed, there may be room to further investigate the GTS regimen depending on the profile of the patient.
S-1 is sponsored by Jeil Pharmaceutical Co.,Ltd, Seoul, Korea.
Funding
This research was supported by the Hallym University Research Fund (Protocol No. HMC-HO-GI-1201).
Figure 1 Progression-free survival.
Figure 2 Overall survival.
Table 1 Patient characteristics (n=37)
Characteristics No. of patients (%)
Age, median (range) 61.5 (35-88)
Gender
Male 16 (43.2%)
Female 21 (56.8%)
Performance status (ECOG)
0 10 (27.0%)
1 27 (73.0%)
Location of primary tumor site
Head 9 (24.3%)
Body 7 (18.9%)
Tail 9 (24.3%)
Diffuse 4 (10.8%)
Unknown 8 (21.6%)
Histology
Well differentiated 5 (13.5%)
Moderately differentiated 9 (24.3%)
Poorly differentiated 4 (10.8%)
Undifferentiated 1 (2.7%)
Unknown 18 (48.6%)
Disease status at the time of screening
Locally advanced 3 (8.1%)
Metastatic 26 (70.3%)
Recurrence after curative surgery 8 (21.6%)
Metastatic sites
Lymph node 16 (43.2%)
Liver 16 (43.2%)
Lung 11 (29.7%)
Peritoneum 10 (27.0%)
Others 8 (21.6%)
No. of metastatic sites
1 14 (41.2%)
2 11 (32.4%)
≥3 9 (26.5%)
ECOG: Eastern Cooperative Oncology Group.
Table 2 Duration of drug administration and dose intensity
Criteria
No. of cycles 140
Median cycles 3.8 (1-8)
No. of patients with dose reduction 11
Relative dose intensity for gemcitabine, Mean (range) 0.87 (0.81-0.93)
Relative dose intensity for S-1, Mean (range) 0.92 (0.87-0.96)
Table 3 Treatment efficacy result
Response No. of patients
Complete response 0
Partial response 4
Stable disease 19
Progressive disease 9
Overall response rate (Confirmed) 12.5% (95% CI, 5.1-28.9%)
Disease control rate 71.9% (95% CI, 56.8-86.3%)
Table 4 Incidence of grade 3/4 adverse events
Grade 3/4 adverse events Number of patients (%) (Total N=36)
Hematologic
Neutropenia 9 (25%)
Febrile neutropenia 1 (2.8%)
Thrombocytopenia 1 (2.8%)
Non-hematologic
Fatigue 8 (22.2%)
Infection 3 (8.3%)
Vomiting 2 (5.6%)
Mucositis 2 (5.6%)
Nausea 1 (2.8%)
Diarrhea 1 (2.8%)
Hepatopathy 1 (2.8%)
Others 4 (11.1%) | Oral | DrugAdministrationRoute | CC BY | 33403047 | 18,745,930 | 2021 |
What was the administration route of drug 'GEMCITABINE HYDROCHLORIDE'? | A phase II study of gemcitabine, erlotinib and S-1 in patients with advanced pancreatic cancer.
Background: We evaluated the efficacy and safety of gemcitabine in combination with erlotinib and S-1 for the treatment of advanced pancreatic cancer. Methods: Chemotherapy-naïve patients with pathologically-proven locally advanced, recurrent, or metastatic pancreatic adenocarcinoma were assessed for eligibility. Gemcitabine was administered at 1,000 mg/m2 intravenously on days 1 and 8, erlotinib was administered at 100 mg/day on days 1-21, and S-1 was administered at 60 mg/m2 on days 1-14 every 21 days and continued to a maximum of 8 cycles of treatment. Dose escalation of S-1 to 80 mg/m2 was permitted from the second cycle for pre-defined tolerable patients. Results: Thirty-seven patients (median age 61.5 years) were enrolled. A total of 140 cycles of chemotherapy were administered (median of 3.8; range 1-8 cycles). Toxicities were evaluated in 36 patients, and the responses were evaluated in 32 patients. Major grade 3/4 toxicities included neutropenia (25%), febrile neutropenia (2.8%), fatigue (22.2%), infection (8.3%), vomiting (5.6%), and mucositis (5.6%). The confirmed overall response rate was 12.5% [95% confidence interval (CI), 5.1-28.9%] and the disease control rate was 71.9% (95% CI, 56.8-86.3%). The median progression-free survival and overall survival were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively. Conclusion: The combination of gemcitabine, erlotinib, and S-1 provided an acceptable toxicity profile and modest clinical benefits in patients with advanced pancreatic cancer.
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is an intractable disease and is the 7th leading cause of global cancer deaths in industrialized countries 1. Because more than 80% of PDAC is locally advanced unresectable or metastatic at the time of diagnosis 2, the prognosis of PDAC patients is dismal with a 5-year relative survival rate of 11.4% 3. Although various types of targeted agents and immunotherapeutic agents are actively used in other cancers, cytotoxic chemotherapy remains the mainstream treatment for unresectable PDAC.
Following the approval of gemcitabine by the US Food and Drug Administration in 1997 4, gemcitabine-based chemotherapy was considered the standard of care for patients with advanced PDAC for a decade. In the era of gemcitabine, various attempts were made simultaneously to find an optimal drug combination that could function synergistically with gemcitabine. A number of drugs, including cytotoxic agents 5-10 and targeted agents 11, 12, in combination with gemcitabine, were tested in large randomized clinical trials, but they failed to improve the efficacy.
Among the various drugs investigated, erlotinib, a small-molecule inhibitor of epidermal growth factor receptor, improved the efficacy of gemcitabine in a randomized phase III trial 13. In this study, erlotinib in combination with gemcitabine showed a small but statistically significant improvement in overall survival when compared to gemcitabine monotherapy (6.2 months vs. 5.9 months, p=0.038). S-1, an oral fluoropyrimidine derivative, was also studied as a combination partner of gemcitabine and has consistently shown promising results in terms of efficacy and safety in a series of phase II studies 14-18.
At the time this study was proposed and designed, gemcitabine plus erlotinib combination chemotherapy was approved as front-line chemotherapy for unresectable PDAC and was widely used globally. However, since the benefit of gemcitabine plus erlotinib in survival prolongation was too small, there has been a continuing need for new drugs or combination regimens for patients with PDAC. In this background, combination therapy with gemcitabine, erlotinib, and S-1 (GTS regimen) has been proposed as a novel front-line treatment for unresectable PDAC, and this study was conducted to demonstrate the efficacy and safety of this regimen.
With two combination regimens of FOLFIRINOX (a combination of oxaliplatin, folinic acid, irinotecan, and fluorouracil [5-FU]) 19 and albumin-bound paclitaxel/gemcitabine 20 currently accepted as front-line treatments and actively used in fit patients, the clinician's interest and possible range of application for our combination regimen will be limited. However, since GTS combination therapy has never been investigated in PDAC, it would be valuable to report and share efficacy and safety data.
Methods
Patient eligibility
Patients were eligible for this study if they fulfilled all of the following criteria: (1) pathologically confirmed unresectable locally advanced, recurrent, or metastatic adenocarcinoma of the pancreas; (2) measurable disease, as defined using version 1.1 of the Response Evaluation Criteria In Solid Tumors (RECIST); (3) age ≥18 years; (4) Eastern Cooperative Oncology Group (ECOG) performance status of 0-1; (5) prior adjuvant chemotherapy without gemcitabine, erlotinib, or S-1 that had been completed >4 weeks before enrollment; (6) more than 4 weeks since completion of prior radiotherapy (measurable lesions are outside the radiation field); (7) adequate hematological, renal, and hepatic functions, as defined using an absolute neutrophil count of ≥1.5 × 109/L, a platelet count of ≥100 × 109/L, serum creatinine levels of ≤1.5 × upper limit of normal or creatinine clearance ≥50 mL/min, serum bilirubin ≤2× UNL, aspartate aminotransferase and alanine aminotransferase levels of ≤2.5×; and, (8) willingness to provide informed consent to participate in this study.
Patients were excluded based on the following criteria: (1) a history of treatment with gemcitabine, erlotinib, or S-1 as adjuvant chemotherapy; (2) contraindication for any drug contained in the chemotherapy regimen; (3) central nervous system metastasis; (4) serious GI bleeding or obvious bowel obstruction; (5) other previous or concurrent malignancies within the last 5 years, with the exception of cured basal cell carcinoma of the skin or carcinoma in situ of the uterine cervix; (6) pregnant or lactating female patients; (7) sexually active and the partner is unwilling to practice contraception during the study; and (8) other clinically significant comorbid conditions, such as an active infection or severe cardiopulmonary dysfunction.
Treatment and study design
The treatment consisted of intravenous administration of gemcitabine at 1,000 mg/m2 on days 1 and 8 every 3 weeks, continuously orally administered erlotinib at 100 mg/day, and orally administered S-1 at 30 mg/m2 twice daily on days 1-14 of each cycle. Patients with a body surface area of <1.25 m2 received 80 mg of S-1 daily, those with a body surface area of 1.25-1.5 m2 received 100 mg of S-1 daily, and those with a body surface area of ≥1.5 m2 received 120 mg of S-1 daily. Treatment was delivered as a 3-week cycle and repeated up to a maximum of 8 cycles of chemotherapy, or until disease progression, unacceptable toxicity, or the patient's refusal.
This trial was a prospective, single-arm phase II study evaluating combination chemotherapy with gemcitabine, erlotinib, and S-1 in previously untreated patients with unresectable locally advanced or metastatic pancreatic cancer. The primary endpoint was the confirmed objective response rate (ORR), and the secondary endpoints were median progression-free survival (PFS), median overall survival (OS), disease control rate (DCR), and toxicity profiles. The investigation was performed in accordance with the Declaration of Helsinki, and the protocol was approved by the institutional review boards of Hallym University Medical Center, Anyang-si, South Korea, and Asan Medical Center, Seoul, South Korea (protocol number: HMC-HO-GI-1201).
Dose modifications and dose intensity
Dose modifications were performed according to the study protocol. The next treatment cycle was initiated only when the neutrophil count was 1.5 × 109/L or greater and the platelet count was 100 × 109/L or greater. Treatment was delayed in the event of grade 3/4 nonhematologic toxicities until the toxicities were resolved to grade 1 or lower. The doses of gemcitabine and S-1 were reduced by 25% of the initial doses for related grade 3/4 neutropenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, or for the second occurrence of the same grade 2 neutropenia and thrombocytopenia. The doses of gemcitabine were reduced by 50% of the initial doses for grade 4 thrombocytopenia, or for the second occurrence of the grade 3/4 neutropenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, or for the third occurrence of grade 3 neutropenia and thrombocytopenia. In the case of the second occurrence of grade 2 thrombocytopenia, grade 3/4 neutropenia, grade 3 febrile neutropenia, or the third occurrence of grade 2 neutropenia, erlotinib was omitted until recovery and then re-challenged. Treatment was discontinued if, despite the dose reduction, the same toxicity occurred for a fourth time at grade 2, a third time at grade 3, or a second time at grade 4 or any occurrence of life-threatening sepsis during treatment. In addition, if the toxicity had not improved to grade 0 or 1 after 3 weeks, the patient was withdrawn from the study. The dose reduction was maintained in subsequent cycles.
To evaluate a function of the drug and the frequency of administration, we calculated the relative dose intensity (RDI), which is expressed as the ratio of the administered amount of dose per time unit (mg/m2/week) to that of the originally planned dose.
Toxicity and response evaluation
A physical examination with vital signs, complete blood cell counts with differentials, and blood chemistry tests were performed before every administration of gemcitabine in each subsequent cycle. Toxicity was evaluated and graded according to version 4.0 of the Common Terminology Criteria for Adverse Events of the National Cancer Institute. All of the patients who received at least one dose of treatment were included in the toxicity assessment. For the toxicity analysis, the data indicating the worst toxicity for each patient from all of the chemotherapy cycles were used. The proportion of patients who experienced adverse events was calculated by dividing the number of patients who experienced adverse events during the treatment period by the number of patients evaluable for safety analysis. Response to treatment according to RECIST version 1.1 was evaluated every 2 cycles. Patients with CR or PR required a confirmatory disease assessment at least 4 weeks later. PFS was defined as the interval from the date of treatment initiation to the first date of documented disease progression or death due to any cause. OS was defined as the interval from the date of treatment initiation to the date of death.
Statistical analysis
According to Simon's optimal two-stage design, 25 patients were required for enrollment to test the null hypothesis that the true ORR is 10% versus the alternative hypothesis that the true ORR is at least 30%, at a significance level of p<0.05 with a power of 80%. If two or more responses were observed among 15 patients in the first stage, the study was continued with 10 additional patients included. As the drop-out rate was assumed to be 10%, the number of patients necessary for recruitment into the study was calculated to be 28.
Descriptive statistics were used to summarize the patients' characteristics, tumor responses, and safety events. The Kaplan-Meier method was used to estimate the median PFS and OS. All enrolled patients were included in an intent-to-treat analysis.
Results
Patient characteristics
From October 2012 to May 2016, 37 patients who met the inclusion criteria were enrolled in this study. We exceeded the planned number of patients because several unexpected dropouts occurred early in the study and we allowed simultaneous registration of excess patients before the end of the study from multiple institutions. The reasons for dropout are explained below. The demographic and pathologic characteristics of the patients are described in Table 1. The median age was 61.5 years (range 35-88 years). Sixteen patients (43.2%) were male, and the majority of patients (73.0%) had an ECOG PS of 1. Twenty-six patients (70.3%) had metastatic disease, eight patients (21.6%) had recurrent pancreatic cancer after curative surgery, and three patients (8.1%) had locally advanced disease at the time of screening. The most common metastatic sites were distant lymph nodes (43.2%), the liver (43.2%), the lung (29.7%), and the peritoneum (27.0%).
Treatment administration
In total, 140 treatment cycles were administered to 37 patients, with a median of 3.8 cycles (range 1-10 cycles) per patient. Five patients did not complete the first cycle of chemotherapy: two patients died (one patient died of cerebral infarction and one patient died of hepatic tumor rupture), two patients withdrew their informed consent, and one patient was lost to follow-up. Seven patients (18.9%) completed eight or more cycles of chemotherapy. Eleven patients (29.7%) required dose reductions or delays. The mean relative dose intensities (ratio of the dose received to the dose planned) of gemcitabine, S-1 for all of the cycles administered were 0.87 [95% confidence interval (CI) 0.81-0.93], and 0.92 (95% CI 0.87-0.96), respectively (Table 2).
Efficacy
Of the 37 patients, 32 were eligible for response evaluation. Five patients were not available for response evaluation: the detailed reasons for 5 patients who did not complete the first cycle are described in the 'Treatment administration' section. The tumor responses are summarized in Table 3. There were 4 partial responses, 19 cases of stable disease, and 9 cases of disease progression. All partial responses are confirmed in the following CT scan. The confirmed ORR was 12.5% (95% CI 5.1-28.9%) and the disease control rate was 71.9% (95% CI 56.8-86.3%). The median time to response was 1.4 months (95% CI 1.3-1.5 months) and the median duration of response was 7.4 months (95% CI 3.8-11.0 months).
At the time of analysis, 13 patients (35.1%) were still alive with a median follow-up duration of 12.9 months (95% CI 9.6-16.3 months). The median PFS was 3.7 months (95% CI 2.8-4.6 months) and the median OS was 6.7 months (95% CI 3.4-9.9 months; Figures 1 & 2).
Toxicities
Safety was assessed in 36 patients on the basis of 139 cycles. One patient was lost to follow-up after receiving gemcitabine on day 1 of the first cycle, was excluded. One patient died suddenly of abdominal hemorrhage due to hepatic tumor rupture on day 3 of the first cycle. The adverse events are listed in Table 4. The most common grade 3/4 hematologic toxicity was neutropenia (25.0%). Febrile neutropenia developed in one patient (2.8%), who recovered without complications. Nonhematologic toxicities were usually mild and manageable. Grade 3 toxicities with a frequency of 5% or more included fatigue, infection, vomiting, and mucositis.
Discussion
In this study, the confirmed ORR of patients was 12.5%, which is slightly better than that of gemcitabine plus erlotinib 13 and is lower than the results of phase III studies of gemcitabine plus S-1 (GS) 21. The DCR was 71.9% (95% CI, 56.8-86.3%) and the median PFS and OS were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively. The GTS regimen showed an acceptable toxicity profile in the safety analysis. Since, at this point, FOLFIRINOX and albumin-bound paclitaxel/gemcitabine are actively used as standard treatments; the implications of this result are thought to be limited.
5-FU showed a marked synergistic cytotoxic effect with gemcitabine in pancreatic cancer cells in vitro 22 and S-1, which has an equivalent efficacy with a continuous 5-FU infusion in solid cancer, showed promising results in several phase II studies with an ORR of 28-48% 14-18. This study aimed to improve the efficacy of the existing treatment and to investigate a novel triple-combination regimen by adding S-1, which exhibits a synergistic effect with efficacy-proven gemcitabine plus erlotinib.
While this study was in progress, the results of a phase III study (GEST study) comparing GS with gemcitabine alone were published 21. In this trial, despite the improvement in PFS and ORR, GS showed numerically longer OS compared to gemcitabine alone, but it was not statistically significant (10.1 months vs. 8.8 months, p=0.15). In the subgroup analysis of GEST study, GS was associated with significantly improved OS in locally advanced disease compared to metastatic disease. Furthermore, a pooled analysis of subsequent randomized studies comparing GS to gemcitabine alone also re-confirmed that GS showed better OS in locally advanced disease than metastatic disease (16.4 months vs. 11.8 months, HR 0.708, p=0.02) and supported the result of the subgroup analysis from the GEST study. Since most of the participants in this study had recurrent or metastatic disease rather than locally advanced disease, it is assumed that the differences in characteristics of the study population may lead to unsatisfactory results. In our study, the best response of all three patients with locally advanced disease was stable disease but it is difficult to determine statistical significance because the number of patients was too small.
Recently, it was recommended that patients with locally advanced disease should be studied separately from those with metastatic disease because locally advanced and metastatic disease are considered to be two different clinical entities, each with distinctive clinical characteristics 23. Therefore, a study design with an appropriately selected population will be required to further clarify the efficacy of the GTS regimen.
In this study, the median age of the patients was >60 years, and 75% of the patients were symptomatic at the beginning of the study. More than half of the patients had two or more metastatic sites, and 45% and 13% of patients presented with liver metastasis and peritoneal metastasis, respectively. The patients' demographics in our study are relatively inferior to the conditions of other studies, and these differences may have influenced the outcome.
Regarding the safety analysis, GTS showed a modest toxicity profile. Except for neutropenia (25%) and fatigue (22%), the incidence of all other G3 or 4 toxicity profiles did not exceed 10%, which was similar or relatively lower than that of gemcitabine plus erlotinib 13 and GS 21.
Conclusion
In conclusion, GTS did not show the expected efficacy outcome with a confirmed ORR of 12.5%. However, considering the meaningful effect that GS showed in locally advanced disease in a subsequent study and the modest safety profile that our study showed, there may be room to further investigate the GTS regimen depending on the profile of the patient.
S-1 is sponsored by Jeil Pharmaceutical Co.,Ltd, Seoul, Korea.
Funding
This research was supported by the Hallym University Research Fund (Protocol No. HMC-HO-GI-1201).
Figure 1 Progression-free survival.
Figure 2 Overall survival.
Table 1 Patient characteristics (n=37)
Characteristics No. of patients (%)
Age, median (range) 61.5 (35-88)
Gender
Male 16 (43.2%)
Female 21 (56.8%)
Performance status (ECOG)
0 10 (27.0%)
1 27 (73.0%)
Location of primary tumor site
Head 9 (24.3%)
Body 7 (18.9%)
Tail 9 (24.3%)
Diffuse 4 (10.8%)
Unknown 8 (21.6%)
Histology
Well differentiated 5 (13.5%)
Moderately differentiated 9 (24.3%)
Poorly differentiated 4 (10.8%)
Undifferentiated 1 (2.7%)
Unknown 18 (48.6%)
Disease status at the time of screening
Locally advanced 3 (8.1%)
Metastatic 26 (70.3%)
Recurrence after curative surgery 8 (21.6%)
Metastatic sites
Lymph node 16 (43.2%)
Liver 16 (43.2%)
Lung 11 (29.7%)
Peritoneum 10 (27.0%)
Others 8 (21.6%)
No. of metastatic sites
1 14 (41.2%)
2 11 (32.4%)
≥3 9 (26.5%)
ECOG: Eastern Cooperative Oncology Group.
Table 2 Duration of drug administration and dose intensity
Criteria
No. of cycles 140
Median cycles 3.8 (1-8)
No. of patients with dose reduction 11
Relative dose intensity for gemcitabine, Mean (range) 0.87 (0.81-0.93)
Relative dose intensity for S-1, Mean (range) 0.92 (0.87-0.96)
Table 3 Treatment efficacy result
Response No. of patients
Complete response 0
Partial response 4
Stable disease 19
Progressive disease 9
Overall response rate (Confirmed) 12.5% (95% CI, 5.1-28.9%)
Disease control rate 71.9% (95% CI, 56.8-86.3%)
Table 4 Incidence of grade 3/4 adverse events
Grade 3/4 adverse events Number of patients (%) (Total N=36)
Hematologic
Neutropenia 9 (25%)
Febrile neutropenia 1 (2.8%)
Thrombocytopenia 1 (2.8%)
Non-hematologic
Fatigue 8 (22.2%)
Infection 3 (8.3%)
Vomiting 2 (5.6%)
Mucositis 2 (5.6%)
Nausea 1 (2.8%)
Diarrhea 1 (2.8%)
Hepatopathy 1 (2.8%)
Others 4 (11.1%) | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33403047 | 18,745,930 | 2021 |
What was the administration route of drug 'GIMERACIL\OTERACIL\TEGAFUR'? | A phase II study of gemcitabine, erlotinib and S-1 in patients with advanced pancreatic cancer.
Background: We evaluated the efficacy and safety of gemcitabine in combination with erlotinib and S-1 for the treatment of advanced pancreatic cancer. Methods: Chemotherapy-naïve patients with pathologically-proven locally advanced, recurrent, or metastatic pancreatic adenocarcinoma were assessed for eligibility. Gemcitabine was administered at 1,000 mg/m2 intravenously on days 1 and 8, erlotinib was administered at 100 mg/day on days 1-21, and S-1 was administered at 60 mg/m2 on days 1-14 every 21 days and continued to a maximum of 8 cycles of treatment. Dose escalation of S-1 to 80 mg/m2 was permitted from the second cycle for pre-defined tolerable patients. Results: Thirty-seven patients (median age 61.5 years) were enrolled. A total of 140 cycles of chemotherapy were administered (median of 3.8; range 1-8 cycles). Toxicities were evaluated in 36 patients, and the responses were evaluated in 32 patients. Major grade 3/4 toxicities included neutropenia (25%), febrile neutropenia (2.8%), fatigue (22.2%), infection (8.3%), vomiting (5.6%), and mucositis (5.6%). The confirmed overall response rate was 12.5% [95% confidence interval (CI), 5.1-28.9%] and the disease control rate was 71.9% (95% CI, 56.8-86.3%). The median progression-free survival and overall survival were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively. Conclusion: The combination of gemcitabine, erlotinib, and S-1 provided an acceptable toxicity profile and modest clinical benefits in patients with advanced pancreatic cancer.
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is an intractable disease and is the 7th leading cause of global cancer deaths in industrialized countries 1. Because more than 80% of PDAC is locally advanced unresectable or metastatic at the time of diagnosis 2, the prognosis of PDAC patients is dismal with a 5-year relative survival rate of 11.4% 3. Although various types of targeted agents and immunotherapeutic agents are actively used in other cancers, cytotoxic chemotherapy remains the mainstream treatment for unresectable PDAC.
Following the approval of gemcitabine by the US Food and Drug Administration in 1997 4, gemcitabine-based chemotherapy was considered the standard of care for patients with advanced PDAC for a decade. In the era of gemcitabine, various attempts were made simultaneously to find an optimal drug combination that could function synergistically with gemcitabine. A number of drugs, including cytotoxic agents 5-10 and targeted agents 11, 12, in combination with gemcitabine, were tested in large randomized clinical trials, but they failed to improve the efficacy.
Among the various drugs investigated, erlotinib, a small-molecule inhibitor of epidermal growth factor receptor, improved the efficacy of gemcitabine in a randomized phase III trial 13. In this study, erlotinib in combination with gemcitabine showed a small but statistically significant improvement in overall survival when compared to gemcitabine monotherapy (6.2 months vs. 5.9 months, p=0.038). S-1, an oral fluoropyrimidine derivative, was also studied as a combination partner of gemcitabine and has consistently shown promising results in terms of efficacy and safety in a series of phase II studies 14-18.
At the time this study was proposed and designed, gemcitabine plus erlotinib combination chemotherapy was approved as front-line chemotherapy for unresectable PDAC and was widely used globally. However, since the benefit of gemcitabine plus erlotinib in survival prolongation was too small, there has been a continuing need for new drugs or combination regimens for patients with PDAC. In this background, combination therapy with gemcitabine, erlotinib, and S-1 (GTS regimen) has been proposed as a novel front-line treatment for unresectable PDAC, and this study was conducted to demonstrate the efficacy and safety of this regimen.
With two combination regimens of FOLFIRINOX (a combination of oxaliplatin, folinic acid, irinotecan, and fluorouracil [5-FU]) 19 and albumin-bound paclitaxel/gemcitabine 20 currently accepted as front-line treatments and actively used in fit patients, the clinician's interest and possible range of application for our combination regimen will be limited. However, since GTS combination therapy has never been investigated in PDAC, it would be valuable to report and share efficacy and safety data.
Methods
Patient eligibility
Patients were eligible for this study if they fulfilled all of the following criteria: (1) pathologically confirmed unresectable locally advanced, recurrent, or metastatic adenocarcinoma of the pancreas; (2) measurable disease, as defined using version 1.1 of the Response Evaluation Criteria In Solid Tumors (RECIST); (3) age ≥18 years; (4) Eastern Cooperative Oncology Group (ECOG) performance status of 0-1; (5) prior adjuvant chemotherapy without gemcitabine, erlotinib, or S-1 that had been completed >4 weeks before enrollment; (6) more than 4 weeks since completion of prior radiotherapy (measurable lesions are outside the radiation field); (7) adequate hematological, renal, and hepatic functions, as defined using an absolute neutrophil count of ≥1.5 × 109/L, a platelet count of ≥100 × 109/L, serum creatinine levels of ≤1.5 × upper limit of normal or creatinine clearance ≥50 mL/min, serum bilirubin ≤2× UNL, aspartate aminotransferase and alanine aminotransferase levels of ≤2.5×; and, (8) willingness to provide informed consent to participate in this study.
Patients were excluded based on the following criteria: (1) a history of treatment with gemcitabine, erlotinib, or S-1 as adjuvant chemotherapy; (2) contraindication for any drug contained in the chemotherapy regimen; (3) central nervous system metastasis; (4) serious GI bleeding or obvious bowel obstruction; (5) other previous or concurrent malignancies within the last 5 years, with the exception of cured basal cell carcinoma of the skin or carcinoma in situ of the uterine cervix; (6) pregnant or lactating female patients; (7) sexually active and the partner is unwilling to practice contraception during the study; and (8) other clinically significant comorbid conditions, such as an active infection or severe cardiopulmonary dysfunction.
Treatment and study design
The treatment consisted of intravenous administration of gemcitabine at 1,000 mg/m2 on days 1 and 8 every 3 weeks, continuously orally administered erlotinib at 100 mg/day, and orally administered S-1 at 30 mg/m2 twice daily on days 1-14 of each cycle. Patients with a body surface area of <1.25 m2 received 80 mg of S-1 daily, those with a body surface area of 1.25-1.5 m2 received 100 mg of S-1 daily, and those with a body surface area of ≥1.5 m2 received 120 mg of S-1 daily. Treatment was delivered as a 3-week cycle and repeated up to a maximum of 8 cycles of chemotherapy, or until disease progression, unacceptable toxicity, or the patient's refusal.
This trial was a prospective, single-arm phase II study evaluating combination chemotherapy with gemcitabine, erlotinib, and S-1 in previously untreated patients with unresectable locally advanced or metastatic pancreatic cancer. The primary endpoint was the confirmed objective response rate (ORR), and the secondary endpoints were median progression-free survival (PFS), median overall survival (OS), disease control rate (DCR), and toxicity profiles. The investigation was performed in accordance with the Declaration of Helsinki, and the protocol was approved by the institutional review boards of Hallym University Medical Center, Anyang-si, South Korea, and Asan Medical Center, Seoul, South Korea (protocol number: HMC-HO-GI-1201).
Dose modifications and dose intensity
Dose modifications were performed according to the study protocol. The next treatment cycle was initiated only when the neutrophil count was 1.5 × 109/L or greater and the platelet count was 100 × 109/L or greater. Treatment was delayed in the event of grade 3/4 nonhematologic toxicities until the toxicities were resolved to grade 1 or lower. The doses of gemcitabine and S-1 were reduced by 25% of the initial doses for related grade 3/4 neutropenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, or for the second occurrence of the same grade 2 neutropenia and thrombocytopenia. The doses of gemcitabine were reduced by 50% of the initial doses for grade 4 thrombocytopenia, or for the second occurrence of the grade 3/4 neutropenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, or for the third occurrence of grade 3 neutropenia and thrombocytopenia. In the case of the second occurrence of grade 2 thrombocytopenia, grade 3/4 neutropenia, grade 3 febrile neutropenia, or the third occurrence of grade 2 neutropenia, erlotinib was omitted until recovery and then re-challenged. Treatment was discontinued if, despite the dose reduction, the same toxicity occurred for a fourth time at grade 2, a third time at grade 3, or a second time at grade 4 or any occurrence of life-threatening sepsis during treatment. In addition, if the toxicity had not improved to grade 0 or 1 after 3 weeks, the patient was withdrawn from the study. The dose reduction was maintained in subsequent cycles.
To evaluate a function of the drug and the frequency of administration, we calculated the relative dose intensity (RDI), which is expressed as the ratio of the administered amount of dose per time unit (mg/m2/week) to that of the originally planned dose.
Toxicity and response evaluation
A physical examination with vital signs, complete blood cell counts with differentials, and blood chemistry tests were performed before every administration of gemcitabine in each subsequent cycle. Toxicity was evaluated and graded according to version 4.0 of the Common Terminology Criteria for Adverse Events of the National Cancer Institute. All of the patients who received at least one dose of treatment were included in the toxicity assessment. For the toxicity analysis, the data indicating the worst toxicity for each patient from all of the chemotherapy cycles were used. The proportion of patients who experienced adverse events was calculated by dividing the number of patients who experienced adverse events during the treatment period by the number of patients evaluable for safety analysis. Response to treatment according to RECIST version 1.1 was evaluated every 2 cycles. Patients with CR or PR required a confirmatory disease assessment at least 4 weeks later. PFS was defined as the interval from the date of treatment initiation to the first date of documented disease progression or death due to any cause. OS was defined as the interval from the date of treatment initiation to the date of death.
Statistical analysis
According to Simon's optimal two-stage design, 25 patients were required for enrollment to test the null hypothesis that the true ORR is 10% versus the alternative hypothesis that the true ORR is at least 30%, at a significance level of p<0.05 with a power of 80%. If two or more responses were observed among 15 patients in the first stage, the study was continued with 10 additional patients included. As the drop-out rate was assumed to be 10%, the number of patients necessary for recruitment into the study was calculated to be 28.
Descriptive statistics were used to summarize the patients' characteristics, tumor responses, and safety events. The Kaplan-Meier method was used to estimate the median PFS and OS. All enrolled patients were included in an intent-to-treat analysis.
Results
Patient characteristics
From October 2012 to May 2016, 37 patients who met the inclusion criteria were enrolled in this study. We exceeded the planned number of patients because several unexpected dropouts occurred early in the study and we allowed simultaneous registration of excess patients before the end of the study from multiple institutions. The reasons for dropout are explained below. The demographic and pathologic characteristics of the patients are described in Table 1. The median age was 61.5 years (range 35-88 years). Sixteen patients (43.2%) were male, and the majority of patients (73.0%) had an ECOG PS of 1. Twenty-six patients (70.3%) had metastatic disease, eight patients (21.6%) had recurrent pancreatic cancer after curative surgery, and three patients (8.1%) had locally advanced disease at the time of screening. The most common metastatic sites were distant lymph nodes (43.2%), the liver (43.2%), the lung (29.7%), and the peritoneum (27.0%).
Treatment administration
In total, 140 treatment cycles were administered to 37 patients, with a median of 3.8 cycles (range 1-10 cycles) per patient. Five patients did not complete the first cycle of chemotherapy: two patients died (one patient died of cerebral infarction and one patient died of hepatic tumor rupture), two patients withdrew their informed consent, and one patient was lost to follow-up. Seven patients (18.9%) completed eight or more cycles of chemotherapy. Eleven patients (29.7%) required dose reductions or delays. The mean relative dose intensities (ratio of the dose received to the dose planned) of gemcitabine, S-1 for all of the cycles administered were 0.87 [95% confidence interval (CI) 0.81-0.93], and 0.92 (95% CI 0.87-0.96), respectively (Table 2).
Efficacy
Of the 37 patients, 32 were eligible for response evaluation. Five patients were not available for response evaluation: the detailed reasons for 5 patients who did not complete the first cycle are described in the 'Treatment administration' section. The tumor responses are summarized in Table 3. There were 4 partial responses, 19 cases of stable disease, and 9 cases of disease progression. All partial responses are confirmed in the following CT scan. The confirmed ORR was 12.5% (95% CI 5.1-28.9%) and the disease control rate was 71.9% (95% CI 56.8-86.3%). The median time to response was 1.4 months (95% CI 1.3-1.5 months) and the median duration of response was 7.4 months (95% CI 3.8-11.0 months).
At the time of analysis, 13 patients (35.1%) were still alive with a median follow-up duration of 12.9 months (95% CI 9.6-16.3 months). The median PFS was 3.7 months (95% CI 2.8-4.6 months) and the median OS was 6.7 months (95% CI 3.4-9.9 months; Figures 1 & 2).
Toxicities
Safety was assessed in 36 patients on the basis of 139 cycles. One patient was lost to follow-up after receiving gemcitabine on day 1 of the first cycle, was excluded. One patient died suddenly of abdominal hemorrhage due to hepatic tumor rupture on day 3 of the first cycle. The adverse events are listed in Table 4. The most common grade 3/4 hematologic toxicity was neutropenia (25.0%). Febrile neutropenia developed in one patient (2.8%), who recovered without complications. Nonhematologic toxicities were usually mild and manageable. Grade 3 toxicities with a frequency of 5% or more included fatigue, infection, vomiting, and mucositis.
Discussion
In this study, the confirmed ORR of patients was 12.5%, which is slightly better than that of gemcitabine plus erlotinib 13 and is lower than the results of phase III studies of gemcitabine plus S-1 (GS) 21. The DCR was 71.9% (95% CI, 56.8-86.3%) and the median PFS and OS were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively. The GTS regimen showed an acceptable toxicity profile in the safety analysis. Since, at this point, FOLFIRINOX and albumin-bound paclitaxel/gemcitabine are actively used as standard treatments; the implications of this result are thought to be limited.
5-FU showed a marked synergistic cytotoxic effect with gemcitabine in pancreatic cancer cells in vitro 22 and S-1, which has an equivalent efficacy with a continuous 5-FU infusion in solid cancer, showed promising results in several phase II studies with an ORR of 28-48% 14-18. This study aimed to improve the efficacy of the existing treatment and to investigate a novel triple-combination regimen by adding S-1, which exhibits a synergistic effect with efficacy-proven gemcitabine plus erlotinib.
While this study was in progress, the results of a phase III study (GEST study) comparing GS with gemcitabine alone were published 21. In this trial, despite the improvement in PFS and ORR, GS showed numerically longer OS compared to gemcitabine alone, but it was not statistically significant (10.1 months vs. 8.8 months, p=0.15). In the subgroup analysis of GEST study, GS was associated with significantly improved OS in locally advanced disease compared to metastatic disease. Furthermore, a pooled analysis of subsequent randomized studies comparing GS to gemcitabine alone also re-confirmed that GS showed better OS in locally advanced disease than metastatic disease (16.4 months vs. 11.8 months, HR 0.708, p=0.02) and supported the result of the subgroup analysis from the GEST study. Since most of the participants in this study had recurrent or metastatic disease rather than locally advanced disease, it is assumed that the differences in characteristics of the study population may lead to unsatisfactory results. In our study, the best response of all three patients with locally advanced disease was stable disease but it is difficult to determine statistical significance because the number of patients was too small.
Recently, it was recommended that patients with locally advanced disease should be studied separately from those with metastatic disease because locally advanced and metastatic disease are considered to be two different clinical entities, each with distinctive clinical characteristics 23. Therefore, a study design with an appropriately selected population will be required to further clarify the efficacy of the GTS regimen.
In this study, the median age of the patients was >60 years, and 75% of the patients were symptomatic at the beginning of the study. More than half of the patients had two or more metastatic sites, and 45% and 13% of patients presented with liver metastasis and peritoneal metastasis, respectively. The patients' demographics in our study are relatively inferior to the conditions of other studies, and these differences may have influenced the outcome.
Regarding the safety analysis, GTS showed a modest toxicity profile. Except for neutropenia (25%) and fatigue (22%), the incidence of all other G3 or 4 toxicity profiles did not exceed 10%, which was similar or relatively lower than that of gemcitabine plus erlotinib 13 and GS 21.
Conclusion
In conclusion, GTS did not show the expected efficacy outcome with a confirmed ORR of 12.5%. However, considering the meaningful effect that GS showed in locally advanced disease in a subsequent study and the modest safety profile that our study showed, there may be room to further investigate the GTS regimen depending on the profile of the patient.
S-1 is sponsored by Jeil Pharmaceutical Co.,Ltd, Seoul, Korea.
Funding
This research was supported by the Hallym University Research Fund (Protocol No. HMC-HO-GI-1201).
Figure 1 Progression-free survival.
Figure 2 Overall survival.
Table 1 Patient characteristics (n=37)
Characteristics No. of patients (%)
Age, median (range) 61.5 (35-88)
Gender
Male 16 (43.2%)
Female 21 (56.8%)
Performance status (ECOG)
0 10 (27.0%)
1 27 (73.0%)
Location of primary tumor site
Head 9 (24.3%)
Body 7 (18.9%)
Tail 9 (24.3%)
Diffuse 4 (10.8%)
Unknown 8 (21.6%)
Histology
Well differentiated 5 (13.5%)
Moderately differentiated 9 (24.3%)
Poorly differentiated 4 (10.8%)
Undifferentiated 1 (2.7%)
Unknown 18 (48.6%)
Disease status at the time of screening
Locally advanced 3 (8.1%)
Metastatic 26 (70.3%)
Recurrence after curative surgery 8 (21.6%)
Metastatic sites
Lymph node 16 (43.2%)
Liver 16 (43.2%)
Lung 11 (29.7%)
Peritoneum 10 (27.0%)
Others 8 (21.6%)
No. of metastatic sites
1 14 (41.2%)
2 11 (32.4%)
≥3 9 (26.5%)
ECOG: Eastern Cooperative Oncology Group.
Table 2 Duration of drug administration and dose intensity
Criteria
No. of cycles 140
Median cycles 3.8 (1-8)
No. of patients with dose reduction 11
Relative dose intensity for gemcitabine, Mean (range) 0.87 (0.81-0.93)
Relative dose intensity for S-1, Mean (range) 0.92 (0.87-0.96)
Table 3 Treatment efficacy result
Response No. of patients
Complete response 0
Partial response 4
Stable disease 19
Progressive disease 9
Overall response rate (Confirmed) 12.5% (95% CI, 5.1-28.9%)
Disease control rate 71.9% (95% CI, 56.8-86.3%)
Table 4 Incidence of grade 3/4 adverse events
Grade 3/4 adverse events Number of patients (%) (Total N=36)
Hematologic
Neutropenia 9 (25%)
Febrile neutropenia 1 (2.8%)
Thrombocytopenia 1 (2.8%)
Non-hematologic
Fatigue 8 (22.2%)
Infection 3 (8.3%)
Vomiting 2 (5.6%)
Mucositis 2 (5.6%)
Nausea 1 (2.8%)
Diarrhea 1 (2.8%)
Hepatopathy 1 (2.8%)
Others 4 (11.1%) | Oral | DrugAdministrationRoute | CC BY | 33403047 | 18,745,930 | 2021 |
What was the dosage of drug 'ERLOTINIB'? | A phase II study of gemcitabine, erlotinib and S-1 in patients with advanced pancreatic cancer.
Background: We evaluated the efficacy and safety of gemcitabine in combination with erlotinib and S-1 for the treatment of advanced pancreatic cancer. Methods: Chemotherapy-naïve patients with pathologically-proven locally advanced, recurrent, or metastatic pancreatic adenocarcinoma were assessed for eligibility. Gemcitabine was administered at 1,000 mg/m2 intravenously on days 1 and 8, erlotinib was administered at 100 mg/day on days 1-21, and S-1 was administered at 60 mg/m2 on days 1-14 every 21 days and continued to a maximum of 8 cycles of treatment. Dose escalation of S-1 to 80 mg/m2 was permitted from the second cycle for pre-defined tolerable patients. Results: Thirty-seven patients (median age 61.5 years) were enrolled. A total of 140 cycles of chemotherapy were administered (median of 3.8; range 1-8 cycles). Toxicities were evaluated in 36 patients, and the responses were evaluated in 32 patients. Major grade 3/4 toxicities included neutropenia (25%), febrile neutropenia (2.8%), fatigue (22.2%), infection (8.3%), vomiting (5.6%), and mucositis (5.6%). The confirmed overall response rate was 12.5% [95% confidence interval (CI), 5.1-28.9%] and the disease control rate was 71.9% (95% CI, 56.8-86.3%). The median progression-free survival and overall survival were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively. Conclusion: The combination of gemcitabine, erlotinib, and S-1 provided an acceptable toxicity profile and modest clinical benefits in patients with advanced pancreatic cancer.
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is an intractable disease and is the 7th leading cause of global cancer deaths in industrialized countries 1. Because more than 80% of PDAC is locally advanced unresectable or metastatic at the time of diagnosis 2, the prognosis of PDAC patients is dismal with a 5-year relative survival rate of 11.4% 3. Although various types of targeted agents and immunotherapeutic agents are actively used in other cancers, cytotoxic chemotherapy remains the mainstream treatment for unresectable PDAC.
Following the approval of gemcitabine by the US Food and Drug Administration in 1997 4, gemcitabine-based chemotherapy was considered the standard of care for patients with advanced PDAC for a decade. In the era of gemcitabine, various attempts were made simultaneously to find an optimal drug combination that could function synergistically with gemcitabine. A number of drugs, including cytotoxic agents 5-10 and targeted agents 11, 12, in combination with gemcitabine, were tested in large randomized clinical trials, but they failed to improve the efficacy.
Among the various drugs investigated, erlotinib, a small-molecule inhibitor of epidermal growth factor receptor, improved the efficacy of gemcitabine in a randomized phase III trial 13. In this study, erlotinib in combination with gemcitabine showed a small but statistically significant improvement in overall survival when compared to gemcitabine monotherapy (6.2 months vs. 5.9 months, p=0.038). S-1, an oral fluoropyrimidine derivative, was also studied as a combination partner of gemcitabine and has consistently shown promising results in terms of efficacy and safety in a series of phase II studies 14-18.
At the time this study was proposed and designed, gemcitabine plus erlotinib combination chemotherapy was approved as front-line chemotherapy for unresectable PDAC and was widely used globally. However, since the benefit of gemcitabine plus erlotinib in survival prolongation was too small, there has been a continuing need for new drugs or combination regimens for patients with PDAC. In this background, combination therapy with gemcitabine, erlotinib, and S-1 (GTS regimen) has been proposed as a novel front-line treatment for unresectable PDAC, and this study was conducted to demonstrate the efficacy and safety of this regimen.
With two combination regimens of FOLFIRINOX (a combination of oxaliplatin, folinic acid, irinotecan, and fluorouracil [5-FU]) 19 and albumin-bound paclitaxel/gemcitabine 20 currently accepted as front-line treatments and actively used in fit patients, the clinician's interest and possible range of application for our combination regimen will be limited. However, since GTS combination therapy has never been investigated in PDAC, it would be valuable to report and share efficacy and safety data.
Methods
Patient eligibility
Patients were eligible for this study if they fulfilled all of the following criteria: (1) pathologically confirmed unresectable locally advanced, recurrent, or metastatic adenocarcinoma of the pancreas; (2) measurable disease, as defined using version 1.1 of the Response Evaluation Criteria In Solid Tumors (RECIST); (3) age ≥18 years; (4) Eastern Cooperative Oncology Group (ECOG) performance status of 0-1; (5) prior adjuvant chemotherapy without gemcitabine, erlotinib, or S-1 that had been completed >4 weeks before enrollment; (6) more than 4 weeks since completion of prior radiotherapy (measurable lesions are outside the radiation field); (7) adequate hematological, renal, and hepatic functions, as defined using an absolute neutrophil count of ≥1.5 × 109/L, a platelet count of ≥100 × 109/L, serum creatinine levels of ≤1.5 × upper limit of normal or creatinine clearance ≥50 mL/min, serum bilirubin ≤2× UNL, aspartate aminotransferase and alanine aminotransferase levels of ≤2.5×; and, (8) willingness to provide informed consent to participate in this study.
Patients were excluded based on the following criteria: (1) a history of treatment with gemcitabine, erlotinib, or S-1 as adjuvant chemotherapy; (2) contraindication for any drug contained in the chemotherapy regimen; (3) central nervous system metastasis; (4) serious GI bleeding or obvious bowel obstruction; (5) other previous or concurrent malignancies within the last 5 years, with the exception of cured basal cell carcinoma of the skin or carcinoma in situ of the uterine cervix; (6) pregnant or lactating female patients; (7) sexually active and the partner is unwilling to practice contraception during the study; and (8) other clinically significant comorbid conditions, such as an active infection or severe cardiopulmonary dysfunction.
Treatment and study design
The treatment consisted of intravenous administration of gemcitabine at 1,000 mg/m2 on days 1 and 8 every 3 weeks, continuously orally administered erlotinib at 100 mg/day, and orally administered S-1 at 30 mg/m2 twice daily on days 1-14 of each cycle. Patients with a body surface area of <1.25 m2 received 80 mg of S-1 daily, those with a body surface area of 1.25-1.5 m2 received 100 mg of S-1 daily, and those with a body surface area of ≥1.5 m2 received 120 mg of S-1 daily. Treatment was delivered as a 3-week cycle and repeated up to a maximum of 8 cycles of chemotherapy, or until disease progression, unacceptable toxicity, or the patient's refusal.
This trial was a prospective, single-arm phase II study evaluating combination chemotherapy with gemcitabine, erlotinib, and S-1 in previously untreated patients with unresectable locally advanced or metastatic pancreatic cancer. The primary endpoint was the confirmed objective response rate (ORR), and the secondary endpoints were median progression-free survival (PFS), median overall survival (OS), disease control rate (DCR), and toxicity profiles. The investigation was performed in accordance with the Declaration of Helsinki, and the protocol was approved by the institutional review boards of Hallym University Medical Center, Anyang-si, South Korea, and Asan Medical Center, Seoul, South Korea (protocol number: HMC-HO-GI-1201).
Dose modifications and dose intensity
Dose modifications were performed according to the study protocol. The next treatment cycle was initiated only when the neutrophil count was 1.5 × 109/L or greater and the platelet count was 100 × 109/L or greater. Treatment was delayed in the event of grade 3/4 nonhematologic toxicities until the toxicities were resolved to grade 1 or lower. The doses of gemcitabine and S-1 were reduced by 25% of the initial doses for related grade 3/4 neutropenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, or for the second occurrence of the same grade 2 neutropenia and thrombocytopenia. The doses of gemcitabine were reduced by 50% of the initial doses for grade 4 thrombocytopenia, or for the second occurrence of the grade 3/4 neutropenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, or for the third occurrence of grade 3 neutropenia and thrombocytopenia. In the case of the second occurrence of grade 2 thrombocytopenia, grade 3/4 neutropenia, grade 3 febrile neutropenia, or the third occurrence of grade 2 neutropenia, erlotinib was omitted until recovery and then re-challenged. Treatment was discontinued if, despite the dose reduction, the same toxicity occurred for a fourth time at grade 2, a third time at grade 3, or a second time at grade 4 or any occurrence of life-threatening sepsis during treatment. In addition, if the toxicity had not improved to grade 0 or 1 after 3 weeks, the patient was withdrawn from the study. The dose reduction was maintained in subsequent cycles.
To evaluate a function of the drug and the frequency of administration, we calculated the relative dose intensity (RDI), which is expressed as the ratio of the administered amount of dose per time unit (mg/m2/week) to that of the originally planned dose.
Toxicity and response evaluation
A physical examination with vital signs, complete blood cell counts with differentials, and blood chemistry tests were performed before every administration of gemcitabine in each subsequent cycle. Toxicity was evaluated and graded according to version 4.0 of the Common Terminology Criteria for Adverse Events of the National Cancer Institute. All of the patients who received at least one dose of treatment were included in the toxicity assessment. For the toxicity analysis, the data indicating the worst toxicity for each patient from all of the chemotherapy cycles were used. The proportion of patients who experienced adverse events was calculated by dividing the number of patients who experienced adverse events during the treatment period by the number of patients evaluable for safety analysis. Response to treatment according to RECIST version 1.1 was evaluated every 2 cycles. Patients with CR or PR required a confirmatory disease assessment at least 4 weeks later. PFS was defined as the interval from the date of treatment initiation to the first date of documented disease progression or death due to any cause. OS was defined as the interval from the date of treatment initiation to the date of death.
Statistical analysis
According to Simon's optimal two-stage design, 25 patients were required for enrollment to test the null hypothesis that the true ORR is 10% versus the alternative hypothesis that the true ORR is at least 30%, at a significance level of p<0.05 with a power of 80%. If two or more responses were observed among 15 patients in the first stage, the study was continued with 10 additional patients included. As the drop-out rate was assumed to be 10%, the number of patients necessary for recruitment into the study was calculated to be 28.
Descriptive statistics were used to summarize the patients' characteristics, tumor responses, and safety events. The Kaplan-Meier method was used to estimate the median PFS and OS. All enrolled patients were included in an intent-to-treat analysis.
Results
Patient characteristics
From October 2012 to May 2016, 37 patients who met the inclusion criteria were enrolled in this study. We exceeded the planned number of patients because several unexpected dropouts occurred early in the study and we allowed simultaneous registration of excess patients before the end of the study from multiple institutions. The reasons for dropout are explained below. The demographic and pathologic characteristics of the patients are described in Table 1. The median age was 61.5 years (range 35-88 years). Sixteen patients (43.2%) were male, and the majority of patients (73.0%) had an ECOG PS of 1. Twenty-six patients (70.3%) had metastatic disease, eight patients (21.6%) had recurrent pancreatic cancer after curative surgery, and three patients (8.1%) had locally advanced disease at the time of screening. The most common metastatic sites were distant lymph nodes (43.2%), the liver (43.2%), the lung (29.7%), and the peritoneum (27.0%).
Treatment administration
In total, 140 treatment cycles were administered to 37 patients, with a median of 3.8 cycles (range 1-10 cycles) per patient. Five patients did not complete the first cycle of chemotherapy: two patients died (one patient died of cerebral infarction and one patient died of hepatic tumor rupture), two patients withdrew their informed consent, and one patient was lost to follow-up. Seven patients (18.9%) completed eight or more cycles of chemotherapy. Eleven patients (29.7%) required dose reductions or delays. The mean relative dose intensities (ratio of the dose received to the dose planned) of gemcitabine, S-1 for all of the cycles administered were 0.87 [95% confidence interval (CI) 0.81-0.93], and 0.92 (95% CI 0.87-0.96), respectively (Table 2).
Efficacy
Of the 37 patients, 32 were eligible for response evaluation. Five patients were not available for response evaluation: the detailed reasons for 5 patients who did not complete the first cycle are described in the 'Treatment administration' section. The tumor responses are summarized in Table 3. There were 4 partial responses, 19 cases of stable disease, and 9 cases of disease progression. All partial responses are confirmed in the following CT scan. The confirmed ORR was 12.5% (95% CI 5.1-28.9%) and the disease control rate was 71.9% (95% CI 56.8-86.3%). The median time to response was 1.4 months (95% CI 1.3-1.5 months) and the median duration of response was 7.4 months (95% CI 3.8-11.0 months).
At the time of analysis, 13 patients (35.1%) were still alive with a median follow-up duration of 12.9 months (95% CI 9.6-16.3 months). The median PFS was 3.7 months (95% CI 2.8-4.6 months) and the median OS was 6.7 months (95% CI 3.4-9.9 months; Figures 1 & 2).
Toxicities
Safety was assessed in 36 patients on the basis of 139 cycles. One patient was lost to follow-up after receiving gemcitabine on day 1 of the first cycle, was excluded. One patient died suddenly of abdominal hemorrhage due to hepatic tumor rupture on day 3 of the first cycle. The adverse events are listed in Table 4. The most common grade 3/4 hematologic toxicity was neutropenia (25.0%). Febrile neutropenia developed in one patient (2.8%), who recovered without complications. Nonhematologic toxicities were usually mild and manageable. Grade 3 toxicities with a frequency of 5% or more included fatigue, infection, vomiting, and mucositis.
Discussion
In this study, the confirmed ORR of patients was 12.5%, which is slightly better than that of gemcitabine plus erlotinib 13 and is lower than the results of phase III studies of gemcitabine plus S-1 (GS) 21. The DCR was 71.9% (95% CI, 56.8-86.3%) and the median PFS and OS were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively. The GTS regimen showed an acceptable toxicity profile in the safety analysis. Since, at this point, FOLFIRINOX and albumin-bound paclitaxel/gemcitabine are actively used as standard treatments; the implications of this result are thought to be limited.
5-FU showed a marked synergistic cytotoxic effect with gemcitabine in pancreatic cancer cells in vitro 22 and S-1, which has an equivalent efficacy with a continuous 5-FU infusion in solid cancer, showed promising results in several phase II studies with an ORR of 28-48% 14-18. This study aimed to improve the efficacy of the existing treatment and to investigate a novel triple-combination regimen by adding S-1, which exhibits a synergistic effect with efficacy-proven gemcitabine plus erlotinib.
While this study was in progress, the results of a phase III study (GEST study) comparing GS with gemcitabine alone were published 21. In this trial, despite the improvement in PFS and ORR, GS showed numerically longer OS compared to gemcitabine alone, but it was not statistically significant (10.1 months vs. 8.8 months, p=0.15). In the subgroup analysis of GEST study, GS was associated with significantly improved OS in locally advanced disease compared to metastatic disease. Furthermore, a pooled analysis of subsequent randomized studies comparing GS to gemcitabine alone also re-confirmed that GS showed better OS in locally advanced disease than metastatic disease (16.4 months vs. 11.8 months, HR 0.708, p=0.02) and supported the result of the subgroup analysis from the GEST study. Since most of the participants in this study had recurrent or metastatic disease rather than locally advanced disease, it is assumed that the differences in characteristics of the study population may lead to unsatisfactory results. In our study, the best response of all three patients with locally advanced disease was stable disease but it is difficult to determine statistical significance because the number of patients was too small.
Recently, it was recommended that patients with locally advanced disease should be studied separately from those with metastatic disease because locally advanced and metastatic disease are considered to be two different clinical entities, each with distinctive clinical characteristics 23. Therefore, a study design with an appropriately selected population will be required to further clarify the efficacy of the GTS regimen.
In this study, the median age of the patients was >60 years, and 75% of the patients were symptomatic at the beginning of the study. More than half of the patients had two or more metastatic sites, and 45% and 13% of patients presented with liver metastasis and peritoneal metastasis, respectively. The patients' demographics in our study are relatively inferior to the conditions of other studies, and these differences may have influenced the outcome.
Regarding the safety analysis, GTS showed a modest toxicity profile. Except for neutropenia (25%) and fatigue (22%), the incidence of all other G3 or 4 toxicity profiles did not exceed 10%, which was similar or relatively lower than that of gemcitabine plus erlotinib 13 and GS 21.
Conclusion
In conclusion, GTS did not show the expected efficacy outcome with a confirmed ORR of 12.5%. However, considering the meaningful effect that GS showed in locally advanced disease in a subsequent study and the modest safety profile that our study showed, there may be room to further investigate the GTS regimen depending on the profile of the patient.
S-1 is sponsored by Jeil Pharmaceutical Co.,Ltd, Seoul, Korea.
Funding
This research was supported by the Hallym University Research Fund (Protocol No. HMC-HO-GI-1201).
Figure 1 Progression-free survival.
Figure 2 Overall survival.
Table 1 Patient characteristics (n=37)
Characteristics No. of patients (%)
Age, median (range) 61.5 (35-88)
Gender
Male 16 (43.2%)
Female 21 (56.8%)
Performance status (ECOG)
0 10 (27.0%)
1 27 (73.0%)
Location of primary tumor site
Head 9 (24.3%)
Body 7 (18.9%)
Tail 9 (24.3%)
Diffuse 4 (10.8%)
Unknown 8 (21.6%)
Histology
Well differentiated 5 (13.5%)
Moderately differentiated 9 (24.3%)
Poorly differentiated 4 (10.8%)
Undifferentiated 1 (2.7%)
Unknown 18 (48.6%)
Disease status at the time of screening
Locally advanced 3 (8.1%)
Metastatic 26 (70.3%)
Recurrence after curative surgery 8 (21.6%)
Metastatic sites
Lymph node 16 (43.2%)
Liver 16 (43.2%)
Lung 11 (29.7%)
Peritoneum 10 (27.0%)
Others 8 (21.6%)
No. of metastatic sites
1 14 (41.2%)
2 11 (32.4%)
≥3 9 (26.5%)
ECOG: Eastern Cooperative Oncology Group.
Table 2 Duration of drug administration and dose intensity
Criteria
No. of cycles 140
Median cycles 3.8 (1-8)
No. of patients with dose reduction 11
Relative dose intensity for gemcitabine, Mean (range) 0.87 (0.81-0.93)
Relative dose intensity for S-1, Mean (range) 0.92 (0.87-0.96)
Table 3 Treatment efficacy result
Response No. of patients
Complete response 0
Partial response 4
Stable disease 19
Progressive disease 9
Overall response rate (Confirmed) 12.5% (95% CI, 5.1-28.9%)
Disease control rate 71.9% (95% CI, 56.8-86.3%)
Table 4 Incidence of grade 3/4 adverse events
Grade 3/4 adverse events Number of patients (%) (Total N=36)
Hematologic
Neutropenia 9 (25%)
Febrile neutropenia 1 (2.8%)
Thrombocytopenia 1 (2.8%)
Non-hematologic
Fatigue 8 (22.2%)
Infection 3 (8.3%)
Vomiting 2 (5.6%)
Mucositis 2 (5.6%)
Nausea 1 (2.8%)
Diarrhea 1 (2.8%)
Hepatopathy 1 (2.8%)
Others 4 (11.1%) | 100 MG, 1X/DAY | DrugDosageText | CC BY | 33403047 | 18,745,930 | 2021 |
What was the dosage of drug 'GEMCITABINE HYDROCHLORIDE'? | A phase II study of gemcitabine, erlotinib and S-1 in patients with advanced pancreatic cancer.
Background: We evaluated the efficacy and safety of gemcitabine in combination with erlotinib and S-1 for the treatment of advanced pancreatic cancer. Methods: Chemotherapy-naïve patients with pathologically-proven locally advanced, recurrent, or metastatic pancreatic adenocarcinoma were assessed for eligibility. Gemcitabine was administered at 1,000 mg/m2 intravenously on days 1 and 8, erlotinib was administered at 100 mg/day on days 1-21, and S-1 was administered at 60 mg/m2 on days 1-14 every 21 days and continued to a maximum of 8 cycles of treatment. Dose escalation of S-1 to 80 mg/m2 was permitted from the second cycle for pre-defined tolerable patients. Results: Thirty-seven patients (median age 61.5 years) were enrolled. A total of 140 cycles of chemotherapy were administered (median of 3.8; range 1-8 cycles). Toxicities were evaluated in 36 patients, and the responses were evaluated in 32 patients. Major grade 3/4 toxicities included neutropenia (25%), febrile neutropenia (2.8%), fatigue (22.2%), infection (8.3%), vomiting (5.6%), and mucositis (5.6%). The confirmed overall response rate was 12.5% [95% confidence interval (CI), 5.1-28.9%] and the disease control rate was 71.9% (95% CI, 56.8-86.3%). The median progression-free survival and overall survival were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively. Conclusion: The combination of gemcitabine, erlotinib, and S-1 provided an acceptable toxicity profile and modest clinical benefits in patients with advanced pancreatic cancer.
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is an intractable disease and is the 7th leading cause of global cancer deaths in industrialized countries 1. Because more than 80% of PDAC is locally advanced unresectable or metastatic at the time of diagnosis 2, the prognosis of PDAC patients is dismal with a 5-year relative survival rate of 11.4% 3. Although various types of targeted agents and immunotherapeutic agents are actively used in other cancers, cytotoxic chemotherapy remains the mainstream treatment for unresectable PDAC.
Following the approval of gemcitabine by the US Food and Drug Administration in 1997 4, gemcitabine-based chemotherapy was considered the standard of care for patients with advanced PDAC for a decade. In the era of gemcitabine, various attempts were made simultaneously to find an optimal drug combination that could function synergistically with gemcitabine. A number of drugs, including cytotoxic agents 5-10 and targeted agents 11, 12, in combination with gemcitabine, were tested in large randomized clinical trials, but they failed to improve the efficacy.
Among the various drugs investigated, erlotinib, a small-molecule inhibitor of epidermal growth factor receptor, improved the efficacy of gemcitabine in a randomized phase III trial 13. In this study, erlotinib in combination with gemcitabine showed a small but statistically significant improvement in overall survival when compared to gemcitabine monotherapy (6.2 months vs. 5.9 months, p=0.038). S-1, an oral fluoropyrimidine derivative, was also studied as a combination partner of gemcitabine and has consistently shown promising results in terms of efficacy and safety in a series of phase II studies 14-18.
At the time this study was proposed and designed, gemcitabine plus erlotinib combination chemotherapy was approved as front-line chemotherapy for unresectable PDAC and was widely used globally. However, since the benefit of gemcitabine plus erlotinib in survival prolongation was too small, there has been a continuing need for new drugs or combination regimens for patients with PDAC. In this background, combination therapy with gemcitabine, erlotinib, and S-1 (GTS regimen) has been proposed as a novel front-line treatment for unresectable PDAC, and this study was conducted to demonstrate the efficacy and safety of this regimen.
With two combination regimens of FOLFIRINOX (a combination of oxaliplatin, folinic acid, irinotecan, and fluorouracil [5-FU]) 19 and albumin-bound paclitaxel/gemcitabine 20 currently accepted as front-line treatments and actively used in fit patients, the clinician's interest and possible range of application for our combination regimen will be limited. However, since GTS combination therapy has never been investigated in PDAC, it would be valuable to report and share efficacy and safety data.
Methods
Patient eligibility
Patients were eligible for this study if they fulfilled all of the following criteria: (1) pathologically confirmed unresectable locally advanced, recurrent, or metastatic adenocarcinoma of the pancreas; (2) measurable disease, as defined using version 1.1 of the Response Evaluation Criteria In Solid Tumors (RECIST); (3) age ≥18 years; (4) Eastern Cooperative Oncology Group (ECOG) performance status of 0-1; (5) prior adjuvant chemotherapy without gemcitabine, erlotinib, or S-1 that had been completed >4 weeks before enrollment; (6) more than 4 weeks since completion of prior radiotherapy (measurable lesions are outside the radiation field); (7) adequate hematological, renal, and hepatic functions, as defined using an absolute neutrophil count of ≥1.5 × 109/L, a platelet count of ≥100 × 109/L, serum creatinine levels of ≤1.5 × upper limit of normal or creatinine clearance ≥50 mL/min, serum bilirubin ≤2× UNL, aspartate aminotransferase and alanine aminotransferase levels of ≤2.5×; and, (8) willingness to provide informed consent to participate in this study.
Patients were excluded based on the following criteria: (1) a history of treatment with gemcitabine, erlotinib, or S-1 as adjuvant chemotherapy; (2) contraindication for any drug contained in the chemotherapy regimen; (3) central nervous system metastasis; (4) serious GI bleeding or obvious bowel obstruction; (5) other previous or concurrent malignancies within the last 5 years, with the exception of cured basal cell carcinoma of the skin or carcinoma in situ of the uterine cervix; (6) pregnant or lactating female patients; (7) sexually active and the partner is unwilling to practice contraception during the study; and (8) other clinically significant comorbid conditions, such as an active infection or severe cardiopulmonary dysfunction.
Treatment and study design
The treatment consisted of intravenous administration of gemcitabine at 1,000 mg/m2 on days 1 and 8 every 3 weeks, continuously orally administered erlotinib at 100 mg/day, and orally administered S-1 at 30 mg/m2 twice daily on days 1-14 of each cycle. Patients with a body surface area of <1.25 m2 received 80 mg of S-1 daily, those with a body surface area of 1.25-1.5 m2 received 100 mg of S-1 daily, and those with a body surface area of ≥1.5 m2 received 120 mg of S-1 daily. Treatment was delivered as a 3-week cycle and repeated up to a maximum of 8 cycles of chemotherapy, or until disease progression, unacceptable toxicity, or the patient's refusal.
This trial was a prospective, single-arm phase II study evaluating combination chemotherapy with gemcitabine, erlotinib, and S-1 in previously untreated patients with unresectable locally advanced or metastatic pancreatic cancer. The primary endpoint was the confirmed objective response rate (ORR), and the secondary endpoints were median progression-free survival (PFS), median overall survival (OS), disease control rate (DCR), and toxicity profiles. The investigation was performed in accordance with the Declaration of Helsinki, and the protocol was approved by the institutional review boards of Hallym University Medical Center, Anyang-si, South Korea, and Asan Medical Center, Seoul, South Korea (protocol number: HMC-HO-GI-1201).
Dose modifications and dose intensity
Dose modifications were performed according to the study protocol. The next treatment cycle was initiated only when the neutrophil count was 1.5 × 109/L or greater and the platelet count was 100 × 109/L or greater. Treatment was delayed in the event of grade 3/4 nonhematologic toxicities until the toxicities were resolved to grade 1 or lower. The doses of gemcitabine and S-1 were reduced by 25% of the initial doses for related grade 3/4 neutropenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, or for the second occurrence of the same grade 2 neutropenia and thrombocytopenia. The doses of gemcitabine were reduced by 50% of the initial doses for grade 4 thrombocytopenia, or for the second occurrence of the grade 3/4 neutropenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, or for the third occurrence of grade 3 neutropenia and thrombocytopenia. In the case of the second occurrence of grade 2 thrombocytopenia, grade 3/4 neutropenia, grade 3 febrile neutropenia, or the third occurrence of grade 2 neutropenia, erlotinib was omitted until recovery and then re-challenged. Treatment was discontinued if, despite the dose reduction, the same toxicity occurred for a fourth time at grade 2, a third time at grade 3, or a second time at grade 4 or any occurrence of life-threatening sepsis during treatment. In addition, if the toxicity had not improved to grade 0 or 1 after 3 weeks, the patient was withdrawn from the study. The dose reduction was maintained in subsequent cycles.
To evaluate a function of the drug and the frequency of administration, we calculated the relative dose intensity (RDI), which is expressed as the ratio of the administered amount of dose per time unit (mg/m2/week) to that of the originally planned dose.
Toxicity and response evaluation
A physical examination with vital signs, complete blood cell counts with differentials, and blood chemistry tests were performed before every administration of gemcitabine in each subsequent cycle. Toxicity was evaluated and graded according to version 4.0 of the Common Terminology Criteria for Adverse Events of the National Cancer Institute. All of the patients who received at least one dose of treatment were included in the toxicity assessment. For the toxicity analysis, the data indicating the worst toxicity for each patient from all of the chemotherapy cycles were used. The proportion of patients who experienced adverse events was calculated by dividing the number of patients who experienced adverse events during the treatment period by the number of patients evaluable for safety analysis. Response to treatment according to RECIST version 1.1 was evaluated every 2 cycles. Patients with CR or PR required a confirmatory disease assessment at least 4 weeks later. PFS was defined as the interval from the date of treatment initiation to the first date of documented disease progression or death due to any cause. OS was defined as the interval from the date of treatment initiation to the date of death.
Statistical analysis
According to Simon's optimal two-stage design, 25 patients were required for enrollment to test the null hypothesis that the true ORR is 10% versus the alternative hypothesis that the true ORR is at least 30%, at a significance level of p<0.05 with a power of 80%. If two or more responses were observed among 15 patients in the first stage, the study was continued with 10 additional patients included. As the drop-out rate was assumed to be 10%, the number of patients necessary for recruitment into the study was calculated to be 28.
Descriptive statistics were used to summarize the patients' characteristics, tumor responses, and safety events. The Kaplan-Meier method was used to estimate the median PFS and OS. All enrolled patients were included in an intent-to-treat analysis.
Results
Patient characteristics
From October 2012 to May 2016, 37 patients who met the inclusion criteria were enrolled in this study. We exceeded the planned number of patients because several unexpected dropouts occurred early in the study and we allowed simultaneous registration of excess patients before the end of the study from multiple institutions. The reasons for dropout are explained below. The demographic and pathologic characteristics of the patients are described in Table 1. The median age was 61.5 years (range 35-88 years). Sixteen patients (43.2%) were male, and the majority of patients (73.0%) had an ECOG PS of 1. Twenty-six patients (70.3%) had metastatic disease, eight patients (21.6%) had recurrent pancreatic cancer after curative surgery, and three patients (8.1%) had locally advanced disease at the time of screening. The most common metastatic sites were distant lymph nodes (43.2%), the liver (43.2%), the lung (29.7%), and the peritoneum (27.0%).
Treatment administration
In total, 140 treatment cycles were administered to 37 patients, with a median of 3.8 cycles (range 1-10 cycles) per patient. Five patients did not complete the first cycle of chemotherapy: two patients died (one patient died of cerebral infarction and one patient died of hepatic tumor rupture), two patients withdrew their informed consent, and one patient was lost to follow-up. Seven patients (18.9%) completed eight or more cycles of chemotherapy. Eleven patients (29.7%) required dose reductions or delays. The mean relative dose intensities (ratio of the dose received to the dose planned) of gemcitabine, S-1 for all of the cycles administered were 0.87 [95% confidence interval (CI) 0.81-0.93], and 0.92 (95% CI 0.87-0.96), respectively (Table 2).
Efficacy
Of the 37 patients, 32 were eligible for response evaluation. Five patients were not available for response evaluation: the detailed reasons for 5 patients who did not complete the first cycle are described in the 'Treatment administration' section. The tumor responses are summarized in Table 3. There were 4 partial responses, 19 cases of stable disease, and 9 cases of disease progression. All partial responses are confirmed in the following CT scan. The confirmed ORR was 12.5% (95% CI 5.1-28.9%) and the disease control rate was 71.9% (95% CI 56.8-86.3%). The median time to response was 1.4 months (95% CI 1.3-1.5 months) and the median duration of response was 7.4 months (95% CI 3.8-11.0 months).
At the time of analysis, 13 patients (35.1%) were still alive with a median follow-up duration of 12.9 months (95% CI 9.6-16.3 months). The median PFS was 3.7 months (95% CI 2.8-4.6 months) and the median OS was 6.7 months (95% CI 3.4-9.9 months; Figures 1 & 2).
Toxicities
Safety was assessed in 36 patients on the basis of 139 cycles. One patient was lost to follow-up after receiving gemcitabine on day 1 of the first cycle, was excluded. One patient died suddenly of abdominal hemorrhage due to hepatic tumor rupture on day 3 of the first cycle. The adverse events are listed in Table 4. The most common grade 3/4 hematologic toxicity was neutropenia (25.0%). Febrile neutropenia developed in one patient (2.8%), who recovered without complications. Nonhematologic toxicities were usually mild and manageable. Grade 3 toxicities with a frequency of 5% or more included fatigue, infection, vomiting, and mucositis.
Discussion
In this study, the confirmed ORR of patients was 12.5%, which is slightly better than that of gemcitabine plus erlotinib 13 and is lower than the results of phase III studies of gemcitabine plus S-1 (GS) 21. The DCR was 71.9% (95% CI, 56.8-86.3%) and the median PFS and OS were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively. The GTS regimen showed an acceptable toxicity profile in the safety analysis. Since, at this point, FOLFIRINOX and albumin-bound paclitaxel/gemcitabine are actively used as standard treatments; the implications of this result are thought to be limited.
5-FU showed a marked synergistic cytotoxic effect with gemcitabine in pancreatic cancer cells in vitro 22 and S-1, which has an equivalent efficacy with a continuous 5-FU infusion in solid cancer, showed promising results in several phase II studies with an ORR of 28-48% 14-18. This study aimed to improve the efficacy of the existing treatment and to investigate a novel triple-combination regimen by adding S-1, which exhibits a synergistic effect with efficacy-proven gemcitabine plus erlotinib.
While this study was in progress, the results of a phase III study (GEST study) comparing GS with gemcitabine alone were published 21. In this trial, despite the improvement in PFS and ORR, GS showed numerically longer OS compared to gemcitabine alone, but it was not statistically significant (10.1 months vs. 8.8 months, p=0.15). In the subgroup analysis of GEST study, GS was associated with significantly improved OS in locally advanced disease compared to metastatic disease. Furthermore, a pooled analysis of subsequent randomized studies comparing GS to gemcitabine alone also re-confirmed that GS showed better OS in locally advanced disease than metastatic disease (16.4 months vs. 11.8 months, HR 0.708, p=0.02) and supported the result of the subgroup analysis from the GEST study. Since most of the participants in this study had recurrent or metastatic disease rather than locally advanced disease, it is assumed that the differences in characteristics of the study population may lead to unsatisfactory results. In our study, the best response of all three patients with locally advanced disease was stable disease but it is difficult to determine statistical significance because the number of patients was too small.
Recently, it was recommended that patients with locally advanced disease should be studied separately from those with metastatic disease because locally advanced and metastatic disease are considered to be two different clinical entities, each with distinctive clinical characteristics 23. Therefore, a study design with an appropriately selected population will be required to further clarify the efficacy of the GTS regimen.
In this study, the median age of the patients was >60 years, and 75% of the patients were symptomatic at the beginning of the study. More than half of the patients had two or more metastatic sites, and 45% and 13% of patients presented with liver metastasis and peritoneal metastasis, respectively. The patients' demographics in our study are relatively inferior to the conditions of other studies, and these differences may have influenced the outcome.
Regarding the safety analysis, GTS showed a modest toxicity profile. Except for neutropenia (25%) and fatigue (22%), the incidence of all other G3 or 4 toxicity profiles did not exceed 10%, which was similar or relatively lower than that of gemcitabine plus erlotinib 13 and GS 21.
Conclusion
In conclusion, GTS did not show the expected efficacy outcome with a confirmed ORR of 12.5%. However, considering the meaningful effect that GS showed in locally advanced disease in a subsequent study and the modest safety profile that our study showed, there may be room to further investigate the GTS regimen depending on the profile of the patient.
S-1 is sponsored by Jeil Pharmaceutical Co.,Ltd, Seoul, Korea.
Funding
This research was supported by the Hallym University Research Fund (Protocol No. HMC-HO-GI-1201).
Figure 1 Progression-free survival.
Figure 2 Overall survival.
Table 1 Patient characteristics (n=37)
Characteristics No. of patients (%)
Age, median (range) 61.5 (35-88)
Gender
Male 16 (43.2%)
Female 21 (56.8%)
Performance status (ECOG)
0 10 (27.0%)
1 27 (73.0%)
Location of primary tumor site
Head 9 (24.3%)
Body 7 (18.9%)
Tail 9 (24.3%)
Diffuse 4 (10.8%)
Unknown 8 (21.6%)
Histology
Well differentiated 5 (13.5%)
Moderately differentiated 9 (24.3%)
Poorly differentiated 4 (10.8%)
Undifferentiated 1 (2.7%)
Unknown 18 (48.6%)
Disease status at the time of screening
Locally advanced 3 (8.1%)
Metastatic 26 (70.3%)
Recurrence after curative surgery 8 (21.6%)
Metastatic sites
Lymph node 16 (43.2%)
Liver 16 (43.2%)
Lung 11 (29.7%)
Peritoneum 10 (27.0%)
Others 8 (21.6%)
No. of metastatic sites
1 14 (41.2%)
2 11 (32.4%)
≥3 9 (26.5%)
ECOG: Eastern Cooperative Oncology Group.
Table 2 Duration of drug administration and dose intensity
Criteria
No. of cycles 140
Median cycles 3.8 (1-8)
No. of patients with dose reduction 11
Relative dose intensity for gemcitabine, Mean (range) 0.87 (0.81-0.93)
Relative dose intensity for S-1, Mean (range) 0.92 (0.87-0.96)
Table 3 Treatment efficacy result
Response No. of patients
Complete response 0
Partial response 4
Stable disease 19
Progressive disease 9
Overall response rate (Confirmed) 12.5% (95% CI, 5.1-28.9%)
Disease control rate 71.9% (95% CI, 56.8-86.3%)
Table 4 Incidence of grade 3/4 adverse events
Grade 3/4 adverse events Number of patients (%) (Total N=36)
Hematologic
Neutropenia 9 (25%)
Febrile neutropenia 1 (2.8%)
Thrombocytopenia 1 (2.8%)
Non-hematologic
Fatigue 8 (22.2%)
Infection 3 (8.3%)
Vomiting 2 (5.6%)
Mucositis 2 (5.6%)
Nausea 1 (2.8%)
Diarrhea 1 (2.8%)
Hepatopathy 1 (2.8%)
Others 4 (11.1%) | 1000 MG/M2, CYCLIC (ON DAYS 1 AND 8 EVERY 3 WEEKS) | DrugDosageText | CC BY | 33403047 | 18,745,930 | 2021 |
What was the dosage of drug 'GIMERACIL\OTERACIL\TEGAFUR'? | A phase II study of gemcitabine, erlotinib and S-1 in patients with advanced pancreatic cancer.
Background: We evaluated the efficacy and safety of gemcitabine in combination with erlotinib and S-1 for the treatment of advanced pancreatic cancer. Methods: Chemotherapy-naïve patients with pathologically-proven locally advanced, recurrent, or metastatic pancreatic adenocarcinoma were assessed for eligibility. Gemcitabine was administered at 1,000 mg/m2 intravenously on days 1 and 8, erlotinib was administered at 100 mg/day on days 1-21, and S-1 was administered at 60 mg/m2 on days 1-14 every 21 days and continued to a maximum of 8 cycles of treatment. Dose escalation of S-1 to 80 mg/m2 was permitted from the second cycle for pre-defined tolerable patients. Results: Thirty-seven patients (median age 61.5 years) were enrolled. A total of 140 cycles of chemotherapy were administered (median of 3.8; range 1-8 cycles). Toxicities were evaluated in 36 patients, and the responses were evaluated in 32 patients. Major grade 3/4 toxicities included neutropenia (25%), febrile neutropenia (2.8%), fatigue (22.2%), infection (8.3%), vomiting (5.6%), and mucositis (5.6%). The confirmed overall response rate was 12.5% [95% confidence interval (CI), 5.1-28.9%] and the disease control rate was 71.9% (95% CI, 56.8-86.3%). The median progression-free survival and overall survival were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively. Conclusion: The combination of gemcitabine, erlotinib, and S-1 provided an acceptable toxicity profile and modest clinical benefits in patients with advanced pancreatic cancer.
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is an intractable disease and is the 7th leading cause of global cancer deaths in industrialized countries 1. Because more than 80% of PDAC is locally advanced unresectable or metastatic at the time of diagnosis 2, the prognosis of PDAC patients is dismal with a 5-year relative survival rate of 11.4% 3. Although various types of targeted agents and immunotherapeutic agents are actively used in other cancers, cytotoxic chemotherapy remains the mainstream treatment for unresectable PDAC.
Following the approval of gemcitabine by the US Food and Drug Administration in 1997 4, gemcitabine-based chemotherapy was considered the standard of care for patients with advanced PDAC for a decade. In the era of gemcitabine, various attempts were made simultaneously to find an optimal drug combination that could function synergistically with gemcitabine. A number of drugs, including cytotoxic agents 5-10 and targeted agents 11, 12, in combination with gemcitabine, were tested in large randomized clinical trials, but they failed to improve the efficacy.
Among the various drugs investigated, erlotinib, a small-molecule inhibitor of epidermal growth factor receptor, improved the efficacy of gemcitabine in a randomized phase III trial 13. In this study, erlotinib in combination with gemcitabine showed a small but statistically significant improvement in overall survival when compared to gemcitabine monotherapy (6.2 months vs. 5.9 months, p=0.038). S-1, an oral fluoropyrimidine derivative, was also studied as a combination partner of gemcitabine and has consistently shown promising results in terms of efficacy and safety in a series of phase II studies 14-18.
At the time this study was proposed and designed, gemcitabine plus erlotinib combination chemotherapy was approved as front-line chemotherapy for unresectable PDAC and was widely used globally. However, since the benefit of gemcitabine plus erlotinib in survival prolongation was too small, there has been a continuing need for new drugs or combination regimens for patients with PDAC. In this background, combination therapy with gemcitabine, erlotinib, and S-1 (GTS regimen) has been proposed as a novel front-line treatment for unresectable PDAC, and this study was conducted to demonstrate the efficacy and safety of this regimen.
With two combination regimens of FOLFIRINOX (a combination of oxaliplatin, folinic acid, irinotecan, and fluorouracil [5-FU]) 19 and albumin-bound paclitaxel/gemcitabine 20 currently accepted as front-line treatments and actively used in fit patients, the clinician's interest and possible range of application for our combination regimen will be limited. However, since GTS combination therapy has never been investigated in PDAC, it would be valuable to report and share efficacy and safety data.
Methods
Patient eligibility
Patients were eligible for this study if they fulfilled all of the following criteria: (1) pathologically confirmed unresectable locally advanced, recurrent, or metastatic adenocarcinoma of the pancreas; (2) measurable disease, as defined using version 1.1 of the Response Evaluation Criteria In Solid Tumors (RECIST); (3) age ≥18 years; (4) Eastern Cooperative Oncology Group (ECOG) performance status of 0-1; (5) prior adjuvant chemotherapy without gemcitabine, erlotinib, or S-1 that had been completed >4 weeks before enrollment; (6) more than 4 weeks since completion of prior radiotherapy (measurable lesions are outside the radiation field); (7) adequate hematological, renal, and hepatic functions, as defined using an absolute neutrophil count of ≥1.5 × 109/L, a platelet count of ≥100 × 109/L, serum creatinine levels of ≤1.5 × upper limit of normal or creatinine clearance ≥50 mL/min, serum bilirubin ≤2× UNL, aspartate aminotransferase and alanine aminotransferase levels of ≤2.5×; and, (8) willingness to provide informed consent to participate in this study.
Patients were excluded based on the following criteria: (1) a history of treatment with gemcitabine, erlotinib, or S-1 as adjuvant chemotherapy; (2) contraindication for any drug contained in the chemotherapy regimen; (3) central nervous system metastasis; (4) serious GI bleeding or obvious bowel obstruction; (5) other previous or concurrent malignancies within the last 5 years, with the exception of cured basal cell carcinoma of the skin or carcinoma in situ of the uterine cervix; (6) pregnant or lactating female patients; (7) sexually active and the partner is unwilling to practice contraception during the study; and (8) other clinically significant comorbid conditions, such as an active infection or severe cardiopulmonary dysfunction.
Treatment and study design
The treatment consisted of intravenous administration of gemcitabine at 1,000 mg/m2 on days 1 and 8 every 3 weeks, continuously orally administered erlotinib at 100 mg/day, and orally administered S-1 at 30 mg/m2 twice daily on days 1-14 of each cycle. Patients with a body surface area of <1.25 m2 received 80 mg of S-1 daily, those with a body surface area of 1.25-1.5 m2 received 100 mg of S-1 daily, and those with a body surface area of ≥1.5 m2 received 120 mg of S-1 daily. Treatment was delivered as a 3-week cycle and repeated up to a maximum of 8 cycles of chemotherapy, or until disease progression, unacceptable toxicity, or the patient's refusal.
This trial was a prospective, single-arm phase II study evaluating combination chemotherapy with gemcitabine, erlotinib, and S-1 in previously untreated patients with unresectable locally advanced or metastatic pancreatic cancer. The primary endpoint was the confirmed objective response rate (ORR), and the secondary endpoints were median progression-free survival (PFS), median overall survival (OS), disease control rate (DCR), and toxicity profiles. The investigation was performed in accordance with the Declaration of Helsinki, and the protocol was approved by the institutional review boards of Hallym University Medical Center, Anyang-si, South Korea, and Asan Medical Center, Seoul, South Korea (protocol number: HMC-HO-GI-1201).
Dose modifications and dose intensity
Dose modifications were performed according to the study protocol. The next treatment cycle was initiated only when the neutrophil count was 1.5 × 109/L or greater and the platelet count was 100 × 109/L or greater. Treatment was delayed in the event of grade 3/4 nonhematologic toxicities until the toxicities were resolved to grade 1 or lower. The doses of gemcitabine and S-1 were reduced by 25% of the initial doses for related grade 3/4 neutropenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, or for the second occurrence of the same grade 2 neutropenia and thrombocytopenia. The doses of gemcitabine were reduced by 50% of the initial doses for grade 4 thrombocytopenia, or for the second occurrence of the grade 3/4 neutropenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, or for the third occurrence of grade 3 neutropenia and thrombocytopenia. In the case of the second occurrence of grade 2 thrombocytopenia, grade 3/4 neutropenia, grade 3 febrile neutropenia, or the third occurrence of grade 2 neutropenia, erlotinib was omitted until recovery and then re-challenged. Treatment was discontinued if, despite the dose reduction, the same toxicity occurred for a fourth time at grade 2, a third time at grade 3, or a second time at grade 4 or any occurrence of life-threatening sepsis during treatment. In addition, if the toxicity had not improved to grade 0 or 1 after 3 weeks, the patient was withdrawn from the study. The dose reduction was maintained in subsequent cycles.
To evaluate a function of the drug and the frequency of administration, we calculated the relative dose intensity (RDI), which is expressed as the ratio of the administered amount of dose per time unit (mg/m2/week) to that of the originally planned dose.
Toxicity and response evaluation
A physical examination with vital signs, complete blood cell counts with differentials, and blood chemistry tests were performed before every administration of gemcitabine in each subsequent cycle. Toxicity was evaluated and graded according to version 4.0 of the Common Terminology Criteria for Adverse Events of the National Cancer Institute. All of the patients who received at least one dose of treatment were included in the toxicity assessment. For the toxicity analysis, the data indicating the worst toxicity for each patient from all of the chemotherapy cycles were used. The proportion of patients who experienced adverse events was calculated by dividing the number of patients who experienced adverse events during the treatment period by the number of patients evaluable for safety analysis. Response to treatment according to RECIST version 1.1 was evaluated every 2 cycles. Patients with CR or PR required a confirmatory disease assessment at least 4 weeks later. PFS was defined as the interval from the date of treatment initiation to the first date of documented disease progression or death due to any cause. OS was defined as the interval from the date of treatment initiation to the date of death.
Statistical analysis
According to Simon's optimal two-stage design, 25 patients were required for enrollment to test the null hypothesis that the true ORR is 10% versus the alternative hypothesis that the true ORR is at least 30%, at a significance level of p<0.05 with a power of 80%. If two or more responses were observed among 15 patients in the first stage, the study was continued with 10 additional patients included. As the drop-out rate was assumed to be 10%, the number of patients necessary for recruitment into the study was calculated to be 28.
Descriptive statistics were used to summarize the patients' characteristics, tumor responses, and safety events. The Kaplan-Meier method was used to estimate the median PFS and OS. All enrolled patients were included in an intent-to-treat analysis.
Results
Patient characteristics
From October 2012 to May 2016, 37 patients who met the inclusion criteria were enrolled in this study. We exceeded the planned number of patients because several unexpected dropouts occurred early in the study and we allowed simultaneous registration of excess patients before the end of the study from multiple institutions. The reasons for dropout are explained below. The demographic and pathologic characteristics of the patients are described in Table 1. The median age was 61.5 years (range 35-88 years). Sixteen patients (43.2%) were male, and the majority of patients (73.0%) had an ECOG PS of 1. Twenty-six patients (70.3%) had metastatic disease, eight patients (21.6%) had recurrent pancreatic cancer after curative surgery, and three patients (8.1%) had locally advanced disease at the time of screening. The most common metastatic sites were distant lymph nodes (43.2%), the liver (43.2%), the lung (29.7%), and the peritoneum (27.0%).
Treatment administration
In total, 140 treatment cycles were administered to 37 patients, with a median of 3.8 cycles (range 1-10 cycles) per patient. Five patients did not complete the first cycle of chemotherapy: two patients died (one patient died of cerebral infarction and one patient died of hepatic tumor rupture), two patients withdrew their informed consent, and one patient was lost to follow-up. Seven patients (18.9%) completed eight or more cycles of chemotherapy. Eleven patients (29.7%) required dose reductions or delays. The mean relative dose intensities (ratio of the dose received to the dose planned) of gemcitabine, S-1 for all of the cycles administered were 0.87 [95% confidence interval (CI) 0.81-0.93], and 0.92 (95% CI 0.87-0.96), respectively (Table 2).
Efficacy
Of the 37 patients, 32 were eligible for response evaluation. Five patients were not available for response evaluation: the detailed reasons for 5 patients who did not complete the first cycle are described in the 'Treatment administration' section. The tumor responses are summarized in Table 3. There were 4 partial responses, 19 cases of stable disease, and 9 cases of disease progression. All partial responses are confirmed in the following CT scan. The confirmed ORR was 12.5% (95% CI 5.1-28.9%) and the disease control rate was 71.9% (95% CI 56.8-86.3%). The median time to response was 1.4 months (95% CI 1.3-1.5 months) and the median duration of response was 7.4 months (95% CI 3.8-11.0 months).
At the time of analysis, 13 patients (35.1%) were still alive with a median follow-up duration of 12.9 months (95% CI 9.6-16.3 months). The median PFS was 3.7 months (95% CI 2.8-4.6 months) and the median OS was 6.7 months (95% CI 3.4-9.9 months; Figures 1 & 2).
Toxicities
Safety was assessed in 36 patients on the basis of 139 cycles. One patient was lost to follow-up after receiving gemcitabine on day 1 of the first cycle, was excluded. One patient died suddenly of abdominal hemorrhage due to hepatic tumor rupture on day 3 of the first cycle. The adverse events are listed in Table 4. The most common grade 3/4 hematologic toxicity was neutropenia (25.0%). Febrile neutropenia developed in one patient (2.8%), who recovered without complications. Nonhematologic toxicities were usually mild and manageable. Grade 3 toxicities with a frequency of 5% or more included fatigue, infection, vomiting, and mucositis.
Discussion
In this study, the confirmed ORR of patients was 12.5%, which is slightly better than that of gemcitabine plus erlotinib 13 and is lower than the results of phase III studies of gemcitabine plus S-1 (GS) 21. The DCR was 71.9% (95% CI, 56.8-86.3%) and the median PFS and OS were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively. The GTS regimen showed an acceptable toxicity profile in the safety analysis. Since, at this point, FOLFIRINOX and albumin-bound paclitaxel/gemcitabine are actively used as standard treatments; the implications of this result are thought to be limited.
5-FU showed a marked synergistic cytotoxic effect with gemcitabine in pancreatic cancer cells in vitro 22 and S-1, which has an equivalent efficacy with a continuous 5-FU infusion in solid cancer, showed promising results in several phase II studies with an ORR of 28-48% 14-18. This study aimed to improve the efficacy of the existing treatment and to investigate a novel triple-combination regimen by adding S-1, which exhibits a synergistic effect with efficacy-proven gemcitabine plus erlotinib.
While this study was in progress, the results of a phase III study (GEST study) comparing GS with gemcitabine alone were published 21. In this trial, despite the improvement in PFS and ORR, GS showed numerically longer OS compared to gemcitabine alone, but it was not statistically significant (10.1 months vs. 8.8 months, p=0.15). In the subgroup analysis of GEST study, GS was associated with significantly improved OS in locally advanced disease compared to metastatic disease. Furthermore, a pooled analysis of subsequent randomized studies comparing GS to gemcitabine alone also re-confirmed that GS showed better OS in locally advanced disease than metastatic disease (16.4 months vs. 11.8 months, HR 0.708, p=0.02) and supported the result of the subgroup analysis from the GEST study. Since most of the participants in this study had recurrent or metastatic disease rather than locally advanced disease, it is assumed that the differences in characteristics of the study population may lead to unsatisfactory results. In our study, the best response of all three patients with locally advanced disease was stable disease but it is difficult to determine statistical significance because the number of patients was too small.
Recently, it was recommended that patients with locally advanced disease should be studied separately from those with metastatic disease because locally advanced and metastatic disease are considered to be two different clinical entities, each with distinctive clinical characteristics 23. Therefore, a study design with an appropriately selected population will be required to further clarify the efficacy of the GTS regimen.
In this study, the median age of the patients was >60 years, and 75% of the patients were symptomatic at the beginning of the study. More than half of the patients had two or more metastatic sites, and 45% and 13% of patients presented with liver metastasis and peritoneal metastasis, respectively. The patients' demographics in our study are relatively inferior to the conditions of other studies, and these differences may have influenced the outcome.
Regarding the safety analysis, GTS showed a modest toxicity profile. Except for neutropenia (25%) and fatigue (22%), the incidence of all other G3 or 4 toxicity profiles did not exceed 10%, which was similar or relatively lower than that of gemcitabine plus erlotinib 13 and GS 21.
Conclusion
In conclusion, GTS did not show the expected efficacy outcome with a confirmed ORR of 12.5%. However, considering the meaningful effect that GS showed in locally advanced disease in a subsequent study and the modest safety profile that our study showed, there may be room to further investigate the GTS regimen depending on the profile of the patient.
S-1 is sponsored by Jeil Pharmaceutical Co.,Ltd, Seoul, Korea.
Funding
This research was supported by the Hallym University Research Fund (Protocol No. HMC-HO-GI-1201).
Figure 1 Progression-free survival.
Figure 2 Overall survival.
Table 1 Patient characteristics (n=37)
Characteristics No. of patients (%)
Age, median (range) 61.5 (35-88)
Gender
Male 16 (43.2%)
Female 21 (56.8%)
Performance status (ECOG)
0 10 (27.0%)
1 27 (73.0%)
Location of primary tumor site
Head 9 (24.3%)
Body 7 (18.9%)
Tail 9 (24.3%)
Diffuse 4 (10.8%)
Unknown 8 (21.6%)
Histology
Well differentiated 5 (13.5%)
Moderately differentiated 9 (24.3%)
Poorly differentiated 4 (10.8%)
Undifferentiated 1 (2.7%)
Unknown 18 (48.6%)
Disease status at the time of screening
Locally advanced 3 (8.1%)
Metastatic 26 (70.3%)
Recurrence after curative surgery 8 (21.6%)
Metastatic sites
Lymph node 16 (43.2%)
Liver 16 (43.2%)
Lung 11 (29.7%)
Peritoneum 10 (27.0%)
Others 8 (21.6%)
No. of metastatic sites
1 14 (41.2%)
2 11 (32.4%)
≥3 9 (26.5%)
ECOG: Eastern Cooperative Oncology Group.
Table 2 Duration of drug administration and dose intensity
Criteria
No. of cycles 140
Median cycles 3.8 (1-8)
No. of patients with dose reduction 11
Relative dose intensity for gemcitabine, Mean (range) 0.87 (0.81-0.93)
Relative dose intensity for S-1, Mean (range) 0.92 (0.87-0.96)
Table 3 Treatment efficacy result
Response No. of patients
Complete response 0
Partial response 4
Stable disease 19
Progressive disease 9
Overall response rate (Confirmed) 12.5% (95% CI, 5.1-28.9%)
Disease control rate 71.9% (95% CI, 56.8-86.3%)
Table 4 Incidence of grade 3/4 adverse events
Grade 3/4 adverse events Number of patients (%) (Total N=36)
Hematologic
Neutropenia 9 (25%)
Febrile neutropenia 1 (2.8%)
Thrombocytopenia 1 (2.8%)
Non-hematologic
Fatigue 8 (22.2%)
Infection 3 (8.3%)
Vomiting 2 (5.6%)
Mucositis 2 (5.6%)
Nausea 1 (2.8%)
Diarrhea 1 (2.8%)
Hepatopathy 1 (2.8%)
Others 4 (11.1%) | 30 MG/M2, 2X/DAY, ON DAYS 1?14 OF EACH CYCLE | DrugDosageText | CC BY | 33403047 | 18,745,930 | 2021 |
What was the outcome of reaction 'Intra-abdominal haemorrhage'? | A phase II study of gemcitabine, erlotinib and S-1 in patients with advanced pancreatic cancer.
Background: We evaluated the efficacy and safety of gemcitabine in combination with erlotinib and S-1 for the treatment of advanced pancreatic cancer. Methods: Chemotherapy-naïve patients with pathologically-proven locally advanced, recurrent, or metastatic pancreatic adenocarcinoma were assessed for eligibility. Gemcitabine was administered at 1,000 mg/m2 intravenously on days 1 and 8, erlotinib was administered at 100 mg/day on days 1-21, and S-1 was administered at 60 mg/m2 on days 1-14 every 21 days and continued to a maximum of 8 cycles of treatment. Dose escalation of S-1 to 80 mg/m2 was permitted from the second cycle for pre-defined tolerable patients. Results: Thirty-seven patients (median age 61.5 years) were enrolled. A total of 140 cycles of chemotherapy were administered (median of 3.8; range 1-8 cycles). Toxicities were evaluated in 36 patients, and the responses were evaluated in 32 patients. Major grade 3/4 toxicities included neutropenia (25%), febrile neutropenia (2.8%), fatigue (22.2%), infection (8.3%), vomiting (5.6%), and mucositis (5.6%). The confirmed overall response rate was 12.5% [95% confidence interval (CI), 5.1-28.9%] and the disease control rate was 71.9% (95% CI, 56.8-86.3%). The median progression-free survival and overall survival were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively. Conclusion: The combination of gemcitabine, erlotinib, and S-1 provided an acceptable toxicity profile and modest clinical benefits in patients with advanced pancreatic cancer.
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is an intractable disease and is the 7th leading cause of global cancer deaths in industrialized countries 1. Because more than 80% of PDAC is locally advanced unresectable or metastatic at the time of diagnosis 2, the prognosis of PDAC patients is dismal with a 5-year relative survival rate of 11.4% 3. Although various types of targeted agents and immunotherapeutic agents are actively used in other cancers, cytotoxic chemotherapy remains the mainstream treatment for unresectable PDAC.
Following the approval of gemcitabine by the US Food and Drug Administration in 1997 4, gemcitabine-based chemotherapy was considered the standard of care for patients with advanced PDAC for a decade. In the era of gemcitabine, various attempts were made simultaneously to find an optimal drug combination that could function synergistically with gemcitabine. A number of drugs, including cytotoxic agents 5-10 and targeted agents 11, 12, in combination with gemcitabine, were tested in large randomized clinical trials, but they failed to improve the efficacy.
Among the various drugs investigated, erlotinib, a small-molecule inhibitor of epidermal growth factor receptor, improved the efficacy of gemcitabine in a randomized phase III trial 13. In this study, erlotinib in combination with gemcitabine showed a small but statistically significant improvement in overall survival when compared to gemcitabine monotherapy (6.2 months vs. 5.9 months, p=0.038). S-1, an oral fluoropyrimidine derivative, was also studied as a combination partner of gemcitabine and has consistently shown promising results in terms of efficacy and safety in a series of phase II studies 14-18.
At the time this study was proposed and designed, gemcitabine plus erlotinib combination chemotherapy was approved as front-line chemotherapy for unresectable PDAC and was widely used globally. However, since the benefit of gemcitabine plus erlotinib in survival prolongation was too small, there has been a continuing need for new drugs or combination regimens for patients with PDAC. In this background, combination therapy with gemcitabine, erlotinib, and S-1 (GTS regimen) has been proposed as a novel front-line treatment for unresectable PDAC, and this study was conducted to demonstrate the efficacy and safety of this regimen.
With two combination regimens of FOLFIRINOX (a combination of oxaliplatin, folinic acid, irinotecan, and fluorouracil [5-FU]) 19 and albumin-bound paclitaxel/gemcitabine 20 currently accepted as front-line treatments and actively used in fit patients, the clinician's interest and possible range of application for our combination regimen will be limited. However, since GTS combination therapy has never been investigated in PDAC, it would be valuable to report and share efficacy and safety data.
Methods
Patient eligibility
Patients were eligible for this study if they fulfilled all of the following criteria: (1) pathologically confirmed unresectable locally advanced, recurrent, or metastatic adenocarcinoma of the pancreas; (2) measurable disease, as defined using version 1.1 of the Response Evaluation Criteria In Solid Tumors (RECIST); (3) age ≥18 years; (4) Eastern Cooperative Oncology Group (ECOG) performance status of 0-1; (5) prior adjuvant chemotherapy without gemcitabine, erlotinib, or S-1 that had been completed >4 weeks before enrollment; (6) more than 4 weeks since completion of prior radiotherapy (measurable lesions are outside the radiation field); (7) adequate hematological, renal, and hepatic functions, as defined using an absolute neutrophil count of ≥1.5 × 109/L, a platelet count of ≥100 × 109/L, serum creatinine levels of ≤1.5 × upper limit of normal or creatinine clearance ≥50 mL/min, serum bilirubin ≤2× UNL, aspartate aminotransferase and alanine aminotransferase levels of ≤2.5×; and, (8) willingness to provide informed consent to participate in this study.
Patients were excluded based on the following criteria: (1) a history of treatment with gemcitabine, erlotinib, or S-1 as adjuvant chemotherapy; (2) contraindication for any drug contained in the chemotherapy regimen; (3) central nervous system metastasis; (4) serious GI bleeding or obvious bowel obstruction; (5) other previous or concurrent malignancies within the last 5 years, with the exception of cured basal cell carcinoma of the skin or carcinoma in situ of the uterine cervix; (6) pregnant or lactating female patients; (7) sexually active and the partner is unwilling to practice contraception during the study; and (8) other clinically significant comorbid conditions, such as an active infection or severe cardiopulmonary dysfunction.
Treatment and study design
The treatment consisted of intravenous administration of gemcitabine at 1,000 mg/m2 on days 1 and 8 every 3 weeks, continuously orally administered erlotinib at 100 mg/day, and orally administered S-1 at 30 mg/m2 twice daily on days 1-14 of each cycle. Patients with a body surface area of <1.25 m2 received 80 mg of S-1 daily, those with a body surface area of 1.25-1.5 m2 received 100 mg of S-1 daily, and those with a body surface area of ≥1.5 m2 received 120 mg of S-1 daily. Treatment was delivered as a 3-week cycle and repeated up to a maximum of 8 cycles of chemotherapy, or until disease progression, unacceptable toxicity, or the patient's refusal.
This trial was a prospective, single-arm phase II study evaluating combination chemotherapy with gemcitabine, erlotinib, and S-1 in previously untreated patients with unresectable locally advanced or metastatic pancreatic cancer. The primary endpoint was the confirmed objective response rate (ORR), and the secondary endpoints were median progression-free survival (PFS), median overall survival (OS), disease control rate (DCR), and toxicity profiles. The investigation was performed in accordance with the Declaration of Helsinki, and the protocol was approved by the institutional review boards of Hallym University Medical Center, Anyang-si, South Korea, and Asan Medical Center, Seoul, South Korea (protocol number: HMC-HO-GI-1201).
Dose modifications and dose intensity
Dose modifications were performed according to the study protocol. The next treatment cycle was initiated only when the neutrophil count was 1.5 × 109/L or greater and the platelet count was 100 × 109/L or greater. Treatment was delayed in the event of grade 3/4 nonhematologic toxicities until the toxicities were resolved to grade 1 or lower. The doses of gemcitabine and S-1 were reduced by 25% of the initial doses for related grade 3/4 neutropenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, or for the second occurrence of the same grade 2 neutropenia and thrombocytopenia. The doses of gemcitabine were reduced by 50% of the initial doses for grade 4 thrombocytopenia, or for the second occurrence of the grade 3/4 neutropenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, or for the third occurrence of grade 3 neutropenia and thrombocytopenia. In the case of the second occurrence of grade 2 thrombocytopenia, grade 3/4 neutropenia, grade 3 febrile neutropenia, or the third occurrence of grade 2 neutropenia, erlotinib was omitted until recovery and then re-challenged. Treatment was discontinued if, despite the dose reduction, the same toxicity occurred for a fourth time at grade 2, a third time at grade 3, or a second time at grade 4 or any occurrence of life-threatening sepsis during treatment. In addition, if the toxicity had not improved to grade 0 or 1 after 3 weeks, the patient was withdrawn from the study. The dose reduction was maintained in subsequent cycles.
To evaluate a function of the drug and the frequency of administration, we calculated the relative dose intensity (RDI), which is expressed as the ratio of the administered amount of dose per time unit (mg/m2/week) to that of the originally planned dose.
Toxicity and response evaluation
A physical examination with vital signs, complete blood cell counts with differentials, and blood chemistry tests were performed before every administration of gemcitabine in each subsequent cycle. Toxicity was evaluated and graded according to version 4.0 of the Common Terminology Criteria for Adverse Events of the National Cancer Institute. All of the patients who received at least one dose of treatment were included in the toxicity assessment. For the toxicity analysis, the data indicating the worst toxicity for each patient from all of the chemotherapy cycles were used. The proportion of patients who experienced adverse events was calculated by dividing the number of patients who experienced adverse events during the treatment period by the number of patients evaluable for safety analysis. Response to treatment according to RECIST version 1.1 was evaluated every 2 cycles. Patients with CR or PR required a confirmatory disease assessment at least 4 weeks later. PFS was defined as the interval from the date of treatment initiation to the first date of documented disease progression or death due to any cause. OS was defined as the interval from the date of treatment initiation to the date of death.
Statistical analysis
According to Simon's optimal two-stage design, 25 patients were required for enrollment to test the null hypothesis that the true ORR is 10% versus the alternative hypothesis that the true ORR is at least 30%, at a significance level of p<0.05 with a power of 80%. If two or more responses were observed among 15 patients in the first stage, the study was continued with 10 additional patients included. As the drop-out rate was assumed to be 10%, the number of patients necessary for recruitment into the study was calculated to be 28.
Descriptive statistics were used to summarize the patients' characteristics, tumor responses, and safety events. The Kaplan-Meier method was used to estimate the median PFS and OS. All enrolled patients were included in an intent-to-treat analysis.
Results
Patient characteristics
From October 2012 to May 2016, 37 patients who met the inclusion criteria were enrolled in this study. We exceeded the planned number of patients because several unexpected dropouts occurred early in the study and we allowed simultaneous registration of excess patients before the end of the study from multiple institutions. The reasons for dropout are explained below. The demographic and pathologic characteristics of the patients are described in Table 1. The median age was 61.5 years (range 35-88 years). Sixteen patients (43.2%) were male, and the majority of patients (73.0%) had an ECOG PS of 1. Twenty-six patients (70.3%) had metastatic disease, eight patients (21.6%) had recurrent pancreatic cancer after curative surgery, and three patients (8.1%) had locally advanced disease at the time of screening. The most common metastatic sites were distant lymph nodes (43.2%), the liver (43.2%), the lung (29.7%), and the peritoneum (27.0%).
Treatment administration
In total, 140 treatment cycles were administered to 37 patients, with a median of 3.8 cycles (range 1-10 cycles) per patient. Five patients did not complete the first cycle of chemotherapy: two patients died (one patient died of cerebral infarction and one patient died of hepatic tumor rupture), two patients withdrew their informed consent, and one patient was lost to follow-up. Seven patients (18.9%) completed eight or more cycles of chemotherapy. Eleven patients (29.7%) required dose reductions or delays. The mean relative dose intensities (ratio of the dose received to the dose planned) of gemcitabine, S-1 for all of the cycles administered were 0.87 [95% confidence interval (CI) 0.81-0.93], and 0.92 (95% CI 0.87-0.96), respectively (Table 2).
Efficacy
Of the 37 patients, 32 were eligible for response evaluation. Five patients were not available for response evaluation: the detailed reasons for 5 patients who did not complete the first cycle are described in the 'Treatment administration' section. The tumor responses are summarized in Table 3. There were 4 partial responses, 19 cases of stable disease, and 9 cases of disease progression. All partial responses are confirmed in the following CT scan. The confirmed ORR was 12.5% (95% CI 5.1-28.9%) and the disease control rate was 71.9% (95% CI 56.8-86.3%). The median time to response was 1.4 months (95% CI 1.3-1.5 months) and the median duration of response was 7.4 months (95% CI 3.8-11.0 months).
At the time of analysis, 13 patients (35.1%) were still alive with a median follow-up duration of 12.9 months (95% CI 9.6-16.3 months). The median PFS was 3.7 months (95% CI 2.8-4.6 months) and the median OS was 6.7 months (95% CI 3.4-9.9 months; Figures 1 & 2).
Toxicities
Safety was assessed in 36 patients on the basis of 139 cycles. One patient was lost to follow-up after receiving gemcitabine on day 1 of the first cycle, was excluded. One patient died suddenly of abdominal hemorrhage due to hepatic tumor rupture on day 3 of the first cycle. The adverse events are listed in Table 4. The most common grade 3/4 hematologic toxicity was neutropenia (25.0%). Febrile neutropenia developed in one patient (2.8%), who recovered without complications. Nonhematologic toxicities were usually mild and manageable. Grade 3 toxicities with a frequency of 5% or more included fatigue, infection, vomiting, and mucositis.
Discussion
In this study, the confirmed ORR of patients was 12.5%, which is slightly better than that of gemcitabine plus erlotinib 13 and is lower than the results of phase III studies of gemcitabine plus S-1 (GS) 21. The DCR was 71.9% (95% CI, 56.8-86.3%) and the median PFS and OS were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively. The GTS regimen showed an acceptable toxicity profile in the safety analysis. Since, at this point, FOLFIRINOX and albumin-bound paclitaxel/gemcitabine are actively used as standard treatments; the implications of this result are thought to be limited.
5-FU showed a marked synergistic cytotoxic effect with gemcitabine in pancreatic cancer cells in vitro 22 and S-1, which has an equivalent efficacy with a continuous 5-FU infusion in solid cancer, showed promising results in several phase II studies with an ORR of 28-48% 14-18. This study aimed to improve the efficacy of the existing treatment and to investigate a novel triple-combination regimen by adding S-1, which exhibits a synergistic effect with efficacy-proven gemcitabine plus erlotinib.
While this study was in progress, the results of a phase III study (GEST study) comparing GS with gemcitabine alone were published 21. In this trial, despite the improvement in PFS and ORR, GS showed numerically longer OS compared to gemcitabine alone, but it was not statistically significant (10.1 months vs. 8.8 months, p=0.15). In the subgroup analysis of GEST study, GS was associated with significantly improved OS in locally advanced disease compared to metastatic disease. Furthermore, a pooled analysis of subsequent randomized studies comparing GS to gemcitabine alone also re-confirmed that GS showed better OS in locally advanced disease than metastatic disease (16.4 months vs. 11.8 months, HR 0.708, p=0.02) and supported the result of the subgroup analysis from the GEST study. Since most of the participants in this study had recurrent or metastatic disease rather than locally advanced disease, it is assumed that the differences in characteristics of the study population may lead to unsatisfactory results. In our study, the best response of all three patients with locally advanced disease was stable disease but it is difficult to determine statistical significance because the number of patients was too small.
Recently, it was recommended that patients with locally advanced disease should be studied separately from those with metastatic disease because locally advanced and metastatic disease are considered to be two different clinical entities, each with distinctive clinical characteristics 23. Therefore, a study design with an appropriately selected population will be required to further clarify the efficacy of the GTS regimen.
In this study, the median age of the patients was >60 years, and 75% of the patients were symptomatic at the beginning of the study. More than half of the patients had two or more metastatic sites, and 45% and 13% of patients presented with liver metastasis and peritoneal metastasis, respectively. The patients' demographics in our study are relatively inferior to the conditions of other studies, and these differences may have influenced the outcome.
Regarding the safety analysis, GTS showed a modest toxicity profile. Except for neutropenia (25%) and fatigue (22%), the incidence of all other G3 or 4 toxicity profiles did not exceed 10%, which was similar or relatively lower than that of gemcitabine plus erlotinib 13 and GS 21.
Conclusion
In conclusion, GTS did not show the expected efficacy outcome with a confirmed ORR of 12.5%. However, considering the meaningful effect that GS showed in locally advanced disease in a subsequent study and the modest safety profile that our study showed, there may be room to further investigate the GTS regimen depending on the profile of the patient.
S-1 is sponsored by Jeil Pharmaceutical Co.,Ltd, Seoul, Korea.
Funding
This research was supported by the Hallym University Research Fund (Protocol No. HMC-HO-GI-1201).
Figure 1 Progression-free survival.
Figure 2 Overall survival.
Table 1 Patient characteristics (n=37)
Characteristics No. of patients (%)
Age, median (range) 61.5 (35-88)
Gender
Male 16 (43.2%)
Female 21 (56.8%)
Performance status (ECOG)
0 10 (27.0%)
1 27 (73.0%)
Location of primary tumor site
Head 9 (24.3%)
Body 7 (18.9%)
Tail 9 (24.3%)
Diffuse 4 (10.8%)
Unknown 8 (21.6%)
Histology
Well differentiated 5 (13.5%)
Moderately differentiated 9 (24.3%)
Poorly differentiated 4 (10.8%)
Undifferentiated 1 (2.7%)
Unknown 18 (48.6%)
Disease status at the time of screening
Locally advanced 3 (8.1%)
Metastatic 26 (70.3%)
Recurrence after curative surgery 8 (21.6%)
Metastatic sites
Lymph node 16 (43.2%)
Liver 16 (43.2%)
Lung 11 (29.7%)
Peritoneum 10 (27.0%)
Others 8 (21.6%)
No. of metastatic sites
1 14 (41.2%)
2 11 (32.4%)
≥3 9 (26.5%)
ECOG: Eastern Cooperative Oncology Group.
Table 2 Duration of drug administration and dose intensity
Criteria
No. of cycles 140
Median cycles 3.8 (1-8)
No. of patients with dose reduction 11
Relative dose intensity for gemcitabine, Mean (range) 0.87 (0.81-0.93)
Relative dose intensity for S-1, Mean (range) 0.92 (0.87-0.96)
Table 3 Treatment efficacy result
Response No. of patients
Complete response 0
Partial response 4
Stable disease 19
Progressive disease 9
Overall response rate (Confirmed) 12.5% (95% CI, 5.1-28.9%)
Disease control rate 71.9% (95% CI, 56.8-86.3%)
Table 4 Incidence of grade 3/4 adverse events
Grade 3/4 adverse events Number of patients (%) (Total N=36)
Hematologic
Neutropenia 9 (25%)
Febrile neutropenia 1 (2.8%)
Thrombocytopenia 1 (2.8%)
Non-hematologic
Fatigue 8 (22.2%)
Infection 3 (8.3%)
Vomiting 2 (5.6%)
Mucositis 2 (5.6%)
Nausea 1 (2.8%)
Diarrhea 1 (2.8%)
Hepatopathy 1 (2.8%)
Others 4 (11.1%) | Fatal | ReactionOutcome | CC BY | 33403047 | 18,745,930 | 2021 |
What was the outcome of reaction 'Tumour rupture'? | A phase II study of gemcitabine, erlotinib and S-1 in patients with advanced pancreatic cancer.
Background: We evaluated the efficacy and safety of gemcitabine in combination with erlotinib and S-1 for the treatment of advanced pancreatic cancer. Methods: Chemotherapy-naïve patients with pathologically-proven locally advanced, recurrent, or metastatic pancreatic adenocarcinoma were assessed for eligibility. Gemcitabine was administered at 1,000 mg/m2 intravenously on days 1 and 8, erlotinib was administered at 100 mg/day on days 1-21, and S-1 was administered at 60 mg/m2 on days 1-14 every 21 days and continued to a maximum of 8 cycles of treatment. Dose escalation of S-1 to 80 mg/m2 was permitted from the second cycle for pre-defined tolerable patients. Results: Thirty-seven patients (median age 61.5 years) were enrolled. A total of 140 cycles of chemotherapy were administered (median of 3.8; range 1-8 cycles). Toxicities were evaluated in 36 patients, and the responses were evaluated in 32 patients. Major grade 3/4 toxicities included neutropenia (25%), febrile neutropenia (2.8%), fatigue (22.2%), infection (8.3%), vomiting (5.6%), and mucositis (5.6%). The confirmed overall response rate was 12.5% [95% confidence interval (CI), 5.1-28.9%] and the disease control rate was 71.9% (95% CI, 56.8-86.3%). The median progression-free survival and overall survival were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively. Conclusion: The combination of gemcitabine, erlotinib, and S-1 provided an acceptable toxicity profile and modest clinical benefits in patients with advanced pancreatic cancer.
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is an intractable disease and is the 7th leading cause of global cancer deaths in industrialized countries 1. Because more than 80% of PDAC is locally advanced unresectable or metastatic at the time of diagnosis 2, the prognosis of PDAC patients is dismal with a 5-year relative survival rate of 11.4% 3. Although various types of targeted agents and immunotherapeutic agents are actively used in other cancers, cytotoxic chemotherapy remains the mainstream treatment for unresectable PDAC.
Following the approval of gemcitabine by the US Food and Drug Administration in 1997 4, gemcitabine-based chemotherapy was considered the standard of care for patients with advanced PDAC for a decade. In the era of gemcitabine, various attempts were made simultaneously to find an optimal drug combination that could function synergistically with gemcitabine. A number of drugs, including cytotoxic agents 5-10 and targeted agents 11, 12, in combination with gemcitabine, were tested in large randomized clinical trials, but they failed to improve the efficacy.
Among the various drugs investigated, erlotinib, a small-molecule inhibitor of epidermal growth factor receptor, improved the efficacy of gemcitabine in a randomized phase III trial 13. In this study, erlotinib in combination with gemcitabine showed a small but statistically significant improvement in overall survival when compared to gemcitabine monotherapy (6.2 months vs. 5.9 months, p=0.038). S-1, an oral fluoropyrimidine derivative, was also studied as a combination partner of gemcitabine and has consistently shown promising results in terms of efficacy and safety in a series of phase II studies 14-18.
At the time this study was proposed and designed, gemcitabine plus erlotinib combination chemotherapy was approved as front-line chemotherapy for unresectable PDAC and was widely used globally. However, since the benefit of gemcitabine plus erlotinib in survival prolongation was too small, there has been a continuing need for new drugs or combination regimens for patients with PDAC. In this background, combination therapy with gemcitabine, erlotinib, and S-1 (GTS regimen) has been proposed as a novel front-line treatment for unresectable PDAC, and this study was conducted to demonstrate the efficacy and safety of this regimen.
With two combination regimens of FOLFIRINOX (a combination of oxaliplatin, folinic acid, irinotecan, and fluorouracil [5-FU]) 19 and albumin-bound paclitaxel/gemcitabine 20 currently accepted as front-line treatments and actively used in fit patients, the clinician's interest and possible range of application for our combination regimen will be limited. However, since GTS combination therapy has never been investigated in PDAC, it would be valuable to report and share efficacy and safety data.
Methods
Patient eligibility
Patients were eligible for this study if they fulfilled all of the following criteria: (1) pathologically confirmed unresectable locally advanced, recurrent, or metastatic adenocarcinoma of the pancreas; (2) measurable disease, as defined using version 1.1 of the Response Evaluation Criteria In Solid Tumors (RECIST); (3) age ≥18 years; (4) Eastern Cooperative Oncology Group (ECOG) performance status of 0-1; (5) prior adjuvant chemotherapy without gemcitabine, erlotinib, or S-1 that had been completed >4 weeks before enrollment; (6) more than 4 weeks since completion of prior radiotherapy (measurable lesions are outside the radiation field); (7) adequate hematological, renal, and hepatic functions, as defined using an absolute neutrophil count of ≥1.5 × 109/L, a platelet count of ≥100 × 109/L, serum creatinine levels of ≤1.5 × upper limit of normal or creatinine clearance ≥50 mL/min, serum bilirubin ≤2× UNL, aspartate aminotransferase and alanine aminotransferase levels of ≤2.5×; and, (8) willingness to provide informed consent to participate in this study.
Patients were excluded based on the following criteria: (1) a history of treatment with gemcitabine, erlotinib, or S-1 as adjuvant chemotherapy; (2) contraindication for any drug contained in the chemotherapy regimen; (3) central nervous system metastasis; (4) serious GI bleeding or obvious bowel obstruction; (5) other previous or concurrent malignancies within the last 5 years, with the exception of cured basal cell carcinoma of the skin or carcinoma in situ of the uterine cervix; (6) pregnant or lactating female patients; (7) sexually active and the partner is unwilling to practice contraception during the study; and (8) other clinically significant comorbid conditions, such as an active infection or severe cardiopulmonary dysfunction.
Treatment and study design
The treatment consisted of intravenous administration of gemcitabine at 1,000 mg/m2 on days 1 and 8 every 3 weeks, continuously orally administered erlotinib at 100 mg/day, and orally administered S-1 at 30 mg/m2 twice daily on days 1-14 of each cycle. Patients with a body surface area of <1.25 m2 received 80 mg of S-1 daily, those with a body surface area of 1.25-1.5 m2 received 100 mg of S-1 daily, and those with a body surface area of ≥1.5 m2 received 120 mg of S-1 daily. Treatment was delivered as a 3-week cycle and repeated up to a maximum of 8 cycles of chemotherapy, or until disease progression, unacceptable toxicity, or the patient's refusal.
This trial was a prospective, single-arm phase II study evaluating combination chemotherapy with gemcitabine, erlotinib, and S-1 in previously untreated patients with unresectable locally advanced or metastatic pancreatic cancer. The primary endpoint was the confirmed objective response rate (ORR), and the secondary endpoints were median progression-free survival (PFS), median overall survival (OS), disease control rate (DCR), and toxicity profiles. The investigation was performed in accordance with the Declaration of Helsinki, and the protocol was approved by the institutional review boards of Hallym University Medical Center, Anyang-si, South Korea, and Asan Medical Center, Seoul, South Korea (protocol number: HMC-HO-GI-1201).
Dose modifications and dose intensity
Dose modifications were performed according to the study protocol. The next treatment cycle was initiated only when the neutrophil count was 1.5 × 109/L or greater and the platelet count was 100 × 109/L or greater. Treatment was delayed in the event of grade 3/4 nonhematologic toxicities until the toxicities were resolved to grade 1 or lower. The doses of gemcitabine and S-1 were reduced by 25% of the initial doses for related grade 3/4 neutropenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, or for the second occurrence of the same grade 2 neutropenia and thrombocytopenia. The doses of gemcitabine were reduced by 50% of the initial doses for grade 4 thrombocytopenia, or for the second occurrence of the grade 3/4 neutropenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, or for the third occurrence of grade 3 neutropenia and thrombocytopenia. In the case of the second occurrence of grade 2 thrombocytopenia, grade 3/4 neutropenia, grade 3 febrile neutropenia, or the third occurrence of grade 2 neutropenia, erlotinib was omitted until recovery and then re-challenged. Treatment was discontinued if, despite the dose reduction, the same toxicity occurred for a fourth time at grade 2, a third time at grade 3, or a second time at grade 4 or any occurrence of life-threatening sepsis during treatment. In addition, if the toxicity had not improved to grade 0 or 1 after 3 weeks, the patient was withdrawn from the study. The dose reduction was maintained in subsequent cycles.
To evaluate a function of the drug and the frequency of administration, we calculated the relative dose intensity (RDI), which is expressed as the ratio of the administered amount of dose per time unit (mg/m2/week) to that of the originally planned dose.
Toxicity and response evaluation
A physical examination with vital signs, complete blood cell counts with differentials, and blood chemistry tests were performed before every administration of gemcitabine in each subsequent cycle. Toxicity was evaluated and graded according to version 4.0 of the Common Terminology Criteria for Adverse Events of the National Cancer Institute. All of the patients who received at least one dose of treatment were included in the toxicity assessment. For the toxicity analysis, the data indicating the worst toxicity for each patient from all of the chemotherapy cycles were used. The proportion of patients who experienced adverse events was calculated by dividing the number of patients who experienced adverse events during the treatment period by the number of patients evaluable for safety analysis. Response to treatment according to RECIST version 1.1 was evaluated every 2 cycles. Patients with CR or PR required a confirmatory disease assessment at least 4 weeks later. PFS was defined as the interval from the date of treatment initiation to the first date of documented disease progression or death due to any cause. OS was defined as the interval from the date of treatment initiation to the date of death.
Statistical analysis
According to Simon's optimal two-stage design, 25 patients were required for enrollment to test the null hypothesis that the true ORR is 10% versus the alternative hypothesis that the true ORR is at least 30%, at a significance level of p<0.05 with a power of 80%. If two or more responses were observed among 15 patients in the first stage, the study was continued with 10 additional patients included. As the drop-out rate was assumed to be 10%, the number of patients necessary for recruitment into the study was calculated to be 28.
Descriptive statistics were used to summarize the patients' characteristics, tumor responses, and safety events. The Kaplan-Meier method was used to estimate the median PFS and OS. All enrolled patients were included in an intent-to-treat analysis.
Results
Patient characteristics
From October 2012 to May 2016, 37 patients who met the inclusion criteria were enrolled in this study. We exceeded the planned number of patients because several unexpected dropouts occurred early in the study and we allowed simultaneous registration of excess patients before the end of the study from multiple institutions. The reasons for dropout are explained below. The demographic and pathologic characteristics of the patients are described in Table 1. The median age was 61.5 years (range 35-88 years). Sixteen patients (43.2%) were male, and the majority of patients (73.0%) had an ECOG PS of 1. Twenty-six patients (70.3%) had metastatic disease, eight patients (21.6%) had recurrent pancreatic cancer after curative surgery, and three patients (8.1%) had locally advanced disease at the time of screening. The most common metastatic sites were distant lymph nodes (43.2%), the liver (43.2%), the lung (29.7%), and the peritoneum (27.0%).
Treatment administration
In total, 140 treatment cycles were administered to 37 patients, with a median of 3.8 cycles (range 1-10 cycles) per patient. Five patients did not complete the first cycle of chemotherapy: two patients died (one patient died of cerebral infarction and one patient died of hepatic tumor rupture), two patients withdrew their informed consent, and one patient was lost to follow-up. Seven patients (18.9%) completed eight or more cycles of chemotherapy. Eleven patients (29.7%) required dose reductions or delays. The mean relative dose intensities (ratio of the dose received to the dose planned) of gemcitabine, S-1 for all of the cycles administered were 0.87 [95% confidence interval (CI) 0.81-0.93], and 0.92 (95% CI 0.87-0.96), respectively (Table 2).
Efficacy
Of the 37 patients, 32 were eligible for response evaluation. Five patients were not available for response evaluation: the detailed reasons for 5 patients who did not complete the first cycle are described in the 'Treatment administration' section. The tumor responses are summarized in Table 3. There were 4 partial responses, 19 cases of stable disease, and 9 cases of disease progression. All partial responses are confirmed in the following CT scan. The confirmed ORR was 12.5% (95% CI 5.1-28.9%) and the disease control rate was 71.9% (95% CI 56.8-86.3%). The median time to response was 1.4 months (95% CI 1.3-1.5 months) and the median duration of response was 7.4 months (95% CI 3.8-11.0 months).
At the time of analysis, 13 patients (35.1%) were still alive with a median follow-up duration of 12.9 months (95% CI 9.6-16.3 months). The median PFS was 3.7 months (95% CI 2.8-4.6 months) and the median OS was 6.7 months (95% CI 3.4-9.9 months; Figures 1 & 2).
Toxicities
Safety was assessed in 36 patients on the basis of 139 cycles. One patient was lost to follow-up after receiving gemcitabine on day 1 of the first cycle, was excluded. One patient died suddenly of abdominal hemorrhage due to hepatic tumor rupture on day 3 of the first cycle. The adverse events are listed in Table 4. The most common grade 3/4 hematologic toxicity was neutropenia (25.0%). Febrile neutropenia developed in one patient (2.8%), who recovered without complications. Nonhematologic toxicities were usually mild and manageable. Grade 3 toxicities with a frequency of 5% or more included fatigue, infection, vomiting, and mucositis.
Discussion
In this study, the confirmed ORR of patients was 12.5%, which is slightly better than that of gemcitabine plus erlotinib 13 and is lower than the results of phase III studies of gemcitabine plus S-1 (GS) 21. The DCR was 71.9% (95% CI, 56.8-86.3%) and the median PFS and OS were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively. The GTS regimen showed an acceptable toxicity profile in the safety analysis. Since, at this point, FOLFIRINOX and albumin-bound paclitaxel/gemcitabine are actively used as standard treatments; the implications of this result are thought to be limited.
5-FU showed a marked synergistic cytotoxic effect with gemcitabine in pancreatic cancer cells in vitro 22 and S-1, which has an equivalent efficacy with a continuous 5-FU infusion in solid cancer, showed promising results in several phase II studies with an ORR of 28-48% 14-18. This study aimed to improve the efficacy of the existing treatment and to investigate a novel triple-combination regimen by adding S-1, which exhibits a synergistic effect with efficacy-proven gemcitabine plus erlotinib.
While this study was in progress, the results of a phase III study (GEST study) comparing GS with gemcitabine alone were published 21. In this trial, despite the improvement in PFS and ORR, GS showed numerically longer OS compared to gemcitabine alone, but it was not statistically significant (10.1 months vs. 8.8 months, p=0.15). In the subgroup analysis of GEST study, GS was associated with significantly improved OS in locally advanced disease compared to metastatic disease. Furthermore, a pooled analysis of subsequent randomized studies comparing GS to gemcitabine alone also re-confirmed that GS showed better OS in locally advanced disease than metastatic disease (16.4 months vs. 11.8 months, HR 0.708, p=0.02) and supported the result of the subgroup analysis from the GEST study. Since most of the participants in this study had recurrent or metastatic disease rather than locally advanced disease, it is assumed that the differences in characteristics of the study population may lead to unsatisfactory results. In our study, the best response of all three patients with locally advanced disease was stable disease but it is difficult to determine statistical significance because the number of patients was too small.
Recently, it was recommended that patients with locally advanced disease should be studied separately from those with metastatic disease because locally advanced and metastatic disease are considered to be two different clinical entities, each with distinctive clinical characteristics 23. Therefore, a study design with an appropriately selected population will be required to further clarify the efficacy of the GTS regimen.
In this study, the median age of the patients was >60 years, and 75% of the patients were symptomatic at the beginning of the study. More than half of the patients had two or more metastatic sites, and 45% and 13% of patients presented with liver metastasis and peritoneal metastasis, respectively. The patients' demographics in our study are relatively inferior to the conditions of other studies, and these differences may have influenced the outcome.
Regarding the safety analysis, GTS showed a modest toxicity profile. Except for neutropenia (25%) and fatigue (22%), the incidence of all other G3 or 4 toxicity profiles did not exceed 10%, which was similar or relatively lower than that of gemcitabine plus erlotinib 13 and GS 21.
Conclusion
In conclusion, GTS did not show the expected efficacy outcome with a confirmed ORR of 12.5%. However, considering the meaningful effect that GS showed in locally advanced disease in a subsequent study and the modest safety profile that our study showed, there may be room to further investigate the GTS regimen depending on the profile of the patient.
S-1 is sponsored by Jeil Pharmaceutical Co.,Ltd, Seoul, Korea.
Funding
This research was supported by the Hallym University Research Fund (Protocol No. HMC-HO-GI-1201).
Figure 1 Progression-free survival.
Figure 2 Overall survival.
Table 1 Patient characteristics (n=37)
Characteristics No. of patients (%)
Age, median (range) 61.5 (35-88)
Gender
Male 16 (43.2%)
Female 21 (56.8%)
Performance status (ECOG)
0 10 (27.0%)
1 27 (73.0%)
Location of primary tumor site
Head 9 (24.3%)
Body 7 (18.9%)
Tail 9 (24.3%)
Diffuse 4 (10.8%)
Unknown 8 (21.6%)
Histology
Well differentiated 5 (13.5%)
Moderately differentiated 9 (24.3%)
Poorly differentiated 4 (10.8%)
Undifferentiated 1 (2.7%)
Unknown 18 (48.6%)
Disease status at the time of screening
Locally advanced 3 (8.1%)
Metastatic 26 (70.3%)
Recurrence after curative surgery 8 (21.6%)
Metastatic sites
Lymph node 16 (43.2%)
Liver 16 (43.2%)
Lung 11 (29.7%)
Peritoneum 10 (27.0%)
Others 8 (21.6%)
No. of metastatic sites
1 14 (41.2%)
2 11 (32.4%)
≥3 9 (26.5%)
ECOG: Eastern Cooperative Oncology Group.
Table 2 Duration of drug administration and dose intensity
Criteria
No. of cycles 140
Median cycles 3.8 (1-8)
No. of patients with dose reduction 11
Relative dose intensity for gemcitabine, Mean (range) 0.87 (0.81-0.93)
Relative dose intensity for S-1, Mean (range) 0.92 (0.87-0.96)
Table 3 Treatment efficacy result
Response No. of patients
Complete response 0
Partial response 4
Stable disease 19
Progressive disease 9
Overall response rate (Confirmed) 12.5% (95% CI, 5.1-28.9%)
Disease control rate 71.9% (95% CI, 56.8-86.3%)
Table 4 Incidence of grade 3/4 adverse events
Grade 3/4 adverse events Number of patients (%) (Total N=36)
Hematologic
Neutropenia 9 (25%)
Febrile neutropenia 1 (2.8%)
Thrombocytopenia 1 (2.8%)
Non-hematologic
Fatigue 8 (22.2%)
Infection 3 (8.3%)
Vomiting 2 (5.6%)
Mucositis 2 (5.6%)
Nausea 1 (2.8%)
Diarrhea 1 (2.8%)
Hepatopathy 1 (2.8%)
Others 4 (11.1%) | Fatal | ReactionOutcome | CC BY | 33403047 | 18,745,930 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Axonal neuropathy'. | Iatrogenic Kaposi's sarcoma in myasthenia gravis: learnings from two case reports.
BACKGROUND
Myasthenia gravis (MG) is an autoimmune neuromuscular disease whose treatment encompasses acetylcholinesterase inhibitors, oral steroids, and other immunosuppressants. Kaposi's sarcoma (KS) is a lymphangioproliferative disease associated with human herpesvirus 8 (HHV-8) infection and immunodeficiency or immunosuppression, mainly corticosteroids.
METHODS
We present two cases of MG patients treated with oral steroids who developed KS. Patient 1 was diagnosed with three oral KS lesions. Prednisone was discontinued with lesion regression and stabilization, while azathioprine and pyridostigmine prompted control of MG. Patient 2 developed KS lesions on the trunk and lower limbs while taking prednisone and azathioprine. Steroid tapering was started but new oral and lymph nodal lesions appeared. Paclitaxel therapy was introduced and the patient experienced pulmonary embolism and developed sensitive neuropathy. Complete remission of KS lesions was achieved and maintained with azathioprine and pyridostigmine as MG medications.
CONCLUSIONS
KS is an uncommon but clinically relevant adverse event (AE) often induced by steroid therapy. It can be controlled by steroid withdrawal but could necessitate chemotherapy, which associates with further potential AEs. Skin evaluation should be performed in all patients with chronic steroid therapy. Steroid-sparing strategies, including new drugs, could reduce KS and other steroid-related comorbidities. HHV-8 testing should be considered before starting chronic immunosuppression.
Background
Myasthenia gravis (MG) is an autoimmune disease mostly associated with anti-acetylcholine receptor (AChR) antibodies. The clinical hallmark is weakness worsened by exercise. Therapy encompasses acetylcholinesterase inhibitors, oral steroids, and other immunosuppressants [1]. Kaposi’s sarcoma (KS) is a lymphangioproliferative disease associated with human herpesvirus 8 (HHV-8) infection and immunodeficiency or pharmacological immunosuppression, mainly corticosteroids [2]. Here, we describe two patients with MG who developed iatrogenic-KS (iKS). Both patients provided written informed consent.
Case report
Patient 1 is a male diagnosed with anti-AChR-positive generalized MG (gMG) without thymus involvement, at 83 years of age (March 2015). As pyridostigmine provided partial improvement, prednisone 50 mg/day was initiated 6 months after diagnosis, with benefit. Body weight was 80 kg, corresponding to a 0.63 mg/kg/day dose of prednisone. Steroid-induced diabetes developed; hence, azathioprine was initiated, and prednisone tapered to 5 mg/day (May 2016), corresponding to a 0.06 mg/kg/day dose of prednisone. Body weight remained stable and steroid therapy maintained at this dosage. In September 2017, the patient was referred to a dermatologist to assess a small violaceous and two bluish macules on the tongue and hard palate (Fig. 1a). Biopsy analyses revealed typical KS features. Serology tested negative for HIV and positive for HHV-8. Staging examinations for KS, including fecal occult blood test, esophagogastroduodenoscopy, abdomen ultrasound, and otolaryngologic examination were negative [3]. iKS diagnosis was made and steroid was discontinued. Follow-up at 3, 6, and 12 months confirmed the presence of the small nodule on the tongue, while the two macules had completely regressed. To date, the nodule remains stable and MG is controlled with pyridostigmine and azathioprine 100 mg/day.Fig. 1 Clinical images showing Kaposi’s sarcoma lesions. a One nodule and two macules (arrows) on the tongue in Patient 1; b angiomatous nodules, plaques, and edema on the lower limbs in Patient 2; voluminous tumor on the hard palate in Patient 2 c before and d after steroid interruption and paclitaxel chemotherapy. e Hematoxylin-eosin stain of a biopsy specimen from Patient 2 showed proliferation of spindle cells and numerous extravasated erythrocytes between dermal collagen bundles. f The spindle cells stained positively with HHV-8 latency-associated nuclear antigen (LNA)-1
Patient 2 is a male diagnosed with anti-AChR-positive gMG at the age of 60 (October 2015), without thymus involvement. Pyridostigmine 60 mg four times daily (QID) and prednisone 65 mg/day were started. Body weight was 108 kg, corresponding to a 0.60 mg/kg/day dose of prednisone. In December 2015, azathioprine 150 mg/day was introduced and, due to limited efficacy, plasmapheresis was often used. Body weight was 100 kg, and prednisone 62.5 mg/day (0.63 mg/kg/day). In October 2016, the patient was referred to the dermatology department for numerous violaceous macules, plaques, and nodules on the lower limbs and reddish-purple plaques on the trunk. Bilateral ankle lymphoedema was present (Fig. 1b). A biopsy confirmed the diagnosis of KS, with serology positive for HHV-8 and negative for HIV. Staging examinations for KS were negative [3]. Whole blood count and biochemistry were normal. Patient body weight was 94 kg. MG therapy was prednisone 50 mg/day (0.53 mg/kg/day), azathioprine 150 mg/day, and pyridostigmine 90 mg QID. Upon iKS diagnosis, over the next 3 months, prednisone was tapered to 30 mg/day (0.32 mg/kg/day) and azathioprine was increased to 175 mg/day. Nevertheless, new KS lesions developed on the hard palate (Fig. 1c) and in left inguinal lymph nodes. Further lesions appeared on lower limbs and external ear during prednisone tapering to 5 mg/day. Thus, the patient stopped prednisone and started intravenous paclitaxel 100 mg/m2 weekly for 13 administrations with regression of all KS lesions (Fig. 1d). Five days after paclitaxel initiation, pulmonary embolism was detected and treated with enoxaparin with complete resolution. Moreover, the patient developed paclitaxel-induced axonal sensitive neuropathy. Three years after treatment, KS was still in remission, and MG symptoms were stable with azathioprine 200 mg/day plus pyridostigmine 60 mg QID.
Discussion
Presented cases show the uncommon but clinically relevant adverse event of iKS, often induced by chronic steroid treatment. Notably, iKS generally occurs within the first 2 years of steroid treatment and about 8% of patients with iKS unrelated to organ transplants had MG [2]. iKS can be effectively controlled by steroid withdrawal (Patient 1). Additional chemotherapy is sometimes necessary, possibly causing additional severe comorbidities such as polyneuropathy and pulmonary embolism (Patient 2).
Oral corticosteroids are a cornerstone treatment in MG, though associated with relevant adverse events including iKS, interestingly even at low doses [2, 4, 5]. Notably, our patients received a maximum prednisone dose of 0.63 mg/kg/day. These doses are conformant to national recommendations of 0.75–1 mg/kg/day for initial gMG treatment, and even lower [6]. Patient 1 developed iKS when he was assuming 0.06 mg/kg/day of prednisone dose while being clinically stable for more than a year. Patient 2 developed iKS when he was slowly tapering prednisone (0.53 mg/kg/day) after the initial dose while being not clinically stable and often needing plasmaphereses.
iKS onset associates with immune-suppression through a direct effect on lymphangioendothelial cells, by downregulating the inhibition of endothelial cell growth [2]. It would be advisable to check for any suspicious skin or mucosal lesions, which are the most frequent localizations of iKS [2], in all patients on chronic corticosteroids. Moreover, considering the high seroprevalence of HHV-8 in regions such as the Mediterranean area (ranging 40 to 80%), it would be also advisable to test for HHV-8 to identify high-risk patients in which to possibly avoid corticosteroid treatment and to perform regular dermatologic assessments [7].
Reduction of iKS and other frequent steroid-related comorbidities might be achieved using new drugs, such as neonatal Fc receptor or complement inhibitors, which do not associate with reduced cellular immunity. As HHV-8 exploits the complement system to promote latent infection, targeting complement could be a useful therapeutic strategy but must be carefully investigated [8].
Awareness of iKS as a consequence of chronic corticosteroid treatment should be fostered and screening for HHV-8 considered before starting chronic immunosuppression.
Authors’ contributions
R.F. and R.G. equally contributed to paper conception, data acquisition and interpretation, and paper drafting. F.V. and A.T. contributed to data acquisition and interpretation, and paper drafting. L.B. contributed to data acquisition. L.M. and R.M. contributed to data acquisition and interpretation and revised the paper.
Compliance with ethical standards
Conflicts of interest
R.F. received support for congress participations from Argenx, Biogen, Catalyst, Merck, Momenta, Novartis, and Sanofi Genzyme. R.G. received support for congress participation from Mylan. F.V. received support for congress participations from Biogen, Kedrion, and Sanofi Genzyme. A.T. reports no competing interest. L.B. reports no competing interest. L.M. received honoraria for speaking and compensation for congress participations from Biogen and Sanofi Genzyme. R.M. received fees and honoraria for meeting, travel, and advisory board from Alexion, Argenx, Biomarin, Catalyst, Merck Serono, UCB.
Ethics approval
The Ethics Committee of Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta requires the patient consent for case reports publication.
Consent for publication
Written informed consent for publication was received by the patients for the usage of anonymized clinical data and images.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rita Frangiamore and Riccardo Giossi contributed equally to this work. | AZATHIOPRINE, PACLITAXEL, PREDNISONE, PYRIDOSTIGMINE | DrugsGivenReaction | CC BY | 33404862 | 18,876,256 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diabetes mellitus'. | Iatrogenic Kaposi's sarcoma in myasthenia gravis: learnings from two case reports.
BACKGROUND
Myasthenia gravis (MG) is an autoimmune neuromuscular disease whose treatment encompasses acetylcholinesterase inhibitors, oral steroids, and other immunosuppressants. Kaposi's sarcoma (KS) is a lymphangioproliferative disease associated with human herpesvirus 8 (HHV-8) infection and immunodeficiency or immunosuppression, mainly corticosteroids.
METHODS
We present two cases of MG patients treated with oral steroids who developed KS. Patient 1 was diagnosed with three oral KS lesions. Prednisone was discontinued with lesion regression and stabilization, while azathioprine and pyridostigmine prompted control of MG. Patient 2 developed KS lesions on the trunk and lower limbs while taking prednisone and azathioprine. Steroid tapering was started but new oral and lymph nodal lesions appeared. Paclitaxel therapy was introduced and the patient experienced pulmonary embolism and developed sensitive neuropathy. Complete remission of KS lesions was achieved and maintained with azathioprine and pyridostigmine as MG medications.
CONCLUSIONS
KS is an uncommon but clinically relevant adverse event (AE) often induced by steroid therapy. It can be controlled by steroid withdrawal but could necessitate chemotherapy, which associates with further potential AEs. Skin evaluation should be performed in all patients with chronic steroid therapy. Steroid-sparing strategies, including new drugs, could reduce KS and other steroid-related comorbidities. HHV-8 testing should be considered before starting chronic immunosuppression.
Background
Myasthenia gravis (MG) is an autoimmune disease mostly associated with anti-acetylcholine receptor (AChR) antibodies. The clinical hallmark is weakness worsened by exercise. Therapy encompasses acetylcholinesterase inhibitors, oral steroids, and other immunosuppressants [1]. Kaposi’s sarcoma (KS) is a lymphangioproliferative disease associated with human herpesvirus 8 (HHV-8) infection and immunodeficiency or pharmacological immunosuppression, mainly corticosteroids [2]. Here, we describe two patients with MG who developed iatrogenic-KS (iKS). Both patients provided written informed consent.
Case report
Patient 1 is a male diagnosed with anti-AChR-positive generalized MG (gMG) without thymus involvement, at 83 years of age (March 2015). As pyridostigmine provided partial improvement, prednisone 50 mg/day was initiated 6 months after diagnosis, with benefit. Body weight was 80 kg, corresponding to a 0.63 mg/kg/day dose of prednisone. Steroid-induced diabetes developed; hence, azathioprine was initiated, and prednisone tapered to 5 mg/day (May 2016), corresponding to a 0.06 mg/kg/day dose of prednisone. Body weight remained stable and steroid therapy maintained at this dosage. In September 2017, the patient was referred to a dermatologist to assess a small violaceous and two bluish macules on the tongue and hard palate (Fig. 1a). Biopsy analyses revealed typical KS features. Serology tested negative for HIV and positive for HHV-8. Staging examinations for KS, including fecal occult blood test, esophagogastroduodenoscopy, abdomen ultrasound, and otolaryngologic examination were negative [3]. iKS diagnosis was made and steroid was discontinued. Follow-up at 3, 6, and 12 months confirmed the presence of the small nodule on the tongue, while the two macules had completely regressed. To date, the nodule remains stable and MG is controlled with pyridostigmine and azathioprine 100 mg/day.Fig. 1 Clinical images showing Kaposi’s sarcoma lesions. a One nodule and two macules (arrows) on the tongue in Patient 1; b angiomatous nodules, plaques, and edema on the lower limbs in Patient 2; voluminous tumor on the hard palate in Patient 2 c before and d after steroid interruption and paclitaxel chemotherapy. e Hematoxylin-eosin stain of a biopsy specimen from Patient 2 showed proliferation of spindle cells and numerous extravasated erythrocytes between dermal collagen bundles. f The spindle cells stained positively with HHV-8 latency-associated nuclear antigen (LNA)-1
Patient 2 is a male diagnosed with anti-AChR-positive gMG at the age of 60 (October 2015), without thymus involvement. Pyridostigmine 60 mg four times daily (QID) and prednisone 65 mg/day were started. Body weight was 108 kg, corresponding to a 0.60 mg/kg/day dose of prednisone. In December 2015, azathioprine 150 mg/day was introduced and, due to limited efficacy, plasmapheresis was often used. Body weight was 100 kg, and prednisone 62.5 mg/day (0.63 mg/kg/day). In October 2016, the patient was referred to the dermatology department for numerous violaceous macules, plaques, and nodules on the lower limbs and reddish-purple plaques on the trunk. Bilateral ankle lymphoedema was present (Fig. 1b). A biopsy confirmed the diagnosis of KS, with serology positive for HHV-8 and negative for HIV. Staging examinations for KS were negative [3]. Whole blood count and biochemistry were normal. Patient body weight was 94 kg. MG therapy was prednisone 50 mg/day (0.53 mg/kg/day), azathioprine 150 mg/day, and pyridostigmine 90 mg QID. Upon iKS diagnosis, over the next 3 months, prednisone was tapered to 30 mg/day (0.32 mg/kg/day) and azathioprine was increased to 175 mg/day. Nevertheless, new KS lesions developed on the hard palate (Fig. 1c) and in left inguinal lymph nodes. Further lesions appeared on lower limbs and external ear during prednisone tapering to 5 mg/day. Thus, the patient stopped prednisone and started intravenous paclitaxel 100 mg/m2 weekly for 13 administrations with regression of all KS lesions (Fig. 1d). Five days after paclitaxel initiation, pulmonary embolism was detected and treated with enoxaparin with complete resolution. Moreover, the patient developed paclitaxel-induced axonal sensitive neuropathy. Three years after treatment, KS was still in remission, and MG symptoms were stable with azathioprine 200 mg/day plus pyridostigmine 60 mg QID.
Discussion
Presented cases show the uncommon but clinically relevant adverse event of iKS, often induced by chronic steroid treatment. Notably, iKS generally occurs within the first 2 years of steroid treatment and about 8% of patients with iKS unrelated to organ transplants had MG [2]. iKS can be effectively controlled by steroid withdrawal (Patient 1). Additional chemotherapy is sometimes necessary, possibly causing additional severe comorbidities such as polyneuropathy and pulmonary embolism (Patient 2).
Oral corticosteroids are a cornerstone treatment in MG, though associated with relevant adverse events including iKS, interestingly even at low doses [2, 4, 5]. Notably, our patients received a maximum prednisone dose of 0.63 mg/kg/day. These doses are conformant to national recommendations of 0.75–1 mg/kg/day for initial gMG treatment, and even lower [6]. Patient 1 developed iKS when he was assuming 0.06 mg/kg/day of prednisone dose while being clinically stable for more than a year. Patient 2 developed iKS when he was slowly tapering prednisone (0.53 mg/kg/day) after the initial dose while being not clinically stable and often needing plasmaphereses.
iKS onset associates with immune-suppression through a direct effect on lymphangioendothelial cells, by downregulating the inhibition of endothelial cell growth [2]. It would be advisable to check for any suspicious skin or mucosal lesions, which are the most frequent localizations of iKS [2], in all patients on chronic corticosteroids. Moreover, considering the high seroprevalence of HHV-8 in regions such as the Mediterranean area (ranging 40 to 80%), it would be also advisable to test for HHV-8 to identify high-risk patients in which to possibly avoid corticosteroid treatment and to perform regular dermatologic assessments [7].
Reduction of iKS and other frequent steroid-related comorbidities might be achieved using new drugs, such as neonatal Fc receptor or complement inhibitors, which do not associate with reduced cellular immunity. As HHV-8 exploits the complement system to promote latent infection, targeting complement could be a useful therapeutic strategy but must be carefully investigated [8].
Awareness of iKS as a consequence of chronic corticosteroid treatment should be fostered and screening for HHV-8 considered before starting chronic immunosuppression.
Authors’ contributions
R.F. and R.G. equally contributed to paper conception, data acquisition and interpretation, and paper drafting. F.V. and A.T. contributed to data acquisition and interpretation, and paper drafting. L.B. contributed to data acquisition. L.M. and R.M. contributed to data acquisition and interpretation and revised the paper.
Compliance with ethical standards
Conflicts of interest
R.F. received support for congress participations from Argenx, Biogen, Catalyst, Merck, Momenta, Novartis, and Sanofi Genzyme. R.G. received support for congress participation from Mylan. F.V. received support for congress participations from Biogen, Kedrion, and Sanofi Genzyme. A.T. reports no competing interest. L.B. reports no competing interest. L.M. received honoraria for speaking and compensation for congress participations from Biogen and Sanofi Genzyme. R.M. received fees and honoraria for meeting, travel, and advisory board from Alexion, Argenx, Biomarin, Catalyst, Merck Serono, UCB.
Ethics approval
The Ethics Committee of Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta requires the patient consent for case reports publication.
Consent for publication
Written informed consent for publication was received by the patients for the usage of anonymized clinical data and images.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rita Frangiamore and Riccardo Giossi contributed equally to this work. | PREDNISONE | DrugsGivenReaction | CC BY | 33404862 | 18,817,174 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pulmonary embolism'. | Iatrogenic Kaposi's sarcoma in myasthenia gravis: learnings from two case reports.
BACKGROUND
Myasthenia gravis (MG) is an autoimmune neuromuscular disease whose treatment encompasses acetylcholinesterase inhibitors, oral steroids, and other immunosuppressants. Kaposi's sarcoma (KS) is a lymphangioproliferative disease associated with human herpesvirus 8 (HHV-8) infection and immunodeficiency or immunosuppression, mainly corticosteroids.
METHODS
We present two cases of MG patients treated with oral steroids who developed KS. Patient 1 was diagnosed with three oral KS lesions. Prednisone was discontinued with lesion regression and stabilization, while azathioprine and pyridostigmine prompted control of MG. Patient 2 developed KS lesions on the trunk and lower limbs while taking prednisone and azathioprine. Steroid tapering was started but new oral and lymph nodal lesions appeared. Paclitaxel therapy was introduced and the patient experienced pulmonary embolism and developed sensitive neuropathy. Complete remission of KS lesions was achieved and maintained with azathioprine and pyridostigmine as MG medications.
CONCLUSIONS
KS is an uncommon but clinically relevant adverse event (AE) often induced by steroid therapy. It can be controlled by steroid withdrawal but could necessitate chemotherapy, which associates with further potential AEs. Skin evaluation should be performed in all patients with chronic steroid therapy. Steroid-sparing strategies, including new drugs, could reduce KS and other steroid-related comorbidities. HHV-8 testing should be considered before starting chronic immunosuppression.
Background
Myasthenia gravis (MG) is an autoimmune disease mostly associated with anti-acetylcholine receptor (AChR) antibodies. The clinical hallmark is weakness worsened by exercise. Therapy encompasses acetylcholinesterase inhibitors, oral steroids, and other immunosuppressants [1]. Kaposi’s sarcoma (KS) is a lymphangioproliferative disease associated with human herpesvirus 8 (HHV-8) infection and immunodeficiency or pharmacological immunosuppression, mainly corticosteroids [2]. Here, we describe two patients with MG who developed iatrogenic-KS (iKS). Both patients provided written informed consent.
Case report
Patient 1 is a male diagnosed with anti-AChR-positive generalized MG (gMG) without thymus involvement, at 83 years of age (March 2015). As pyridostigmine provided partial improvement, prednisone 50 mg/day was initiated 6 months after diagnosis, with benefit. Body weight was 80 kg, corresponding to a 0.63 mg/kg/day dose of prednisone. Steroid-induced diabetes developed; hence, azathioprine was initiated, and prednisone tapered to 5 mg/day (May 2016), corresponding to a 0.06 mg/kg/day dose of prednisone. Body weight remained stable and steroid therapy maintained at this dosage. In September 2017, the patient was referred to a dermatologist to assess a small violaceous and two bluish macules on the tongue and hard palate (Fig. 1a). Biopsy analyses revealed typical KS features. Serology tested negative for HIV and positive for HHV-8. Staging examinations for KS, including fecal occult blood test, esophagogastroduodenoscopy, abdomen ultrasound, and otolaryngologic examination were negative [3]. iKS diagnosis was made and steroid was discontinued. Follow-up at 3, 6, and 12 months confirmed the presence of the small nodule on the tongue, while the two macules had completely regressed. To date, the nodule remains stable and MG is controlled with pyridostigmine and azathioprine 100 mg/day.Fig. 1 Clinical images showing Kaposi’s sarcoma lesions. a One nodule and two macules (arrows) on the tongue in Patient 1; b angiomatous nodules, plaques, and edema on the lower limbs in Patient 2; voluminous tumor on the hard palate in Patient 2 c before and d after steroid interruption and paclitaxel chemotherapy. e Hematoxylin-eosin stain of a biopsy specimen from Patient 2 showed proliferation of spindle cells and numerous extravasated erythrocytes between dermal collagen bundles. f The spindle cells stained positively with HHV-8 latency-associated nuclear antigen (LNA)-1
Patient 2 is a male diagnosed with anti-AChR-positive gMG at the age of 60 (October 2015), without thymus involvement. Pyridostigmine 60 mg four times daily (QID) and prednisone 65 mg/day were started. Body weight was 108 kg, corresponding to a 0.60 mg/kg/day dose of prednisone. In December 2015, azathioprine 150 mg/day was introduced and, due to limited efficacy, plasmapheresis was often used. Body weight was 100 kg, and prednisone 62.5 mg/day (0.63 mg/kg/day). In October 2016, the patient was referred to the dermatology department for numerous violaceous macules, plaques, and nodules on the lower limbs and reddish-purple plaques on the trunk. Bilateral ankle lymphoedema was present (Fig. 1b). A biopsy confirmed the diagnosis of KS, with serology positive for HHV-8 and negative for HIV. Staging examinations for KS were negative [3]. Whole blood count and biochemistry were normal. Patient body weight was 94 kg. MG therapy was prednisone 50 mg/day (0.53 mg/kg/day), azathioprine 150 mg/day, and pyridostigmine 90 mg QID. Upon iKS diagnosis, over the next 3 months, prednisone was tapered to 30 mg/day (0.32 mg/kg/day) and azathioprine was increased to 175 mg/day. Nevertheless, new KS lesions developed on the hard palate (Fig. 1c) and in left inguinal lymph nodes. Further lesions appeared on lower limbs and external ear during prednisone tapering to 5 mg/day. Thus, the patient stopped prednisone and started intravenous paclitaxel 100 mg/m2 weekly for 13 administrations with regression of all KS lesions (Fig. 1d). Five days after paclitaxel initiation, pulmonary embolism was detected and treated with enoxaparin with complete resolution. Moreover, the patient developed paclitaxel-induced axonal sensitive neuropathy. Three years after treatment, KS was still in remission, and MG symptoms were stable with azathioprine 200 mg/day plus pyridostigmine 60 mg QID.
Discussion
Presented cases show the uncommon but clinically relevant adverse event of iKS, often induced by chronic steroid treatment. Notably, iKS generally occurs within the first 2 years of steroid treatment and about 8% of patients with iKS unrelated to organ transplants had MG [2]. iKS can be effectively controlled by steroid withdrawal (Patient 1). Additional chemotherapy is sometimes necessary, possibly causing additional severe comorbidities such as polyneuropathy and pulmonary embolism (Patient 2).
Oral corticosteroids are a cornerstone treatment in MG, though associated with relevant adverse events including iKS, interestingly even at low doses [2, 4, 5]. Notably, our patients received a maximum prednisone dose of 0.63 mg/kg/day. These doses are conformant to national recommendations of 0.75–1 mg/kg/day for initial gMG treatment, and even lower [6]. Patient 1 developed iKS when he was assuming 0.06 mg/kg/day of prednisone dose while being clinically stable for more than a year. Patient 2 developed iKS when he was slowly tapering prednisone (0.53 mg/kg/day) after the initial dose while being not clinically stable and often needing plasmaphereses.
iKS onset associates with immune-suppression through a direct effect on lymphangioendothelial cells, by downregulating the inhibition of endothelial cell growth [2]. It would be advisable to check for any suspicious skin or mucosal lesions, which are the most frequent localizations of iKS [2], in all patients on chronic corticosteroids. Moreover, considering the high seroprevalence of HHV-8 in regions such as the Mediterranean area (ranging 40 to 80%), it would be also advisable to test for HHV-8 to identify high-risk patients in which to possibly avoid corticosteroid treatment and to perform regular dermatologic assessments [7].
Reduction of iKS and other frequent steroid-related comorbidities might be achieved using new drugs, such as neonatal Fc receptor or complement inhibitors, which do not associate with reduced cellular immunity. As HHV-8 exploits the complement system to promote latent infection, targeting complement could be a useful therapeutic strategy but must be carefully investigated [8].
Awareness of iKS as a consequence of chronic corticosteroid treatment should be fostered and screening for HHV-8 considered before starting chronic immunosuppression.
Authors’ contributions
R.F. and R.G. equally contributed to paper conception, data acquisition and interpretation, and paper drafting. F.V. and A.T. contributed to data acquisition and interpretation, and paper drafting. L.B. contributed to data acquisition. L.M. and R.M. contributed to data acquisition and interpretation and revised the paper.
Compliance with ethical standards
Conflicts of interest
R.F. received support for congress participations from Argenx, Biogen, Catalyst, Merck, Momenta, Novartis, and Sanofi Genzyme. R.G. received support for congress participation from Mylan. F.V. received support for congress participations from Biogen, Kedrion, and Sanofi Genzyme. A.T. reports no competing interest. L.B. reports no competing interest. L.M. received honoraria for speaking and compensation for congress participations from Biogen and Sanofi Genzyme. R.M. received fees and honoraria for meeting, travel, and advisory board from Alexion, Argenx, Biomarin, Catalyst, Merck Serono, UCB.
Ethics approval
The Ethics Committee of Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta requires the patient consent for case reports publication.
Consent for publication
Written informed consent for publication was received by the patients for the usage of anonymized clinical data and images.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rita Frangiamore and Riccardo Giossi contributed equally to this work. | AZATHIOPRINE, PACLITAXEL, PREDNISONE, PYRIDOSTIGMINE | DrugsGivenReaction | CC BY | 33404862 | 18,876,256 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Steroid diabetes'. | Iatrogenic Kaposi's sarcoma in myasthenia gravis: learnings from two case reports.
BACKGROUND
Myasthenia gravis (MG) is an autoimmune neuromuscular disease whose treatment encompasses acetylcholinesterase inhibitors, oral steroids, and other immunosuppressants. Kaposi's sarcoma (KS) is a lymphangioproliferative disease associated with human herpesvirus 8 (HHV-8) infection and immunodeficiency or immunosuppression, mainly corticosteroids.
METHODS
We present two cases of MG patients treated with oral steroids who developed KS. Patient 1 was diagnosed with three oral KS lesions. Prednisone was discontinued with lesion regression and stabilization, while azathioprine and pyridostigmine prompted control of MG. Patient 2 developed KS lesions on the trunk and lower limbs while taking prednisone and azathioprine. Steroid tapering was started but new oral and lymph nodal lesions appeared. Paclitaxel therapy was introduced and the patient experienced pulmonary embolism and developed sensitive neuropathy. Complete remission of KS lesions was achieved and maintained with azathioprine and pyridostigmine as MG medications.
CONCLUSIONS
KS is an uncommon but clinically relevant adverse event (AE) often induced by steroid therapy. It can be controlled by steroid withdrawal but could necessitate chemotherapy, which associates with further potential AEs. Skin evaluation should be performed in all patients with chronic steroid therapy. Steroid-sparing strategies, including new drugs, could reduce KS and other steroid-related comorbidities. HHV-8 testing should be considered before starting chronic immunosuppression.
Background
Myasthenia gravis (MG) is an autoimmune disease mostly associated with anti-acetylcholine receptor (AChR) antibodies. The clinical hallmark is weakness worsened by exercise. Therapy encompasses acetylcholinesterase inhibitors, oral steroids, and other immunosuppressants [1]. Kaposi’s sarcoma (KS) is a lymphangioproliferative disease associated with human herpesvirus 8 (HHV-8) infection and immunodeficiency or pharmacological immunosuppression, mainly corticosteroids [2]. Here, we describe two patients with MG who developed iatrogenic-KS (iKS). Both patients provided written informed consent.
Case report
Patient 1 is a male diagnosed with anti-AChR-positive generalized MG (gMG) without thymus involvement, at 83 years of age (March 2015). As pyridostigmine provided partial improvement, prednisone 50 mg/day was initiated 6 months after diagnosis, with benefit. Body weight was 80 kg, corresponding to a 0.63 mg/kg/day dose of prednisone. Steroid-induced diabetes developed; hence, azathioprine was initiated, and prednisone tapered to 5 mg/day (May 2016), corresponding to a 0.06 mg/kg/day dose of prednisone. Body weight remained stable and steroid therapy maintained at this dosage. In September 2017, the patient was referred to a dermatologist to assess a small violaceous and two bluish macules on the tongue and hard palate (Fig. 1a). Biopsy analyses revealed typical KS features. Serology tested negative for HIV and positive for HHV-8. Staging examinations for KS, including fecal occult blood test, esophagogastroduodenoscopy, abdomen ultrasound, and otolaryngologic examination were negative [3]. iKS diagnosis was made and steroid was discontinued. Follow-up at 3, 6, and 12 months confirmed the presence of the small nodule on the tongue, while the two macules had completely regressed. To date, the nodule remains stable and MG is controlled with pyridostigmine and azathioprine 100 mg/day.Fig. 1 Clinical images showing Kaposi’s sarcoma lesions. a One nodule and two macules (arrows) on the tongue in Patient 1; b angiomatous nodules, plaques, and edema on the lower limbs in Patient 2; voluminous tumor on the hard palate in Patient 2 c before and d after steroid interruption and paclitaxel chemotherapy. e Hematoxylin-eosin stain of a biopsy specimen from Patient 2 showed proliferation of spindle cells and numerous extravasated erythrocytes between dermal collagen bundles. f The spindle cells stained positively with HHV-8 latency-associated nuclear antigen (LNA)-1
Patient 2 is a male diagnosed with anti-AChR-positive gMG at the age of 60 (October 2015), without thymus involvement. Pyridostigmine 60 mg four times daily (QID) and prednisone 65 mg/day were started. Body weight was 108 kg, corresponding to a 0.60 mg/kg/day dose of prednisone. In December 2015, azathioprine 150 mg/day was introduced and, due to limited efficacy, plasmapheresis was often used. Body weight was 100 kg, and prednisone 62.5 mg/day (0.63 mg/kg/day). In October 2016, the patient was referred to the dermatology department for numerous violaceous macules, plaques, and nodules on the lower limbs and reddish-purple plaques on the trunk. Bilateral ankle lymphoedema was present (Fig. 1b). A biopsy confirmed the diagnosis of KS, with serology positive for HHV-8 and negative for HIV. Staging examinations for KS were negative [3]. Whole blood count and biochemistry were normal. Patient body weight was 94 kg. MG therapy was prednisone 50 mg/day (0.53 mg/kg/day), azathioprine 150 mg/day, and pyridostigmine 90 mg QID. Upon iKS diagnosis, over the next 3 months, prednisone was tapered to 30 mg/day (0.32 mg/kg/day) and azathioprine was increased to 175 mg/day. Nevertheless, new KS lesions developed on the hard palate (Fig. 1c) and in left inguinal lymph nodes. Further lesions appeared on lower limbs and external ear during prednisone tapering to 5 mg/day. Thus, the patient stopped prednisone and started intravenous paclitaxel 100 mg/m2 weekly for 13 administrations with regression of all KS lesions (Fig. 1d). Five days after paclitaxel initiation, pulmonary embolism was detected and treated with enoxaparin with complete resolution. Moreover, the patient developed paclitaxel-induced axonal sensitive neuropathy. Three years after treatment, KS was still in remission, and MG symptoms were stable with azathioprine 200 mg/day plus pyridostigmine 60 mg QID.
Discussion
Presented cases show the uncommon but clinically relevant adverse event of iKS, often induced by chronic steroid treatment. Notably, iKS generally occurs within the first 2 years of steroid treatment and about 8% of patients with iKS unrelated to organ transplants had MG [2]. iKS can be effectively controlled by steroid withdrawal (Patient 1). Additional chemotherapy is sometimes necessary, possibly causing additional severe comorbidities such as polyneuropathy and pulmonary embolism (Patient 2).
Oral corticosteroids are a cornerstone treatment in MG, though associated with relevant adverse events including iKS, interestingly even at low doses [2, 4, 5]. Notably, our patients received a maximum prednisone dose of 0.63 mg/kg/day. These doses are conformant to national recommendations of 0.75–1 mg/kg/day for initial gMG treatment, and even lower [6]. Patient 1 developed iKS when he was assuming 0.06 mg/kg/day of prednisone dose while being clinically stable for more than a year. Patient 2 developed iKS when he was slowly tapering prednisone (0.53 mg/kg/day) after the initial dose while being not clinically stable and often needing plasmaphereses.
iKS onset associates with immune-suppression through a direct effect on lymphangioendothelial cells, by downregulating the inhibition of endothelial cell growth [2]. It would be advisable to check for any suspicious skin or mucosal lesions, which are the most frequent localizations of iKS [2], in all patients on chronic corticosteroids. Moreover, considering the high seroprevalence of HHV-8 in regions such as the Mediterranean area (ranging 40 to 80%), it would be also advisable to test for HHV-8 to identify high-risk patients in which to possibly avoid corticosteroid treatment and to perform regular dermatologic assessments [7].
Reduction of iKS and other frequent steroid-related comorbidities might be achieved using new drugs, such as neonatal Fc receptor or complement inhibitors, which do not associate with reduced cellular immunity. As HHV-8 exploits the complement system to promote latent infection, targeting complement could be a useful therapeutic strategy but must be carefully investigated [8].
Awareness of iKS as a consequence of chronic corticosteroid treatment should be fostered and screening for HHV-8 considered before starting chronic immunosuppression.
Authors’ contributions
R.F. and R.G. equally contributed to paper conception, data acquisition and interpretation, and paper drafting. F.V. and A.T. contributed to data acquisition and interpretation, and paper drafting. L.B. contributed to data acquisition. L.M. and R.M. contributed to data acquisition and interpretation and revised the paper.
Compliance with ethical standards
Conflicts of interest
R.F. received support for congress participations from Argenx, Biogen, Catalyst, Merck, Momenta, Novartis, and Sanofi Genzyme. R.G. received support for congress participation from Mylan. F.V. received support for congress participations from Biogen, Kedrion, and Sanofi Genzyme. A.T. reports no competing interest. L.B. reports no competing interest. L.M. received honoraria for speaking and compensation for congress participations from Biogen and Sanofi Genzyme. R.M. received fees and honoraria for meeting, travel, and advisory board from Alexion, Argenx, Biomarin, Catalyst, Merck Serono, UCB.
Ethics approval
The Ethics Committee of Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta requires the patient consent for case reports publication.
Consent for publication
Written informed consent for publication was received by the patients for the usage of anonymized clinical data and images.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rita Frangiamore and Riccardo Giossi contributed equally to this work. | AZATHIOPRINE, PREDNISONE, PYRIDOSTIGMINE | DrugsGivenReaction | CC BY | 33404862 | 18,876,255 | 2021-05 |
What was the administration route of drug 'PACLITAXEL'? | Iatrogenic Kaposi's sarcoma in myasthenia gravis: learnings from two case reports.
BACKGROUND
Myasthenia gravis (MG) is an autoimmune neuromuscular disease whose treatment encompasses acetylcholinesterase inhibitors, oral steroids, and other immunosuppressants. Kaposi's sarcoma (KS) is a lymphangioproliferative disease associated with human herpesvirus 8 (HHV-8) infection and immunodeficiency or immunosuppression, mainly corticosteroids.
METHODS
We present two cases of MG patients treated with oral steroids who developed KS. Patient 1 was diagnosed with three oral KS lesions. Prednisone was discontinued with lesion regression and stabilization, while azathioprine and pyridostigmine prompted control of MG. Patient 2 developed KS lesions on the trunk and lower limbs while taking prednisone and azathioprine. Steroid tapering was started but new oral and lymph nodal lesions appeared. Paclitaxel therapy was introduced and the patient experienced pulmonary embolism and developed sensitive neuropathy. Complete remission of KS lesions was achieved and maintained with azathioprine and pyridostigmine as MG medications.
CONCLUSIONS
KS is an uncommon but clinically relevant adverse event (AE) often induced by steroid therapy. It can be controlled by steroid withdrawal but could necessitate chemotherapy, which associates with further potential AEs. Skin evaluation should be performed in all patients with chronic steroid therapy. Steroid-sparing strategies, including new drugs, could reduce KS and other steroid-related comorbidities. HHV-8 testing should be considered before starting chronic immunosuppression.
Background
Myasthenia gravis (MG) is an autoimmune disease mostly associated with anti-acetylcholine receptor (AChR) antibodies. The clinical hallmark is weakness worsened by exercise. Therapy encompasses acetylcholinesterase inhibitors, oral steroids, and other immunosuppressants [1]. Kaposi’s sarcoma (KS) is a lymphangioproliferative disease associated with human herpesvirus 8 (HHV-8) infection and immunodeficiency or pharmacological immunosuppression, mainly corticosteroids [2]. Here, we describe two patients with MG who developed iatrogenic-KS (iKS). Both patients provided written informed consent.
Case report
Patient 1 is a male diagnosed with anti-AChR-positive generalized MG (gMG) without thymus involvement, at 83 years of age (March 2015). As pyridostigmine provided partial improvement, prednisone 50 mg/day was initiated 6 months after diagnosis, with benefit. Body weight was 80 kg, corresponding to a 0.63 mg/kg/day dose of prednisone. Steroid-induced diabetes developed; hence, azathioprine was initiated, and prednisone tapered to 5 mg/day (May 2016), corresponding to a 0.06 mg/kg/day dose of prednisone. Body weight remained stable and steroid therapy maintained at this dosage. In September 2017, the patient was referred to a dermatologist to assess a small violaceous and two bluish macules on the tongue and hard palate (Fig. 1a). Biopsy analyses revealed typical KS features. Serology tested negative for HIV and positive for HHV-8. Staging examinations for KS, including fecal occult blood test, esophagogastroduodenoscopy, abdomen ultrasound, and otolaryngologic examination were negative [3]. iKS diagnosis was made and steroid was discontinued. Follow-up at 3, 6, and 12 months confirmed the presence of the small nodule on the tongue, while the two macules had completely regressed. To date, the nodule remains stable and MG is controlled with pyridostigmine and azathioprine 100 mg/day.Fig. 1 Clinical images showing Kaposi’s sarcoma lesions. a One nodule and two macules (arrows) on the tongue in Patient 1; b angiomatous nodules, plaques, and edema on the lower limbs in Patient 2; voluminous tumor on the hard palate in Patient 2 c before and d after steroid interruption and paclitaxel chemotherapy. e Hematoxylin-eosin stain of a biopsy specimen from Patient 2 showed proliferation of spindle cells and numerous extravasated erythrocytes between dermal collagen bundles. f The spindle cells stained positively with HHV-8 latency-associated nuclear antigen (LNA)-1
Patient 2 is a male diagnosed with anti-AChR-positive gMG at the age of 60 (October 2015), without thymus involvement. Pyridostigmine 60 mg four times daily (QID) and prednisone 65 mg/day were started. Body weight was 108 kg, corresponding to a 0.60 mg/kg/day dose of prednisone. In December 2015, azathioprine 150 mg/day was introduced and, due to limited efficacy, plasmapheresis was often used. Body weight was 100 kg, and prednisone 62.5 mg/day (0.63 mg/kg/day). In October 2016, the patient was referred to the dermatology department for numerous violaceous macules, plaques, and nodules on the lower limbs and reddish-purple plaques on the trunk. Bilateral ankle lymphoedema was present (Fig. 1b). A biopsy confirmed the diagnosis of KS, with serology positive for HHV-8 and negative for HIV. Staging examinations for KS were negative [3]. Whole blood count and biochemistry were normal. Patient body weight was 94 kg. MG therapy was prednisone 50 mg/day (0.53 mg/kg/day), azathioprine 150 mg/day, and pyridostigmine 90 mg QID. Upon iKS diagnosis, over the next 3 months, prednisone was tapered to 30 mg/day (0.32 mg/kg/day) and azathioprine was increased to 175 mg/day. Nevertheless, new KS lesions developed on the hard palate (Fig. 1c) and in left inguinal lymph nodes. Further lesions appeared on lower limbs and external ear during prednisone tapering to 5 mg/day. Thus, the patient stopped prednisone and started intravenous paclitaxel 100 mg/m2 weekly for 13 administrations with regression of all KS lesions (Fig. 1d). Five days after paclitaxel initiation, pulmonary embolism was detected and treated with enoxaparin with complete resolution. Moreover, the patient developed paclitaxel-induced axonal sensitive neuropathy. Three years after treatment, KS was still in remission, and MG symptoms were stable with azathioprine 200 mg/day plus pyridostigmine 60 mg QID.
Discussion
Presented cases show the uncommon but clinically relevant adverse event of iKS, often induced by chronic steroid treatment. Notably, iKS generally occurs within the first 2 years of steroid treatment and about 8% of patients with iKS unrelated to organ transplants had MG [2]. iKS can be effectively controlled by steroid withdrawal (Patient 1). Additional chemotherapy is sometimes necessary, possibly causing additional severe comorbidities such as polyneuropathy and pulmonary embolism (Patient 2).
Oral corticosteroids are a cornerstone treatment in MG, though associated with relevant adverse events including iKS, interestingly even at low doses [2, 4, 5]. Notably, our patients received a maximum prednisone dose of 0.63 mg/kg/day. These doses are conformant to national recommendations of 0.75–1 mg/kg/day for initial gMG treatment, and even lower [6]. Patient 1 developed iKS when he was assuming 0.06 mg/kg/day of prednisone dose while being clinically stable for more than a year. Patient 2 developed iKS when he was slowly tapering prednisone (0.53 mg/kg/day) after the initial dose while being not clinically stable and often needing plasmaphereses.
iKS onset associates with immune-suppression through a direct effect on lymphangioendothelial cells, by downregulating the inhibition of endothelial cell growth [2]. It would be advisable to check for any suspicious skin or mucosal lesions, which are the most frequent localizations of iKS [2], in all patients on chronic corticosteroids. Moreover, considering the high seroprevalence of HHV-8 in regions such as the Mediterranean area (ranging 40 to 80%), it would be also advisable to test for HHV-8 to identify high-risk patients in which to possibly avoid corticosteroid treatment and to perform regular dermatologic assessments [7].
Reduction of iKS and other frequent steroid-related comorbidities might be achieved using new drugs, such as neonatal Fc receptor or complement inhibitors, which do not associate with reduced cellular immunity. As HHV-8 exploits the complement system to promote latent infection, targeting complement could be a useful therapeutic strategy but must be carefully investigated [8].
Awareness of iKS as a consequence of chronic corticosteroid treatment should be fostered and screening for HHV-8 considered before starting chronic immunosuppression.
Authors’ contributions
R.F. and R.G. equally contributed to paper conception, data acquisition and interpretation, and paper drafting. F.V. and A.T. contributed to data acquisition and interpretation, and paper drafting. L.B. contributed to data acquisition. L.M. and R.M. contributed to data acquisition and interpretation and revised the paper.
Compliance with ethical standards
Conflicts of interest
R.F. received support for congress participations from Argenx, Biogen, Catalyst, Merck, Momenta, Novartis, and Sanofi Genzyme. R.G. received support for congress participation from Mylan. F.V. received support for congress participations from Biogen, Kedrion, and Sanofi Genzyme. A.T. reports no competing interest. L.B. reports no competing interest. L.M. received honoraria for speaking and compensation for congress participations from Biogen and Sanofi Genzyme. R.M. received fees and honoraria for meeting, travel, and advisory board from Alexion, Argenx, Biomarin, Catalyst, Merck Serono, UCB.
Ethics approval
The Ethics Committee of Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta requires the patient consent for case reports publication.
Consent for publication
Written informed consent for publication was received by the patients for the usage of anonymized clinical data and images.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rita Frangiamore and Riccardo Giossi contributed equally to this work. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33404862 | 18,876,256 | 2021-05 |
What was the administration route of drug 'PREDNISONE'? | Iatrogenic Kaposi's sarcoma in myasthenia gravis: learnings from two case reports.
BACKGROUND
Myasthenia gravis (MG) is an autoimmune neuromuscular disease whose treatment encompasses acetylcholinesterase inhibitors, oral steroids, and other immunosuppressants. Kaposi's sarcoma (KS) is a lymphangioproliferative disease associated with human herpesvirus 8 (HHV-8) infection and immunodeficiency or immunosuppression, mainly corticosteroids.
METHODS
We present two cases of MG patients treated with oral steroids who developed KS. Patient 1 was diagnosed with three oral KS lesions. Prednisone was discontinued with lesion regression and stabilization, while azathioprine and pyridostigmine prompted control of MG. Patient 2 developed KS lesions on the trunk and lower limbs while taking prednisone and azathioprine. Steroid tapering was started but new oral and lymph nodal lesions appeared. Paclitaxel therapy was introduced and the patient experienced pulmonary embolism and developed sensitive neuropathy. Complete remission of KS lesions was achieved and maintained with azathioprine and pyridostigmine as MG medications.
CONCLUSIONS
KS is an uncommon but clinically relevant adverse event (AE) often induced by steroid therapy. It can be controlled by steroid withdrawal but could necessitate chemotherapy, which associates with further potential AEs. Skin evaluation should be performed in all patients with chronic steroid therapy. Steroid-sparing strategies, including new drugs, could reduce KS and other steroid-related comorbidities. HHV-8 testing should be considered before starting chronic immunosuppression.
Background
Myasthenia gravis (MG) is an autoimmune disease mostly associated with anti-acetylcholine receptor (AChR) antibodies. The clinical hallmark is weakness worsened by exercise. Therapy encompasses acetylcholinesterase inhibitors, oral steroids, and other immunosuppressants [1]. Kaposi’s sarcoma (KS) is a lymphangioproliferative disease associated with human herpesvirus 8 (HHV-8) infection and immunodeficiency or pharmacological immunosuppression, mainly corticosteroids [2]. Here, we describe two patients with MG who developed iatrogenic-KS (iKS). Both patients provided written informed consent.
Case report
Patient 1 is a male diagnosed with anti-AChR-positive generalized MG (gMG) without thymus involvement, at 83 years of age (March 2015). As pyridostigmine provided partial improvement, prednisone 50 mg/day was initiated 6 months after diagnosis, with benefit. Body weight was 80 kg, corresponding to a 0.63 mg/kg/day dose of prednisone. Steroid-induced diabetes developed; hence, azathioprine was initiated, and prednisone tapered to 5 mg/day (May 2016), corresponding to a 0.06 mg/kg/day dose of prednisone. Body weight remained stable and steroid therapy maintained at this dosage. In September 2017, the patient was referred to a dermatologist to assess a small violaceous and two bluish macules on the tongue and hard palate (Fig. 1a). Biopsy analyses revealed typical KS features. Serology tested negative for HIV and positive for HHV-8. Staging examinations for KS, including fecal occult blood test, esophagogastroduodenoscopy, abdomen ultrasound, and otolaryngologic examination were negative [3]. iKS diagnosis was made and steroid was discontinued. Follow-up at 3, 6, and 12 months confirmed the presence of the small nodule on the tongue, while the two macules had completely regressed. To date, the nodule remains stable and MG is controlled with pyridostigmine and azathioprine 100 mg/day.Fig. 1 Clinical images showing Kaposi’s sarcoma lesions. a One nodule and two macules (arrows) on the tongue in Patient 1; b angiomatous nodules, plaques, and edema on the lower limbs in Patient 2; voluminous tumor on the hard palate in Patient 2 c before and d after steroid interruption and paclitaxel chemotherapy. e Hematoxylin-eosin stain of a biopsy specimen from Patient 2 showed proliferation of spindle cells and numerous extravasated erythrocytes between dermal collagen bundles. f The spindle cells stained positively with HHV-8 latency-associated nuclear antigen (LNA)-1
Patient 2 is a male diagnosed with anti-AChR-positive gMG at the age of 60 (October 2015), without thymus involvement. Pyridostigmine 60 mg four times daily (QID) and prednisone 65 mg/day were started. Body weight was 108 kg, corresponding to a 0.60 mg/kg/day dose of prednisone. In December 2015, azathioprine 150 mg/day was introduced and, due to limited efficacy, plasmapheresis was often used. Body weight was 100 kg, and prednisone 62.5 mg/day (0.63 mg/kg/day). In October 2016, the patient was referred to the dermatology department for numerous violaceous macules, plaques, and nodules on the lower limbs and reddish-purple plaques on the trunk. Bilateral ankle lymphoedema was present (Fig. 1b). A biopsy confirmed the diagnosis of KS, with serology positive for HHV-8 and negative for HIV. Staging examinations for KS were negative [3]. Whole blood count and biochemistry were normal. Patient body weight was 94 kg. MG therapy was prednisone 50 mg/day (0.53 mg/kg/day), azathioprine 150 mg/day, and pyridostigmine 90 mg QID. Upon iKS diagnosis, over the next 3 months, prednisone was tapered to 30 mg/day (0.32 mg/kg/day) and azathioprine was increased to 175 mg/day. Nevertheless, new KS lesions developed on the hard palate (Fig. 1c) and in left inguinal lymph nodes. Further lesions appeared on lower limbs and external ear during prednisone tapering to 5 mg/day. Thus, the patient stopped prednisone and started intravenous paclitaxel 100 mg/m2 weekly for 13 administrations with regression of all KS lesions (Fig. 1d). Five days after paclitaxel initiation, pulmonary embolism was detected and treated with enoxaparin with complete resolution. Moreover, the patient developed paclitaxel-induced axonal sensitive neuropathy. Three years after treatment, KS was still in remission, and MG symptoms were stable with azathioprine 200 mg/day plus pyridostigmine 60 mg QID.
Discussion
Presented cases show the uncommon but clinically relevant adverse event of iKS, often induced by chronic steroid treatment. Notably, iKS generally occurs within the first 2 years of steroid treatment and about 8% of patients with iKS unrelated to organ transplants had MG [2]. iKS can be effectively controlled by steroid withdrawal (Patient 1). Additional chemotherapy is sometimes necessary, possibly causing additional severe comorbidities such as polyneuropathy and pulmonary embolism (Patient 2).
Oral corticosteroids are a cornerstone treatment in MG, though associated with relevant adverse events including iKS, interestingly even at low doses [2, 4, 5]. Notably, our patients received a maximum prednisone dose of 0.63 mg/kg/day. These doses are conformant to national recommendations of 0.75–1 mg/kg/day for initial gMG treatment, and even lower [6]. Patient 1 developed iKS when he was assuming 0.06 mg/kg/day of prednisone dose while being clinically stable for more than a year. Patient 2 developed iKS when he was slowly tapering prednisone (0.53 mg/kg/day) after the initial dose while being not clinically stable and often needing plasmaphereses.
iKS onset associates with immune-suppression through a direct effect on lymphangioendothelial cells, by downregulating the inhibition of endothelial cell growth [2]. It would be advisable to check for any suspicious skin or mucosal lesions, which are the most frequent localizations of iKS [2], in all patients on chronic corticosteroids. Moreover, considering the high seroprevalence of HHV-8 in regions such as the Mediterranean area (ranging 40 to 80%), it would be also advisable to test for HHV-8 to identify high-risk patients in which to possibly avoid corticosteroid treatment and to perform regular dermatologic assessments [7].
Reduction of iKS and other frequent steroid-related comorbidities might be achieved using new drugs, such as neonatal Fc receptor or complement inhibitors, which do not associate with reduced cellular immunity. As HHV-8 exploits the complement system to promote latent infection, targeting complement could be a useful therapeutic strategy but must be carefully investigated [8].
Awareness of iKS as a consequence of chronic corticosteroid treatment should be fostered and screening for HHV-8 considered before starting chronic immunosuppression.
Authors’ contributions
R.F. and R.G. equally contributed to paper conception, data acquisition and interpretation, and paper drafting. F.V. and A.T. contributed to data acquisition and interpretation, and paper drafting. L.B. contributed to data acquisition. L.M. and R.M. contributed to data acquisition and interpretation and revised the paper.
Compliance with ethical standards
Conflicts of interest
R.F. received support for congress participations from Argenx, Biogen, Catalyst, Merck, Momenta, Novartis, and Sanofi Genzyme. R.G. received support for congress participation from Mylan. F.V. received support for congress participations from Biogen, Kedrion, and Sanofi Genzyme. A.T. reports no competing interest. L.B. reports no competing interest. L.M. received honoraria for speaking and compensation for congress participations from Biogen and Sanofi Genzyme. R.M. received fees and honoraria for meeting, travel, and advisory board from Alexion, Argenx, Biomarin, Catalyst, Merck Serono, UCB.
Ethics approval
The Ethics Committee of Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta requires the patient consent for case reports publication.
Consent for publication
Written informed consent for publication was received by the patients for the usage of anonymized clinical data and images.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rita Frangiamore and Riccardo Giossi contributed equally to this work. | Oral | DrugAdministrationRoute | CC BY | 33404862 | 18,817,174 | 2021-05 |
What was the outcome of reaction 'Axonal neuropathy'? | Iatrogenic Kaposi's sarcoma in myasthenia gravis: learnings from two case reports.
BACKGROUND
Myasthenia gravis (MG) is an autoimmune neuromuscular disease whose treatment encompasses acetylcholinesterase inhibitors, oral steroids, and other immunosuppressants. Kaposi's sarcoma (KS) is a lymphangioproliferative disease associated with human herpesvirus 8 (HHV-8) infection and immunodeficiency or immunosuppression, mainly corticosteroids.
METHODS
We present two cases of MG patients treated with oral steroids who developed KS. Patient 1 was diagnosed with three oral KS lesions. Prednisone was discontinued with lesion regression and stabilization, while azathioprine and pyridostigmine prompted control of MG. Patient 2 developed KS lesions on the trunk and lower limbs while taking prednisone and azathioprine. Steroid tapering was started but new oral and lymph nodal lesions appeared. Paclitaxel therapy was introduced and the patient experienced pulmonary embolism and developed sensitive neuropathy. Complete remission of KS lesions was achieved and maintained with azathioprine and pyridostigmine as MG medications.
CONCLUSIONS
KS is an uncommon but clinically relevant adverse event (AE) often induced by steroid therapy. It can be controlled by steroid withdrawal but could necessitate chemotherapy, which associates with further potential AEs. Skin evaluation should be performed in all patients with chronic steroid therapy. Steroid-sparing strategies, including new drugs, could reduce KS and other steroid-related comorbidities. HHV-8 testing should be considered before starting chronic immunosuppression.
Background
Myasthenia gravis (MG) is an autoimmune disease mostly associated with anti-acetylcholine receptor (AChR) antibodies. The clinical hallmark is weakness worsened by exercise. Therapy encompasses acetylcholinesterase inhibitors, oral steroids, and other immunosuppressants [1]. Kaposi’s sarcoma (KS) is a lymphangioproliferative disease associated with human herpesvirus 8 (HHV-8) infection and immunodeficiency or pharmacological immunosuppression, mainly corticosteroids [2]. Here, we describe two patients with MG who developed iatrogenic-KS (iKS). Both patients provided written informed consent.
Case report
Patient 1 is a male diagnosed with anti-AChR-positive generalized MG (gMG) without thymus involvement, at 83 years of age (March 2015). As pyridostigmine provided partial improvement, prednisone 50 mg/day was initiated 6 months after diagnosis, with benefit. Body weight was 80 kg, corresponding to a 0.63 mg/kg/day dose of prednisone. Steroid-induced diabetes developed; hence, azathioprine was initiated, and prednisone tapered to 5 mg/day (May 2016), corresponding to a 0.06 mg/kg/day dose of prednisone. Body weight remained stable and steroid therapy maintained at this dosage. In September 2017, the patient was referred to a dermatologist to assess a small violaceous and two bluish macules on the tongue and hard palate (Fig. 1a). Biopsy analyses revealed typical KS features. Serology tested negative for HIV and positive for HHV-8. Staging examinations for KS, including fecal occult blood test, esophagogastroduodenoscopy, abdomen ultrasound, and otolaryngologic examination were negative [3]. iKS diagnosis was made and steroid was discontinued. Follow-up at 3, 6, and 12 months confirmed the presence of the small nodule on the tongue, while the two macules had completely regressed. To date, the nodule remains stable and MG is controlled with pyridostigmine and azathioprine 100 mg/day.Fig. 1 Clinical images showing Kaposi’s sarcoma lesions. a One nodule and two macules (arrows) on the tongue in Patient 1; b angiomatous nodules, plaques, and edema on the lower limbs in Patient 2; voluminous tumor on the hard palate in Patient 2 c before and d after steroid interruption and paclitaxel chemotherapy. e Hematoxylin-eosin stain of a biopsy specimen from Patient 2 showed proliferation of spindle cells and numerous extravasated erythrocytes between dermal collagen bundles. f The spindle cells stained positively with HHV-8 latency-associated nuclear antigen (LNA)-1
Patient 2 is a male diagnosed with anti-AChR-positive gMG at the age of 60 (October 2015), without thymus involvement. Pyridostigmine 60 mg four times daily (QID) and prednisone 65 mg/day were started. Body weight was 108 kg, corresponding to a 0.60 mg/kg/day dose of prednisone. In December 2015, azathioprine 150 mg/day was introduced and, due to limited efficacy, plasmapheresis was often used. Body weight was 100 kg, and prednisone 62.5 mg/day (0.63 mg/kg/day). In October 2016, the patient was referred to the dermatology department for numerous violaceous macules, plaques, and nodules on the lower limbs and reddish-purple plaques on the trunk. Bilateral ankle lymphoedema was present (Fig. 1b). A biopsy confirmed the diagnosis of KS, with serology positive for HHV-8 and negative for HIV. Staging examinations for KS were negative [3]. Whole blood count and biochemistry were normal. Patient body weight was 94 kg. MG therapy was prednisone 50 mg/day (0.53 mg/kg/day), azathioprine 150 mg/day, and pyridostigmine 90 mg QID. Upon iKS diagnosis, over the next 3 months, prednisone was tapered to 30 mg/day (0.32 mg/kg/day) and azathioprine was increased to 175 mg/day. Nevertheless, new KS lesions developed on the hard palate (Fig. 1c) and in left inguinal lymph nodes. Further lesions appeared on lower limbs and external ear during prednisone tapering to 5 mg/day. Thus, the patient stopped prednisone and started intravenous paclitaxel 100 mg/m2 weekly for 13 administrations with regression of all KS lesions (Fig. 1d). Five days after paclitaxel initiation, pulmonary embolism was detected and treated with enoxaparin with complete resolution. Moreover, the patient developed paclitaxel-induced axonal sensitive neuropathy. Three years after treatment, KS was still in remission, and MG symptoms were stable with azathioprine 200 mg/day plus pyridostigmine 60 mg QID.
Discussion
Presented cases show the uncommon but clinically relevant adverse event of iKS, often induced by chronic steroid treatment. Notably, iKS generally occurs within the first 2 years of steroid treatment and about 8% of patients with iKS unrelated to organ transplants had MG [2]. iKS can be effectively controlled by steroid withdrawal (Patient 1). Additional chemotherapy is sometimes necessary, possibly causing additional severe comorbidities such as polyneuropathy and pulmonary embolism (Patient 2).
Oral corticosteroids are a cornerstone treatment in MG, though associated with relevant adverse events including iKS, interestingly even at low doses [2, 4, 5]. Notably, our patients received a maximum prednisone dose of 0.63 mg/kg/day. These doses are conformant to national recommendations of 0.75–1 mg/kg/day for initial gMG treatment, and even lower [6]. Patient 1 developed iKS when he was assuming 0.06 mg/kg/day of prednisone dose while being clinically stable for more than a year. Patient 2 developed iKS when he was slowly tapering prednisone (0.53 mg/kg/day) after the initial dose while being not clinically stable and often needing plasmaphereses.
iKS onset associates with immune-suppression through a direct effect on lymphangioendothelial cells, by downregulating the inhibition of endothelial cell growth [2]. It would be advisable to check for any suspicious skin or mucosal lesions, which are the most frequent localizations of iKS [2], in all patients on chronic corticosteroids. Moreover, considering the high seroprevalence of HHV-8 in regions such as the Mediterranean area (ranging 40 to 80%), it would be also advisable to test for HHV-8 to identify high-risk patients in which to possibly avoid corticosteroid treatment and to perform regular dermatologic assessments [7].
Reduction of iKS and other frequent steroid-related comorbidities might be achieved using new drugs, such as neonatal Fc receptor or complement inhibitors, which do not associate with reduced cellular immunity. As HHV-8 exploits the complement system to promote latent infection, targeting complement could be a useful therapeutic strategy but must be carefully investigated [8].
Awareness of iKS as a consequence of chronic corticosteroid treatment should be fostered and screening for HHV-8 considered before starting chronic immunosuppression.
Authors’ contributions
R.F. and R.G. equally contributed to paper conception, data acquisition and interpretation, and paper drafting. F.V. and A.T. contributed to data acquisition and interpretation, and paper drafting. L.B. contributed to data acquisition. L.M. and R.M. contributed to data acquisition and interpretation and revised the paper.
Compliance with ethical standards
Conflicts of interest
R.F. received support for congress participations from Argenx, Biogen, Catalyst, Merck, Momenta, Novartis, and Sanofi Genzyme. R.G. received support for congress participation from Mylan. F.V. received support for congress participations from Biogen, Kedrion, and Sanofi Genzyme. A.T. reports no competing interest. L.B. reports no competing interest. L.M. received honoraria for speaking and compensation for congress participations from Biogen and Sanofi Genzyme. R.M. received fees and honoraria for meeting, travel, and advisory board from Alexion, Argenx, Biomarin, Catalyst, Merck Serono, UCB.
Ethics approval
The Ethics Committee of Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta requires the patient consent for case reports publication.
Consent for publication
Written informed consent for publication was received by the patients for the usage of anonymized clinical data and images.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rita Frangiamore and Riccardo Giossi contributed equally to this work. | Recovering | ReactionOutcome | CC BY | 33404862 | 18,941,249 | 2021-05 |
What was the outcome of reaction 'Human herpesvirus 8 infection'? | Iatrogenic Kaposi's sarcoma in myasthenia gravis: learnings from two case reports.
BACKGROUND
Myasthenia gravis (MG) is an autoimmune neuromuscular disease whose treatment encompasses acetylcholinesterase inhibitors, oral steroids, and other immunosuppressants. Kaposi's sarcoma (KS) is a lymphangioproliferative disease associated with human herpesvirus 8 (HHV-8) infection and immunodeficiency or immunosuppression, mainly corticosteroids.
METHODS
We present two cases of MG patients treated with oral steroids who developed KS. Patient 1 was diagnosed with three oral KS lesions. Prednisone was discontinued with lesion regression and stabilization, while azathioprine and pyridostigmine prompted control of MG. Patient 2 developed KS lesions on the trunk and lower limbs while taking prednisone and azathioprine. Steroid tapering was started but new oral and lymph nodal lesions appeared. Paclitaxel therapy was introduced and the patient experienced pulmonary embolism and developed sensitive neuropathy. Complete remission of KS lesions was achieved and maintained with azathioprine and pyridostigmine as MG medications.
CONCLUSIONS
KS is an uncommon but clinically relevant adverse event (AE) often induced by steroid therapy. It can be controlled by steroid withdrawal but could necessitate chemotherapy, which associates with further potential AEs. Skin evaluation should be performed in all patients with chronic steroid therapy. Steroid-sparing strategies, including new drugs, could reduce KS and other steroid-related comorbidities. HHV-8 testing should be considered before starting chronic immunosuppression.
Background
Myasthenia gravis (MG) is an autoimmune disease mostly associated with anti-acetylcholine receptor (AChR) antibodies. The clinical hallmark is weakness worsened by exercise. Therapy encompasses acetylcholinesterase inhibitors, oral steroids, and other immunosuppressants [1]. Kaposi’s sarcoma (KS) is a lymphangioproliferative disease associated with human herpesvirus 8 (HHV-8) infection and immunodeficiency or pharmacological immunosuppression, mainly corticosteroids [2]. Here, we describe two patients with MG who developed iatrogenic-KS (iKS). Both patients provided written informed consent.
Case report
Patient 1 is a male diagnosed with anti-AChR-positive generalized MG (gMG) without thymus involvement, at 83 years of age (March 2015). As pyridostigmine provided partial improvement, prednisone 50 mg/day was initiated 6 months after diagnosis, with benefit. Body weight was 80 kg, corresponding to a 0.63 mg/kg/day dose of prednisone. Steroid-induced diabetes developed; hence, azathioprine was initiated, and prednisone tapered to 5 mg/day (May 2016), corresponding to a 0.06 mg/kg/day dose of prednisone. Body weight remained stable and steroid therapy maintained at this dosage. In September 2017, the patient was referred to a dermatologist to assess a small violaceous and two bluish macules on the tongue and hard palate (Fig. 1a). Biopsy analyses revealed typical KS features. Serology tested negative for HIV and positive for HHV-8. Staging examinations for KS, including fecal occult blood test, esophagogastroduodenoscopy, abdomen ultrasound, and otolaryngologic examination were negative [3]. iKS diagnosis was made and steroid was discontinued. Follow-up at 3, 6, and 12 months confirmed the presence of the small nodule on the tongue, while the two macules had completely regressed. To date, the nodule remains stable and MG is controlled with pyridostigmine and azathioprine 100 mg/day.Fig. 1 Clinical images showing Kaposi’s sarcoma lesions. a One nodule and two macules (arrows) on the tongue in Patient 1; b angiomatous nodules, plaques, and edema on the lower limbs in Patient 2; voluminous tumor on the hard palate in Patient 2 c before and d after steroid interruption and paclitaxel chemotherapy. e Hematoxylin-eosin stain of a biopsy specimen from Patient 2 showed proliferation of spindle cells and numerous extravasated erythrocytes between dermal collagen bundles. f The spindle cells stained positively with HHV-8 latency-associated nuclear antigen (LNA)-1
Patient 2 is a male diagnosed with anti-AChR-positive gMG at the age of 60 (October 2015), without thymus involvement. Pyridostigmine 60 mg four times daily (QID) and prednisone 65 mg/day were started. Body weight was 108 kg, corresponding to a 0.60 mg/kg/day dose of prednisone. In December 2015, azathioprine 150 mg/day was introduced and, due to limited efficacy, plasmapheresis was often used. Body weight was 100 kg, and prednisone 62.5 mg/day (0.63 mg/kg/day). In October 2016, the patient was referred to the dermatology department for numerous violaceous macules, plaques, and nodules on the lower limbs and reddish-purple plaques on the trunk. Bilateral ankle lymphoedema was present (Fig. 1b). A biopsy confirmed the diagnosis of KS, with serology positive for HHV-8 and negative for HIV. Staging examinations for KS were negative [3]. Whole blood count and biochemistry were normal. Patient body weight was 94 kg. MG therapy was prednisone 50 mg/day (0.53 mg/kg/day), azathioprine 150 mg/day, and pyridostigmine 90 mg QID. Upon iKS diagnosis, over the next 3 months, prednisone was tapered to 30 mg/day (0.32 mg/kg/day) and azathioprine was increased to 175 mg/day. Nevertheless, new KS lesions developed on the hard palate (Fig. 1c) and in left inguinal lymph nodes. Further lesions appeared on lower limbs and external ear during prednisone tapering to 5 mg/day. Thus, the patient stopped prednisone and started intravenous paclitaxel 100 mg/m2 weekly for 13 administrations with regression of all KS lesions (Fig. 1d). Five days after paclitaxel initiation, pulmonary embolism was detected and treated with enoxaparin with complete resolution. Moreover, the patient developed paclitaxel-induced axonal sensitive neuropathy. Three years after treatment, KS was still in remission, and MG symptoms were stable with azathioprine 200 mg/day plus pyridostigmine 60 mg QID.
Discussion
Presented cases show the uncommon but clinically relevant adverse event of iKS, often induced by chronic steroid treatment. Notably, iKS generally occurs within the first 2 years of steroid treatment and about 8% of patients with iKS unrelated to organ transplants had MG [2]. iKS can be effectively controlled by steroid withdrawal (Patient 1). Additional chemotherapy is sometimes necessary, possibly causing additional severe comorbidities such as polyneuropathy and pulmonary embolism (Patient 2).
Oral corticosteroids are a cornerstone treatment in MG, though associated with relevant adverse events including iKS, interestingly even at low doses [2, 4, 5]. Notably, our patients received a maximum prednisone dose of 0.63 mg/kg/day. These doses are conformant to national recommendations of 0.75–1 mg/kg/day for initial gMG treatment, and even lower [6]. Patient 1 developed iKS when he was assuming 0.06 mg/kg/day of prednisone dose while being clinically stable for more than a year. Patient 2 developed iKS when he was slowly tapering prednisone (0.53 mg/kg/day) after the initial dose while being not clinically stable and often needing plasmaphereses.
iKS onset associates with immune-suppression through a direct effect on lymphangioendothelial cells, by downregulating the inhibition of endothelial cell growth [2]. It would be advisable to check for any suspicious skin or mucosal lesions, which are the most frequent localizations of iKS [2], in all patients on chronic corticosteroids. Moreover, considering the high seroprevalence of HHV-8 in regions such as the Mediterranean area (ranging 40 to 80%), it would be also advisable to test for HHV-8 to identify high-risk patients in which to possibly avoid corticosteroid treatment and to perform regular dermatologic assessments [7].
Reduction of iKS and other frequent steroid-related comorbidities might be achieved using new drugs, such as neonatal Fc receptor or complement inhibitors, which do not associate with reduced cellular immunity. As HHV-8 exploits the complement system to promote latent infection, targeting complement could be a useful therapeutic strategy but must be carefully investigated [8].
Awareness of iKS as a consequence of chronic corticosteroid treatment should be fostered and screening for HHV-8 considered before starting chronic immunosuppression.
Authors’ contributions
R.F. and R.G. equally contributed to paper conception, data acquisition and interpretation, and paper drafting. F.V. and A.T. contributed to data acquisition and interpretation, and paper drafting. L.B. contributed to data acquisition. L.M. and R.M. contributed to data acquisition and interpretation and revised the paper.
Compliance with ethical standards
Conflicts of interest
R.F. received support for congress participations from Argenx, Biogen, Catalyst, Merck, Momenta, Novartis, and Sanofi Genzyme. R.G. received support for congress participation from Mylan. F.V. received support for congress participations from Biogen, Kedrion, and Sanofi Genzyme. A.T. reports no competing interest. L.B. reports no competing interest. L.M. received honoraria for speaking and compensation for congress participations from Biogen and Sanofi Genzyme. R.M. received fees and honoraria for meeting, travel, and advisory board from Alexion, Argenx, Biomarin, Catalyst, Merck Serono, UCB.
Ethics approval
The Ethics Committee of Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta requires the patient consent for case reports publication.
Consent for publication
Written informed consent for publication was received by the patients for the usage of anonymized clinical data and images.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rita Frangiamore and Riccardo Giossi contributed equally to this work. | Recovering | ReactionOutcome | CC BY | 33404862 | 18,876,256 | 2021-05 |
What was the outcome of reaction 'Pulmonary embolism'? | Iatrogenic Kaposi's sarcoma in myasthenia gravis: learnings from two case reports.
BACKGROUND
Myasthenia gravis (MG) is an autoimmune neuromuscular disease whose treatment encompasses acetylcholinesterase inhibitors, oral steroids, and other immunosuppressants. Kaposi's sarcoma (KS) is a lymphangioproliferative disease associated with human herpesvirus 8 (HHV-8) infection and immunodeficiency or immunosuppression, mainly corticosteroids.
METHODS
We present two cases of MG patients treated with oral steroids who developed KS. Patient 1 was diagnosed with three oral KS lesions. Prednisone was discontinued with lesion regression and stabilization, while azathioprine and pyridostigmine prompted control of MG. Patient 2 developed KS lesions on the trunk and lower limbs while taking prednisone and azathioprine. Steroid tapering was started but new oral and lymph nodal lesions appeared. Paclitaxel therapy was introduced and the patient experienced pulmonary embolism and developed sensitive neuropathy. Complete remission of KS lesions was achieved and maintained with azathioprine and pyridostigmine as MG medications.
CONCLUSIONS
KS is an uncommon but clinically relevant adverse event (AE) often induced by steroid therapy. It can be controlled by steroid withdrawal but could necessitate chemotherapy, which associates with further potential AEs. Skin evaluation should be performed in all patients with chronic steroid therapy. Steroid-sparing strategies, including new drugs, could reduce KS and other steroid-related comorbidities. HHV-8 testing should be considered before starting chronic immunosuppression.
Background
Myasthenia gravis (MG) is an autoimmune disease mostly associated with anti-acetylcholine receptor (AChR) antibodies. The clinical hallmark is weakness worsened by exercise. Therapy encompasses acetylcholinesterase inhibitors, oral steroids, and other immunosuppressants [1]. Kaposi’s sarcoma (KS) is a lymphangioproliferative disease associated with human herpesvirus 8 (HHV-8) infection and immunodeficiency or pharmacological immunosuppression, mainly corticosteroids [2]. Here, we describe two patients with MG who developed iatrogenic-KS (iKS). Both patients provided written informed consent.
Case report
Patient 1 is a male diagnosed with anti-AChR-positive generalized MG (gMG) without thymus involvement, at 83 years of age (March 2015). As pyridostigmine provided partial improvement, prednisone 50 mg/day was initiated 6 months after diagnosis, with benefit. Body weight was 80 kg, corresponding to a 0.63 mg/kg/day dose of prednisone. Steroid-induced diabetes developed; hence, azathioprine was initiated, and prednisone tapered to 5 mg/day (May 2016), corresponding to a 0.06 mg/kg/day dose of prednisone. Body weight remained stable and steroid therapy maintained at this dosage. In September 2017, the patient was referred to a dermatologist to assess a small violaceous and two bluish macules on the tongue and hard palate (Fig. 1a). Biopsy analyses revealed typical KS features. Serology tested negative for HIV and positive for HHV-8. Staging examinations for KS, including fecal occult blood test, esophagogastroduodenoscopy, abdomen ultrasound, and otolaryngologic examination were negative [3]. iKS diagnosis was made and steroid was discontinued. Follow-up at 3, 6, and 12 months confirmed the presence of the small nodule on the tongue, while the two macules had completely regressed. To date, the nodule remains stable and MG is controlled with pyridostigmine and azathioprine 100 mg/day.Fig. 1 Clinical images showing Kaposi’s sarcoma lesions. a One nodule and two macules (arrows) on the tongue in Patient 1; b angiomatous nodules, plaques, and edema on the lower limbs in Patient 2; voluminous tumor on the hard palate in Patient 2 c before and d after steroid interruption and paclitaxel chemotherapy. e Hematoxylin-eosin stain of a biopsy specimen from Patient 2 showed proliferation of spindle cells and numerous extravasated erythrocytes between dermal collagen bundles. f The spindle cells stained positively with HHV-8 latency-associated nuclear antigen (LNA)-1
Patient 2 is a male diagnosed with anti-AChR-positive gMG at the age of 60 (October 2015), without thymus involvement. Pyridostigmine 60 mg four times daily (QID) and prednisone 65 mg/day were started. Body weight was 108 kg, corresponding to a 0.60 mg/kg/day dose of prednisone. In December 2015, azathioprine 150 mg/day was introduced and, due to limited efficacy, plasmapheresis was often used. Body weight was 100 kg, and prednisone 62.5 mg/day (0.63 mg/kg/day). In October 2016, the patient was referred to the dermatology department for numerous violaceous macules, plaques, and nodules on the lower limbs and reddish-purple plaques on the trunk. Bilateral ankle lymphoedema was present (Fig. 1b). A biopsy confirmed the diagnosis of KS, with serology positive for HHV-8 and negative for HIV. Staging examinations for KS were negative [3]. Whole blood count and biochemistry were normal. Patient body weight was 94 kg. MG therapy was prednisone 50 mg/day (0.53 mg/kg/day), azathioprine 150 mg/day, and pyridostigmine 90 mg QID. Upon iKS diagnosis, over the next 3 months, prednisone was tapered to 30 mg/day (0.32 mg/kg/day) and azathioprine was increased to 175 mg/day. Nevertheless, new KS lesions developed on the hard palate (Fig. 1c) and in left inguinal lymph nodes. Further lesions appeared on lower limbs and external ear during prednisone tapering to 5 mg/day. Thus, the patient stopped prednisone and started intravenous paclitaxel 100 mg/m2 weekly for 13 administrations with regression of all KS lesions (Fig. 1d). Five days after paclitaxel initiation, pulmonary embolism was detected and treated with enoxaparin with complete resolution. Moreover, the patient developed paclitaxel-induced axonal sensitive neuropathy. Three years after treatment, KS was still in remission, and MG symptoms were stable with azathioprine 200 mg/day plus pyridostigmine 60 mg QID.
Discussion
Presented cases show the uncommon but clinically relevant adverse event of iKS, often induced by chronic steroid treatment. Notably, iKS generally occurs within the first 2 years of steroid treatment and about 8% of patients with iKS unrelated to organ transplants had MG [2]. iKS can be effectively controlled by steroid withdrawal (Patient 1). Additional chemotherapy is sometimes necessary, possibly causing additional severe comorbidities such as polyneuropathy and pulmonary embolism (Patient 2).
Oral corticosteroids are a cornerstone treatment in MG, though associated with relevant adverse events including iKS, interestingly even at low doses [2, 4, 5]. Notably, our patients received a maximum prednisone dose of 0.63 mg/kg/day. These doses are conformant to national recommendations of 0.75–1 mg/kg/day for initial gMG treatment, and even lower [6]. Patient 1 developed iKS when he was assuming 0.06 mg/kg/day of prednisone dose while being clinically stable for more than a year. Patient 2 developed iKS when he was slowly tapering prednisone (0.53 mg/kg/day) after the initial dose while being not clinically stable and often needing plasmaphereses.
iKS onset associates with immune-suppression through a direct effect on lymphangioendothelial cells, by downregulating the inhibition of endothelial cell growth [2]. It would be advisable to check for any suspicious skin or mucosal lesions, which are the most frequent localizations of iKS [2], in all patients on chronic corticosteroids. Moreover, considering the high seroprevalence of HHV-8 in regions such as the Mediterranean area (ranging 40 to 80%), it would be also advisable to test for HHV-8 to identify high-risk patients in which to possibly avoid corticosteroid treatment and to perform regular dermatologic assessments [7].
Reduction of iKS and other frequent steroid-related comorbidities might be achieved using new drugs, such as neonatal Fc receptor or complement inhibitors, which do not associate with reduced cellular immunity. As HHV-8 exploits the complement system to promote latent infection, targeting complement could be a useful therapeutic strategy but must be carefully investigated [8].
Awareness of iKS as a consequence of chronic corticosteroid treatment should be fostered and screening for HHV-8 considered before starting chronic immunosuppression.
Authors’ contributions
R.F. and R.G. equally contributed to paper conception, data acquisition and interpretation, and paper drafting. F.V. and A.T. contributed to data acquisition and interpretation, and paper drafting. L.B. contributed to data acquisition. L.M. and R.M. contributed to data acquisition and interpretation and revised the paper.
Compliance with ethical standards
Conflicts of interest
R.F. received support for congress participations from Argenx, Biogen, Catalyst, Merck, Momenta, Novartis, and Sanofi Genzyme. R.G. received support for congress participation from Mylan. F.V. received support for congress participations from Biogen, Kedrion, and Sanofi Genzyme. A.T. reports no competing interest. L.B. reports no competing interest. L.M. received honoraria for speaking and compensation for congress participations from Biogen and Sanofi Genzyme. R.M. received fees and honoraria for meeting, travel, and advisory board from Alexion, Argenx, Biomarin, Catalyst, Merck Serono, UCB.
Ethics approval
The Ethics Committee of Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta requires the patient consent for case reports publication.
Consent for publication
Written informed consent for publication was received by the patients for the usage of anonymized clinical data and images.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rita Frangiamore and Riccardo Giossi contributed equally to this work. | Recovered | ReactionOutcome | CC BY | 33404862 | 18,941,249 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective for unapproved indication'. | COVID-19 in Pediatric Granulomatosis with Polyangiitis.
The confirmed cases with COVID-19 in children account for just 1% of the overall confirmed cases. Severe COVID-19 in children is rare. Case Presentation: Our patient was 16 years old with a severe case of COVID-19 and did not survive due to the presence of Granulomatosis with polyangiitis and being treated with immunosuppressive drugs. We used lopinavir, ritonavir, hydroxy chloroquine, intravenous immunoglobulin and continuous veno-venous hemodialysis for treatment. Conclusion: In this patient, an underlying disease and delayed admission to the hospital were two factors complicating his condition.
1. Introduction
The outbreak of COVID-19 started as an epidemic in Wuhan, China and caught world-wide attention as a pandemic in January 2020. Confirmed pediatric cases account for just 1% of total cases [1].
Severe COVID-19 infections in children are rare. To date, the largest review of children with COVID-19 included 2143 children in China. Only 112 (5.6%) of 2143 children infected presented with severe symptoms (defined as hypoxia) and 13 (0.6%) children developed respiratory distress syndrome (ARDS) or multi-organ failure [2].
Our patient had a severe case of COVID-19 and did not survive due to the presence of Granulomatosis with polyangiitis and being treated with immunosuppressive drugs.
Rheumatological diseases and inflammatory bowel disease are immune disorders that are associated with an increased risk of opportunistic and community-acquired infections such as respiratory virus infections. They are at risk of high mortality and co-morbidity [3].
For patients with rheumatic disease, there is little data to understand the real consequences of the infection. Pediatric rheumatologists are expected to play a supporting role in treatment of COVID-19, both as pediatricians treating infected children, and as rheumatologists taking care of their rheumatic patients, as well as offering their experience in the possible alternative use of immunomodulatory drugs [4].
2. Case Presentation
A 16 year-old, 80-kg patient was referred to a tertiary hospital in Shiraz, Iran on 27 March 2020. He had a known case of Granulomatosis with polyangiitis and was diagnosed 2 years prior. At that time the patient presented with headache, sore throat, conjunctivitis for 1 month that was followed by lower extremities edema and joints pain and skin rash, and the Granulomatosis with polyangiitis was distinguished. His condition was in remission according to the Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis Evaluation Form [5] before recent disease. The patient was on these medications before admission: prednisolone 10 milligrams (mg) daily, mycophenolate 360 mg twice per day, aspirin 80 mg daily, valsartan 10 mg daily, allopurinol 100 mg daily and folic acid. The patient’s complaint started with coughing and rhinorrhea 7 days prior to admission. His condition worsened over the following few days. He had very limited activity in the 3 days prior to admission. He displayed shortness of breath and preferred to lie down in a prone position.
On the day of admission, he was intubated in the emergency room due to respiratory distress and decreased O2 Saturation (O2 Sat) of 70%. He was transferred to the pediatric intensive care unit (PICU). In the PICU, a ventilator was set up on SIMV with a respiratory rate of 20/min, tidal volume of 500 mL, inspiratory time: 1min, peak end expiratory pressure (PEEP): 15 cm H2O and FIO2: 100%. An infusion of norepinephrine was administered due to hypotension. Covid-19 RT-PCR came back positive. There was no history of exposure to confirmed or suspected coronavirus cases.
His medication continued except valsartan. Prednisolone changed to stress dose of hydrocortisone.
Lopinavir, ritonavir, hydroxy chloroquine, vancomycin and meropenem started. He also received intravenous immunoglobulin (IVIG) the first day of admission because of his refractory shock.
Chest X-ray on admission showed bilateral patchy infiltration which deteriorated to white lung on day 6 (Figure 1). A CT scan was not done due to his severe condition and the lack of a portable ventilator with high PEEP set up. All lab tests are shown in Table 1.
On day 3 he had atrial fibrillation with rapid ventricular response. After emergency intervention, flecainide began with pediatric cardiologist consultation.
He also became anuric on day 4 and continuous veno-venous hemodialysis started for him. His condition deteriorated over time with a decrease in O2 Sat in spite of 100% of FIO2 and an increase in PEEP to 22cm H2O. On day 3, he was put into a prone positioning which helped to increase O2 Sat (up to 97%). However, it started to decline again after 36 h.
Unfortunately, the patient expired on day 6 of admission with low O2 Sat and bradycardia.
3. Discussion
COVID-19 mortality in children is very rare. The data from a low number of children suggest that even children who are on immunosuppressive treatment for various indications have a mild clinical course of COVID-19. Additionally, a study with eight children with inflammatory bowel disease (IBS), despite treatment with immunomodulators, biologics, or both, shows that all children diagnosed with COVID-19 had a mild infection [6].
But in this patient, an underlying disease and delayed admission to the hospital were two factors complicating his condition.
In addition, while there was extensive publicity for home quarantine, it is important to note that fears of contracting coronavirus may cause people to delay going to health centers until it is too late to treat them effectively. Some patients, concerned about over-burdening the healthcare system, may also delay seeking hospital treatment until their symptoms become critical.
The existing data on past and present coronavirus outbreaks show that immunosuppressed patients are not at increased risk of severe pulmonary disease compared with the general population. Children under the age of 12 years do not progress to severe coronavirus pneumonia, without paying attention to their immune status, although they get infected and can spread the infection [7].
Screening those who care for these high-risk patients is also suggested.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
A.S. and E.S. wrote the manuscript. E.S. gathered patient’s data and submitted the manuscript. Z.S. and S.A. edited the manuscript and were scientific consultant. All authors discussed the results and contributed to the final manuscript. All authors have read and agreed to the published version of the manuscript.
Funding
The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Institutional Review Board Statement
This study was approved by the ethics committee of Shiraz University of Medical Sciences (IR.SUMS.MED.REC.1399.216).
Informed Consent Statement
Written informed consent was obtained from the parents and sent to the ethics committee.
Data Availability Statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Chest X-ray on day 1 (left) and day 4 (right).
pediatrrep-13-00004-t001_Table 1Table 1 Lab tests from day 1 to day 6 of admission.
Day of Admission → 1 2 3 4 5 6
Lab Data ↓
COVID RT-PCR Positive
Influenza RT-PCR Negative
Blood urea nitrogen (mg/dl) 53 59 67 68 87 96
creatinine 4.8 5.5 5.2 5.9 7.9 8.8
Sodium (mEq/L) 130 135 139 134 135 136
Potassium (mEq/L) 6 5.4 3.7 4.5 5.6 5.2
Calcium (mg/dL) 8.3
8.9
8.4
Troponin (ng/mL) 450 1688
D.Dimer (ng/mL)
650
7627
Lactate dehydrogenase (U/L) 1350 1340
Creatine phosphokinase (U/L)
119 137 537 1030 1040
Magnesium (mg/dL) 2.4
1.9
3.1
Ferritin (ng/mL)
1310
Procalcitonin (ng/mL) 5.77
Aspartate transaminase (U/L)
43
Alanine aminotransferase (U/L)
13
White blood cells(count/mL) 22,800 14,800 17,200 22,900 15,800 16,200
Hemoglobin (g/dL) 9.6 7.8 11.1 * 10.5 9 8
Platelet (count/mL) 494,000 338,000 339,000 325,000 234,000 196,000
Prothrombin time 12 12.1 13.6 18.1+ 20+ 15.3
Partial thromboplastin time 25 24 33 41 47 38
INR 1 1.01 1.2 1.8 2.13 1.4
HIV antibody, HCV antibody, HBS antigen were negative. TB work up was negative. * red blood cell transfusion, +fresh frozen plasma transfusion. | ALLOPURINOL, ASPIRIN, FOLIC ACID, HYDROCORTISONE, HYDROXYCHLOROQUINE, LOPINAVIR, MEROPENEM, MYCOPHENOLIC ACID, RITONAVIR, VANCOMYCIN | DrugsGivenReaction | CC BY | 33406578 | 19,063,353 | 2021-01-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | COVID-19 in Pediatric Granulomatosis with Polyangiitis.
The confirmed cases with COVID-19 in children account for just 1% of the overall confirmed cases. Severe COVID-19 in children is rare. Case Presentation: Our patient was 16 years old with a severe case of COVID-19 and did not survive due to the presence of Granulomatosis with polyangiitis and being treated with immunosuppressive drugs. We used lopinavir, ritonavir, hydroxy chloroquine, intravenous immunoglobulin and continuous veno-venous hemodialysis for treatment. Conclusion: In this patient, an underlying disease and delayed admission to the hospital were two factors complicating his condition.
1. Introduction
The outbreak of COVID-19 started as an epidemic in Wuhan, China and caught world-wide attention as a pandemic in January 2020. Confirmed pediatric cases account for just 1% of total cases [1].
Severe COVID-19 infections in children are rare. To date, the largest review of children with COVID-19 included 2143 children in China. Only 112 (5.6%) of 2143 children infected presented with severe symptoms (defined as hypoxia) and 13 (0.6%) children developed respiratory distress syndrome (ARDS) or multi-organ failure [2].
Our patient had a severe case of COVID-19 and did not survive due to the presence of Granulomatosis with polyangiitis and being treated with immunosuppressive drugs.
Rheumatological diseases and inflammatory bowel disease are immune disorders that are associated with an increased risk of opportunistic and community-acquired infections such as respiratory virus infections. They are at risk of high mortality and co-morbidity [3].
For patients with rheumatic disease, there is little data to understand the real consequences of the infection. Pediatric rheumatologists are expected to play a supporting role in treatment of COVID-19, both as pediatricians treating infected children, and as rheumatologists taking care of their rheumatic patients, as well as offering their experience in the possible alternative use of immunomodulatory drugs [4].
2. Case Presentation
A 16 year-old, 80-kg patient was referred to a tertiary hospital in Shiraz, Iran on 27 March 2020. He had a known case of Granulomatosis with polyangiitis and was diagnosed 2 years prior. At that time the patient presented with headache, sore throat, conjunctivitis for 1 month that was followed by lower extremities edema and joints pain and skin rash, and the Granulomatosis with polyangiitis was distinguished. His condition was in remission according to the Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis Evaluation Form [5] before recent disease. The patient was on these medications before admission: prednisolone 10 milligrams (mg) daily, mycophenolate 360 mg twice per day, aspirin 80 mg daily, valsartan 10 mg daily, allopurinol 100 mg daily and folic acid. The patient’s complaint started with coughing and rhinorrhea 7 days prior to admission. His condition worsened over the following few days. He had very limited activity in the 3 days prior to admission. He displayed shortness of breath and preferred to lie down in a prone position.
On the day of admission, he was intubated in the emergency room due to respiratory distress and decreased O2 Saturation (O2 Sat) of 70%. He was transferred to the pediatric intensive care unit (PICU). In the PICU, a ventilator was set up on SIMV with a respiratory rate of 20/min, tidal volume of 500 mL, inspiratory time: 1min, peak end expiratory pressure (PEEP): 15 cm H2O and FIO2: 100%. An infusion of norepinephrine was administered due to hypotension. Covid-19 RT-PCR came back positive. There was no history of exposure to confirmed or suspected coronavirus cases.
His medication continued except valsartan. Prednisolone changed to stress dose of hydrocortisone.
Lopinavir, ritonavir, hydroxy chloroquine, vancomycin and meropenem started. He also received intravenous immunoglobulin (IVIG) the first day of admission because of his refractory shock.
Chest X-ray on admission showed bilateral patchy infiltration which deteriorated to white lung on day 6 (Figure 1). A CT scan was not done due to his severe condition and the lack of a portable ventilator with high PEEP set up. All lab tests are shown in Table 1.
On day 3 he had atrial fibrillation with rapid ventricular response. After emergency intervention, flecainide began with pediatric cardiologist consultation.
He also became anuric on day 4 and continuous veno-venous hemodialysis started for him. His condition deteriorated over time with a decrease in O2 Sat in spite of 100% of FIO2 and an increase in PEEP to 22cm H2O. On day 3, he was put into a prone positioning which helped to increase O2 Sat (up to 97%). However, it started to decline again after 36 h.
Unfortunately, the patient expired on day 6 of admission with low O2 Sat and bradycardia.
3. Discussion
COVID-19 mortality in children is very rare. The data from a low number of children suggest that even children who are on immunosuppressive treatment for various indications have a mild clinical course of COVID-19. Additionally, a study with eight children with inflammatory bowel disease (IBS), despite treatment with immunomodulators, biologics, or both, shows that all children diagnosed with COVID-19 had a mild infection [6].
But in this patient, an underlying disease and delayed admission to the hospital were two factors complicating his condition.
In addition, while there was extensive publicity for home quarantine, it is important to note that fears of contracting coronavirus may cause people to delay going to health centers until it is too late to treat them effectively. Some patients, concerned about over-burdening the healthcare system, may also delay seeking hospital treatment until their symptoms become critical.
The existing data on past and present coronavirus outbreaks show that immunosuppressed patients are not at increased risk of severe pulmonary disease compared with the general population. Children under the age of 12 years do not progress to severe coronavirus pneumonia, without paying attention to their immune status, although they get infected and can spread the infection [7].
Screening those who care for these high-risk patients is also suggested.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
A.S. and E.S. wrote the manuscript. E.S. gathered patient’s data and submitted the manuscript. Z.S. and S.A. edited the manuscript and were scientific consultant. All authors discussed the results and contributed to the final manuscript. All authors have read and agreed to the published version of the manuscript.
Funding
The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Institutional Review Board Statement
This study was approved by the ethics committee of Shiraz University of Medical Sciences (IR.SUMS.MED.REC.1399.216).
Informed Consent Statement
Written informed consent was obtained from the parents and sent to the ethics committee.
Data Availability Statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Chest X-ray on day 1 (left) and day 4 (right).
pediatrrep-13-00004-t001_Table 1Table 1 Lab tests from day 1 to day 6 of admission.
Day of Admission → 1 2 3 4 5 6
Lab Data ↓
COVID RT-PCR Positive
Influenza RT-PCR Negative
Blood urea nitrogen (mg/dl) 53 59 67 68 87 96
creatinine 4.8 5.5 5.2 5.9 7.9 8.8
Sodium (mEq/L) 130 135 139 134 135 136
Potassium (mEq/L) 6 5.4 3.7 4.5 5.6 5.2
Calcium (mg/dL) 8.3
8.9
8.4
Troponin (ng/mL) 450 1688
D.Dimer (ng/mL)
650
7627
Lactate dehydrogenase (U/L) 1350 1340
Creatine phosphokinase (U/L)
119 137 537 1030 1040
Magnesium (mg/dL) 2.4
1.9
3.1
Ferritin (ng/mL)
1310
Procalcitonin (ng/mL) 5.77
Aspartate transaminase (U/L)
43
Alanine aminotransferase (U/L)
13
White blood cells(count/mL) 22,800 14,800 17,200 22,900 15,800 16,200
Hemoglobin (g/dL) 9.6 7.8 11.1 * 10.5 9 8
Platelet (count/mL) 494,000 338,000 339,000 325,000 234,000 196,000
Prothrombin time 12 12.1 13.6 18.1+ 20+ 15.3
Partial thromboplastin time 25 24 33 41 47 38
INR 1 1.01 1.2 1.8 2.13 1.4
HIV antibody, HCV antibody, HBS antigen were negative. TB work up was negative. * red blood cell transfusion, +fresh frozen plasma transfusion. | ALLOPURINOL, ASPIRIN, FOLIC ACID, HYDROCORTISONE, HYDROXYCHLOROQUINE, LOPINAVIR, MEROPENEM, MYCOPHENOLIC ACID, RITONAVIR, VANCOMYCIN | DrugsGivenReaction | CC BY | 33406578 | 19,063,353 | 2021-01-04 |
What is the weight of the patient? | COVID-19 in Pediatric Granulomatosis with Polyangiitis.
The confirmed cases with COVID-19 in children account for just 1% of the overall confirmed cases. Severe COVID-19 in children is rare. Case Presentation: Our patient was 16 years old with a severe case of COVID-19 and did not survive due to the presence of Granulomatosis with polyangiitis and being treated with immunosuppressive drugs. We used lopinavir, ritonavir, hydroxy chloroquine, intravenous immunoglobulin and continuous veno-venous hemodialysis for treatment. Conclusion: In this patient, an underlying disease and delayed admission to the hospital were two factors complicating his condition.
1. Introduction
The outbreak of COVID-19 started as an epidemic in Wuhan, China and caught world-wide attention as a pandemic in January 2020. Confirmed pediatric cases account for just 1% of total cases [1].
Severe COVID-19 infections in children are rare. To date, the largest review of children with COVID-19 included 2143 children in China. Only 112 (5.6%) of 2143 children infected presented with severe symptoms (defined as hypoxia) and 13 (0.6%) children developed respiratory distress syndrome (ARDS) or multi-organ failure [2].
Our patient had a severe case of COVID-19 and did not survive due to the presence of Granulomatosis with polyangiitis and being treated with immunosuppressive drugs.
Rheumatological diseases and inflammatory bowel disease are immune disorders that are associated with an increased risk of opportunistic and community-acquired infections such as respiratory virus infections. They are at risk of high mortality and co-morbidity [3].
For patients with rheumatic disease, there is little data to understand the real consequences of the infection. Pediatric rheumatologists are expected to play a supporting role in treatment of COVID-19, both as pediatricians treating infected children, and as rheumatologists taking care of their rheumatic patients, as well as offering their experience in the possible alternative use of immunomodulatory drugs [4].
2. Case Presentation
A 16 year-old, 80-kg patient was referred to a tertiary hospital in Shiraz, Iran on 27 March 2020. He had a known case of Granulomatosis with polyangiitis and was diagnosed 2 years prior. At that time the patient presented with headache, sore throat, conjunctivitis for 1 month that was followed by lower extremities edema and joints pain and skin rash, and the Granulomatosis with polyangiitis was distinguished. His condition was in remission according to the Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis Evaluation Form [5] before recent disease. The patient was on these medications before admission: prednisolone 10 milligrams (mg) daily, mycophenolate 360 mg twice per day, aspirin 80 mg daily, valsartan 10 mg daily, allopurinol 100 mg daily and folic acid. The patient’s complaint started with coughing and rhinorrhea 7 days prior to admission. His condition worsened over the following few days. He had very limited activity in the 3 days prior to admission. He displayed shortness of breath and preferred to lie down in a prone position.
On the day of admission, he was intubated in the emergency room due to respiratory distress and decreased O2 Saturation (O2 Sat) of 70%. He was transferred to the pediatric intensive care unit (PICU). In the PICU, a ventilator was set up on SIMV with a respiratory rate of 20/min, tidal volume of 500 mL, inspiratory time: 1min, peak end expiratory pressure (PEEP): 15 cm H2O and FIO2: 100%. An infusion of norepinephrine was administered due to hypotension. Covid-19 RT-PCR came back positive. There was no history of exposure to confirmed or suspected coronavirus cases.
His medication continued except valsartan. Prednisolone changed to stress dose of hydrocortisone.
Lopinavir, ritonavir, hydroxy chloroquine, vancomycin and meropenem started. He also received intravenous immunoglobulin (IVIG) the first day of admission because of his refractory shock.
Chest X-ray on admission showed bilateral patchy infiltration which deteriorated to white lung on day 6 (Figure 1). A CT scan was not done due to his severe condition and the lack of a portable ventilator with high PEEP set up. All lab tests are shown in Table 1.
On day 3 he had atrial fibrillation with rapid ventricular response. After emergency intervention, flecainide began with pediatric cardiologist consultation.
He also became anuric on day 4 and continuous veno-venous hemodialysis started for him. His condition deteriorated over time with a decrease in O2 Sat in spite of 100% of FIO2 and an increase in PEEP to 22cm H2O. On day 3, he was put into a prone positioning which helped to increase O2 Sat (up to 97%). However, it started to decline again after 36 h.
Unfortunately, the patient expired on day 6 of admission with low O2 Sat and bradycardia.
3. Discussion
COVID-19 mortality in children is very rare. The data from a low number of children suggest that even children who are on immunosuppressive treatment for various indications have a mild clinical course of COVID-19. Additionally, a study with eight children with inflammatory bowel disease (IBS), despite treatment with immunomodulators, biologics, or both, shows that all children diagnosed with COVID-19 had a mild infection [6].
But in this patient, an underlying disease and delayed admission to the hospital were two factors complicating his condition.
In addition, while there was extensive publicity for home quarantine, it is important to note that fears of contracting coronavirus may cause people to delay going to health centers until it is too late to treat them effectively. Some patients, concerned about over-burdening the healthcare system, may also delay seeking hospital treatment until their symptoms become critical.
The existing data on past and present coronavirus outbreaks show that immunosuppressed patients are not at increased risk of severe pulmonary disease compared with the general population. Children under the age of 12 years do not progress to severe coronavirus pneumonia, without paying attention to their immune status, although they get infected and can spread the infection [7].
Screening those who care for these high-risk patients is also suggested.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
A.S. and E.S. wrote the manuscript. E.S. gathered patient’s data and submitted the manuscript. Z.S. and S.A. edited the manuscript and were scientific consultant. All authors discussed the results and contributed to the final manuscript. All authors have read and agreed to the published version of the manuscript.
Funding
The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Institutional Review Board Statement
This study was approved by the ethics committee of Shiraz University of Medical Sciences (IR.SUMS.MED.REC.1399.216).
Informed Consent Statement
Written informed consent was obtained from the parents and sent to the ethics committee.
Data Availability Statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Chest X-ray on day 1 (left) and day 4 (right).
pediatrrep-13-00004-t001_Table 1Table 1 Lab tests from day 1 to day 6 of admission.
Day of Admission → 1 2 3 4 5 6
Lab Data ↓
COVID RT-PCR Positive
Influenza RT-PCR Negative
Blood urea nitrogen (mg/dl) 53 59 67 68 87 96
creatinine 4.8 5.5 5.2 5.9 7.9 8.8
Sodium (mEq/L) 130 135 139 134 135 136
Potassium (mEq/L) 6 5.4 3.7 4.5 5.6 5.2
Calcium (mg/dL) 8.3
8.9
8.4
Troponin (ng/mL) 450 1688
D.Dimer (ng/mL)
650
7627
Lactate dehydrogenase (U/L) 1350 1340
Creatine phosphokinase (U/L)
119 137 537 1030 1040
Magnesium (mg/dL) 2.4
1.9
3.1
Ferritin (ng/mL)
1310
Procalcitonin (ng/mL) 5.77
Aspartate transaminase (U/L)
43
Alanine aminotransferase (U/L)
13
White blood cells(count/mL) 22,800 14,800 17,200 22,900 15,800 16,200
Hemoglobin (g/dL) 9.6 7.8 11.1 * 10.5 9 8
Platelet (count/mL) 494,000 338,000 339,000 325,000 234,000 196,000
Prothrombin time 12 12.1 13.6 18.1+ 20+ 15.3
Partial thromboplastin time 25 24 33 41 47 38
INR 1 1.01 1.2 1.8 2.13 1.4
HIV antibody, HCV antibody, HBS antigen were negative. TB work up was negative. * red blood cell transfusion, +fresh frozen plasma transfusion. | 80 kg. | Weight | CC BY | 33406578 | 19,063,353 | 2021-01-04 |
What was the dosage of drug 'HYDROCORTISONE'? | COVID-19 in Pediatric Granulomatosis with Polyangiitis.
The confirmed cases with COVID-19 in children account for just 1% of the overall confirmed cases. Severe COVID-19 in children is rare. Case Presentation: Our patient was 16 years old with a severe case of COVID-19 and did not survive due to the presence of Granulomatosis with polyangiitis and being treated with immunosuppressive drugs. We used lopinavir, ritonavir, hydroxy chloroquine, intravenous immunoglobulin and continuous veno-venous hemodialysis for treatment. Conclusion: In this patient, an underlying disease and delayed admission to the hospital were two factors complicating his condition.
1. Introduction
The outbreak of COVID-19 started as an epidemic in Wuhan, China and caught world-wide attention as a pandemic in January 2020. Confirmed pediatric cases account for just 1% of total cases [1].
Severe COVID-19 infections in children are rare. To date, the largest review of children with COVID-19 included 2143 children in China. Only 112 (5.6%) of 2143 children infected presented with severe symptoms (defined as hypoxia) and 13 (0.6%) children developed respiratory distress syndrome (ARDS) or multi-organ failure [2].
Our patient had a severe case of COVID-19 and did not survive due to the presence of Granulomatosis with polyangiitis and being treated with immunosuppressive drugs.
Rheumatological diseases and inflammatory bowel disease are immune disorders that are associated with an increased risk of opportunistic and community-acquired infections such as respiratory virus infections. They are at risk of high mortality and co-morbidity [3].
For patients with rheumatic disease, there is little data to understand the real consequences of the infection. Pediatric rheumatologists are expected to play a supporting role in treatment of COVID-19, both as pediatricians treating infected children, and as rheumatologists taking care of their rheumatic patients, as well as offering their experience in the possible alternative use of immunomodulatory drugs [4].
2. Case Presentation
A 16 year-old, 80-kg patient was referred to a tertiary hospital in Shiraz, Iran on 27 March 2020. He had a known case of Granulomatosis with polyangiitis and was diagnosed 2 years prior. At that time the patient presented with headache, sore throat, conjunctivitis for 1 month that was followed by lower extremities edema and joints pain and skin rash, and the Granulomatosis with polyangiitis was distinguished. His condition was in remission according to the Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis Evaluation Form [5] before recent disease. The patient was on these medications before admission: prednisolone 10 milligrams (mg) daily, mycophenolate 360 mg twice per day, aspirin 80 mg daily, valsartan 10 mg daily, allopurinol 100 mg daily and folic acid. The patient’s complaint started with coughing and rhinorrhea 7 days prior to admission. His condition worsened over the following few days. He had very limited activity in the 3 days prior to admission. He displayed shortness of breath and preferred to lie down in a prone position.
On the day of admission, he was intubated in the emergency room due to respiratory distress and decreased O2 Saturation (O2 Sat) of 70%. He was transferred to the pediatric intensive care unit (PICU). In the PICU, a ventilator was set up on SIMV with a respiratory rate of 20/min, tidal volume of 500 mL, inspiratory time: 1min, peak end expiratory pressure (PEEP): 15 cm H2O and FIO2: 100%. An infusion of norepinephrine was administered due to hypotension. Covid-19 RT-PCR came back positive. There was no history of exposure to confirmed or suspected coronavirus cases.
His medication continued except valsartan. Prednisolone changed to stress dose of hydrocortisone.
Lopinavir, ritonavir, hydroxy chloroquine, vancomycin and meropenem started. He also received intravenous immunoglobulin (IVIG) the first day of admission because of his refractory shock.
Chest X-ray on admission showed bilateral patchy infiltration which deteriorated to white lung on day 6 (Figure 1). A CT scan was not done due to his severe condition and the lack of a portable ventilator with high PEEP set up. All lab tests are shown in Table 1.
On day 3 he had atrial fibrillation with rapid ventricular response. After emergency intervention, flecainide began with pediatric cardiologist consultation.
He also became anuric on day 4 and continuous veno-venous hemodialysis started for him. His condition deteriorated over time with a decrease in O2 Sat in spite of 100% of FIO2 and an increase in PEEP to 22cm H2O. On day 3, he was put into a prone positioning which helped to increase O2 Sat (up to 97%). However, it started to decline again after 36 h.
Unfortunately, the patient expired on day 6 of admission with low O2 Sat and bradycardia.
3. Discussion
COVID-19 mortality in children is very rare. The data from a low number of children suggest that even children who are on immunosuppressive treatment for various indications have a mild clinical course of COVID-19. Additionally, a study with eight children with inflammatory bowel disease (IBS), despite treatment with immunomodulators, biologics, or both, shows that all children diagnosed with COVID-19 had a mild infection [6].
But in this patient, an underlying disease and delayed admission to the hospital were two factors complicating his condition.
In addition, while there was extensive publicity for home quarantine, it is important to note that fears of contracting coronavirus may cause people to delay going to health centers until it is too late to treat them effectively. Some patients, concerned about over-burdening the healthcare system, may also delay seeking hospital treatment until their symptoms become critical.
The existing data on past and present coronavirus outbreaks show that immunosuppressed patients are not at increased risk of severe pulmonary disease compared with the general population. Children under the age of 12 years do not progress to severe coronavirus pneumonia, without paying attention to their immune status, although they get infected and can spread the infection [7].
Screening those who care for these high-risk patients is also suggested.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
A.S. and E.S. wrote the manuscript. E.S. gathered patient’s data and submitted the manuscript. Z.S. and S.A. edited the manuscript and were scientific consultant. All authors discussed the results and contributed to the final manuscript. All authors have read and agreed to the published version of the manuscript.
Funding
The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Institutional Review Board Statement
This study was approved by the ethics committee of Shiraz University of Medical Sciences (IR.SUMS.MED.REC.1399.216).
Informed Consent Statement
Written informed consent was obtained from the parents and sent to the ethics committee.
Data Availability Statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Chest X-ray on day 1 (left) and day 4 (right).
pediatrrep-13-00004-t001_Table 1Table 1 Lab tests from day 1 to day 6 of admission.
Day of Admission → 1 2 3 4 5 6
Lab Data ↓
COVID RT-PCR Positive
Influenza RT-PCR Negative
Blood urea nitrogen (mg/dl) 53 59 67 68 87 96
creatinine 4.8 5.5 5.2 5.9 7.9 8.8
Sodium (mEq/L) 130 135 139 134 135 136
Potassium (mEq/L) 6 5.4 3.7 4.5 5.6 5.2
Calcium (mg/dL) 8.3
8.9
8.4
Troponin (ng/mL) 450 1688
D.Dimer (ng/mL)
650
7627
Lactate dehydrogenase (U/L) 1350 1340
Creatine phosphokinase (U/L)
119 137 537 1030 1040
Magnesium (mg/dL) 2.4
1.9
3.1
Ferritin (ng/mL)
1310
Procalcitonin (ng/mL) 5.77
Aspartate transaminase (U/L)
43
Alanine aminotransferase (U/L)
13
White blood cells(count/mL) 22,800 14,800 17,200 22,900 15,800 16,200
Hemoglobin (g/dL) 9.6 7.8 11.1 * 10.5 9 8
Platelet (count/mL) 494,000 338,000 339,000 325,000 234,000 196,000
Prothrombin time 12 12.1 13.6 18.1+ 20+ 15.3
Partial thromboplastin time 25 24 33 41 47 38
INR 1 1.01 1.2 1.8 2.13 1.4
HIV antibody, HCV antibody, HBS antigen were negative. TB work up was negative. * red blood cell transfusion, +fresh frozen plasma transfusion. | STRESS DOSE | DrugDosageText | CC BY | 33406578 | 19,063,353 | 2021-01-04 |
What was the outcome of reaction 'Drug ineffective for unapproved indication'? | COVID-19 in Pediatric Granulomatosis with Polyangiitis.
The confirmed cases with COVID-19 in children account for just 1% of the overall confirmed cases. Severe COVID-19 in children is rare. Case Presentation: Our patient was 16 years old with a severe case of COVID-19 and did not survive due to the presence of Granulomatosis with polyangiitis and being treated with immunosuppressive drugs. We used lopinavir, ritonavir, hydroxy chloroquine, intravenous immunoglobulin and continuous veno-venous hemodialysis for treatment. Conclusion: In this patient, an underlying disease and delayed admission to the hospital were two factors complicating his condition.
1. Introduction
The outbreak of COVID-19 started as an epidemic in Wuhan, China and caught world-wide attention as a pandemic in January 2020. Confirmed pediatric cases account for just 1% of total cases [1].
Severe COVID-19 infections in children are rare. To date, the largest review of children with COVID-19 included 2143 children in China. Only 112 (5.6%) of 2143 children infected presented with severe symptoms (defined as hypoxia) and 13 (0.6%) children developed respiratory distress syndrome (ARDS) or multi-organ failure [2].
Our patient had a severe case of COVID-19 and did not survive due to the presence of Granulomatosis with polyangiitis and being treated with immunosuppressive drugs.
Rheumatological diseases and inflammatory bowel disease are immune disorders that are associated with an increased risk of opportunistic and community-acquired infections such as respiratory virus infections. They are at risk of high mortality and co-morbidity [3].
For patients with rheumatic disease, there is little data to understand the real consequences of the infection. Pediatric rheumatologists are expected to play a supporting role in treatment of COVID-19, both as pediatricians treating infected children, and as rheumatologists taking care of their rheumatic patients, as well as offering their experience in the possible alternative use of immunomodulatory drugs [4].
2. Case Presentation
A 16 year-old, 80-kg patient was referred to a tertiary hospital in Shiraz, Iran on 27 March 2020. He had a known case of Granulomatosis with polyangiitis and was diagnosed 2 years prior. At that time the patient presented with headache, sore throat, conjunctivitis for 1 month that was followed by lower extremities edema and joints pain and skin rash, and the Granulomatosis with polyangiitis was distinguished. His condition was in remission according to the Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis Evaluation Form [5] before recent disease. The patient was on these medications before admission: prednisolone 10 milligrams (mg) daily, mycophenolate 360 mg twice per day, aspirin 80 mg daily, valsartan 10 mg daily, allopurinol 100 mg daily and folic acid. The patient’s complaint started with coughing and rhinorrhea 7 days prior to admission. His condition worsened over the following few days. He had very limited activity in the 3 days prior to admission. He displayed shortness of breath and preferred to lie down in a prone position.
On the day of admission, he was intubated in the emergency room due to respiratory distress and decreased O2 Saturation (O2 Sat) of 70%. He was transferred to the pediatric intensive care unit (PICU). In the PICU, a ventilator was set up on SIMV with a respiratory rate of 20/min, tidal volume of 500 mL, inspiratory time: 1min, peak end expiratory pressure (PEEP): 15 cm H2O and FIO2: 100%. An infusion of norepinephrine was administered due to hypotension. Covid-19 RT-PCR came back positive. There was no history of exposure to confirmed or suspected coronavirus cases.
His medication continued except valsartan. Prednisolone changed to stress dose of hydrocortisone.
Lopinavir, ritonavir, hydroxy chloroquine, vancomycin and meropenem started. He also received intravenous immunoglobulin (IVIG) the first day of admission because of his refractory shock.
Chest X-ray on admission showed bilateral patchy infiltration which deteriorated to white lung on day 6 (Figure 1). A CT scan was not done due to his severe condition and the lack of a portable ventilator with high PEEP set up. All lab tests are shown in Table 1.
On day 3 he had atrial fibrillation with rapid ventricular response. After emergency intervention, flecainide began with pediatric cardiologist consultation.
He also became anuric on day 4 and continuous veno-venous hemodialysis started for him. His condition deteriorated over time with a decrease in O2 Sat in spite of 100% of FIO2 and an increase in PEEP to 22cm H2O. On day 3, he was put into a prone positioning which helped to increase O2 Sat (up to 97%). However, it started to decline again after 36 h.
Unfortunately, the patient expired on day 6 of admission with low O2 Sat and bradycardia.
3. Discussion
COVID-19 mortality in children is very rare. The data from a low number of children suggest that even children who are on immunosuppressive treatment for various indications have a mild clinical course of COVID-19. Additionally, a study with eight children with inflammatory bowel disease (IBS), despite treatment with immunomodulators, biologics, or both, shows that all children diagnosed with COVID-19 had a mild infection [6].
But in this patient, an underlying disease and delayed admission to the hospital were two factors complicating his condition.
In addition, while there was extensive publicity for home quarantine, it is important to note that fears of contracting coronavirus may cause people to delay going to health centers until it is too late to treat them effectively. Some patients, concerned about over-burdening the healthcare system, may also delay seeking hospital treatment until their symptoms become critical.
The existing data on past and present coronavirus outbreaks show that immunosuppressed patients are not at increased risk of severe pulmonary disease compared with the general population. Children under the age of 12 years do not progress to severe coronavirus pneumonia, without paying attention to their immune status, although they get infected and can spread the infection [7].
Screening those who care for these high-risk patients is also suggested.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
A.S. and E.S. wrote the manuscript. E.S. gathered patient’s data and submitted the manuscript. Z.S. and S.A. edited the manuscript and were scientific consultant. All authors discussed the results and contributed to the final manuscript. All authors have read and agreed to the published version of the manuscript.
Funding
The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Institutional Review Board Statement
This study was approved by the ethics committee of Shiraz University of Medical Sciences (IR.SUMS.MED.REC.1399.216).
Informed Consent Statement
Written informed consent was obtained from the parents and sent to the ethics committee.
Data Availability Statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Chest X-ray on day 1 (left) and day 4 (right).
pediatrrep-13-00004-t001_Table 1Table 1 Lab tests from day 1 to day 6 of admission.
Day of Admission → 1 2 3 4 5 6
Lab Data ↓
COVID RT-PCR Positive
Influenza RT-PCR Negative
Blood urea nitrogen (mg/dl) 53 59 67 68 87 96
creatinine 4.8 5.5 5.2 5.9 7.9 8.8
Sodium (mEq/L) 130 135 139 134 135 136
Potassium (mEq/L) 6 5.4 3.7 4.5 5.6 5.2
Calcium (mg/dL) 8.3
8.9
8.4
Troponin (ng/mL) 450 1688
D.Dimer (ng/mL)
650
7627
Lactate dehydrogenase (U/L) 1350 1340
Creatine phosphokinase (U/L)
119 137 537 1030 1040
Magnesium (mg/dL) 2.4
1.9
3.1
Ferritin (ng/mL)
1310
Procalcitonin (ng/mL) 5.77
Aspartate transaminase (U/L)
43
Alanine aminotransferase (U/L)
13
White blood cells(count/mL) 22,800 14,800 17,200 22,900 15,800 16,200
Hemoglobin (g/dL) 9.6 7.8 11.1 * 10.5 9 8
Platelet (count/mL) 494,000 338,000 339,000 325,000 234,000 196,000
Prothrombin time 12 12.1 13.6 18.1+ 20+ 15.3
Partial thromboplastin time 25 24 33 41 47 38
INR 1 1.01 1.2 1.8 2.13 1.4
HIV antibody, HCV antibody, HBS antigen were negative. TB work up was negative. * red blood cell transfusion, +fresh frozen plasma transfusion. | Fatal | ReactionOutcome | CC BY | 33406578 | 19,063,353 | 2021-01-04 |
What was the outcome of reaction 'Off label use'? | COVID-19 in Pediatric Granulomatosis with Polyangiitis.
The confirmed cases with COVID-19 in children account for just 1% of the overall confirmed cases. Severe COVID-19 in children is rare. Case Presentation: Our patient was 16 years old with a severe case of COVID-19 and did not survive due to the presence of Granulomatosis with polyangiitis and being treated with immunosuppressive drugs. We used lopinavir, ritonavir, hydroxy chloroquine, intravenous immunoglobulin and continuous veno-venous hemodialysis for treatment. Conclusion: In this patient, an underlying disease and delayed admission to the hospital were two factors complicating his condition.
1. Introduction
The outbreak of COVID-19 started as an epidemic in Wuhan, China and caught world-wide attention as a pandemic in January 2020. Confirmed pediatric cases account for just 1% of total cases [1].
Severe COVID-19 infections in children are rare. To date, the largest review of children with COVID-19 included 2143 children in China. Only 112 (5.6%) of 2143 children infected presented with severe symptoms (defined as hypoxia) and 13 (0.6%) children developed respiratory distress syndrome (ARDS) or multi-organ failure [2].
Our patient had a severe case of COVID-19 and did not survive due to the presence of Granulomatosis with polyangiitis and being treated with immunosuppressive drugs.
Rheumatological diseases and inflammatory bowel disease are immune disorders that are associated with an increased risk of opportunistic and community-acquired infections such as respiratory virus infections. They are at risk of high mortality and co-morbidity [3].
For patients with rheumatic disease, there is little data to understand the real consequences of the infection. Pediatric rheumatologists are expected to play a supporting role in treatment of COVID-19, both as pediatricians treating infected children, and as rheumatologists taking care of their rheumatic patients, as well as offering their experience in the possible alternative use of immunomodulatory drugs [4].
2. Case Presentation
A 16 year-old, 80-kg patient was referred to a tertiary hospital in Shiraz, Iran on 27 March 2020. He had a known case of Granulomatosis with polyangiitis and was diagnosed 2 years prior. At that time the patient presented with headache, sore throat, conjunctivitis for 1 month that was followed by lower extremities edema and joints pain and skin rash, and the Granulomatosis with polyangiitis was distinguished. His condition was in remission according to the Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis Evaluation Form [5] before recent disease. The patient was on these medications before admission: prednisolone 10 milligrams (mg) daily, mycophenolate 360 mg twice per day, aspirin 80 mg daily, valsartan 10 mg daily, allopurinol 100 mg daily and folic acid. The patient’s complaint started with coughing and rhinorrhea 7 days prior to admission. His condition worsened over the following few days. He had very limited activity in the 3 days prior to admission. He displayed shortness of breath and preferred to lie down in a prone position.
On the day of admission, he was intubated in the emergency room due to respiratory distress and decreased O2 Saturation (O2 Sat) of 70%. He was transferred to the pediatric intensive care unit (PICU). In the PICU, a ventilator was set up on SIMV with a respiratory rate of 20/min, tidal volume of 500 mL, inspiratory time: 1min, peak end expiratory pressure (PEEP): 15 cm H2O and FIO2: 100%. An infusion of norepinephrine was administered due to hypotension. Covid-19 RT-PCR came back positive. There was no history of exposure to confirmed or suspected coronavirus cases.
His medication continued except valsartan. Prednisolone changed to stress dose of hydrocortisone.
Lopinavir, ritonavir, hydroxy chloroquine, vancomycin and meropenem started. He also received intravenous immunoglobulin (IVIG) the first day of admission because of his refractory shock.
Chest X-ray on admission showed bilateral patchy infiltration which deteriorated to white lung on day 6 (Figure 1). A CT scan was not done due to his severe condition and the lack of a portable ventilator with high PEEP set up. All lab tests are shown in Table 1.
On day 3 he had atrial fibrillation with rapid ventricular response. After emergency intervention, flecainide began with pediatric cardiologist consultation.
He also became anuric on day 4 and continuous veno-venous hemodialysis started for him. His condition deteriorated over time with a decrease in O2 Sat in spite of 100% of FIO2 and an increase in PEEP to 22cm H2O. On day 3, he was put into a prone positioning which helped to increase O2 Sat (up to 97%). However, it started to decline again after 36 h.
Unfortunately, the patient expired on day 6 of admission with low O2 Sat and bradycardia.
3. Discussion
COVID-19 mortality in children is very rare. The data from a low number of children suggest that even children who are on immunosuppressive treatment for various indications have a mild clinical course of COVID-19. Additionally, a study with eight children with inflammatory bowel disease (IBS), despite treatment with immunomodulators, biologics, or both, shows that all children diagnosed with COVID-19 had a mild infection [6].
But in this patient, an underlying disease and delayed admission to the hospital were two factors complicating his condition.
In addition, while there was extensive publicity for home quarantine, it is important to note that fears of contracting coronavirus may cause people to delay going to health centers until it is too late to treat them effectively. Some patients, concerned about over-burdening the healthcare system, may also delay seeking hospital treatment until their symptoms become critical.
The existing data on past and present coronavirus outbreaks show that immunosuppressed patients are not at increased risk of severe pulmonary disease compared with the general population. Children under the age of 12 years do not progress to severe coronavirus pneumonia, without paying attention to their immune status, although they get infected and can spread the infection [7].
Screening those who care for these high-risk patients is also suggested.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
A.S. and E.S. wrote the manuscript. E.S. gathered patient’s data and submitted the manuscript. Z.S. and S.A. edited the manuscript and were scientific consultant. All authors discussed the results and contributed to the final manuscript. All authors have read and agreed to the published version of the manuscript.
Funding
The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Institutional Review Board Statement
This study was approved by the ethics committee of Shiraz University of Medical Sciences (IR.SUMS.MED.REC.1399.216).
Informed Consent Statement
Written informed consent was obtained from the parents and sent to the ethics committee.
Data Availability Statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Chest X-ray on day 1 (left) and day 4 (right).
pediatrrep-13-00004-t001_Table 1Table 1 Lab tests from day 1 to day 6 of admission.
Day of Admission → 1 2 3 4 5 6
Lab Data ↓
COVID RT-PCR Positive
Influenza RT-PCR Negative
Blood urea nitrogen (mg/dl) 53 59 67 68 87 96
creatinine 4.8 5.5 5.2 5.9 7.9 8.8
Sodium (mEq/L) 130 135 139 134 135 136
Potassium (mEq/L) 6 5.4 3.7 4.5 5.6 5.2
Calcium (mg/dL) 8.3
8.9
8.4
Troponin (ng/mL) 450 1688
D.Dimer (ng/mL)
650
7627
Lactate dehydrogenase (U/L) 1350 1340
Creatine phosphokinase (U/L)
119 137 537 1030 1040
Magnesium (mg/dL) 2.4
1.9
3.1
Ferritin (ng/mL)
1310
Procalcitonin (ng/mL) 5.77
Aspartate transaminase (U/L)
43
Alanine aminotransferase (U/L)
13
White blood cells(count/mL) 22,800 14,800 17,200 22,900 15,800 16,200
Hemoglobin (g/dL) 9.6 7.8 11.1 * 10.5 9 8
Platelet (count/mL) 494,000 338,000 339,000 325,000 234,000 196,000
Prothrombin time 12 12.1 13.6 18.1+ 20+ 15.3
Partial thromboplastin time 25 24 33 41 47 38
INR 1 1.01 1.2 1.8 2.13 1.4
HIV antibody, HCV antibody, HBS antigen were negative. TB work up was negative. * red blood cell transfusion, +fresh frozen plasma transfusion. | Fatal | ReactionOutcome | CC BY | 33406578 | 19,063,353 | 2021-01-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pruritus'. | Influenza Vaccination and Myo-Pericarditis in Patients Receiving Immune Checkpoint Inhibitors: Investigating the Likelihood of Interaction through the Vaccine Adverse Event Reporting System and VigiBase.
BACKGROUND
Evidence on whether the influenza vaccine could exacerbate immune-related adverse events, including myopericarditis (MP), in patients treated with immune checkpoint inhibitors (ICIs), is still conflicting. We explored this issue through a global real-world approach.
METHODS
We queried the Vaccine Adverse Event Reporting System (VAERS) and VigiBase to retrieve cases of MP in which the influenza vaccine and ICIs were recorded as suspect and were concomitantly reported. For the included cases, causality assessment and Drug Interaction Probability Scale (DIPS) algorithms were applied.
RESULTS
There were 191 and 399 reports of MP with the influenza vaccine that were retrieved (VAERS and VigiBase, respectively). No case of MP reporting the concomitant use of ICIs and the influenza vaccine was found in VAERS, while three cases of myocarditis were retrieved in VigiBase. All of the cases were unclassifiable for a causality assessment because of the lack of data concerning latency. According to the DIPS, one report was categorized as possible and two as doubtful.
CONCLUSIONS
The paucity of cases coupled with the doubtful causality assessment make the potential interaction between influenza vaccines and ICIs in cancer patients negligible from clinical and epidemiological standpoints. These findings support the cardiovascular safety of the influenza vaccination, which remains strongly recommended in cancer patients, especially in the current COVID-19 era.
1. Introduction
The safety of vaccines and medications is a current global safety issue. The annual vaccination against the influenza virus is the primary means of preventing influenza and its complications in high-risk subjects, including adult cancer patients, as described by observational studies, suggesting lower mortality and infection-related outcomes with influenza vaccination [1]. However, in the recent past, potential pharmacokinetic interactions have been proposed, considering that vaccines can influence the drug metabolism via inflammatory cytokines [2]. Therefore, potential interactions between influenza vaccines and drugs used for chronic diseases (e.g., immunosuppressive agents) cannot be excluded [3]. Moreover, cases of myo-pericarditis (MP) after immunization, although rarely, are reported [4,5].
Myocarditis and pericarditis represent serious and life-threatening inflammatory diseases involving myocardium and pericardium, potentially associated with the use of several drugs and vaccines [6,7,8]. In particular, cases of MP were described with the smallpox vaccine in early 2000 and, more recently, very rarely are reported after influenza immunization [4,5]. Immune checkpoint inhibitors (ICIs), such as anti-PD1, anti-PDL1, and anti-CTLA4 monoclonal antibodies, are approved as first-line agents in the management of melanoma and non-small cell lung cancer. They may cause a variegate spectrum of cardiovascular events, including MP, with a higher mortality compared with other immune-related adverse events (irAEs) [9,10,11,12,13]. In a summary of the product characteristics of the different ICIs, pericarditis and myocarditis are reported as uncommon (≥1/1000 to <1/100) and rare (≥1/10,000 to <1/1000, respectively) AEs. Notably, the detection of myocarditis with ICIs requires the permanent discontinuation of treatment, no matter the severity.
Consequently, the question arises as to whether pharmacokinetic and pharmacodynamic interactions occur in patients receiving the influenza vaccination (recommended both by oncologists and cardiologists) and ICIs, possibly causing or exacerbating irAEs such MP. Although no cases of myocarditis have been reported, evidence on whether the influenza vaccine exacerbates irAEs is still conflicting and poorly investigated [14]. Only a retrospective study investigated the clinical features of myocarditis with ICIs in patients receiving the influenza vaccine; reduced myocardial injury and a lower risk of major adverse cardiac events among recipients of the influenza vaccine was found compared with not vaccinated patients [15].
In the recent past, analysis of the spontaneous reporting systems (SRSs) has attracted considerable interest among clinicians for the accurate and timely characterization of drug- and vaccine-related risks occurring in the real world, where comorbidities and polypharmacotherapy exist. By offering a global epidemiological perspective, these pharmacovigilance studies have been pursued to test the hypothesis of potential associations, including refusing the likelihood of interactions [3,16,17], especially for rare, unexpected, and delayed AEs, such as MP.
In this study, we investigated the likelihood of interaction between the influenza vaccination and ICIs by analyzing spontaneous reports of MP collected from the Vaccine Adverse Event Reporting System (VAERS; P.O. Box 1100; Rockville, MD 20849-1100) and the World Health Organization’s (WHO) global Individual Case Safety Report database (VigiBase®; Uppsala Monitoring Centre Box, 1051 SE-751 40, Uppsala, Sweden).
2. Materials and Methods
2.1. Study Conception and Design
The study was conceived as an observational retrospective analysis of spontaneous reports of MP collected from the VAERS and the VigiBase® to (a) characterize relevant clinical features; (b) highlight the concomitant use of agents known to cause MP, including ICIs; and (c) assess the causality and probability of interaction between the influenza vaccine and ICIs.
VAERS is a national system to monitor the safety of US-licensed vaccines [18], whereas VigiBase® collects worldwide reports on vaccines and drugs, thus making these archives act as complementary approaches [19].
VAERS transmits its vaccine adverse event reports to the VigiBase, in order to contribute to the global pharmacovigilance effort along with other countries that employ passive vaccine safety monitoring systems [18], thus possible duplicates between the two databases may exist.
2.2. Data Source
Established in 1990, the VAERS is co-managed by the Centers for Disease Control and Prevention and the US Food and Drug Administration (FDA); it collects and analyzes reports of AEs following immunization (AEFI) for vaccines licensed in the US, receiving approximately 28,000 reports of AEFI annually.
AEFI may be any unfavorable or unintended sign, abnormal laboratory finding, symptom, or disease that occurs following or during the administration of a vaccine. AEs are temporally associated events that may either be caused by a vaccine or be coincidental to it, i.e., not necessarily related to the vaccination [20]. VAERS may be used to detect unexpected and rare patterns of AEFI, unlikely to arise in pivotal trials because of the limited number of patients involved [21]. Health-care professionals, vaccine manufacturers, and consumers (patients, parents, and caregivers) can submit reports of AEs to VAERS.
VigiBase® is one of the largest and most comprehensive pharmacovigilance databases, maintained by the Uppsala Monitoring Centre in Sweden, and containing over 20 million of Individual Case Safety Reports from 110 countries over the five continents. VigiBase® collects reports of AEs for authorized drugs, vaccines, and food supplements, submitted from healthcare professionals, pharmaceutical companies, and patients.
For each vaccine/drug, the characterization of the vaccine/drug role indicated by the primary reporter (i.e., the original source of the information) includes the following three categories: suspect, concomitant, and interacting. All spontaneous reports should have at least one suspect vaccine/drug, namely involved, presumably, in the occurrence of AEFI. If the reporter indicates a suspected interaction, all interacting vaccines/drugs are considered to be suspect vaccines/drugs.
In both databases, AEs are codified through the Medical Dictionary for Regulatory Activities (MedDRA) terminology, and described and organized in terms of Preferred Terms (PTs).
2.3. Data Extraction and Analysis
A multi-step approach was followed for data extraction in each database:(1) Reports for individuals receiving any type of vaccine against the influenza virus categorized as suspect AEFI submitted to VAERS (from July 1990 to September 2020) and VigiBase® (from inception to October 2020) were selected.
(2) Cases of myocarditis or pericarditis were extracted through specific PTs and lowest level terms, in line with previous studies on the influenza vaccination [4] and the potential immune-related basis of cardiotoxicity documented for ICIs by recent pharmacovigilance analyses [9,10]: myocarditis, pericarditis, immune-mediated myocarditis, and myopericarditis.
(3) Reports recording AEs of interest were finally assessed for co-reported drugs/vaccines of interest.
In VigiBase, retained reports (refer to point 2) with ICIs, namely PD-1 inhibitors (nivolumab, pembrolizumab, and cemiplimab), PD-L1 inhibitors (atezolizumab, avelumab, and durvalumab), and CTLA-4 inhibitors (ipilimumab and tremelimumab), were evaluated by extracting the following data: demographic features (age, gender, weight, year, and reporter country), reporter qualification, comorbidities, concomitant medications (including dose and route of administration when available), latency, degree of seriousness, outcome, and management of the AE. The same approach was applied to identify cases of interest reported for vaccines against the influenza virus, both as suspect alone or concomitant to ICI exposure.
In VAERS, for each report of interest with the influenza vaccines, the following data were extracted: demographic features (age, gender, year, and reporter country), type of vaccine against the influenza virus, medical history, concomitant drugs or administered vaccines, laboratory data, AEs codified as PTs, latency, AE degree of seriousness, outcome, and narratives, when available.
According to WHO criteria, a serious AE is any untoward medical occurrence that, no matter the dose, results as fatal, causing a life-threatening event, requiring hospitalization of the patient, causing serious/permanent disability, causing congenital abnormalities, or other clinically relevant conditions [22].
Co-reported medications and comorbidities known to cause myocarditis or pericarditis (i.e., potential confounders) were further characterized according to the lists proposed by Adler et al. [6], Caforio et al. [7], and Butany et al. [8].
2.4. Causality Assessment and Evaluation of Drug–Vaccine Interaction
The probability of interaction when the influenza vaccine and ICIs are co-reported was evaluated by applying the established WHO criteria for causality assessment [20], as well as the Drug Interaction Probability Scale (DIPS) [23].
The following items were accounted for in the AEFI causality assessment: temporal relationship, alternate explanations, proof of association, prior evidence, population-based evidence, and biological plausibility [20]. Cases without adequate information were classified as “unclassifiable”; cases with adequate information were categorized as: (1) “consistent with a causal relationship”, when the available evidence supported a causal relationship between the vaccine and the AEFI in the individual, but it did not rule out the possibility that the AEFI may have been caused by a factor other than the vaccine; (2) “inconsistent with a causal association”, when the available evidence did not support a causal relationship between vaccine administration and the reported AEFI in the individual; and (3) “indeterminate”, when the temporal relationship was consistent but the available evidence insufficient to support or rule out a causal relationship in the individual.
The DIPS is a 10-item tool specifically developed to assess the likelihood of drug–drug interactions [23]. ICIs were considered as the objective drugs (i.e., the one affected by the presence of another vaccine/drug), while the influenza vaccine was considered as the precipitant agent (i.e., the one causing a change on the object drug). To avoid overemphasis on the role of the vaccine, the answer to the second question was always “unknown” (knowledge on the mechanism of the interaction is hypothesized and literature data are very scarce/uncertain); in addition, questions 5, 6, and 10 were not assessable/applicable (dechallenge, rechallenge, and dose adjustments are unfeasible for vaccines considering the peculiarities of their administration), as previously performed [3]. The final summary score could reach 10 points. Higher total scores correspond to a higher likelihood of drug–vaccine interaction (i.e., >8 = highly probable; 5–8 = probable; 2–4 = possible; <2 = doubtful).
3. Results
3.1. Demographic and Clinical Data
Over the observed period, out of a total of 712,776 AEFI, 191 (0.03%) reports of MP mentioning the influenza vaccine as suspect were collected within the VAERS.
The clinical and demographic characteristics are provided in Table 1. The reports included 124 men (64.9%) and 62 women (in five cases gender was not reported), aged between 1 and 88 years (mean age 44.5 years). Pericarditis were reported in 117 cases (61.3%), followed by myocarditis (81 cases; 42.4%) and MP (7 cases; 3.7%). No cases of immune-mediated myocarditis were retrieved.
The median onset was seven days; in 34.0% of reports, the AEFI of interest occurred in the first 3 days after the administration of the influenza vaccine. Comorbidities potentially implicated in the occurrence of the AEFI of interest were retrieved in six cases (3.1%), with ulcerative colitis and systemic lupus erythematosus being the most represented. Other vaccines were concomitantly administered in 59 cases (30.9%), accounting for a mean number of 3.1 vaccines per patient.
In 141 cases (73.8%), the report was classified as serious, and 16 fatal cases (8.4%) were found. Recovery occurred in 31.4% of cases.
In the VigiBase®, 246,864 reports mentioning the influenza vaccine as a suspect agent were found, and myocarditis/pericarditis were reported in 399 cases (0.16%; Table 1).
The cases showed a mean age of 46.7 years, with a male preponderance (65.9%). Reports were largely submitted from US (45.9%) and Europe (45.1%). Pericarditis was reported in 225 cases (56.4%), followed by myocarditis (193 cases; 48.4%) and myopericarditis (29; 7.3%). No cases of immune-mediated myocarditis were found.
Median onset was five days, and in 29.8% of reports, AEs of interest occurred in the first three days after the administration of the influenza vaccine. Comorbidities potentially implicated in the occurrence of myocarditis/pericarditis were retrieved in two patients (0.5%) affected by ulcerative colitis. Other vaccines were concomitantly administered in 87 cases (21.8%), accounting for a mean number of 2.5 vaccines per patient.
In 303 cases (76.0%), the report was classified as serious, and 28 fatal cases (7.0%) were found. Recovering occurred in 41.1% of cases.
3.2. Co-Reported Medications and Detection of Cases with ICI Administration
Overall, concomitant medications were found in 49 (25.7%) and 57 (14.3%) cases with the influenza vaccine in VAERS and VigiBase®, respectively (Table 1). In 14 (7.3%) and 13 (3.3%) cases, five or more concomitant drugs were reported in VAERS and VigiBase®, respectively.
Concomitant medications potentially implicated in the occurrence of myocarditis/pericarditis were retrieved in 21 (11.0%) and 24 (6.0%) cases in VAERS and VigiBase®, respectively, with hydrochlorothiazide being the most frequent in both databases (in six and five cases, respectively).
Only six cases (one classified as serious, where Guillain-Barré syndrome was recorded) with the concomitant use of ICIs and the influenza vaccine were found in VAERS (Table S1), but no cases of myocarditis/pericarditis. In VigiBase®, two cases of myocarditis reporting the concomitant administration of ICIs and the influenza vaccine both mentioned as suspect agents were retrieved. A third case of myocarditis in which the influenza vaccine was classified as a concomitant agent was detected (Table 2).
The three cases were classified as serious (causing prolonged hospitalization), included two men and one woman, aged 67–77 years, and affected by lung or renal carcinoma. Nivolumab, pembrolizumab, and ipilimumab/nivolumab combination therapy were reported as the ICI regimen. In two cases ICI was withdrawn, while recovering occurred in only one case.
3.3. Causality Assessment and Evaluation of Drug–Vaccine Interaction
These three cases showed an unclassifiable causality assessment due to the lack of data concerning the latency and time window of increased risk (Table 2).
By applying the adapted DIPS algorithm, one report was categorized as possible (due to the lack of underlying diseases or co-reported agents known to cause or precipitate myocarditis, and to the detection of troponin increase) and two as doubtful (only the absence of underlying diseases or co-reported agents known to cause or precipitate myocarditis were recognized; Table S2).
4. Discussion
To the best of our knowledge, this is the first real-world study investigating the potential interactions between influenza vaccines and ICIs resulting in myocarditis or pericarditis in cancer patients, by assessing spontaneous reports submitted to the VAERS and VigiBase®. This global post-marketing safety study stems from recent conflicting real-world evidence surrounding the possible exacerbation of irAEs with influenza vaccines in patients treated with ICIs [14,15,24,25,26,27,28,29], thus joining in the wider debate on the bidirectional relationship between immunotherapy and the influenza vaccination, potentially affecting the clinical and humoral efficacy of the vaccine, performance of ICIs, and safety [14].
Four major findings emerged from our analysis: (a) myocarditis and pericarditis represented a very rare AEFI (with a non-negligible proportion of death, approximately 8–9%), based on the low reporting frequency retrieved in both SRSs (<0.1–0.2% of overall AEs), also considering the influenza vaccination coverage rates (estimated at about 25% per year in Europe [30,31]) and the relevant million doses distributed worldwide; (b) the reporting of myocarditis in patients concomitantly receiving influenza vaccines and ICIs is limited to only three out of a total of 1465 cases of myocarditis/pericarditis found with influenza vaccines or ICIs (considered as suspect agents) in the two databases; (c) these cases were unclassifiable for causality assessment with a doubtful probability of drug–vaccine interaction (according to the adapted DIPS algorithm), thus suggesting that the vaccine is not directly involved in the occurrence of myocarditis (and in one of the three cases, influenza vaccine was reported only as concomitant and not as suspect or interacting agent); and (d) no other cardiovascular AEs were found in patients concomitantly receiving influenza vaccination and ICIs, as well as no other irAEs were reported, except for a single case of Guillain-Barré syndrome, a condition already associated with both ICIs and the influenza vaccine [32,33,34].
Theoretically, a possible pharmacodynamic interaction between influenza vaccines and ICIs leading to the exacerbation of irAEs (including MP), could be supposed. The blockade of a PD-1/PD-L1 pathway together with the vaccination (particularly in conjunction with a strong vaccine adjuvant) could enhance one or more of the mechanisms associated with irAEs onset (infiltration of central memory T cells into the tissues, cross-presentation of shared antigens, and exacerbation of previously subclinical auto-immune syndromes) [24].
Our specific focus on the myo-pericardium stems from the peculiar clinical features of myocarditis in terms of severity and mortality compared with other irAEs, usually requiring immunotherapy discontinuation [9,10,11,12,13], as reported in two out of our three cases. Although, in all three cases, no underlying diseases or other agents known to cause or precipitate myocarditis were recorded, the lack of data concerning latency and solid literature studies allows for minimizing, if not completely excluding, the clinically relevant contribution of a potential drug–vaccine interaction in our cases.
Furthermore, the only study investigating the association between influenza vaccine and the development of myocarditis among patients on ICIs found that the administration of the vaccine was not associated with an increased risk of subsequent myocarditis [15]. Additionally, myocarditis cases in which the influenza vaccine was administered showed lower troponin levels at presentation and a lower risk of major adverse cardiac events at follow-up compared with non-vaccinate patients developing myocarditis with ICIs [15], thus suggesting a protective role for the influenza vaccine in this setting.
ICIs caused a paradigm shift in cancer treatment, and are currently used as first-line agents in the management of non-small cell lung cancer, melanoma, and renal carcinoma [35]. Considering their evolving role and expected increasing uptake, the assessment of cardiovascular safety is of paramount importance. Likewise, the safety of influenza vaccines represents an important issue, given the high morbidity and mortality rates caused by influenza in cancer patients [36]. Notably, the development of influenza infection may also, albeit rarely, be associated itself with an increased risk of myocarditis and major adverse cardiovascular events [37,38]. Therefore, the suggested protective role of the influenza vaccine on cardiovascular outcome [15] cannot be overlooked.
Collectively, our findings provide a reassuring message in terms of cardiovascular safety for cancer patients treated with ICIs and requiring the influenza vaccination. Of note, less than 20% of patients affected by malignancies received the influenza vaccine, with a gradual decline in the last decade [39]. We support and promote the achievement of an optimal vaccination coverage rate in cancer patients for several reasons, including the following: (a) direct association with a lower mortality and infection-related outcomes in immunosuppressed adults [1]; (b) a better overall survival recently reported in patients treated with ICIs receiving influenza vaccination [40]; and (c) the current COVID-19 pandemic, to reduce the strain on the healthcare system while protecting vulnerable subjects from the dramatic impact of a possible co-infection [41]. Cancer patients receiving immunotherapy are at high risk of severe events as a result of COVID-19 systemic involvement, including pneumonitis and myocarditis [42], and a recent systematic review found no significant increase in the risk of infection or in the illness severity or lethality of COVID-19 in subjects receiving the influenza vaccine, with some studies reporting a significantly inverse association [43]. Therefore, the implementation of measures aimed at raising influenza vaccination coverage in frail patients is strongly recommended.
We acknowledge the limitations of our study, mainly inherent to the nature of SRSs data. VAERS and VigiBase® are subject to reporting bias, including under- and over-reporting of adverse events, although there are not clues for major distortions, considering that serious events such as MP are less prone to under-reporting, and no specific warnings were posted by regulatory agencies, thus minimizing the existence and impact of a stimulated reporting [3,18]. We recognize the potential occurrence of subclinical myocarditis, which may be under-diagnosed/under-detected, and is thus likely to be under-reported. Furthermore, the quality and completeness of the reports collected in both databases are variable, and many records lack valid medical diagnoses, thus making the assessment of causality challenging. Additionally, DIPS was not specifically developed to assess drug–vaccine interactions, although we implemented an adapted version in order to the better focus on the possible precipitating role of the influenza vaccine.
Notwithstanding these limitations, pharmacovigilance assessment represents an invaluable opportunity to monitor vaccine safety and identify novel rare signals, potentially arising from drug–vaccine interactions, both from a local and international perspective. Furthermore, our findings are consistent between the two databases, thus supporting the lack of evidence of a clinically relevant drug–vaccine interaction. The identification of myocarditis with ICIs, in line with previous findings [9,10,11], further corroborates the ability of our post-marketing approach to identify actual true-positive associations.
In conclusion, the paucity of cases coupled with a lack of certainty in terms of causality assessment and doubtful probability make the risk of myocarditis and pericarditis by interaction between influenza vaccines and ICIs in cancer patients negligible from both clinical and epidemiological standpoints. Our findings support the cardiovascular safety of influenza vaccines in subjects treated with immunotherapy, thereby emphasizing the importance of a flu vaccination in this population, especially in the current COVID-19 era.
Acknowledgments
We would like to thank Annette Rudolph for data extraction from VigiBase®. Authors at the University of Bologna are supported by institutional research funds (Ricerca Fondamentale Orientata). No sources of funding were received for the preparation of this article.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2076-393X/9/1/19/s1. Table S1: Case-by-case assessment of reports recorded in VAERS in which influenza vaccine and immune checkpoint inhibitors (ICIs) were concomitantly used. Table S2: Application of the adapted version of Drug Interaction Probability Scale in cases of myocarditis/pericarditis in which immune checkpoint inhibitors (ICIs) and influenza vaccine were concomitantly administered.
Click here for additional data file.
Author Contributions
M.G.: methodology, investigation, formal analysis, and writing—original draft. E.R.: conceptualization, methodology, formal analysis, and writing—reviewing and editing. U.M.: writing—reviewing and editing. A.A.: writing—reviewing and editing. E.P.: conceptualization, methodology, formal analysis, and writing—reviewing and editing. I.D.: conceptualization and writing—reviewing and editing. All authors have read and agreed to the published version of the manuscript.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Institutional Review Board Statement
Under current legislation, institutional review board approval is not required when performing analysis of the publicly available VAERS and VigiBase databases, because it contains anonymized data that cannot allow patients’ identification.
Informed Consent Statement
Patient consent was waived due to VAERS and VigiBase databases contain anonymized data that cannot allow patients’ identification.
Data Availability Statement
Data supporting the findings of this study were derived from the following resource available in the public domains: https://wonder.cdc.gov/vaers.html and http://www.vigiaccess.org/.
Conflicts of Interest
M.G., E.R., E.P., U.M., and I.D. have no conflicts of interest relevant to the content of the present work. A.A. reports grants and personal fees from BMS, as well as grants from MSD, Roche, Astra Zeneca, Eli-Lilly, Takeda, and Bayer, outside of the submitted work.
vaccines-09-00019-t001_Table 1Table 1 Demographic and clinical feature of cases of myocarditis/pericarditis reported with influenza vaccine as suspect in Vaccine Adverse Event Reporting System (VAERS) and the World Health Organization’s (WHO) global Individual Case Safety Report database (VigiBase®).
Demographic Features VAERS VigiBase
Overall number of cases 191 399
Proportion of cases (based on overall number of reports with the flu vaccine) 0.03% (712,776) 0.16% (246,864)
Age (mean) 44.5 ± 22.9 46.7 ± 22.3
Sex
Female 62 (32.5%) 131 (32.8%)
Male 124 (64.9%) 263 (65.9%)
Not specified 5 (2.6%) 5 (1.3%)
Reporter country
US 109 (57.1%) 183 (45.9%)
Non-US 60 (31.4%) -
Europe - 180 (45.1%)
Asia - 10 (2.5%)
Oceania - 19 (4.8%)
America (except US) - 7 (1.7%)
Not specified 22 (11.5%) -
Reported symptoms (preferred terms) *
Myocarditis 81 (42.4%) 193 (48.4%)
Pericarditis 117 (61.3%) 225 (56.4%)
Myopericarditis 7 (3.7%) 29 (7.3%)
Immune-mediated myocarditis 0 (0.0%) 0 (0.0%)
Co-medications
Overall number of cases 49 (25.7%) 57 (14.3%)
≥5 concomitant drugs 14 (7.3%) 13 (3.3%)
1–4 concomitant drugs 35 (18.4%) 44 (11.0%)
No concomitant drugs 142 (74.3%) 342 (85.7%)
Co-medications potentially implicated in the occurrence of myocarditis/pericarditis **
Number of cases 21 (11.0%) § 24 (6.0%) #
Immune checkpoint inhibitors (ICIs) None 2
Hydrochlorothiazide 6 5
Indomethacin 2 2
Glipizide 2 -
Clonazepam 2 -
Alprazolam 2 -
Furosemide 1 1
Bendroflumethiazide 1 2
Mesalazine 1 2
Colchicine 1 1
Doxycycline 1 2
Cotrimoxazole 1 1
Lorazepam 1 -
Amoxicillin 1 1
Isosorbide dinitrate 1 2
Tetracycline - 2
Spironolactone - 1
Cefuroxime - 1
Heparin - 1
Bromazepam - 1
Comorbidities potentially implicated in occurrence of myocarditis/pericarditis **
Number of cases 6 (3.1%) 2 (0.5%)
Ulcerative colitis 2 2
Systemic lupus erythematosus 2 -
Juvenile rheumatoid arthritis 1 -
Insulin-dependent diabetes mellitus 1 -
Onset (days; median) 7 (1.5–13) 5 (1–12)
≤3 days 65 (34.0%) 119 (29.8%)
4–7 days 19 (10.0%) 50 (12.5%)
8–14 days 35 (18.4%) 61 (15.3%)
≥15 days 36 (18.8%) 56 (14.0%)
Not specified 36 (18.8%) 113 (28.4%)
Seriousness
Serious 141 (73.8%) 303 (76.0%)
Non-serious 50 (26.2%) 48 (12.0%)
Not specified - 48 (12.0%)
Seriousness criteria *
Congenital anomaly 0 (0.0%) 0 (0.0%)
Death 16 (8.4%) 28 (7.0%)
Hospitalization 125 (65.5%) 222 (55.6%)
Life-threatening 30 (15.7%) 46 (11.5%)
Permanent disability 12 (6.3%) 12 (3.0%)
Other outcomes 30 (15.7%) 60 (15.0%)
Median time of hospitalization (days) 3 (2–4) NA
Recovering
Recovered 60 (31.4%) 164 (41.1%)
Not recovered 64 (33.5%) 61 (15.3%)
Not specified 67 (35.1%) 174 (43.6%)
Concomitant other vaccines
Overall number of cases 59 (30.9%) 87 (21.8%)
Mean number of vaccines per patient 3.1 ± 1.4 2.5 ± 1.7
* One case may exhibit more than one seriousness criteria. ** According to 2015 the European Society of Cardiology (ESC) guidelines for the diagnosis and management of pericardial diseases [6], Caforio et al. [7] and Butany et al. [8]. § In one case, the concomitant use of glipizide and indomethacin, and colchicine and indomethacin. # In one case, concomitant use of amoxicillin and tetracycline, hydrochlorothiazide and cotrimoxazole, and bromazepam and heparin. Flu vaccine types (VAERS): FLU 3 (trivalent injected): 69 patients (36.1%); FLUX SEASONAL (influenza virus vaccine, no brand name): 62 (32.5%); FLU 4 (quadrivalent injected): 20 (10.5%); FLUN 3 (trivalent intranasal spray): 19 (9.9%); FLUN 4 (quadrivalent intranasal spray): 7 (3.7%); FLU H1N1 (monovalent injected): 5 (2.6%); FLUA 3 (trivalent adjuvant injected): 3 (1.6%); FLUN H1N1 (monovalent intranasal spray): 2 (1.1%); FLUX H1N1 (monovalent unknown manufacturer): 2 (1.1%); FLUC 4 (quadrivalent cell-culture-derived injected): 2 (1.1%); FLUC 3 (trivalent cell-culture-derived injected): 1 (0.5%). One patient received both FLUX SEASONAL and FLUX (H1N1).
vaccines-09-00019-t002_Table 2Table 2 Case-by-case assessment of reports concerning myocarditis or pericarditis in which the influenza vaccine and immune checkpoint inhibitors (ICIs) were concomitantly used.
Case ID Drugs/Role Dose Year Age/Sex Reporter Country Reporter Qualification Reactions Seriousness Outcome Concomitant Medications Comorbidities Management Causality Assessment Adapted DIPS Score
#1 Nivolumab (suspect)
Influenza vaccine(suspect) 3 mg/kg every 2 weeks IV- 2018 70/F Japan Physician Myocarditis Serious
(life-threatening; prolonged hospitalization; other outcomes) Recovered Ursodeoxycholic acid 200 mg/day
Bezafibrate
200 mg/day
Calcitriol
0.5 mcg/day NSCLC
Liver disorder
Hyperlipidemia
Osteoporosis Nivolumab withdrawn Unclassifiable (data on latency and time window of increased risk are lacking) Synergistic effect between influenza vaccine and ICIs cannot be excluded 1
Doubtful
#2 Pembrolizumab
(suspect)
Influenza vaccine (suspect) NA
IV
0.5 mL
IM 2018 67/M US Pharmacist Myocarditis,
stress, cardiomyopathy,
weight decreased,
headache,
cardiac failure, congestive,
cerebral infarction,
confusional state, and
dyspnoea Serious
(life-threatening; prolonged hospitalization) NA NA Lung neoplasm malignant NA Unclassifiable
(data on latency and time window of increased risk are lacking)
Synergistic effect between influenza vaccine and ICIs cannot be excluded 1
Doubtful
#3 Ipilimumab
(suspect)
Nivolumab
(suspect)
Influenza vaccine (concomitant) 80 mg every 3 weeks IV
240 mg every 3 weeks IV- 2019 77/M Canada Physician Myocarditis,
pulmonary hypertension,
dyspnoea chest discomfort asthenia, troponin increased c-reactive protein, increased diastolic dysfunction, oedema, peripheral urticaria, and pruritus Serious
(prolonged hospitalization; other outcomes) NA NA Metastatic renal cell carcinoma Ipilimumab and nivolumab withdrawn Unclassifiable
(data on latency and time window of increased risk are lacking)
Synergistic effect between influenza vaccine and ICIs cannot be excluded 2
Possible
US—United States of America; NSCLC—non-small cell lung cancer; NA—not available; IV—intravenous; IM—intramuscular; DIPS—drug-interaction probability scale. | INFLUENZA VIRUS VACCINE, IPILIMUMAB, NIVOLUMAB | DrugsGivenReaction | CC BY | 33406694 | 19,221,966 | 2021-01-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pulmonary hypertension'. | Influenza Vaccination and Myo-Pericarditis in Patients Receiving Immune Checkpoint Inhibitors: Investigating the Likelihood of Interaction through the Vaccine Adverse Event Reporting System and VigiBase.
BACKGROUND
Evidence on whether the influenza vaccine could exacerbate immune-related adverse events, including myopericarditis (MP), in patients treated with immune checkpoint inhibitors (ICIs), is still conflicting. We explored this issue through a global real-world approach.
METHODS
We queried the Vaccine Adverse Event Reporting System (VAERS) and VigiBase to retrieve cases of MP in which the influenza vaccine and ICIs were recorded as suspect and were concomitantly reported. For the included cases, causality assessment and Drug Interaction Probability Scale (DIPS) algorithms were applied.
RESULTS
There were 191 and 399 reports of MP with the influenza vaccine that were retrieved (VAERS and VigiBase, respectively). No case of MP reporting the concomitant use of ICIs and the influenza vaccine was found in VAERS, while three cases of myocarditis were retrieved in VigiBase. All of the cases were unclassifiable for a causality assessment because of the lack of data concerning latency. According to the DIPS, one report was categorized as possible and two as doubtful.
CONCLUSIONS
The paucity of cases coupled with the doubtful causality assessment make the potential interaction between influenza vaccines and ICIs in cancer patients negligible from clinical and epidemiological standpoints. These findings support the cardiovascular safety of the influenza vaccination, which remains strongly recommended in cancer patients, especially in the current COVID-19 era.
1. Introduction
The safety of vaccines and medications is a current global safety issue. The annual vaccination against the influenza virus is the primary means of preventing influenza and its complications in high-risk subjects, including adult cancer patients, as described by observational studies, suggesting lower mortality and infection-related outcomes with influenza vaccination [1]. However, in the recent past, potential pharmacokinetic interactions have been proposed, considering that vaccines can influence the drug metabolism via inflammatory cytokines [2]. Therefore, potential interactions between influenza vaccines and drugs used for chronic diseases (e.g., immunosuppressive agents) cannot be excluded [3]. Moreover, cases of myo-pericarditis (MP) after immunization, although rarely, are reported [4,5].
Myocarditis and pericarditis represent serious and life-threatening inflammatory diseases involving myocardium and pericardium, potentially associated with the use of several drugs and vaccines [6,7,8]. In particular, cases of MP were described with the smallpox vaccine in early 2000 and, more recently, very rarely are reported after influenza immunization [4,5]. Immune checkpoint inhibitors (ICIs), such as anti-PD1, anti-PDL1, and anti-CTLA4 monoclonal antibodies, are approved as first-line agents in the management of melanoma and non-small cell lung cancer. They may cause a variegate spectrum of cardiovascular events, including MP, with a higher mortality compared with other immune-related adverse events (irAEs) [9,10,11,12,13]. In a summary of the product characteristics of the different ICIs, pericarditis and myocarditis are reported as uncommon (≥1/1000 to <1/100) and rare (≥1/10,000 to <1/1000, respectively) AEs. Notably, the detection of myocarditis with ICIs requires the permanent discontinuation of treatment, no matter the severity.
Consequently, the question arises as to whether pharmacokinetic and pharmacodynamic interactions occur in patients receiving the influenza vaccination (recommended both by oncologists and cardiologists) and ICIs, possibly causing or exacerbating irAEs such MP. Although no cases of myocarditis have been reported, evidence on whether the influenza vaccine exacerbates irAEs is still conflicting and poorly investigated [14]. Only a retrospective study investigated the clinical features of myocarditis with ICIs in patients receiving the influenza vaccine; reduced myocardial injury and a lower risk of major adverse cardiac events among recipients of the influenza vaccine was found compared with not vaccinated patients [15].
In the recent past, analysis of the spontaneous reporting systems (SRSs) has attracted considerable interest among clinicians for the accurate and timely characterization of drug- and vaccine-related risks occurring in the real world, where comorbidities and polypharmacotherapy exist. By offering a global epidemiological perspective, these pharmacovigilance studies have been pursued to test the hypothesis of potential associations, including refusing the likelihood of interactions [3,16,17], especially for rare, unexpected, and delayed AEs, such as MP.
In this study, we investigated the likelihood of interaction between the influenza vaccination and ICIs by analyzing spontaneous reports of MP collected from the Vaccine Adverse Event Reporting System (VAERS; P.O. Box 1100; Rockville, MD 20849-1100) and the World Health Organization’s (WHO) global Individual Case Safety Report database (VigiBase®; Uppsala Monitoring Centre Box, 1051 SE-751 40, Uppsala, Sweden).
2. Materials and Methods
2.1. Study Conception and Design
The study was conceived as an observational retrospective analysis of spontaneous reports of MP collected from the VAERS and the VigiBase® to (a) characterize relevant clinical features; (b) highlight the concomitant use of agents known to cause MP, including ICIs; and (c) assess the causality and probability of interaction between the influenza vaccine and ICIs.
VAERS is a national system to monitor the safety of US-licensed vaccines [18], whereas VigiBase® collects worldwide reports on vaccines and drugs, thus making these archives act as complementary approaches [19].
VAERS transmits its vaccine adverse event reports to the VigiBase, in order to contribute to the global pharmacovigilance effort along with other countries that employ passive vaccine safety monitoring systems [18], thus possible duplicates between the two databases may exist.
2.2. Data Source
Established in 1990, the VAERS is co-managed by the Centers for Disease Control and Prevention and the US Food and Drug Administration (FDA); it collects and analyzes reports of AEs following immunization (AEFI) for vaccines licensed in the US, receiving approximately 28,000 reports of AEFI annually.
AEFI may be any unfavorable or unintended sign, abnormal laboratory finding, symptom, or disease that occurs following or during the administration of a vaccine. AEs are temporally associated events that may either be caused by a vaccine or be coincidental to it, i.e., not necessarily related to the vaccination [20]. VAERS may be used to detect unexpected and rare patterns of AEFI, unlikely to arise in pivotal trials because of the limited number of patients involved [21]. Health-care professionals, vaccine manufacturers, and consumers (patients, parents, and caregivers) can submit reports of AEs to VAERS.
VigiBase® is one of the largest and most comprehensive pharmacovigilance databases, maintained by the Uppsala Monitoring Centre in Sweden, and containing over 20 million of Individual Case Safety Reports from 110 countries over the five continents. VigiBase® collects reports of AEs for authorized drugs, vaccines, and food supplements, submitted from healthcare professionals, pharmaceutical companies, and patients.
For each vaccine/drug, the characterization of the vaccine/drug role indicated by the primary reporter (i.e., the original source of the information) includes the following three categories: suspect, concomitant, and interacting. All spontaneous reports should have at least one suspect vaccine/drug, namely involved, presumably, in the occurrence of AEFI. If the reporter indicates a suspected interaction, all interacting vaccines/drugs are considered to be suspect vaccines/drugs.
In both databases, AEs are codified through the Medical Dictionary for Regulatory Activities (MedDRA) terminology, and described and organized in terms of Preferred Terms (PTs).
2.3. Data Extraction and Analysis
A multi-step approach was followed for data extraction in each database:(1) Reports for individuals receiving any type of vaccine against the influenza virus categorized as suspect AEFI submitted to VAERS (from July 1990 to September 2020) and VigiBase® (from inception to October 2020) were selected.
(2) Cases of myocarditis or pericarditis were extracted through specific PTs and lowest level terms, in line with previous studies on the influenza vaccination [4] and the potential immune-related basis of cardiotoxicity documented for ICIs by recent pharmacovigilance analyses [9,10]: myocarditis, pericarditis, immune-mediated myocarditis, and myopericarditis.
(3) Reports recording AEs of interest were finally assessed for co-reported drugs/vaccines of interest.
In VigiBase, retained reports (refer to point 2) with ICIs, namely PD-1 inhibitors (nivolumab, pembrolizumab, and cemiplimab), PD-L1 inhibitors (atezolizumab, avelumab, and durvalumab), and CTLA-4 inhibitors (ipilimumab and tremelimumab), were evaluated by extracting the following data: demographic features (age, gender, weight, year, and reporter country), reporter qualification, comorbidities, concomitant medications (including dose and route of administration when available), latency, degree of seriousness, outcome, and management of the AE. The same approach was applied to identify cases of interest reported for vaccines against the influenza virus, both as suspect alone or concomitant to ICI exposure.
In VAERS, for each report of interest with the influenza vaccines, the following data were extracted: demographic features (age, gender, year, and reporter country), type of vaccine against the influenza virus, medical history, concomitant drugs or administered vaccines, laboratory data, AEs codified as PTs, latency, AE degree of seriousness, outcome, and narratives, when available.
According to WHO criteria, a serious AE is any untoward medical occurrence that, no matter the dose, results as fatal, causing a life-threatening event, requiring hospitalization of the patient, causing serious/permanent disability, causing congenital abnormalities, or other clinically relevant conditions [22].
Co-reported medications and comorbidities known to cause myocarditis or pericarditis (i.e., potential confounders) were further characterized according to the lists proposed by Adler et al. [6], Caforio et al. [7], and Butany et al. [8].
2.4. Causality Assessment and Evaluation of Drug–Vaccine Interaction
The probability of interaction when the influenza vaccine and ICIs are co-reported was evaluated by applying the established WHO criteria for causality assessment [20], as well as the Drug Interaction Probability Scale (DIPS) [23].
The following items were accounted for in the AEFI causality assessment: temporal relationship, alternate explanations, proof of association, prior evidence, population-based evidence, and biological plausibility [20]. Cases without adequate information were classified as “unclassifiable”; cases with adequate information were categorized as: (1) “consistent with a causal relationship”, when the available evidence supported a causal relationship between the vaccine and the AEFI in the individual, but it did not rule out the possibility that the AEFI may have been caused by a factor other than the vaccine; (2) “inconsistent with a causal association”, when the available evidence did not support a causal relationship between vaccine administration and the reported AEFI in the individual; and (3) “indeterminate”, when the temporal relationship was consistent but the available evidence insufficient to support or rule out a causal relationship in the individual.
The DIPS is a 10-item tool specifically developed to assess the likelihood of drug–drug interactions [23]. ICIs were considered as the objective drugs (i.e., the one affected by the presence of another vaccine/drug), while the influenza vaccine was considered as the precipitant agent (i.e., the one causing a change on the object drug). To avoid overemphasis on the role of the vaccine, the answer to the second question was always “unknown” (knowledge on the mechanism of the interaction is hypothesized and literature data are very scarce/uncertain); in addition, questions 5, 6, and 10 were not assessable/applicable (dechallenge, rechallenge, and dose adjustments are unfeasible for vaccines considering the peculiarities of their administration), as previously performed [3]. The final summary score could reach 10 points. Higher total scores correspond to a higher likelihood of drug–vaccine interaction (i.e., >8 = highly probable; 5–8 = probable; 2–4 = possible; <2 = doubtful).
3. Results
3.1. Demographic and Clinical Data
Over the observed period, out of a total of 712,776 AEFI, 191 (0.03%) reports of MP mentioning the influenza vaccine as suspect were collected within the VAERS.
The clinical and demographic characteristics are provided in Table 1. The reports included 124 men (64.9%) and 62 women (in five cases gender was not reported), aged between 1 and 88 years (mean age 44.5 years). Pericarditis were reported in 117 cases (61.3%), followed by myocarditis (81 cases; 42.4%) and MP (7 cases; 3.7%). No cases of immune-mediated myocarditis were retrieved.
The median onset was seven days; in 34.0% of reports, the AEFI of interest occurred in the first 3 days after the administration of the influenza vaccine. Comorbidities potentially implicated in the occurrence of the AEFI of interest were retrieved in six cases (3.1%), with ulcerative colitis and systemic lupus erythematosus being the most represented. Other vaccines were concomitantly administered in 59 cases (30.9%), accounting for a mean number of 3.1 vaccines per patient.
In 141 cases (73.8%), the report was classified as serious, and 16 fatal cases (8.4%) were found. Recovery occurred in 31.4% of cases.
In the VigiBase®, 246,864 reports mentioning the influenza vaccine as a suspect agent were found, and myocarditis/pericarditis were reported in 399 cases (0.16%; Table 1).
The cases showed a mean age of 46.7 years, with a male preponderance (65.9%). Reports were largely submitted from US (45.9%) and Europe (45.1%). Pericarditis was reported in 225 cases (56.4%), followed by myocarditis (193 cases; 48.4%) and myopericarditis (29; 7.3%). No cases of immune-mediated myocarditis were found.
Median onset was five days, and in 29.8% of reports, AEs of interest occurred in the first three days after the administration of the influenza vaccine. Comorbidities potentially implicated in the occurrence of myocarditis/pericarditis were retrieved in two patients (0.5%) affected by ulcerative colitis. Other vaccines were concomitantly administered in 87 cases (21.8%), accounting for a mean number of 2.5 vaccines per patient.
In 303 cases (76.0%), the report was classified as serious, and 28 fatal cases (7.0%) were found. Recovering occurred in 41.1% of cases.
3.2. Co-Reported Medications and Detection of Cases with ICI Administration
Overall, concomitant medications were found in 49 (25.7%) and 57 (14.3%) cases with the influenza vaccine in VAERS and VigiBase®, respectively (Table 1). In 14 (7.3%) and 13 (3.3%) cases, five or more concomitant drugs were reported in VAERS and VigiBase®, respectively.
Concomitant medications potentially implicated in the occurrence of myocarditis/pericarditis were retrieved in 21 (11.0%) and 24 (6.0%) cases in VAERS and VigiBase®, respectively, with hydrochlorothiazide being the most frequent in both databases (in six and five cases, respectively).
Only six cases (one classified as serious, where Guillain-Barré syndrome was recorded) with the concomitant use of ICIs and the influenza vaccine were found in VAERS (Table S1), but no cases of myocarditis/pericarditis. In VigiBase®, two cases of myocarditis reporting the concomitant administration of ICIs and the influenza vaccine both mentioned as suspect agents were retrieved. A third case of myocarditis in which the influenza vaccine was classified as a concomitant agent was detected (Table 2).
The three cases were classified as serious (causing prolonged hospitalization), included two men and one woman, aged 67–77 years, and affected by lung or renal carcinoma. Nivolumab, pembrolizumab, and ipilimumab/nivolumab combination therapy were reported as the ICI regimen. In two cases ICI was withdrawn, while recovering occurred in only one case.
3.3. Causality Assessment and Evaluation of Drug–Vaccine Interaction
These three cases showed an unclassifiable causality assessment due to the lack of data concerning the latency and time window of increased risk (Table 2).
By applying the adapted DIPS algorithm, one report was categorized as possible (due to the lack of underlying diseases or co-reported agents known to cause or precipitate myocarditis, and to the detection of troponin increase) and two as doubtful (only the absence of underlying diseases or co-reported agents known to cause or precipitate myocarditis were recognized; Table S2).
4. Discussion
To the best of our knowledge, this is the first real-world study investigating the potential interactions between influenza vaccines and ICIs resulting in myocarditis or pericarditis in cancer patients, by assessing spontaneous reports submitted to the VAERS and VigiBase®. This global post-marketing safety study stems from recent conflicting real-world evidence surrounding the possible exacerbation of irAEs with influenza vaccines in patients treated with ICIs [14,15,24,25,26,27,28,29], thus joining in the wider debate on the bidirectional relationship between immunotherapy and the influenza vaccination, potentially affecting the clinical and humoral efficacy of the vaccine, performance of ICIs, and safety [14].
Four major findings emerged from our analysis: (a) myocarditis and pericarditis represented a very rare AEFI (with a non-negligible proportion of death, approximately 8–9%), based on the low reporting frequency retrieved in both SRSs (<0.1–0.2% of overall AEs), also considering the influenza vaccination coverage rates (estimated at about 25% per year in Europe [30,31]) and the relevant million doses distributed worldwide; (b) the reporting of myocarditis in patients concomitantly receiving influenza vaccines and ICIs is limited to only three out of a total of 1465 cases of myocarditis/pericarditis found with influenza vaccines or ICIs (considered as suspect agents) in the two databases; (c) these cases were unclassifiable for causality assessment with a doubtful probability of drug–vaccine interaction (according to the adapted DIPS algorithm), thus suggesting that the vaccine is not directly involved in the occurrence of myocarditis (and in one of the three cases, influenza vaccine was reported only as concomitant and not as suspect or interacting agent); and (d) no other cardiovascular AEs were found in patients concomitantly receiving influenza vaccination and ICIs, as well as no other irAEs were reported, except for a single case of Guillain-Barré syndrome, a condition already associated with both ICIs and the influenza vaccine [32,33,34].
Theoretically, a possible pharmacodynamic interaction between influenza vaccines and ICIs leading to the exacerbation of irAEs (including MP), could be supposed. The blockade of a PD-1/PD-L1 pathway together with the vaccination (particularly in conjunction with a strong vaccine adjuvant) could enhance one or more of the mechanisms associated with irAEs onset (infiltration of central memory T cells into the tissues, cross-presentation of shared antigens, and exacerbation of previously subclinical auto-immune syndromes) [24].
Our specific focus on the myo-pericardium stems from the peculiar clinical features of myocarditis in terms of severity and mortality compared with other irAEs, usually requiring immunotherapy discontinuation [9,10,11,12,13], as reported in two out of our three cases. Although, in all three cases, no underlying diseases or other agents known to cause or precipitate myocarditis were recorded, the lack of data concerning latency and solid literature studies allows for minimizing, if not completely excluding, the clinically relevant contribution of a potential drug–vaccine interaction in our cases.
Furthermore, the only study investigating the association between influenza vaccine and the development of myocarditis among patients on ICIs found that the administration of the vaccine was not associated with an increased risk of subsequent myocarditis [15]. Additionally, myocarditis cases in which the influenza vaccine was administered showed lower troponin levels at presentation and a lower risk of major adverse cardiac events at follow-up compared with non-vaccinate patients developing myocarditis with ICIs [15], thus suggesting a protective role for the influenza vaccine in this setting.
ICIs caused a paradigm shift in cancer treatment, and are currently used as first-line agents in the management of non-small cell lung cancer, melanoma, and renal carcinoma [35]. Considering their evolving role and expected increasing uptake, the assessment of cardiovascular safety is of paramount importance. Likewise, the safety of influenza vaccines represents an important issue, given the high morbidity and mortality rates caused by influenza in cancer patients [36]. Notably, the development of influenza infection may also, albeit rarely, be associated itself with an increased risk of myocarditis and major adverse cardiovascular events [37,38]. Therefore, the suggested protective role of the influenza vaccine on cardiovascular outcome [15] cannot be overlooked.
Collectively, our findings provide a reassuring message in terms of cardiovascular safety for cancer patients treated with ICIs and requiring the influenza vaccination. Of note, less than 20% of patients affected by malignancies received the influenza vaccine, with a gradual decline in the last decade [39]. We support and promote the achievement of an optimal vaccination coverage rate in cancer patients for several reasons, including the following: (a) direct association with a lower mortality and infection-related outcomes in immunosuppressed adults [1]; (b) a better overall survival recently reported in patients treated with ICIs receiving influenza vaccination [40]; and (c) the current COVID-19 pandemic, to reduce the strain on the healthcare system while protecting vulnerable subjects from the dramatic impact of a possible co-infection [41]. Cancer patients receiving immunotherapy are at high risk of severe events as a result of COVID-19 systemic involvement, including pneumonitis and myocarditis [42], and a recent systematic review found no significant increase in the risk of infection or in the illness severity or lethality of COVID-19 in subjects receiving the influenza vaccine, with some studies reporting a significantly inverse association [43]. Therefore, the implementation of measures aimed at raising influenza vaccination coverage in frail patients is strongly recommended.
We acknowledge the limitations of our study, mainly inherent to the nature of SRSs data. VAERS and VigiBase® are subject to reporting bias, including under- and over-reporting of adverse events, although there are not clues for major distortions, considering that serious events such as MP are less prone to under-reporting, and no specific warnings were posted by regulatory agencies, thus minimizing the existence and impact of a stimulated reporting [3,18]. We recognize the potential occurrence of subclinical myocarditis, which may be under-diagnosed/under-detected, and is thus likely to be under-reported. Furthermore, the quality and completeness of the reports collected in both databases are variable, and many records lack valid medical diagnoses, thus making the assessment of causality challenging. Additionally, DIPS was not specifically developed to assess drug–vaccine interactions, although we implemented an adapted version in order to the better focus on the possible precipitating role of the influenza vaccine.
Notwithstanding these limitations, pharmacovigilance assessment represents an invaluable opportunity to monitor vaccine safety and identify novel rare signals, potentially arising from drug–vaccine interactions, both from a local and international perspective. Furthermore, our findings are consistent between the two databases, thus supporting the lack of evidence of a clinically relevant drug–vaccine interaction. The identification of myocarditis with ICIs, in line with previous findings [9,10,11], further corroborates the ability of our post-marketing approach to identify actual true-positive associations.
In conclusion, the paucity of cases coupled with a lack of certainty in terms of causality assessment and doubtful probability make the risk of myocarditis and pericarditis by interaction between influenza vaccines and ICIs in cancer patients negligible from both clinical and epidemiological standpoints. Our findings support the cardiovascular safety of influenza vaccines in subjects treated with immunotherapy, thereby emphasizing the importance of a flu vaccination in this population, especially in the current COVID-19 era.
Acknowledgments
We would like to thank Annette Rudolph for data extraction from VigiBase®. Authors at the University of Bologna are supported by institutional research funds (Ricerca Fondamentale Orientata). No sources of funding were received for the preparation of this article.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2076-393X/9/1/19/s1. Table S1: Case-by-case assessment of reports recorded in VAERS in which influenza vaccine and immune checkpoint inhibitors (ICIs) were concomitantly used. Table S2: Application of the adapted version of Drug Interaction Probability Scale in cases of myocarditis/pericarditis in which immune checkpoint inhibitors (ICIs) and influenza vaccine were concomitantly administered.
Click here for additional data file.
Author Contributions
M.G.: methodology, investigation, formal analysis, and writing—original draft. E.R.: conceptualization, methodology, formal analysis, and writing—reviewing and editing. U.M.: writing—reviewing and editing. A.A.: writing—reviewing and editing. E.P.: conceptualization, methodology, formal analysis, and writing—reviewing and editing. I.D.: conceptualization and writing—reviewing and editing. All authors have read and agreed to the published version of the manuscript.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Institutional Review Board Statement
Under current legislation, institutional review board approval is not required when performing analysis of the publicly available VAERS and VigiBase databases, because it contains anonymized data that cannot allow patients’ identification.
Informed Consent Statement
Patient consent was waived due to VAERS and VigiBase databases contain anonymized data that cannot allow patients’ identification.
Data Availability Statement
Data supporting the findings of this study were derived from the following resource available in the public domains: https://wonder.cdc.gov/vaers.html and http://www.vigiaccess.org/.
Conflicts of Interest
M.G., E.R., E.P., U.M., and I.D. have no conflicts of interest relevant to the content of the present work. A.A. reports grants and personal fees from BMS, as well as grants from MSD, Roche, Astra Zeneca, Eli-Lilly, Takeda, and Bayer, outside of the submitted work.
vaccines-09-00019-t001_Table 1Table 1 Demographic and clinical feature of cases of myocarditis/pericarditis reported with influenza vaccine as suspect in Vaccine Adverse Event Reporting System (VAERS) and the World Health Organization’s (WHO) global Individual Case Safety Report database (VigiBase®).
Demographic Features VAERS VigiBase
Overall number of cases 191 399
Proportion of cases (based on overall number of reports with the flu vaccine) 0.03% (712,776) 0.16% (246,864)
Age (mean) 44.5 ± 22.9 46.7 ± 22.3
Sex
Female 62 (32.5%) 131 (32.8%)
Male 124 (64.9%) 263 (65.9%)
Not specified 5 (2.6%) 5 (1.3%)
Reporter country
US 109 (57.1%) 183 (45.9%)
Non-US 60 (31.4%) -
Europe - 180 (45.1%)
Asia - 10 (2.5%)
Oceania - 19 (4.8%)
America (except US) - 7 (1.7%)
Not specified 22 (11.5%) -
Reported symptoms (preferred terms) *
Myocarditis 81 (42.4%) 193 (48.4%)
Pericarditis 117 (61.3%) 225 (56.4%)
Myopericarditis 7 (3.7%) 29 (7.3%)
Immune-mediated myocarditis 0 (0.0%) 0 (0.0%)
Co-medications
Overall number of cases 49 (25.7%) 57 (14.3%)
≥5 concomitant drugs 14 (7.3%) 13 (3.3%)
1–4 concomitant drugs 35 (18.4%) 44 (11.0%)
No concomitant drugs 142 (74.3%) 342 (85.7%)
Co-medications potentially implicated in the occurrence of myocarditis/pericarditis **
Number of cases 21 (11.0%) § 24 (6.0%) #
Immune checkpoint inhibitors (ICIs) None 2
Hydrochlorothiazide 6 5
Indomethacin 2 2
Glipizide 2 -
Clonazepam 2 -
Alprazolam 2 -
Furosemide 1 1
Bendroflumethiazide 1 2
Mesalazine 1 2
Colchicine 1 1
Doxycycline 1 2
Cotrimoxazole 1 1
Lorazepam 1 -
Amoxicillin 1 1
Isosorbide dinitrate 1 2
Tetracycline - 2
Spironolactone - 1
Cefuroxime - 1
Heparin - 1
Bromazepam - 1
Comorbidities potentially implicated in occurrence of myocarditis/pericarditis **
Number of cases 6 (3.1%) 2 (0.5%)
Ulcerative colitis 2 2
Systemic lupus erythematosus 2 -
Juvenile rheumatoid arthritis 1 -
Insulin-dependent diabetes mellitus 1 -
Onset (days; median) 7 (1.5–13) 5 (1–12)
≤3 days 65 (34.0%) 119 (29.8%)
4–7 days 19 (10.0%) 50 (12.5%)
8–14 days 35 (18.4%) 61 (15.3%)
≥15 days 36 (18.8%) 56 (14.0%)
Not specified 36 (18.8%) 113 (28.4%)
Seriousness
Serious 141 (73.8%) 303 (76.0%)
Non-serious 50 (26.2%) 48 (12.0%)
Not specified - 48 (12.0%)
Seriousness criteria *
Congenital anomaly 0 (0.0%) 0 (0.0%)
Death 16 (8.4%) 28 (7.0%)
Hospitalization 125 (65.5%) 222 (55.6%)
Life-threatening 30 (15.7%) 46 (11.5%)
Permanent disability 12 (6.3%) 12 (3.0%)
Other outcomes 30 (15.7%) 60 (15.0%)
Median time of hospitalization (days) 3 (2–4) NA
Recovering
Recovered 60 (31.4%) 164 (41.1%)
Not recovered 64 (33.5%) 61 (15.3%)
Not specified 67 (35.1%) 174 (43.6%)
Concomitant other vaccines
Overall number of cases 59 (30.9%) 87 (21.8%)
Mean number of vaccines per patient 3.1 ± 1.4 2.5 ± 1.7
* One case may exhibit more than one seriousness criteria. ** According to 2015 the European Society of Cardiology (ESC) guidelines for the diagnosis and management of pericardial diseases [6], Caforio et al. [7] and Butany et al. [8]. § In one case, the concomitant use of glipizide and indomethacin, and colchicine and indomethacin. # In one case, concomitant use of amoxicillin and tetracycline, hydrochlorothiazide and cotrimoxazole, and bromazepam and heparin. Flu vaccine types (VAERS): FLU 3 (trivalent injected): 69 patients (36.1%); FLUX SEASONAL (influenza virus vaccine, no brand name): 62 (32.5%); FLU 4 (quadrivalent injected): 20 (10.5%); FLUN 3 (trivalent intranasal spray): 19 (9.9%); FLUN 4 (quadrivalent intranasal spray): 7 (3.7%); FLU H1N1 (monovalent injected): 5 (2.6%); FLUA 3 (trivalent adjuvant injected): 3 (1.6%); FLUN H1N1 (monovalent intranasal spray): 2 (1.1%); FLUX H1N1 (monovalent unknown manufacturer): 2 (1.1%); FLUC 4 (quadrivalent cell-culture-derived injected): 2 (1.1%); FLUC 3 (trivalent cell-culture-derived injected): 1 (0.5%). One patient received both FLUX SEASONAL and FLUX (H1N1).
vaccines-09-00019-t002_Table 2Table 2 Case-by-case assessment of reports concerning myocarditis or pericarditis in which the influenza vaccine and immune checkpoint inhibitors (ICIs) were concomitantly used.
Case ID Drugs/Role Dose Year Age/Sex Reporter Country Reporter Qualification Reactions Seriousness Outcome Concomitant Medications Comorbidities Management Causality Assessment Adapted DIPS Score
#1 Nivolumab (suspect)
Influenza vaccine(suspect) 3 mg/kg every 2 weeks IV- 2018 70/F Japan Physician Myocarditis Serious
(life-threatening; prolonged hospitalization; other outcomes) Recovered Ursodeoxycholic acid 200 mg/day
Bezafibrate
200 mg/day
Calcitriol
0.5 mcg/day NSCLC
Liver disorder
Hyperlipidemia
Osteoporosis Nivolumab withdrawn Unclassifiable (data on latency and time window of increased risk are lacking) Synergistic effect between influenza vaccine and ICIs cannot be excluded 1
Doubtful
#2 Pembrolizumab
(suspect)
Influenza vaccine (suspect) NA
IV
0.5 mL
IM 2018 67/M US Pharmacist Myocarditis,
stress, cardiomyopathy,
weight decreased,
headache,
cardiac failure, congestive,
cerebral infarction,
confusional state, and
dyspnoea Serious
(life-threatening; prolonged hospitalization) NA NA Lung neoplasm malignant NA Unclassifiable
(data on latency and time window of increased risk are lacking)
Synergistic effect between influenza vaccine and ICIs cannot be excluded 1
Doubtful
#3 Ipilimumab
(suspect)
Nivolumab
(suspect)
Influenza vaccine (concomitant) 80 mg every 3 weeks IV
240 mg every 3 weeks IV- 2019 77/M Canada Physician Myocarditis,
pulmonary hypertension,
dyspnoea chest discomfort asthenia, troponin increased c-reactive protein, increased diastolic dysfunction, oedema, peripheral urticaria, and pruritus Serious
(prolonged hospitalization; other outcomes) NA NA Metastatic renal cell carcinoma Ipilimumab and nivolumab withdrawn Unclassifiable
(data on latency and time window of increased risk are lacking)
Synergistic effect between influenza vaccine and ICIs cannot be excluded 2
Possible
US—United States of America; NSCLC—non-small cell lung cancer; NA—not available; IV—intravenous; IM—intramuscular; DIPS—drug-interaction probability scale. | INFLUENZA VIRUS VACCINE, IPILIMUMAB, NIVOLUMAB | DrugsGivenReaction | CC BY | 33406694 | 19,221,966 | 2021-01-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Urticaria'. | Influenza Vaccination and Myo-Pericarditis in Patients Receiving Immune Checkpoint Inhibitors: Investigating the Likelihood of Interaction through the Vaccine Adverse Event Reporting System and VigiBase.
BACKGROUND
Evidence on whether the influenza vaccine could exacerbate immune-related adverse events, including myopericarditis (MP), in patients treated with immune checkpoint inhibitors (ICIs), is still conflicting. We explored this issue through a global real-world approach.
METHODS
We queried the Vaccine Adverse Event Reporting System (VAERS) and VigiBase to retrieve cases of MP in which the influenza vaccine and ICIs were recorded as suspect and were concomitantly reported. For the included cases, causality assessment and Drug Interaction Probability Scale (DIPS) algorithms were applied.
RESULTS
There were 191 and 399 reports of MP with the influenza vaccine that were retrieved (VAERS and VigiBase, respectively). No case of MP reporting the concomitant use of ICIs and the influenza vaccine was found in VAERS, while three cases of myocarditis were retrieved in VigiBase. All of the cases were unclassifiable for a causality assessment because of the lack of data concerning latency. According to the DIPS, one report was categorized as possible and two as doubtful.
CONCLUSIONS
The paucity of cases coupled with the doubtful causality assessment make the potential interaction between influenza vaccines and ICIs in cancer patients negligible from clinical and epidemiological standpoints. These findings support the cardiovascular safety of the influenza vaccination, which remains strongly recommended in cancer patients, especially in the current COVID-19 era.
1. Introduction
The safety of vaccines and medications is a current global safety issue. The annual vaccination against the influenza virus is the primary means of preventing influenza and its complications in high-risk subjects, including adult cancer patients, as described by observational studies, suggesting lower mortality and infection-related outcomes with influenza vaccination [1]. However, in the recent past, potential pharmacokinetic interactions have been proposed, considering that vaccines can influence the drug metabolism via inflammatory cytokines [2]. Therefore, potential interactions between influenza vaccines and drugs used for chronic diseases (e.g., immunosuppressive agents) cannot be excluded [3]. Moreover, cases of myo-pericarditis (MP) after immunization, although rarely, are reported [4,5].
Myocarditis and pericarditis represent serious and life-threatening inflammatory diseases involving myocardium and pericardium, potentially associated with the use of several drugs and vaccines [6,7,8]. In particular, cases of MP were described with the smallpox vaccine in early 2000 and, more recently, very rarely are reported after influenza immunization [4,5]. Immune checkpoint inhibitors (ICIs), such as anti-PD1, anti-PDL1, and anti-CTLA4 monoclonal antibodies, are approved as first-line agents in the management of melanoma and non-small cell lung cancer. They may cause a variegate spectrum of cardiovascular events, including MP, with a higher mortality compared with other immune-related adverse events (irAEs) [9,10,11,12,13]. In a summary of the product characteristics of the different ICIs, pericarditis and myocarditis are reported as uncommon (≥1/1000 to <1/100) and rare (≥1/10,000 to <1/1000, respectively) AEs. Notably, the detection of myocarditis with ICIs requires the permanent discontinuation of treatment, no matter the severity.
Consequently, the question arises as to whether pharmacokinetic and pharmacodynamic interactions occur in patients receiving the influenza vaccination (recommended both by oncologists and cardiologists) and ICIs, possibly causing or exacerbating irAEs such MP. Although no cases of myocarditis have been reported, evidence on whether the influenza vaccine exacerbates irAEs is still conflicting and poorly investigated [14]. Only a retrospective study investigated the clinical features of myocarditis with ICIs in patients receiving the influenza vaccine; reduced myocardial injury and a lower risk of major adverse cardiac events among recipients of the influenza vaccine was found compared with not vaccinated patients [15].
In the recent past, analysis of the spontaneous reporting systems (SRSs) has attracted considerable interest among clinicians for the accurate and timely characterization of drug- and vaccine-related risks occurring in the real world, where comorbidities and polypharmacotherapy exist. By offering a global epidemiological perspective, these pharmacovigilance studies have been pursued to test the hypothesis of potential associations, including refusing the likelihood of interactions [3,16,17], especially for rare, unexpected, and delayed AEs, such as MP.
In this study, we investigated the likelihood of interaction between the influenza vaccination and ICIs by analyzing spontaneous reports of MP collected from the Vaccine Adverse Event Reporting System (VAERS; P.O. Box 1100; Rockville, MD 20849-1100) and the World Health Organization’s (WHO) global Individual Case Safety Report database (VigiBase®; Uppsala Monitoring Centre Box, 1051 SE-751 40, Uppsala, Sweden).
2. Materials and Methods
2.1. Study Conception and Design
The study was conceived as an observational retrospective analysis of spontaneous reports of MP collected from the VAERS and the VigiBase® to (a) characterize relevant clinical features; (b) highlight the concomitant use of agents known to cause MP, including ICIs; and (c) assess the causality and probability of interaction between the influenza vaccine and ICIs.
VAERS is a national system to monitor the safety of US-licensed vaccines [18], whereas VigiBase® collects worldwide reports on vaccines and drugs, thus making these archives act as complementary approaches [19].
VAERS transmits its vaccine adverse event reports to the VigiBase, in order to contribute to the global pharmacovigilance effort along with other countries that employ passive vaccine safety monitoring systems [18], thus possible duplicates between the two databases may exist.
2.2. Data Source
Established in 1990, the VAERS is co-managed by the Centers for Disease Control and Prevention and the US Food and Drug Administration (FDA); it collects and analyzes reports of AEs following immunization (AEFI) for vaccines licensed in the US, receiving approximately 28,000 reports of AEFI annually.
AEFI may be any unfavorable or unintended sign, abnormal laboratory finding, symptom, or disease that occurs following or during the administration of a vaccine. AEs are temporally associated events that may either be caused by a vaccine or be coincidental to it, i.e., not necessarily related to the vaccination [20]. VAERS may be used to detect unexpected and rare patterns of AEFI, unlikely to arise in pivotal trials because of the limited number of patients involved [21]. Health-care professionals, vaccine manufacturers, and consumers (patients, parents, and caregivers) can submit reports of AEs to VAERS.
VigiBase® is one of the largest and most comprehensive pharmacovigilance databases, maintained by the Uppsala Monitoring Centre in Sweden, and containing over 20 million of Individual Case Safety Reports from 110 countries over the five continents. VigiBase® collects reports of AEs for authorized drugs, vaccines, and food supplements, submitted from healthcare professionals, pharmaceutical companies, and patients.
For each vaccine/drug, the characterization of the vaccine/drug role indicated by the primary reporter (i.e., the original source of the information) includes the following three categories: suspect, concomitant, and interacting. All spontaneous reports should have at least one suspect vaccine/drug, namely involved, presumably, in the occurrence of AEFI. If the reporter indicates a suspected interaction, all interacting vaccines/drugs are considered to be suspect vaccines/drugs.
In both databases, AEs are codified through the Medical Dictionary for Regulatory Activities (MedDRA) terminology, and described and organized in terms of Preferred Terms (PTs).
2.3. Data Extraction and Analysis
A multi-step approach was followed for data extraction in each database:(1) Reports for individuals receiving any type of vaccine against the influenza virus categorized as suspect AEFI submitted to VAERS (from July 1990 to September 2020) and VigiBase® (from inception to October 2020) were selected.
(2) Cases of myocarditis or pericarditis were extracted through specific PTs and lowest level terms, in line with previous studies on the influenza vaccination [4] and the potential immune-related basis of cardiotoxicity documented for ICIs by recent pharmacovigilance analyses [9,10]: myocarditis, pericarditis, immune-mediated myocarditis, and myopericarditis.
(3) Reports recording AEs of interest were finally assessed for co-reported drugs/vaccines of interest.
In VigiBase, retained reports (refer to point 2) with ICIs, namely PD-1 inhibitors (nivolumab, pembrolizumab, and cemiplimab), PD-L1 inhibitors (atezolizumab, avelumab, and durvalumab), and CTLA-4 inhibitors (ipilimumab and tremelimumab), were evaluated by extracting the following data: demographic features (age, gender, weight, year, and reporter country), reporter qualification, comorbidities, concomitant medications (including dose and route of administration when available), latency, degree of seriousness, outcome, and management of the AE. The same approach was applied to identify cases of interest reported for vaccines against the influenza virus, both as suspect alone or concomitant to ICI exposure.
In VAERS, for each report of interest with the influenza vaccines, the following data were extracted: demographic features (age, gender, year, and reporter country), type of vaccine against the influenza virus, medical history, concomitant drugs or administered vaccines, laboratory data, AEs codified as PTs, latency, AE degree of seriousness, outcome, and narratives, when available.
According to WHO criteria, a serious AE is any untoward medical occurrence that, no matter the dose, results as fatal, causing a life-threatening event, requiring hospitalization of the patient, causing serious/permanent disability, causing congenital abnormalities, or other clinically relevant conditions [22].
Co-reported medications and comorbidities known to cause myocarditis or pericarditis (i.e., potential confounders) were further characterized according to the lists proposed by Adler et al. [6], Caforio et al. [7], and Butany et al. [8].
2.4. Causality Assessment and Evaluation of Drug–Vaccine Interaction
The probability of interaction when the influenza vaccine and ICIs are co-reported was evaluated by applying the established WHO criteria for causality assessment [20], as well as the Drug Interaction Probability Scale (DIPS) [23].
The following items were accounted for in the AEFI causality assessment: temporal relationship, alternate explanations, proof of association, prior evidence, population-based evidence, and biological plausibility [20]. Cases without adequate information were classified as “unclassifiable”; cases with adequate information were categorized as: (1) “consistent with a causal relationship”, when the available evidence supported a causal relationship between the vaccine and the AEFI in the individual, but it did not rule out the possibility that the AEFI may have been caused by a factor other than the vaccine; (2) “inconsistent with a causal association”, when the available evidence did not support a causal relationship between vaccine administration and the reported AEFI in the individual; and (3) “indeterminate”, when the temporal relationship was consistent but the available evidence insufficient to support or rule out a causal relationship in the individual.
The DIPS is a 10-item tool specifically developed to assess the likelihood of drug–drug interactions [23]. ICIs were considered as the objective drugs (i.e., the one affected by the presence of another vaccine/drug), while the influenza vaccine was considered as the precipitant agent (i.e., the one causing a change on the object drug). To avoid overemphasis on the role of the vaccine, the answer to the second question was always “unknown” (knowledge on the mechanism of the interaction is hypothesized and literature data are very scarce/uncertain); in addition, questions 5, 6, and 10 were not assessable/applicable (dechallenge, rechallenge, and dose adjustments are unfeasible for vaccines considering the peculiarities of their administration), as previously performed [3]. The final summary score could reach 10 points. Higher total scores correspond to a higher likelihood of drug–vaccine interaction (i.e., >8 = highly probable; 5–8 = probable; 2–4 = possible; <2 = doubtful).
3. Results
3.1. Demographic and Clinical Data
Over the observed period, out of a total of 712,776 AEFI, 191 (0.03%) reports of MP mentioning the influenza vaccine as suspect were collected within the VAERS.
The clinical and demographic characteristics are provided in Table 1. The reports included 124 men (64.9%) and 62 women (in five cases gender was not reported), aged between 1 and 88 years (mean age 44.5 years). Pericarditis were reported in 117 cases (61.3%), followed by myocarditis (81 cases; 42.4%) and MP (7 cases; 3.7%). No cases of immune-mediated myocarditis were retrieved.
The median onset was seven days; in 34.0% of reports, the AEFI of interest occurred in the first 3 days after the administration of the influenza vaccine. Comorbidities potentially implicated in the occurrence of the AEFI of interest were retrieved in six cases (3.1%), with ulcerative colitis and systemic lupus erythematosus being the most represented. Other vaccines were concomitantly administered in 59 cases (30.9%), accounting for a mean number of 3.1 vaccines per patient.
In 141 cases (73.8%), the report was classified as serious, and 16 fatal cases (8.4%) were found. Recovery occurred in 31.4% of cases.
In the VigiBase®, 246,864 reports mentioning the influenza vaccine as a suspect agent were found, and myocarditis/pericarditis were reported in 399 cases (0.16%; Table 1).
The cases showed a mean age of 46.7 years, with a male preponderance (65.9%). Reports were largely submitted from US (45.9%) and Europe (45.1%). Pericarditis was reported in 225 cases (56.4%), followed by myocarditis (193 cases; 48.4%) and myopericarditis (29; 7.3%). No cases of immune-mediated myocarditis were found.
Median onset was five days, and in 29.8% of reports, AEs of interest occurred in the first three days after the administration of the influenza vaccine. Comorbidities potentially implicated in the occurrence of myocarditis/pericarditis were retrieved in two patients (0.5%) affected by ulcerative colitis. Other vaccines were concomitantly administered in 87 cases (21.8%), accounting for a mean number of 2.5 vaccines per patient.
In 303 cases (76.0%), the report was classified as serious, and 28 fatal cases (7.0%) were found. Recovering occurred in 41.1% of cases.
3.2. Co-Reported Medications and Detection of Cases with ICI Administration
Overall, concomitant medications were found in 49 (25.7%) and 57 (14.3%) cases with the influenza vaccine in VAERS and VigiBase®, respectively (Table 1). In 14 (7.3%) and 13 (3.3%) cases, five or more concomitant drugs were reported in VAERS and VigiBase®, respectively.
Concomitant medications potentially implicated in the occurrence of myocarditis/pericarditis were retrieved in 21 (11.0%) and 24 (6.0%) cases in VAERS and VigiBase®, respectively, with hydrochlorothiazide being the most frequent in both databases (in six and five cases, respectively).
Only six cases (one classified as serious, where Guillain-Barré syndrome was recorded) with the concomitant use of ICIs and the influenza vaccine were found in VAERS (Table S1), but no cases of myocarditis/pericarditis. In VigiBase®, two cases of myocarditis reporting the concomitant administration of ICIs and the influenza vaccine both mentioned as suspect agents were retrieved. A third case of myocarditis in which the influenza vaccine was classified as a concomitant agent was detected (Table 2).
The three cases were classified as serious (causing prolonged hospitalization), included two men and one woman, aged 67–77 years, and affected by lung or renal carcinoma. Nivolumab, pembrolizumab, and ipilimumab/nivolumab combination therapy were reported as the ICI regimen. In two cases ICI was withdrawn, while recovering occurred in only one case.
3.3. Causality Assessment and Evaluation of Drug–Vaccine Interaction
These three cases showed an unclassifiable causality assessment due to the lack of data concerning the latency and time window of increased risk (Table 2).
By applying the adapted DIPS algorithm, one report was categorized as possible (due to the lack of underlying diseases or co-reported agents known to cause or precipitate myocarditis, and to the detection of troponin increase) and two as doubtful (only the absence of underlying diseases or co-reported agents known to cause or precipitate myocarditis were recognized; Table S2).
4. Discussion
To the best of our knowledge, this is the first real-world study investigating the potential interactions between influenza vaccines and ICIs resulting in myocarditis or pericarditis in cancer patients, by assessing spontaneous reports submitted to the VAERS and VigiBase®. This global post-marketing safety study stems from recent conflicting real-world evidence surrounding the possible exacerbation of irAEs with influenza vaccines in patients treated with ICIs [14,15,24,25,26,27,28,29], thus joining in the wider debate on the bidirectional relationship between immunotherapy and the influenza vaccination, potentially affecting the clinical and humoral efficacy of the vaccine, performance of ICIs, and safety [14].
Four major findings emerged from our analysis: (a) myocarditis and pericarditis represented a very rare AEFI (with a non-negligible proportion of death, approximately 8–9%), based on the low reporting frequency retrieved in both SRSs (<0.1–0.2% of overall AEs), also considering the influenza vaccination coverage rates (estimated at about 25% per year in Europe [30,31]) and the relevant million doses distributed worldwide; (b) the reporting of myocarditis in patients concomitantly receiving influenza vaccines and ICIs is limited to only three out of a total of 1465 cases of myocarditis/pericarditis found with influenza vaccines or ICIs (considered as suspect agents) in the two databases; (c) these cases were unclassifiable for causality assessment with a doubtful probability of drug–vaccine interaction (according to the adapted DIPS algorithm), thus suggesting that the vaccine is not directly involved in the occurrence of myocarditis (and in one of the three cases, influenza vaccine was reported only as concomitant and not as suspect or interacting agent); and (d) no other cardiovascular AEs were found in patients concomitantly receiving influenza vaccination and ICIs, as well as no other irAEs were reported, except for a single case of Guillain-Barré syndrome, a condition already associated with both ICIs and the influenza vaccine [32,33,34].
Theoretically, a possible pharmacodynamic interaction between influenza vaccines and ICIs leading to the exacerbation of irAEs (including MP), could be supposed. The blockade of a PD-1/PD-L1 pathway together with the vaccination (particularly in conjunction with a strong vaccine adjuvant) could enhance one or more of the mechanisms associated with irAEs onset (infiltration of central memory T cells into the tissues, cross-presentation of shared antigens, and exacerbation of previously subclinical auto-immune syndromes) [24].
Our specific focus on the myo-pericardium stems from the peculiar clinical features of myocarditis in terms of severity and mortality compared with other irAEs, usually requiring immunotherapy discontinuation [9,10,11,12,13], as reported in two out of our three cases. Although, in all three cases, no underlying diseases or other agents known to cause or precipitate myocarditis were recorded, the lack of data concerning latency and solid literature studies allows for minimizing, if not completely excluding, the clinically relevant contribution of a potential drug–vaccine interaction in our cases.
Furthermore, the only study investigating the association between influenza vaccine and the development of myocarditis among patients on ICIs found that the administration of the vaccine was not associated with an increased risk of subsequent myocarditis [15]. Additionally, myocarditis cases in which the influenza vaccine was administered showed lower troponin levels at presentation and a lower risk of major adverse cardiac events at follow-up compared with non-vaccinate patients developing myocarditis with ICIs [15], thus suggesting a protective role for the influenza vaccine in this setting.
ICIs caused a paradigm shift in cancer treatment, and are currently used as first-line agents in the management of non-small cell lung cancer, melanoma, and renal carcinoma [35]. Considering their evolving role and expected increasing uptake, the assessment of cardiovascular safety is of paramount importance. Likewise, the safety of influenza vaccines represents an important issue, given the high morbidity and mortality rates caused by influenza in cancer patients [36]. Notably, the development of influenza infection may also, albeit rarely, be associated itself with an increased risk of myocarditis and major adverse cardiovascular events [37,38]. Therefore, the suggested protective role of the influenza vaccine on cardiovascular outcome [15] cannot be overlooked.
Collectively, our findings provide a reassuring message in terms of cardiovascular safety for cancer patients treated with ICIs and requiring the influenza vaccination. Of note, less than 20% of patients affected by malignancies received the influenza vaccine, with a gradual decline in the last decade [39]. We support and promote the achievement of an optimal vaccination coverage rate in cancer patients for several reasons, including the following: (a) direct association with a lower mortality and infection-related outcomes in immunosuppressed adults [1]; (b) a better overall survival recently reported in patients treated with ICIs receiving influenza vaccination [40]; and (c) the current COVID-19 pandemic, to reduce the strain on the healthcare system while protecting vulnerable subjects from the dramatic impact of a possible co-infection [41]. Cancer patients receiving immunotherapy are at high risk of severe events as a result of COVID-19 systemic involvement, including pneumonitis and myocarditis [42], and a recent systematic review found no significant increase in the risk of infection or in the illness severity or lethality of COVID-19 in subjects receiving the influenza vaccine, with some studies reporting a significantly inverse association [43]. Therefore, the implementation of measures aimed at raising influenza vaccination coverage in frail patients is strongly recommended.
We acknowledge the limitations of our study, mainly inherent to the nature of SRSs data. VAERS and VigiBase® are subject to reporting bias, including under- and over-reporting of adverse events, although there are not clues for major distortions, considering that serious events such as MP are less prone to under-reporting, and no specific warnings were posted by regulatory agencies, thus minimizing the existence and impact of a stimulated reporting [3,18]. We recognize the potential occurrence of subclinical myocarditis, which may be under-diagnosed/under-detected, and is thus likely to be under-reported. Furthermore, the quality and completeness of the reports collected in both databases are variable, and many records lack valid medical diagnoses, thus making the assessment of causality challenging. Additionally, DIPS was not specifically developed to assess drug–vaccine interactions, although we implemented an adapted version in order to the better focus on the possible precipitating role of the influenza vaccine.
Notwithstanding these limitations, pharmacovigilance assessment represents an invaluable opportunity to monitor vaccine safety and identify novel rare signals, potentially arising from drug–vaccine interactions, both from a local and international perspective. Furthermore, our findings are consistent between the two databases, thus supporting the lack of evidence of a clinically relevant drug–vaccine interaction. The identification of myocarditis with ICIs, in line with previous findings [9,10,11], further corroborates the ability of our post-marketing approach to identify actual true-positive associations.
In conclusion, the paucity of cases coupled with a lack of certainty in terms of causality assessment and doubtful probability make the risk of myocarditis and pericarditis by interaction between influenza vaccines and ICIs in cancer patients negligible from both clinical and epidemiological standpoints. Our findings support the cardiovascular safety of influenza vaccines in subjects treated with immunotherapy, thereby emphasizing the importance of a flu vaccination in this population, especially in the current COVID-19 era.
Acknowledgments
We would like to thank Annette Rudolph for data extraction from VigiBase®. Authors at the University of Bologna are supported by institutional research funds (Ricerca Fondamentale Orientata). No sources of funding were received for the preparation of this article.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2076-393X/9/1/19/s1. Table S1: Case-by-case assessment of reports recorded in VAERS in which influenza vaccine and immune checkpoint inhibitors (ICIs) were concomitantly used. Table S2: Application of the adapted version of Drug Interaction Probability Scale in cases of myocarditis/pericarditis in which immune checkpoint inhibitors (ICIs) and influenza vaccine were concomitantly administered.
Click here for additional data file.
Author Contributions
M.G.: methodology, investigation, formal analysis, and writing—original draft. E.R.: conceptualization, methodology, formal analysis, and writing—reviewing and editing. U.M.: writing—reviewing and editing. A.A.: writing—reviewing and editing. E.P.: conceptualization, methodology, formal analysis, and writing—reviewing and editing. I.D.: conceptualization and writing—reviewing and editing. All authors have read and agreed to the published version of the manuscript.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Institutional Review Board Statement
Under current legislation, institutional review board approval is not required when performing analysis of the publicly available VAERS and VigiBase databases, because it contains anonymized data that cannot allow patients’ identification.
Informed Consent Statement
Patient consent was waived due to VAERS and VigiBase databases contain anonymized data that cannot allow patients’ identification.
Data Availability Statement
Data supporting the findings of this study were derived from the following resource available in the public domains: https://wonder.cdc.gov/vaers.html and http://www.vigiaccess.org/.
Conflicts of Interest
M.G., E.R., E.P., U.M., and I.D. have no conflicts of interest relevant to the content of the present work. A.A. reports grants and personal fees from BMS, as well as grants from MSD, Roche, Astra Zeneca, Eli-Lilly, Takeda, and Bayer, outside of the submitted work.
vaccines-09-00019-t001_Table 1Table 1 Demographic and clinical feature of cases of myocarditis/pericarditis reported with influenza vaccine as suspect in Vaccine Adverse Event Reporting System (VAERS) and the World Health Organization’s (WHO) global Individual Case Safety Report database (VigiBase®).
Demographic Features VAERS VigiBase
Overall number of cases 191 399
Proportion of cases (based on overall number of reports with the flu vaccine) 0.03% (712,776) 0.16% (246,864)
Age (mean) 44.5 ± 22.9 46.7 ± 22.3
Sex
Female 62 (32.5%) 131 (32.8%)
Male 124 (64.9%) 263 (65.9%)
Not specified 5 (2.6%) 5 (1.3%)
Reporter country
US 109 (57.1%) 183 (45.9%)
Non-US 60 (31.4%) -
Europe - 180 (45.1%)
Asia - 10 (2.5%)
Oceania - 19 (4.8%)
America (except US) - 7 (1.7%)
Not specified 22 (11.5%) -
Reported symptoms (preferred terms) *
Myocarditis 81 (42.4%) 193 (48.4%)
Pericarditis 117 (61.3%) 225 (56.4%)
Myopericarditis 7 (3.7%) 29 (7.3%)
Immune-mediated myocarditis 0 (0.0%) 0 (0.0%)
Co-medications
Overall number of cases 49 (25.7%) 57 (14.3%)
≥5 concomitant drugs 14 (7.3%) 13 (3.3%)
1–4 concomitant drugs 35 (18.4%) 44 (11.0%)
No concomitant drugs 142 (74.3%) 342 (85.7%)
Co-medications potentially implicated in the occurrence of myocarditis/pericarditis **
Number of cases 21 (11.0%) § 24 (6.0%) #
Immune checkpoint inhibitors (ICIs) None 2
Hydrochlorothiazide 6 5
Indomethacin 2 2
Glipizide 2 -
Clonazepam 2 -
Alprazolam 2 -
Furosemide 1 1
Bendroflumethiazide 1 2
Mesalazine 1 2
Colchicine 1 1
Doxycycline 1 2
Cotrimoxazole 1 1
Lorazepam 1 -
Amoxicillin 1 1
Isosorbide dinitrate 1 2
Tetracycline - 2
Spironolactone - 1
Cefuroxime - 1
Heparin - 1
Bromazepam - 1
Comorbidities potentially implicated in occurrence of myocarditis/pericarditis **
Number of cases 6 (3.1%) 2 (0.5%)
Ulcerative colitis 2 2
Systemic lupus erythematosus 2 -
Juvenile rheumatoid arthritis 1 -
Insulin-dependent diabetes mellitus 1 -
Onset (days; median) 7 (1.5–13) 5 (1–12)
≤3 days 65 (34.0%) 119 (29.8%)
4–7 days 19 (10.0%) 50 (12.5%)
8–14 days 35 (18.4%) 61 (15.3%)
≥15 days 36 (18.8%) 56 (14.0%)
Not specified 36 (18.8%) 113 (28.4%)
Seriousness
Serious 141 (73.8%) 303 (76.0%)
Non-serious 50 (26.2%) 48 (12.0%)
Not specified - 48 (12.0%)
Seriousness criteria *
Congenital anomaly 0 (0.0%) 0 (0.0%)
Death 16 (8.4%) 28 (7.0%)
Hospitalization 125 (65.5%) 222 (55.6%)
Life-threatening 30 (15.7%) 46 (11.5%)
Permanent disability 12 (6.3%) 12 (3.0%)
Other outcomes 30 (15.7%) 60 (15.0%)
Median time of hospitalization (days) 3 (2–4) NA
Recovering
Recovered 60 (31.4%) 164 (41.1%)
Not recovered 64 (33.5%) 61 (15.3%)
Not specified 67 (35.1%) 174 (43.6%)
Concomitant other vaccines
Overall number of cases 59 (30.9%) 87 (21.8%)
Mean number of vaccines per patient 3.1 ± 1.4 2.5 ± 1.7
* One case may exhibit more than one seriousness criteria. ** According to 2015 the European Society of Cardiology (ESC) guidelines for the diagnosis and management of pericardial diseases [6], Caforio et al. [7] and Butany et al. [8]. § In one case, the concomitant use of glipizide and indomethacin, and colchicine and indomethacin. # In one case, concomitant use of amoxicillin and tetracycline, hydrochlorothiazide and cotrimoxazole, and bromazepam and heparin. Flu vaccine types (VAERS): FLU 3 (trivalent injected): 69 patients (36.1%); FLUX SEASONAL (influenza virus vaccine, no brand name): 62 (32.5%); FLU 4 (quadrivalent injected): 20 (10.5%); FLUN 3 (trivalent intranasal spray): 19 (9.9%); FLUN 4 (quadrivalent intranasal spray): 7 (3.7%); FLU H1N1 (monovalent injected): 5 (2.6%); FLUA 3 (trivalent adjuvant injected): 3 (1.6%); FLUN H1N1 (monovalent intranasal spray): 2 (1.1%); FLUX H1N1 (monovalent unknown manufacturer): 2 (1.1%); FLUC 4 (quadrivalent cell-culture-derived injected): 2 (1.1%); FLUC 3 (trivalent cell-culture-derived injected): 1 (0.5%). One patient received both FLUX SEASONAL and FLUX (H1N1).
vaccines-09-00019-t002_Table 2Table 2 Case-by-case assessment of reports concerning myocarditis or pericarditis in which the influenza vaccine and immune checkpoint inhibitors (ICIs) were concomitantly used.
Case ID Drugs/Role Dose Year Age/Sex Reporter Country Reporter Qualification Reactions Seriousness Outcome Concomitant Medications Comorbidities Management Causality Assessment Adapted DIPS Score
#1 Nivolumab (suspect)
Influenza vaccine(suspect) 3 mg/kg every 2 weeks IV- 2018 70/F Japan Physician Myocarditis Serious
(life-threatening; prolonged hospitalization; other outcomes) Recovered Ursodeoxycholic acid 200 mg/day
Bezafibrate
200 mg/day
Calcitriol
0.5 mcg/day NSCLC
Liver disorder
Hyperlipidemia
Osteoporosis Nivolumab withdrawn Unclassifiable (data on latency and time window of increased risk are lacking) Synergistic effect between influenza vaccine and ICIs cannot be excluded 1
Doubtful
#2 Pembrolizumab
(suspect)
Influenza vaccine (suspect) NA
IV
0.5 mL
IM 2018 67/M US Pharmacist Myocarditis,
stress, cardiomyopathy,
weight decreased,
headache,
cardiac failure, congestive,
cerebral infarction,
confusional state, and
dyspnoea Serious
(life-threatening; prolonged hospitalization) NA NA Lung neoplasm malignant NA Unclassifiable
(data on latency and time window of increased risk are lacking)
Synergistic effect between influenza vaccine and ICIs cannot be excluded 1
Doubtful
#3 Ipilimumab
(suspect)
Nivolumab
(suspect)
Influenza vaccine (concomitant) 80 mg every 3 weeks IV
240 mg every 3 weeks IV- 2019 77/M Canada Physician Myocarditis,
pulmonary hypertension,
dyspnoea chest discomfort asthenia, troponin increased c-reactive protein, increased diastolic dysfunction, oedema, peripheral urticaria, and pruritus Serious
(prolonged hospitalization; other outcomes) NA NA Metastatic renal cell carcinoma Ipilimumab and nivolumab withdrawn Unclassifiable
(data on latency and time window of increased risk are lacking)
Synergistic effect between influenza vaccine and ICIs cannot be excluded 2
Possible
US—United States of America; NSCLC—non-small cell lung cancer; NA—not available; IV—intravenous; IM—intramuscular; DIPS—drug-interaction probability scale. | INFLUENZA VIRUS VACCINE, IPILIMUMAB, NIVOLUMAB | DrugsGivenReaction | CC BY | 33406694 | 19,221,966 | 2021-01-04 |
What was the administration route of drug 'IPILIMUMAB'? | Influenza Vaccination and Myo-Pericarditis in Patients Receiving Immune Checkpoint Inhibitors: Investigating the Likelihood of Interaction through the Vaccine Adverse Event Reporting System and VigiBase.
BACKGROUND
Evidence on whether the influenza vaccine could exacerbate immune-related adverse events, including myopericarditis (MP), in patients treated with immune checkpoint inhibitors (ICIs), is still conflicting. We explored this issue through a global real-world approach.
METHODS
We queried the Vaccine Adverse Event Reporting System (VAERS) and VigiBase to retrieve cases of MP in which the influenza vaccine and ICIs were recorded as suspect and were concomitantly reported. For the included cases, causality assessment and Drug Interaction Probability Scale (DIPS) algorithms were applied.
RESULTS
There were 191 and 399 reports of MP with the influenza vaccine that were retrieved (VAERS and VigiBase, respectively). No case of MP reporting the concomitant use of ICIs and the influenza vaccine was found in VAERS, while three cases of myocarditis were retrieved in VigiBase. All of the cases were unclassifiable for a causality assessment because of the lack of data concerning latency. According to the DIPS, one report was categorized as possible and two as doubtful.
CONCLUSIONS
The paucity of cases coupled with the doubtful causality assessment make the potential interaction between influenza vaccines and ICIs in cancer patients negligible from clinical and epidemiological standpoints. These findings support the cardiovascular safety of the influenza vaccination, which remains strongly recommended in cancer patients, especially in the current COVID-19 era.
1. Introduction
The safety of vaccines and medications is a current global safety issue. The annual vaccination against the influenza virus is the primary means of preventing influenza and its complications in high-risk subjects, including adult cancer patients, as described by observational studies, suggesting lower mortality and infection-related outcomes with influenza vaccination [1]. However, in the recent past, potential pharmacokinetic interactions have been proposed, considering that vaccines can influence the drug metabolism via inflammatory cytokines [2]. Therefore, potential interactions between influenza vaccines and drugs used for chronic diseases (e.g., immunosuppressive agents) cannot be excluded [3]. Moreover, cases of myo-pericarditis (MP) after immunization, although rarely, are reported [4,5].
Myocarditis and pericarditis represent serious and life-threatening inflammatory diseases involving myocardium and pericardium, potentially associated with the use of several drugs and vaccines [6,7,8]. In particular, cases of MP were described with the smallpox vaccine in early 2000 and, more recently, very rarely are reported after influenza immunization [4,5]. Immune checkpoint inhibitors (ICIs), such as anti-PD1, anti-PDL1, and anti-CTLA4 monoclonal antibodies, are approved as first-line agents in the management of melanoma and non-small cell lung cancer. They may cause a variegate spectrum of cardiovascular events, including MP, with a higher mortality compared with other immune-related adverse events (irAEs) [9,10,11,12,13]. In a summary of the product characteristics of the different ICIs, pericarditis and myocarditis are reported as uncommon (≥1/1000 to <1/100) and rare (≥1/10,000 to <1/1000, respectively) AEs. Notably, the detection of myocarditis with ICIs requires the permanent discontinuation of treatment, no matter the severity.
Consequently, the question arises as to whether pharmacokinetic and pharmacodynamic interactions occur in patients receiving the influenza vaccination (recommended both by oncologists and cardiologists) and ICIs, possibly causing or exacerbating irAEs such MP. Although no cases of myocarditis have been reported, evidence on whether the influenza vaccine exacerbates irAEs is still conflicting and poorly investigated [14]. Only a retrospective study investigated the clinical features of myocarditis with ICIs in patients receiving the influenza vaccine; reduced myocardial injury and a lower risk of major adverse cardiac events among recipients of the influenza vaccine was found compared with not vaccinated patients [15].
In the recent past, analysis of the spontaneous reporting systems (SRSs) has attracted considerable interest among clinicians for the accurate and timely characterization of drug- and vaccine-related risks occurring in the real world, where comorbidities and polypharmacotherapy exist. By offering a global epidemiological perspective, these pharmacovigilance studies have been pursued to test the hypothesis of potential associations, including refusing the likelihood of interactions [3,16,17], especially for rare, unexpected, and delayed AEs, such as MP.
In this study, we investigated the likelihood of interaction between the influenza vaccination and ICIs by analyzing spontaneous reports of MP collected from the Vaccine Adverse Event Reporting System (VAERS; P.O. Box 1100; Rockville, MD 20849-1100) and the World Health Organization’s (WHO) global Individual Case Safety Report database (VigiBase®; Uppsala Monitoring Centre Box, 1051 SE-751 40, Uppsala, Sweden).
2. Materials and Methods
2.1. Study Conception and Design
The study was conceived as an observational retrospective analysis of spontaneous reports of MP collected from the VAERS and the VigiBase® to (a) characterize relevant clinical features; (b) highlight the concomitant use of agents known to cause MP, including ICIs; and (c) assess the causality and probability of interaction between the influenza vaccine and ICIs.
VAERS is a national system to monitor the safety of US-licensed vaccines [18], whereas VigiBase® collects worldwide reports on vaccines and drugs, thus making these archives act as complementary approaches [19].
VAERS transmits its vaccine adverse event reports to the VigiBase, in order to contribute to the global pharmacovigilance effort along with other countries that employ passive vaccine safety monitoring systems [18], thus possible duplicates between the two databases may exist.
2.2. Data Source
Established in 1990, the VAERS is co-managed by the Centers for Disease Control and Prevention and the US Food and Drug Administration (FDA); it collects and analyzes reports of AEs following immunization (AEFI) for vaccines licensed in the US, receiving approximately 28,000 reports of AEFI annually.
AEFI may be any unfavorable or unintended sign, abnormal laboratory finding, symptom, or disease that occurs following or during the administration of a vaccine. AEs are temporally associated events that may either be caused by a vaccine or be coincidental to it, i.e., not necessarily related to the vaccination [20]. VAERS may be used to detect unexpected and rare patterns of AEFI, unlikely to arise in pivotal trials because of the limited number of patients involved [21]. Health-care professionals, vaccine manufacturers, and consumers (patients, parents, and caregivers) can submit reports of AEs to VAERS.
VigiBase® is one of the largest and most comprehensive pharmacovigilance databases, maintained by the Uppsala Monitoring Centre in Sweden, and containing over 20 million of Individual Case Safety Reports from 110 countries over the five continents. VigiBase® collects reports of AEs for authorized drugs, vaccines, and food supplements, submitted from healthcare professionals, pharmaceutical companies, and patients.
For each vaccine/drug, the characterization of the vaccine/drug role indicated by the primary reporter (i.e., the original source of the information) includes the following three categories: suspect, concomitant, and interacting. All spontaneous reports should have at least one suspect vaccine/drug, namely involved, presumably, in the occurrence of AEFI. If the reporter indicates a suspected interaction, all interacting vaccines/drugs are considered to be suspect vaccines/drugs.
In both databases, AEs are codified through the Medical Dictionary for Regulatory Activities (MedDRA) terminology, and described and organized in terms of Preferred Terms (PTs).
2.3. Data Extraction and Analysis
A multi-step approach was followed for data extraction in each database:(1) Reports for individuals receiving any type of vaccine against the influenza virus categorized as suspect AEFI submitted to VAERS (from July 1990 to September 2020) and VigiBase® (from inception to October 2020) were selected.
(2) Cases of myocarditis or pericarditis were extracted through specific PTs and lowest level terms, in line with previous studies on the influenza vaccination [4] and the potential immune-related basis of cardiotoxicity documented for ICIs by recent pharmacovigilance analyses [9,10]: myocarditis, pericarditis, immune-mediated myocarditis, and myopericarditis.
(3) Reports recording AEs of interest were finally assessed for co-reported drugs/vaccines of interest.
In VigiBase, retained reports (refer to point 2) with ICIs, namely PD-1 inhibitors (nivolumab, pembrolizumab, and cemiplimab), PD-L1 inhibitors (atezolizumab, avelumab, and durvalumab), and CTLA-4 inhibitors (ipilimumab and tremelimumab), were evaluated by extracting the following data: demographic features (age, gender, weight, year, and reporter country), reporter qualification, comorbidities, concomitant medications (including dose and route of administration when available), latency, degree of seriousness, outcome, and management of the AE. The same approach was applied to identify cases of interest reported for vaccines against the influenza virus, both as suspect alone or concomitant to ICI exposure.
In VAERS, for each report of interest with the influenza vaccines, the following data were extracted: demographic features (age, gender, year, and reporter country), type of vaccine against the influenza virus, medical history, concomitant drugs or administered vaccines, laboratory data, AEs codified as PTs, latency, AE degree of seriousness, outcome, and narratives, when available.
According to WHO criteria, a serious AE is any untoward medical occurrence that, no matter the dose, results as fatal, causing a life-threatening event, requiring hospitalization of the patient, causing serious/permanent disability, causing congenital abnormalities, or other clinically relevant conditions [22].
Co-reported medications and comorbidities known to cause myocarditis or pericarditis (i.e., potential confounders) were further characterized according to the lists proposed by Adler et al. [6], Caforio et al. [7], and Butany et al. [8].
2.4. Causality Assessment and Evaluation of Drug–Vaccine Interaction
The probability of interaction when the influenza vaccine and ICIs are co-reported was evaluated by applying the established WHO criteria for causality assessment [20], as well as the Drug Interaction Probability Scale (DIPS) [23].
The following items were accounted for in the AEFI causality assessment: temporal relationship, alternate explanations, proof of association, prior evidence, population-based evidence, and biological plausibility [20]. Cases without adequate information were classified as “unclassifiable”; cases with adequate information were categorized as: (1) “consistent with a causal relationship”, when the available evidence supported a causal relationship between the vaccine and the AEFI in the individual, but it did not rule out the possibility that the AEFI may have been caused by a factor other than the vaccine; (2) “inconsistent with a causal association”, when the available evidence did not support a causal relationship between vaccine administration and the reported AEFI in the individual; and (3) “indeterminate”, when the temporal relationship was consistent but the available evidence insufficient to support or rule out a causal relationship in the individual.
The DIPS is a 10-item tool specifically developed to assess the likelihood of drug–drug interactions [23]. ICIs were considered as the objective drugs (i.e., the one affected by the presence of another vaccine/drug), while the influenza vaccine was considered as the precipitant agent (i.e., the one causing a change on the object drug). To avoid overemphasis on the role of the vaccine, the answer to the second question was always “unknown” (knowledge on the mechanism of the interaction is hypothesized and literature data are very scarce/uncertain); in addition, questions 5, 6, and 10 were not assessable/applicable (dechallenge, rechallenge, and dose adjustments are unfeasible for vaccines considering the peculiarities of their administration), as previously performed [3]. The final summary score could reach 10 points. Higher total scores correspond to a higher likelihood of drug–vaccine interaction (i.e., >8 = highly probable; 5–8 = probable; 2–4 = possible; <2 = doubtful).
3. Results
3.1. Demographic and Clinical Data
Over the observed period, out of a total of 712,776 AEFI, 191 (0.03%) reports of MP mentioning the influenza vaccine as suspect were collected within the VAERS.
The clinical and demographic characteristics are provided in Table 1. The reports included 124 men (64.9%) and 62 women (in five cases gender was not reported), aged between 1 and 88 years (mean age 44.5 years). Pericarditis were reported in 117 cases (61.3%), followed by myocarditis (81 cases; 42.4%) and MP (7 cases; 3.7%). No cases of immune-mediated myocarditis were retrieved.
The median onset was seven days; in 34.0% of reports, the AEFI of interest occurred in the first 3 days after the administration of the influenza vaccine. Comorbidities potentially implicated in the occurrence of the AEFI of interest were retrieved in six cases (3.1%), with ulcerative colitis and systemic lupus erythematosus being the most represented. Other vaccines were concomitantly administered in 59 cases (30.9%), accounting for a mean number of 3.1 vaccines per patient.
In 141 cases (73.8%), the report was classified as serious, and 16 fatal cases (8.4%) were found. Recovery occurred in 31.4% of cases.
In the VigiBase®, 246,864 reports mentioning the influenza vaccine as a suspect agent were found, and myocarditis/pericarditis were reported in 399 cases (0.16%; Table 1).
The cases showed a mean age of 46.7 years, with a male preponderance (65.9%). Reports were largely submitted from US (45.9%) and Europe (45.1%). Pericarditis was reported in 225 cases (56.4%), followed by myocarditis (193 cases; 48.4%) and myopericarditis (29; 7.3%). No cases of immune-mediated myocarditis were found.
Median onset was five days, and in 29.8% of reports, AEs of interest occurred in the first three days after the administration of the influenza vaccine. Comorbidities potentially implicated in the occurrence of myocarditis/pericarditis were retrieved in two patients (0.5%) affected by ulcerative colitis. Other vaccines were concomitantly administered in 87 cases (21.8%), accounting for a mean number of 2.5 vaccines per patient.
In 303 cases (76.0%), the report was classified as serious, and 28 fatal cases (7.0%) were found. Recovering occurred in 41.1% of cases.
3.2. Co-Reported Medications and Detection of Cases with ICI Administration
Overall, concomitant medications were found in 49 (25.7%) and 57 (14.3%) cases with the influenza vaccine in VAERS and VigiBase®, respectively (Table 1). In 14 (7.3%) and 13 (3.3%) cases, five or more concomitant drugs were reported in VAERS and VigiBase®, respectively.
Concomitant medications potentially implicated in the occurrence of myocarditis/pericarditis were retrieved in 21 (11.0%) and 24 (6.0%) cases in VAERS and VigiBase®, respectively, with hydrochlorothiazide being the most frequent in both databases (in six and five cases, respectively).
Only six cases (one classified as serious, where Guillain-Barré syndrome was recorded) with the concomitant use of ICIs and the influenza vaccine were found in VAERS (Table S1), but no cases of myocarditis/pericarditis. In VigiBase®, two cases of myocarditis reporting the concomitant administration of ICIs and the influenza vaccine both mentioned as suspect agents were retrieved. A third case of myocarditis in which the influenza vaccine was classified as a concomitant agent was detected (Table 2).
The three cases were classified as serious (causing prolonged hospitalization), included two men and one woman, aged 67–77 years, and affected by lung or renal carcinoma. Nivolumab, pembrolizumab, and ipilimumab/nivolumab combination therapy were reported as the ICI regimen. In two cases ICI was withdrawn, while recovering occurred in only one case.
3.3. Causality Assessment and Evaluation of Drug–Vaccine Interaction
These three cases showed an unclassifiable causality assessment due to the lack of data concerning the latency and time window of increased risk (Table 2).
By applying the adapted DIPS algorithm, one report was categorized as possible (due to the lack of underlying diseases or co-reported agents known to cause or precipitate myocarditis, and to the detection of troponin increase) and two as doubtful (only the absence of underlying diseases or co-reported agents known to cause or precipitate myocarditis were recognized; Table S2).
4. Discussion
To the best of our knowledge, this is the first real-world study investigating the potential interactions between influenza vaccines and ICIs resulting in myocarditis or pericarditis in cancer patients, by assessing spontaneous reports submitted to the VAERS and VigiBase®. This global post-marketing safety study stems from recent conflicting real-world evidence surrounding the possible exacerbation of irAEs with influenza vaccines in patients treated with ICIs [14,15,24,25,26,27,28,29], thus joining in the wider debate on the bidirectional relationship between immunotherapy and the influenza vaccination, potentially affecting the clinical and humoral efficacy of the vaccine, performance of ICIs, and safety [14].
Four major findings emerged from our analysis: (a) myocarditis and pericarditis represented a very rare AEFI (with a non-negligible proportion of death, approximately 8–9%), based on the low reporting frequency retrieved in both SRSs (<0.1–0.2% of overall AEs), also considering the influenza vaccination coverage rates (estimated at about 25% per year in Europe [30,31]) and the relevant million doses distributed worldwide; (b) the reporting of myocarditis in patients concomitantly receiving influenza vaccines and ICIs is limited to only three out of a total of 1465 cases of myocarditis/pericarditis found with influenza vaccines or ICIs (considered as suspect agents) in the two databases; (c) these cases were unclassifiable for causality assessment with a doubtful probability of drug–vaccine interaction (according to the adapted DIPS algorithm), thus suggesting that the vaccine is not directly involved in the occurrence of myocarditis (and in one of the three cases, influenza vaccine was reported only as concomitant and not as suspect or interacting agent); and (d) no other cardiovascular AEs were found in patients concomitantly receiving influenza vaccination and ICIs, as well as no other irAEs were reported, except for a single case of Guillain-Barré syndrome, a condition already associated with both ICIs and the influenza vaccine [32,33,34].
Theoretically, a possible pharmacodynamic interaction between influenza vaccines and ICIs leading to the exacerbation of irAEs (including MP), could be supposed. The blockade of a PD-1/PD-L1 pathway together with the vaccination (particularly in conjunction with a strong vaccine adjuvant) could enhance one or more of the mechanisms associated with irAEs onset (infiltration of central memory T cells into the tissues, cross-presentation of shared antigens, and exacerbation of previously subclinical auto-immune syndromes) [24].
Our specific focus on the myo-pericardium stems from the peculiar clinical features of myocarditis in terms of severity and mortality compared with other irAEs, usually requiring immunotherapy discontinuation [9,10,11,12,13], as reported in two out of our three cases. Although, in all three cases, no underlying diseases or other agents known to cause or precipitate myocarditis were recorded, the lack of data concerning latency and solid literature studies allows for minimizing, if not completely excluding, the clinically relevant contribution of a potential drug–vaccine interaction in our cases.
Furthermore, the only study investigating the association between influenza vaccine and the development of myocarditis among patients on ICIs found that the administration of the vaccine was not associated with an increased risk of subsequent myocarditis [15]. Additionally, myocarditis cases in which the influenza vaccine was administered showed lower troponin levels at presentation and a lower risk of major adverse cardiac events at follow-up compared with non-vaccinate patients developing myocarditis with ICIs [15], thus suggesting a protective role for the influenza vaccine in this setting.
ICIs caused a paradigm shift in cancer treatment, and are currently used as first-line agents in the management of non-small cell lung cancer, melanoma, and renal carcinoma [35]. Considering their evolving role and expected increasing uptake, the assessment of cardiovascular safety is of paramount importance. Likewise, the safety of influenza vaccines represents an important issue, given the high morbidity and mortality rates caused by influenza in cancer patients [36]. Notably, the development of influenza infection may also, albeit rarely, be associated itself with an increased risk of myocarditis and major adverse cardiovascular events [37,38]. Therefore, the suggested protective role of the influenza vaccine on cardiovascular outcome [15] cannot be overlooked.
Collectively, our findings provide a reassuring message in terms of cardiovascular safety for cancer patients treated with ICIs and requiring the influenza vaccination. Of note, less than 20% of patients affected by malignancies received the influenza vaccine, with a gradual decline in the last decade [39]. We support and promote the achievement of an optimal vaccination coverage rate in cancer patients for several reasons, including the following: (a) direct association with a lower mortality and infection-related outcomes in immunosuppressed adults [1]; (b) a better overall survival recently reported in patients treated with ICIs receiving influenza vaccination [40]; and (c) the current COVID-19 pandemic, to reduce the strain on the healthcare system while protecting vulnerable subjects from the dramatic impact of a possible co-infection [41]. Cancer patients receiving immunotherapy are at high risk of severe events as a result of COVID-19 systemic involvement, including pneumonitis and myocarditis [42], and a recent systematic review found no significant increase in the risk of infection or in the illness severity or lethality of COVID-19 in subjects receiving the influenza vaccine, with some studies reporting a significantly inverse association [43]. Therefore, the implementation of measures aimed at raising influenza vaccination coverage in frail patients is strongly recommended.
We acknowledge the limitations of our study, mainly inherent to the nature of SRSs data. VAERS and VigiBase® are subject to reporting bias, including under- and over-reporting of adverse events, although there are not clues for major distortions, considering that serious events such as MP are less prone to under-reporting, and no specific warnings were posted by regulatory agencies, thus minimizing the existence and impact of a stimulated reporting [3,18]. We recognize the potential occurrence of subclinical myocarditis, which may be under-diagnosed/under-detected, and is thus likely to be under-reported. Furthermore, the quality and completeness of the reports collected in both databases are variable, and many records lack valid medical diagnoses, thus making the assessment of causality challenging. Additionally, DIPS was not specifically developed to assess drug–vaccine interactions, although we implemented an adapted version in order to the better focus on the possible precipitating role of the influenza vaccine.
Notwithstanding these limitations, pharmacovigilance assessment represents an invaluable opportunity to monitor vaccine safety and identify novel rare signals, potentially arising from drug–vaccine interactions, both from a local and international perspective. Furthermore, our findings are consistent between the two databases, thus supporting the lack of evidence of a clinically relevant drug–vaccine interaction. The identification of myocarditis with ICIs, in line with previous findings [9,10,11], further corroborates the ability of our post-marketing approach to identify actual true-positive associations.
In conclusion, the paucity of cases coupled with a lack of certainty in terms of causality assessment and doubtful probability make the risk of myocarditis and pericarditis by interaction between influenza vaccines and ICIs in cancer patients negligible from both clinical and epidemiological standpoints. Our findings support the cardiovascular safety of influenza vaccines in subjects treated with immunotherapy, thereby emphasizing the importance of a flu vaccination in this population, especially in the current COVID-19 era.
Acknowledgments
We would like to thank Annette Rudolph for data extraction from VigiBase®. Authors at the University of Bologna are supported by institutional research funds (Ricerca Fondamentale Orientata). No sources of funding were received for the preparation of this article.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2076-393X/9/1/19/s1. Table S1: Case-by-case assessment of reports recorded in VAERS in which influenza vaccine and immune checkpoint inhibitors (ICIs) were concomitantly used. Table S2: Application of the adapted version of Drug Interaction Probability Scale in cases of myocarditis/pericarditis in which immune checkpoint inhibitors (ICIs) and influenza vaccine were concomitantly administered.
Click here for additional data file.
Author Contributions
M.G.: methodology, investigation, formal analysis, and writing—original draft. E.R.: conceptualization, methodology, formal analysis, and writing—reviewing and editing. U.M.: writing—reviewing and editing. A.A.: writing—reviewing and editing. E.P.: conceptualization, methodology, formal analysis, and writing—reviewing and editing. I.D.: conceptualization and writing—reviewing and editing. All authors have read and agreed to the published version of the manuscript.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Institutional Review Board Statement
Under current legislation, institutional review board approval is not required when performing analysis of the publicly available VAERS and VigiBase databases, because it contains anonymized data that cannot allow patients’ identification.
Informed Consent Statement
Patient consent was waived due to VAERS and VigiBase databases contain anonymized data that cannot allow patients’ identification.
Data Availability Statement
Data supporting the findings of this study were derived from the following resource available in the public domains: https://wonder.cdc.gov/vaers.html and http://www.vigiaccess.org/.
Conflicts of Interest
M.G., E.R., E.P., U.M., and I.D. have no conflicts of interest relevant to the content of the present work. A.A. reports grants and personal fees from BMS, as well as grants from MSD, Roche, Astra Zeneca, Eli-Lilly, Takeda, and Bayer, outside of the submitted work.
vaccines-09-00019-t001_Table 1Table 1 Demographic and clinical feature of cases of myocarditis/pericarditis reported with influenza vaccine as suspect in Vaccine Adverse Event Reporting System (VAERS) and the World Health Organization’s (WHO) global Individual Case Safety Report database (VigiBase®).
Demographic Features VAERS VigiBase
Overall number of cases 191 399
Proportion of cases (based on overall number of reports with the flu vaccine) 0.03% (712,776) 0.16% (246,864)
Age (mean) 44.5 ± 22.9 46.7 ± 22.3
Sex
Female 62 (32.5%) 131 (32.8%)
Male 124 (64.9%) 263 (65.9%)
Not specified 5 (2.6%) 5 (1.3%)
Reporter country
US 109 (57.1%) 183 (45.9%)
Non-US 60 (31.4%) -
Europe - 180 (45.1%)
Asia - 10 (2.5%)
Oceania - 19 (4.8%)
America (except US) - 7 (1.7%)
Not specified 22 (11.5%) -
Reported symptoms (preferred terms) *
Myocarditis 81 (42.4%) 193 (48.4%)
Pericarditis 117 (61.3%) 225 (56.4%)
Myopericarditis 7 (3.7%) 29 (7.3%)
Immune-mediated myocarditis 0 (0.0%) 0 (0.0%)
Co-medications
Overall number of cases 49 (25.7%) 57 (14.3%)
≥5 concomitant drugs 14 (7.3%) 13 (3.3%)
1–4 concomitant drugs 35 (18.4%) 44 (11.0%)
No concomitant drugs 142 (74.3%) 342 (85.7%)
Co-medications potentially implicated in the occurrence of myocarditis/pericarditis **
Number of cases 21 (11.0%) § 24 (6.0%) #
Immune checkpoint inhibitors (ICIs) None 2
Hydrochlorothiazide 6 5
Indomethacin 2 2
Glipizide 2 -
Clonazepam 2 -
Alprazolam 2 -
Furosemide 1 1
Bendroflumethiazide 1 2
Mesalazine 1 2
Colchicine 1 1
Doxycycline 1 2
Cotrimoxazole 1 1
Lorazepam 1 -
Amoxicillin 1 1
Isosorbide dinitrate 1 2
Tetracycline - 2
Spironolactone - 1
Cefuroxime - 1
Heparin - 1
Bromazepam - 1
Comorbidities potentially implicated in occurrence of myocarditis/pericarditis **
Number of cases 6 (3.1%) 2 (0.5%)
Ulcerative colitis 2 2
Systemic lupus erythematosus 2 -
Juvenile rheumatoid arthritis 1 -
Insulin-dependent diabetes mellitus 1 -
Onset (days; median) 7 (1.5–13) 5 (1–12)
≤3 days 65 (34.0%) 119 (29.8%)
4–7 days 19 (10.0%) 50 (12.5%)
8–14 days 35 (18.4%) 61 (15.3%)
≥15 days 36 (18.8%) 56 (14.0%)
Not specified 36 (18.8%) 113 (28.4%)
Seriousness
Serious 141 (73.8%) 303 (76.0%)
Non-serious 50 (26.2%) 48 (12.0%)
Not specified - 48 (12.0%)
Seriousness criteria *
Congenital anomaly 0 (0.0%) 0 (0.0%)
Death 16 (8.4%) 28 (7.0%)
Hospitalization 125 (65.5%) 222 (55.6%)
Life-threatening 30 (15.7%) 46 (11.5%)
Permanent disability 12 (6.3%) 12 (3.0%)
Other outcomes 30 (15.7%) 60 (15.0%)
Median time of hospitalization (days) 3 (2–4) NA
Recovering
Recovered 60 (31.4%) 164 (41.1%)
Not recovered 64 (33.5%) 61 (15.3%)
Not specified 67 (35.1%) 174 (43.6%)
Concomitant other vaccines
Overall number of cases 59 (30.9%) 87 (21.8%)
Mean number of vaccines per patient 3.1 ± 1.4 2.5 ± 1.7
* One case may exhibit more than one seriousness criteria. ** According to 2015 the European Society of Cardiology (ESC) guidelines for the diagnosis and management of pericardial diseases [6], Caforio et al. [7] and Butany et al. [8]. § In one case, the concomitant use of glipizide and indomethacin, and colchicine and indomethacin. # In one case, concomitant use of amoxicillin and tetracycline, hydrochlorothiazide and cotrimoxazole, and bromazepam and heparin. Flu vaccine types (VAERS): FLU 3 (trivalent injected): 69 patients (36.1%); FLUX SEASONAL (influenza virus vaccine, no brand name): 62 (32.5%); FLU 4 (quadrivalent injected): 20 (10.5%); FLUN 3 (trivalent intranasal spray): 19 (9.9%); FLUN 4 (quadrivalent intranasal spray): 7 (3.7%); FLU H1N1 (monovalent injected): 5 (2.6%); FLUA 3 (trivalent adjuvant injected): 3 (1.6%); FLUN H1N1 (monovalent intranasal spray): 2 (1.1%); FLUX H1N1 (monovalent unknown manufacturer): 2 (1.1%); FLUC 4 (quadrivalent cell-culture-derived injected): 2 (1.1%); FLUC 3 (trivalent cell-culture-derived injected): 1 (0.5%). One patient received both FLUX SEASONAL and FLUX (H1N1).
vaccines-09-00019-t002_Table 2Table 2 Case-by-case assessment of reports concerning myocarditis or pericarditis in which the influenza vaccine and immune checkpoint inhibitors (ICIs) were concomitantly used.
Case ID Drugs/Role Dose Year Age/Sex Reporter Country Reporter Qualification Reactions Seriousness Outcome Concomitant Medications Comorbidities Management Causality Assessment Adapted DIPS Score
#1 Nivolumab (suspect)
Influenza vaccine(suspect) 3 mg/kg every 2 weeks IV- 2018 70/F Japan Physician Myocarditis Serious
(life-threatening; prolonged hospitalization; other outcomes) Recovered Ursodeoxycholic acid 200 mg/day
Bezafibrate
200 mg/day
Calcitriol
0.5 mcg/day NSCLC
Liver disorder
Hyperlipidemia
Osteoporosis Nivolumab withdrawn Unclassifiable (data on latency and time window of increased risk are lacking) Synergistic effect between influenza vaccine and ICIs cannot be excluded 1
Doubtful
#2 Pembrolizumab
(suspect)
Influenza vaccine (suspect) NA
IV
0.5 mL
IM 2018 67/M US Pharmacist Myocarditis,
stress, cardiomyopathy,
weight decreased,
headache,
cardiac failure, congestive,
cerebral infarction,
confusional state, and
dyspnoea Serious
(life-threatening; prolonged hospitalization) NA NA Lung neoplasm malignant NA Unclassifiable
(data on latency and time window of increased risk are lacking)
Synergistic effect between influenza vaccine and ICIs cannot be excluded 1
Doubtful
#3 Ipilimumab
(suspect)
Nivolumab
(suspect)
Influenza vaccine (concomitant) 80 mg every 3 weeks IV
240 mg every 3 weeks IV- 2019 77/M Canada Physician Myocarditis,
pulmonary hypertension,
dyspnoea chest discomfort asthenia, troponin increased c-reactive protein, increased diastolic dysfunction, oedema, peripheral urticaria, and pruritus Serious
(prolonged hospitalization; other outcomes) NA NA Metastatic renal cell carcinoma Ipilimumab and nivolumab withdrawn Unclassifiable
(data on latency and time window of increased risk are lacking)
Synergistic effect between influenza vaccine and ICIs cannot be excluded 2
Possible
US—United States of America; NSCLC—non-small cell lung cancer; NA—not available; IV—intravenous; IM—intramuscular; DIPS—drug-interaction probability scale. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33406694 | 19,221,966 | 2021-01-04 |
What was the administration route of drug 'NIVOLUMAB'? | Influenza Vaccination and Myo-Pericarditis in Patients Receiving Immune Checkpoint Inhibitors: Investigating the Likelihood of Interaction through the Vaccine Adverse Event Reporting System and VigiBase.
BACKGROUND
Evidence on whether the influenza vaccine could exacerbate immune-related adverse events, including myopericarditis (MP), in patients treated with immune checkpoint inhibitors (ICIs), is still conflicting. We explored this issue through a global real-world approach.
METHODS
We queried the Vaccine Adverse Event Reporting System (VAERS) and VigiBase to retrieve cases of MP in which the influenza vaccine and ICIs were recorded as suspect and were concomitantly reported. For the included cases, causality assessment and Drug Interaction Probability Scale (DIPS) algorithms were applied.
RESULTS
There were 191 and 399 reports of MP with the influenza vaccine that were retrieved (VAERS and VigiBase, respectively). No case of MP reporting the concomitant use of ICIs and the influenza vaccine was found in VAERS, while three cases of myocarditis were retrieved in VigiBase. All of the cases were unclassifiable for a causality assessment because of the lack of data concerning latency. According to the DIPS, one report was categorized as possible and two as doubtful.
CONCLUSIONS
The paucity of cases coupled with the doubtful causality assessment make the potential interaction between influenza vaccines and ICIs in cancer patients negligible from clinical and epidemiological standpoints. These findings support the cardiovascular safety of the influenza vaccination, which remains strongly recommended in cancer patients, especially in the current COVID-19 era.
1. Introduction
The safety of vaccines and medications is a current global safety issue. The annual vaccination against the influenza virus is the primary means of preventing influenza and its complications in high-risk subjects, including adult cancer patients, as described by observational studies, suggesting lower mortality and infection-related outcomes with influenza vaccination [1]. However, in the recent past, potential pharmacokinetic interactions have been proposed, considering that vaccines can influence the drug metabolism via inflammatory cytokines [2]. Therefore, potential interactions between influenza vaccines and drugs used for chronic diseases (e.g., immunosuppressive agents) cannot be excluded [3]. Moreover, cases of myo-pericarditis (MP) after immunization, although rarely, are reported [4,5].
Myocarditis and pericarditis represent serious and life-threatening inflammatory diseases involving myocardium and pericardium, potentially associated with the use of several drugs and vaccines [6,7,8]. In particular, cases of MP were described with the smallpox vaccine in early 2000 and, more recently, very rarely are reported after influenza immunization [4,5]. Immune checkpoint inhibitors (ICIs), such as anti-PD1, anti-PDL1, and anti-CTLA4 monoclonal antibodies, are approved as first-line agents in the management of melanoma and non-small cell lung cancer. They may cause a variegate spectrum of cardiovascular events, including MP, with a higher mortality compared with other immune-related adverse events (irAEs) [9,10,11,12,13]. In a summary of the product characteristics of the different ICIs, pericarditis and myocarditis are reported as uncommon (≥1/1000 to <1/100) and rare (≥1/10,000 to <1/1000, respectively) AEs. Notably, the detection of myocarditis with ICIs requires the permanent discontinuation of treatment, no matter the severity.
Consequently, the question arises as to whether pharmacokinetic and pharmacodynamic interactions occur in patients receiving the influenza vaccination (recommended both by oncologists and cardiologists) and ICIs, possibly causing or exacerbating irAEs such MP. Although no cases of myocarditis have been reported, evidence on whether the influenza vaccine exacerbates irAEs is still conflicting and poorly investigated [14]. Only a retrospective study investigated the clinical features of myocarditis with ICIs in patients receiving the influenza vaccine; reduced myocardial injury and a lower risk of major adverse cardiac events among recipients of the influenza vaccine was found compared with not vaccinated patients [15].
In the recent past, analysis of the spontaneous reporting systems (SRSs) has attracted considerable interest among clinicians for the accurate and timely characterization of drug- and vaccine-related risks occurring in the real world, where comorbidities and polypharmacotherapy exist. By offering a global epidemiological perspective, these pharmacovigilance studies have been pursued to test the hypothesis of potential associations, including refusing the likelihood of interactions [3,16,17], especially for rare, unexpected, and delayed AEs, such as MP.
In this study, we investigated the likelihood of interaction between the influenza vaccination and ICIs by analyzing spontaneous reports of MP collected from the Vaccine Adverse Event Reporting System (VAERS; P.O. Box 1100; Rockville, MD 20849-1100) and the World Health Organization’s (WHO) global Individual Case Safety Report database (VigiBase®; Uppsala Monitoring Centre Box, 1051 SE-751 40, Uppsala, Sweden).
2. Materials and Methods
2.1. Study Conception and Design
The study was conceived as an observational retrospective analysis of spontaneous reports of MP collected from the VAERS and the VigiBase® to (a) characterize relevant clinical features; (b) highlight the concomitant use of agents known to cause MP, including ICIs; and (c) assess the causality and probability of interaction between the influenza vaccine and ICIs.
VAERS is a national system to monitor the safety of US-licensed vaccines [18], whereas VigiBase® collects worldwide reports on vaccines and drugs, thus making these archives act as complementary approaches [19].
VAERS transmits its vaccine adverse event reports to the VigiBase, in order to contribute to the global pharmacovigilance effort along with other countries that employ passive vaccine safety monitoring systems [18], thus possible duplicates between the two databases may exist.
2.2. Data Source
Established in 1990, the VAERS is co-managed by the Centers for Disease Control and Prevention and the US Food and Drug Administration (FDA); it collects and analyzes reports of AEs following immunization (AEFI) for vaccines licensed in the US, receiving approximately 28,000 reports of AEFI annually.
AEFI may be any unfavorable or unintended sign, abnormal laboratory finding, symptom, or disease that occurs following or during the administration of a vaccine. AEs are temporally associated events that may either be caused by a vaccine or be coincidental to it, i.e., not necessarily related to the vaccination [20]. VAERS may be used to detect unexpected and rare patterns of AEFI, unlikely to arise in pivotal trials because of the limited number of patients involved [21]. Health-care professionals, vaccine manufacturers, and consumers (patients, parents, and caregivers) can submit reports of AEs to VAERS.
VigiBase® is one of the largest and most comprehensive pharmacovigilance databases, maintained by the Uppsala Monitoring Centre in Sweden, and containing over 20 million of Individual Case Safety Reports from 110 countries over the five continents. VigiBase® collects reports of AEs for authorized drugs, vaccines, and food supplements, submitted from healthcare professionals, pharmaceutical companies, and patients.
For each vaccine/drug, the characterization of the vaccine/drug role indicated by the primary reporter (i.e., the original source of the information) includes the following three categories: suspect, concomitant, and interacting. All spontaneous reports should have at least one suspect vaccine/drug, namely involved, presumably, in the occurrence of AEFI. If the reporter indicates a suspected interaction, all interacting vaccines/drugs are considered to be suspect vaccines/drugs.
In both databases, AEs are codified through the Medical Dictionary for Regulatory Activities (MedDRA) terminology, and described and organized in terms of Preferred Terms (PTs).
2.3. Data Extraction and Analysis
A multi-step approach was followed for data extraction in each database:(1) Reports for individuals receiving any type of vaccine against the influenza virus categorized as suspect AEFI submitted to VAERS (from July 1990 to September 2020) and VigiBase® (from inception to October 2020) were selected.
(2) Cases of myocarditis or pericarditis were extracted through specific PTs and lowest level terms, in line with previous studies on the influenza vaccination [4] and the potential immune-related basis of cardiotoxicity documented for ICIs by recent pharmacovigilance analyses [9,10]: myocarditis, pericarditis, immune-mediated myocarditis, and myopericarditis.
(3) Reports recording AEs of interest were finally assessed for co-reported drugs/vaccines of interest.
In VigiBase, retained reports (refer to point 2) with ICIs, namely PD-1 inhibitors (nivolumab, pembrolizumab, and cemiplimab), PD-L1 inhibitors (atezolizumab, avelumab, and durvalumab), and CTLA-4 inhibitors (ipilimumab and tremelimumab), were evaluated by extracting the following data: demographic features (age, gender, weight, year, and reporter country), reporter qualification, comorbidities, concomitant medications (including dose and route of administration when available), latency, degree of seriousness, outcome, and management of the AE. The same approach was applied to identify cases of interest reported for vaccines against the influenza virus, both as suspect alone or concomitant to ICI exposure.
In VAERS, for each report of interest with the influenza vaccines, the following data were extracted: demographic features (age, gender, year, and reporter country), type of vaccine against the influenza virus, medical history, concomitant drugs or administered vaccines, laboratory data, AEs codified as PTs, latency, AE degree of seriousness, outcome, and narratives, when available.
According to WHO criteria, a serious AE is any untoward medical occurrence that, no matter the dose, results as fatal, causing a life-threatening event, requiring hospitalization of the patient, causing serious/permanent disability, causing congenital abnormalities, or other clinically relevant conditions [22].
Co-reported medications and comorbidities known to cause myocarditis or pericarditis (i.e., potential confounders) were further characterized according to the lists proposed by Adler et al. [6], Caforio et al. [7], and Butany et al. [8].
2.4. Causality Assessment and Evaluation of Drug–Vaccine Interaction
The probability of interaction when the influenza vaccine and ICIs are co-reported was evaluated by applying the established WHO criteria for causality assessment [20], as well as the Drug Interaction Probability Scale (DIPS) [23].
The following items were accounted for in the AEFI causality assessment: temporal relationship, alternate explanations, proof of association, prior evidence, population-based evidence, and biological plausibility [20]. Cases without adequate information were classified as “unclassifiable”; cases with adequate information were categorized as: (1) “consistent with a causal relationship”, when the available evidence supported a causal relationship between the vaccine and the AEFI in the individual, but it did not rule out the possibility that the AEFI may have been caused by a factor other than the vaccine; (2) “inconsistent with a causal association”, when the available evidence did not support a causal relationship between vaccine administration and the reported AEFI in the individual; and (3) “indeterminate”, when the temporal relationship was consistent but the available evidence insufficient to support or rule out a causal relationship in the individual.
The DIPS is a 10-item tool specifically developed to assess the likelihood of drug–drug interactions [23]. ICIs were considered as the objective drugs (i.e., the one affected by the presence of another vaccine/drug), while the influenza vaccine was considered as the precipitant agent (i.e., the one causing a change on the object drug). To avoid overemphasis on the role of the vaccine, the answer to the second question was always “unknown” (knowledge on the mechanism of the interaction is hypothesized and literature data are very scarce/uncertain); in addition, questions 5, 6, and 10 were not assessable/applicable (dechallenge, rechallenge, and dose adjustments are unfeasible for vaccines considering the peculiarities of their administration), as previously performed [3]. The final summary score could reach 10 points. Higher total scores correspond to a higher likelihood of drug–vaccine interaction (i.e., >8 = highly probable; 5–8 = probable; 2–4 = possible; <2 = doubtful).
3. Results
3.1. Demographic and Clinical Data
Over the observed period, out of a total of 712,776 AEFI, 191 (0.03%) reports of MP mentioning the influenza vaccine as suspect were collected within the VAERS.
The clinical and demographic characteristics are provided in Table 1. The reports included 124 men (64.9%) and 62 women (in five cases gender was not reported), aged between 1 and 88 years (mean age 44.5 years). Pericarditis were reported in 117 cases (61.3%), followed by myocarditis (81 cases; 42.4%) and MP (7 cases; 3.7%). No cases of immune-mediated myocarditis were retrieved.
The median onset was seven days; in 34.0% of reports, the AEFI of interest occurred in the first 3 days after the administration of the influenza vaccine. Comorbidities potentially implicated in the occurrence of the AEFI of interest were retrieved in six cases (3.1%), with ulcerative colitis and systemic lupus erythematosus being the most represented. Other vaccines were concomitantly administered in 59 cases (30.9%), accounting for a mean number of 3.1 vaccines per patient.
In 141 cases (73.8%), the report was classified as serious, and 16 fatal cases (8.4%) were found. Recovery occurred in 31.4% of cases.
In the VigiBase®, 246,864 reports mentioning the influenza vaccine as a suspect agent were found, and myocarditis/pericarditis were reported in 399 cases (0.16%; Table 1).
The cases showed a mean age of 46.7 years, with a male preponderance (65.9%). Reports were largely submitted from US (45.9%) and Europe (45.1%). Pericarditis was reported in 225 cases (56.4%), followed by myocarditis (193 cases; 48.4%) and myopericarditis (29; 7.3%). No cases of immune-mediated myocarditis were found.
Median onset was five days, and in 29.8% of reports, AEs of interest occurred in the first three days after the administration of the influenza vaccine. Comorbidities potentially implicated in the occurrence of myocarditis/pericarditis were retrieved in two patients (0.5%) affected by ulcerative colitis. Other vaccines were concomitantly administered in 87 cases (21.8%), accounting for a mean number of 2.5 vaccines per patient.
In 303 cases (76.0%), the report was classified as serious, and 28 fatal cases (7.0%) were found. Recovering occurred in 41.1% of cases.
3.2. Co-Reported Medications and Detection of Cases with ICI Administration
Overall, concomitant medications were found in 49 (25.7%) and 57 (14.3%) cases with the influenza vaccine in VAERS and VigiBase®, respectively (Table 1). In 14 (7.3%) and 13 (3.3%) cases, five or more concomitant drugs were reported in VAERS and VigiBase®, respectively.
Concomitant medications potentially implicated in the occurrence of myocarditis/pericarditis were retrieved in 21 (11.0%) and 24 (6.0%) cases in VAERS and VigiBase®, respectively, with hydrochlorothiazide being the most frequent in both databases (in six and five cases, respectively).
Only six cases (one classified as serious, where Guillain-Barré syndrome was recorded) with the concomitant use of ICIs and the influenza vaccine were found in VAERS (Table S1), but no cases of myocarditis/pericarditis. In VigiBase®, two cases of myocarditis reporting the concomitant administration of ICIs and the influenza vaccine both mentioned as suspect agents were retrieved. A third case of myocarditis in which the influenza vaccine was classified as a concomitant agent was detected (Table 2).
The three cases were classified as serious (causing prolonged hospitalization), included two men and one woman, aged 67–77 years, and affected by lung or renal carcinoma. Nivolumab, pembrolizumab, and ipilimumab/nivolumab combination therapy were reported as the ICI regimen. In two cases ICI was withdrawn, while recovering occurred in only one case.
3.3. Causality Assessment and Evaluation of Drug–Vaccine Interaction
These three cases showed an unclassifiable causality assessment due to the lack of data concerning the latency and time window of increased risk (Table 2).
By applying the adapted DIPS algorithm, one report was categorized as possible (due to the lack of underlying diseases or co-reported agents known to cause or precipitate myocarditis, and to the detection of troponin increase) and two as doubtful (only the absence of underlying diseases or co-reported agents known to cause or precipitate myocarditis were recognized; Table S2).
4. Discussion
To the best of our knowledge, this is the first real-world study investigating the potential interactions between influenza vaccines and ICIs resulting in myocarditis or pericarditis in cancer patients, by assessing spontaneous reports submitted to the VAERS and VigiBase®. This global post-marketing safety study stems from recent conflicting real-world evidence surrounding the possible exacerbation of irAEs with influenza vaccines in patients treated with ICIs [14,15,24,25,26,27,28,29], thus joining in the wider debate on the bidirectional relationship between immunotherapy and the influenza vaccination, potentially affecting the clinical and humoral efficacy of the vaccine, performance of ICIs, and safety [14].
Four major findings emerged from our analysis: (a) myocarditis and pericarditis represented a very rare AEFI (with a non-negligible proportion of death, approximately 8–9%), based on the low reporting frequency retrieved in both SRSs (<0.1–0.2% of overall AEs), also considering the influenza vaccination coverage rates (estimated at about 25% per year in Europe [30,31]) and the relevant million doses distributed worldwide; (b) the reporting of myocarditis in patients concomitantly receiving influenza vaccines and ICIs is limited to only three out of a total of 1465 cases of myocarditis/pericarditis found with influenza vaccines or ICIs (considered as suspect agents) in the two databases; (c) these cases were unclassifiable for causality assessment with a doubtful probability of drug–vaccine interaction (according to the adapted DIPS algorithm), thus suggesting that the vaccine is not directly involved in the occurrence of myocarditis (and in one of the three cases, influenza vaccine was reported only as concomitant and not as suspect or interacting agent); and (d) no other cardiovascular AEs were found in patients concomitantly receiving influenza vaccination and ICIs, as well as no other irAEs were reported, except for a single case of Guillain-Barré syndrome, a condition already associated with both ICIs and the influenza vaccine [32,33,34].
Theoretically, a possible pharmacodynamic interaction between influenza vaccines and ICIs leading to the exacerbation of irAEs (including MP), could be supposed. The blockade of a PD-1/PD-L1 pathway together with the vaccination (particularly in conjunction with a strong vaccine adjuvant) could enhance one or more of the mechanisms associated with irAEs onset (infiltration of central memory T cells into the tissues, cross-presentation of shared antigens, and exacerbation of previously subclinical auto-immune syndromes) [24].
Our specific focus on the myo-pericardium stems from the peculiar clinical features of myocarditis in terms of severity and mortality compared with other irAEs, usually requiring immunotherapy discontinuation [9,10,11,12,13], as reported in two out of our three cases. Although, in all three cases, no underlying diseases or other agents known to cause or precipitate myocarditis were recorded, the lack of data concerning latency and solid literature studies allows for minimizing, if not completely excluding, the clinically relevant contribution of a potential drug–vaccine interaction in our cases.
Furthermore, the only study investigating the association between influenza vaccine and the development of myocarditis among patients on ICIs found that the administration of the vaccine was not associated with an increased risk of subsequent myocarditis [15]. Additionally, myocarditis cases in which the influenza vaccine was administered showed lower troponin levels at presentation and a lower risk of major adverse cardiac events at follow-up compared with non-vaccinate patients developing myocarditis with ICIs [15], thus suggesting a protective role for the influenza vaccine in this setting.
ICIs caused a paradigm shift in cancer treatment, and are currently used as first-line agents in the management of non-small cell lung cancer, melanoma, and renal carcinoma [35]. Considering their evolving role and expected increasing uptake, the assessment of cardiovascular safety is of paramount importance. Likewise, the safety of influenza vaccines represents an important issue, given the high morbidity and mortality rates caused by influenza in cancer patients [36]. Notably, the development of influenza infection may also, albeit rarely, be associated itself with an increased risk of myocarditis and major adverse cardiovascular events [37,38]. Therefore, the suggested protective role of the influenza vaccine on cardiovascular outcome [15] cannot be overlooked.
Collectively, our findings provide a reassuring message in terms of cardiovascular safety for cancer patients treated with ICIs and requiring the influenza vaccination. Of note, less than 20% of patients affected by malignancies received the influenza vaccine, with a gradual decline in the last decade [39]. We support and promote the achievement of an optimal vaccination coverage rate in cancer patients for several reasons, including the following: (a) direct association with a lower mortality and infection-related outcomes in immunosuppressed adults [1]; (b) a better overall survival recently reported in patients treated with ICIs receiving influenza vaccination [40]; and (c) the current COVID-19 pandemic, to reduce the strain on the healthcare system while protecting vulnerable subjects from the dramatic impact of a possible co-infection [41]. Cancer patients receiving immunotherapy are at high risk of severe events as a result of COVID-19 systemic involvement, including pneumonitis and myocarditis [42], and a recent systematic review found no significant increase in the risk of infection or in the illness severity or lethality of COVID-19 in subjects receiving the influenza vaccine, with some studies reporting a significantly inverse association [43]. Therefore, the implementation of measures aimed at raising influenza vaccination coverage in frail patients is strongly recommended.
We acknowledge the limitations of our study, mainly inherent to the nature of SRSs data. VAERS and VigiBase® are subject to reporting bias, including under- and over-reporting of adverse events, although there are not clues for major distortions, considering that serious events such as MP are less prone to under-reporting, and no specific warnings were posted by regulatory agencies, thus minimizing the existence and impact of a stimulated reporting [3,18]. We recognize the potential occurrence of subclinical myocarditis, which may be under-diagnosed/under-detected, and is thus likely to be under-reported. Furthermore, the quality and completeness of the reports collected in both databases are variable, and many records lack valid medical diagnoses, thus making the assessment of causality challenging. Additionally, DIPS was not specifically developed to assess drug–vaccine interactions, although we implemented an adapted version in order to the better focus on the possible precipitating role of the influenza vaccine.
Notwithstanding these limitations, pharmacovigilance assessment represents an invaluable opportunity to monitor vaccine safety and identify novel rare signals, potentially arising from drug–vaccine interactions, both from a local and international perspective. Furthermore, our findings are consistent between the two databases, thus supporting the lack of evidence of a clinically relevant drug–vaccine interaction. The identification of myocarditis with ICIs, in line with previous findings [9,10,11], further corroborates the ability of our post-marketing approach to identify actual true-positive associations.
In conclusion, the paucity of cases coupled with a lack of certainty in terms of causality assessment and doubtful probability make the risk of myocarditis and pericarditis by interaction between influenza vaccines and ICIs in cancer patients negligible from both clinical and epidemiological standpoints. Our findings support the cardiovascular safety of influenza vaccines in subjects treated with immunotherapy, thereby emphasizing the importance of a flu vaccination in this population, especially in the current COVID-19 era.
Acknowledgments
We would like to thank Annette Rudolph for data extraction from VigiBase®. Authors at the University of Bologna are supported by institutional research funds (Ricerca Fondamentale Orientata). No sources of funding were received for the preparation of this article.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2076-393X/9/1/19/s1. Table S1: Case-by-case assessment of reports recorded in VAERS in which influenza vaccine and immune checkpoint inhibitors (ICIs) were concomitantly used. Table S2: Application of the adapted version of Drug Interaction Probability Scale in cases of myocarditis/pericarditis in which immune checkpoint inhibitors (ICIs) and influenza vaccine were concomitantly administered.
Click here for additional data file.
Author Contributions
M.G.: methodology, investigation, formal analysis, and writing—original draft. E.R.: conceptualization, methodology, formal analysis, and writing—reviewing and editing. U.M.: writing—reviewing and editing. A.A.: writing—reviewing and editing. E.P.: conceptualization, methodology, formal analysis, and writing—reviewing and editing. I.D.: conceptualization and writing—reviewing and editing. All authors have read and agreed to the published version of the manuscript.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Institutional Review Board Statement
Under current legislation, institutional review board approval is not required when performing analysis of the publicly available VAERS and VigiBase databases, because it contains anonymized data that cannot allow patients’ identification.
Informed Consent Statement
Patient consent was waived due to VAERS and VigiBase databases contain anonymized data that cannot allow patients’ identification.
Data Availability Statement
Data supporting the findings of this study were derived from the following resource available in the public domains: https://wonder.cdc.gov/vaers.html and http://www.vigiaccess.org/.
Conflicts of Interest
M.G., E.R., E.P., U.M., and I.D. have no conflicts of interest relevant to the content of the present work. A.A. reports grants and personal fees from BMS, as well as grants from MSD, Roche, Astra Zeneca, Eli-Lilly, Takeda, and Bayer, outside of the submitted work.
vaccines-09-00019-t001_Table 1Table 1 Demographic and clinical feature of cases of myocarditis/pericarditis reported with influenza vaccine as suspect in Vaccine Adverse Event Reporting System (VAERS) and the World Health Organization’s (WHO) global Individual Case Safety Report database (VigiBase®).
Demographic Features VAERS VigiBase
Overall number of cases 191 399
Proportion of cases (based on overall number of reports with the flu vaccine) 0.03% (712,776) 0.16% (246,864)
Age (mean) 44.5 ± 22.9 46.7 ± 22.3
Sex
Female 62 (32.5%) 131 (32.8%)
Male 124 (64.9%) 263 (65.9%)
Not specified 5 (2.6%) 5 (1.3%)
Reporter country
US 109 (57.1%) 183 (45.9%)
Non-US 60 (31.4%) -
Europe - 180 (45.1%)
Asia - 10 (2.5%)
Oceania - 19 (4.8%)
America (except US) - 7 (1.7%)
Not specified 22 (11.5%) -
Reported symptoms (preferred terms) *
Myocarditis 81 (42.4%) 193 (48.4%)
Pericarditis 117 (61.3%) 225 (56.4%)
Myopericarditis 7 (3.7%) 29 (7.3%)
Immune-mediated myocarditis 0 (0.0%) 0 (0.0%)
Co-medications
Overall number of cases 49 (25.7%) 57 (14.3%)
≥5 concomitant drugs 14 (7.3%) 13 (3.3%)
1–4 concomitant drugs 35 (18.4%) 44 (11.0%)
No concomitant drugs 142 (74.3%) 342 (85.7%)
Co-medications potentially implicated in the occurrence of myocarditis/pericarditis **
Number of cases 21 (11.0%) § 24 (6.0%) #
Immune checkpoint inhibitors (ICIs) None 2
Hydrochlorothiazide 6 5
Indomethacin 2 2
Glipizide 2 -
Clonazepam 2 -
Alprazolam 2 -
Furosemide 1 1
Bendroflumethiazide 1 2
Mesalazine 1 2
Colchicine 1 1
Doxycycline 1 2
Cotrimoxazole 1 1
Lorazepam 1 -
Amoxicillin 1 1
Isosorbide dinitrate 1 2
Tetracycline - 2
Spironolactone - 1
Cefuroxime - 1
Heparin - 1
Bromazepam - 1
Comorbidities potentially implicated in occurrence of myocarditis/pericarditis **
Number of cases 6 (3.1%) 2 (0.5%)
Ulcerative colitis 2 2
Systemic lupus erythematosus 2 -
Juvenile rheumatoid arthritis 1 -
Insulin-dependent diabetes mellitus 1 -
Onset (days; median) 7 (1.5–13) 5 (1–12)
≤3 days 65 (34.0%) 119 (29.8%)
4–7 days 19 (10.0%) 50 (12.5%)
8–14 days 35 (18.4%) 61 (15.3%)
≥15 days 36 (18.8%) 56 (14.0%)
Not specified 36 (18.8%) 113 (28.4%)
Seriousness
Serious 141 (73.8%) 303 (76.0%)
Non-serious 50 (26.2%) 48 (12.0%)
Not specified - 48 (12.0%)
Seriousness criteria *
Congenital anomaly 0 (0.0%) 0 (0.0%)
Death 16 (8.4%) 28 (7.0%)
Hospitalization 125 (65.5%) 222 (55.6%)
Life-threatening 30 (15.7%) 46 (11.5%)
Permanent disability 12 (6.3%) 12 (3.0%)
Other outcomes 30 (15.7%) 60 (15.0%)
Median time of hospitalization (days) 3 (2–4) NA
Recovering
Recovered 60 (31.4%) 164 (41.1%)
Not recovered 64 (33.5%) 61 (15.3%)
Not specified 67 (35.1%) 174 (43.6%)
Concomitant other vaccines
Overall number of cases 59 (30.9%) 87 (21.8%)
Mean number of vaccines per patient 3.1 ± 1.4 2.5 ± 1.7
* One case may exhibit more than one seriousness criteria. ** According to 2015 the European Society of Cardiology (ESC) guidelines for the diagnosis and management of pericardial diseases [6], Caforio et al. [7] and Butany et al. [8]. § In one case, the concomitant use of glipizide and indomethacin, and colchicine and indomethacin. # In one case, concomitant use of amoxicillin and tetracycline, hydrochlorothiazide and cotrimoxazole, and bromazepam and heparin. Flu vaccine types (VAERS): FLU 3 (trivalent injected): 69 patients (36.1%); FLUX SEASONAL (influenza virus vaccine, no brand name): 62 (32.5%); FLU 4 (quadrivalent injected): 20 (10.5%); FLUN 3 (trivalent intranasal spray): 19 (9.9%); FLUN 4 (quadrivalent intranasal spray): 7 (3.7%); FLU H1N1 (monovalent injected): 5 (2.6%); FLUA 3 (trivalent adjuvant injected): 3 (1.6%); FLUN H1N1 (monovalent intranasal spray): 2 (1.1%); FLUX H1N1 (monovalent unknown manufacturer): 2 (1.1%); FLUC 4 (quadrivalent cell-culture-derived injected): 2 (1.1%); FLUC 3 (trivalent cell-culture-derived injected): 1 (0.5%). One patient received both FLUX SEASONAL and FLUX (H1N1).
vaccines-09-00019-t002_Table 2Table 2 Case-by-case assessment of reports concerning myocarditis or pericarditis in which the influenza vaccine and immune checkpoint inhibitors (ICIs) were concomitantly used.
Case ID Drugs/Role Dose Year Age/Sex Reporter Country Reporter Qualification Reactions Seriousness Outcome Concomitant Medications Comorbidities Management Causality Assessment Adapted DIPS Score
#1 Nivolumab (suspect)
Influenza vaccine(suspect) 3 mg/kg every 2 weeks IV- 2018 70/F Japan Physician Myocarditis Serious
(life-threatening; prolonged hospitalization; other outcomes) Recovered Ursodeoxycholic acid 200 mg/day
Bezafibrate
200 mg/day
Calcitriol
0.5 mcg/day NSCLC
Liver disorder
Hyperlipidemia
Osteoporosis Nivolumab withdrawn Unclassifiable (data on latency and time window of increased risk are lacking) Synergistic effect between influenza vaccine and ICIs cannot be excluded 1
Doubtful
#2 Pembrolizumab
(suspect)
Influenza vaccine (suspect) NA
IV
0.5 mL
IM 2018 67/M US Pharmacist Myocarditis,
stress, cardiomyopathy,
weight decreased,
headache,
cardiac failure, congestive,
cerebral infarction,
confusional state, and
dyspnoea Serious
(life-threatening; prolonged hospitalization) NA NA Lung neoplasm malignant NA Unclassifiable
(data on latency and time window of increased risk are lacking)
Synergistic effect between influenza vaccine and ICIs cannot be excluded 1
Doubtful
#3 Ipilimumab
(suspect)
Nivolumab
(suspect)
Influenza vaccine (concomitant) 80 mg every 3 weeks IV
240 mg every 3 weeks IV- 2019 77/M Canada Physician Myocarditis,
pulmonary hypertension,
dyspnoea chest discomfort asthenia, troponin increased c-reactive protein, increased diastolic dysfunction, oedema, peripheral urticaria, and pruritus Serious
(prolonged hospitalization; other outcomes) NA NA Metastatic renal cell carcinoma Ipilimumab and nivolumab withdrawn Unclassifiable
(data on latency and time window of increased risk are lacking)
Synergistic effect between influenza vaccine and ICIs cannot be excluded 2
Possible
US—United States of America; NSCLC—non-small cell lung cancer; NA—not available; IV—intravenous; IM—intramuscular; DIPS—drug-interaction probability scale. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33406694 | 18,811,294 | 2021-01-04 |
What was the dosage of drug 'BEZAFIBRATE'? | Influenza Vaccination and Myo-Pericarditis in Patients Receiving Immune Checkpoint Inhibitors: Investigating the Likelihood of Interaction through the Vaccine Adverse Event Reporting System and VigiBase.
BACKGROUND
Evidence on whether the influenza vaccine could exacerbate immune-related adverse events, including myopericarditis (MP), in patients treated with immune checkpoint inhibitors (ICIs), is still conflicting. We explored this issue through a global real-world approach.
METHODS
We queried the Vaccine Adverse Event Reporting System (VAERS) and VigiBase to retrieve cases of MP in which the influenza vaccine and ICIs were recorded as suspect and were concomitantly reported. For the included cases, causality assessment and Drug Interaction Probability Scale (DIPS) algorithms were applied.
RESULTS
There were 191 and 399 reports of MP with the influenza vaccine that were retrieved (VAERS and VigiBase, respectively). No case of MP reporting the concomitant use of ICIs and the influenza vaccine was found in VAERS, while three cases of myocarditis were retrieved in VigiBase. All of the cases were unclassifiable for a causality assessment because of the lack of data concerning latency. According to the DIPS, one report was categorized as possible and two as doubtful.
CONCLUSIONS
The paucity of cases coupled with the doubtful causality assessment make the potential interaction between influenza vaccines and ICIs in cancer patients negligible from clinical and epidemiological standpoints. These findings support the cardiovascular safety of the influenza vaccination, which remains strongly recommended in cancer patients, especially in the current COVID-19 era.
1. Introduction
The safety of vaccines and medications is a current global safety issue. The annual vaccination against the influenza virus is the primary means of preventing influenza and its complications in high-risk subjects, including adult cancer patients, as described by observational studies, suggesting lower mortality and infection-related outcomes with influenza vaccination [1]. However, in the recent past, potential pharmacokinetic interactions have been proposed, considering that vaccines can influence the drug metabolism via inflammatory cytokines [2]. Therefore, potential interactions between influenza vaccines and drugs used for chronic diseases (e.g., immunosuppressive agents) cannot be excluded [3]. Moreover, cases of myo-pericarditis (MP) after immunization, although rarely, are reported [4,5].
Myocarditis and pericarditis represent serious and life-threatening inflammatory diseases involving myocardium and pericardium, potentially associated with the use of several drugs and vaccines [6,7,8]. In particular, cases of MP were described with the smallpox vaccine in early 2000 and, more recently, very rarely are reported after influenza immunization [4,5]. Immune checkpoint inhibitors (ICIs), such as anti-PD1, anti-PDL1, and anti-CTLA4 monoclonal antibodies, are approved as first-line agents in the management of melanoma and non-small cell lung cancer. They may cause a variegate spectrum of cardiovascular events, including MP, with a higher mortality compared with other immune-related adverse events (irAEs) [9,10,11,12,13]. In a summary of the product characteristics of the different ICIs, pericarditis and myocarditis are reported as uncommon (≥1/1000 to <1/100) and rare (≥1/10,000 to <1/1000, respectively) AEs. Notably, the detection of myocarditis with ICIs requires the permanent discontinuation of treatment, no matter the severity.
Consequently, the question arises as to whether pharmacokinetic and pharmacodynamic interactions occur in patients receiving the influenza vaccination (recommended both by oncologists and cardiologists) and ICIs, possibly causing or exacerbating irAEs such MP. Although no cases of myocarditis have been reported, evidence on whether the influenza vaccine exacerbates irAEs is still conflicting and poorly investigated [14]. Only a retrospective study investigated the clinical features of myocarditis with ICIs in patients receiving the influenza vaccine; reduced myocardial injury and a lower risk of major adverse cardiac events among recipients of the influenza vaccine was found compared with not vaccinated patients [15].
In the recent past, analysis of the spontaneous reporting systems (SRSs) has attracted considerable interest among clinicians for the accurate and timely characterization of drug- and vaccine-related risks occurring in the real world, where comorbidities and polypharmacotherapy exist. By offering a global epidemiological perspective, these pharmacovigilance studies have been pursued to test the hypothesis of potential associations, including refusing the likelihood of interactions [3,16,17], especially for rare, unexpected, and delayed AEs, such as MP.
In this study, we investigated the likelihood of interaction between the influenza vaccination and ICIs by analyzing spontaneous reports of MP collected from the Vaccine Adverse Event Reporting System (VAERS; P.O. Box 1100; Rockville, MD 20849-1100) and the World Health Organization’s (WHO) global Individual Case Safety Report database (VigiBase®; Uppsala Monitoring Centre Box, 1051 SE-751 40, Uppsala, Sweden).
2. Materials and Methods
2.1. Study Conception and Design
The study was conceived as an observational retrospective analysis of spontaneous reports of MP collected from the VAERS and the VigiBase® to (a) characterize relevant clinical features; (b) highlight the concomitant use of agents known to cause MP, including ICIs; and (c) assess the causality and probability of interaction between the influenza vaccine and ICIs.
VAERS is a national system to monitor the safety of US-licensed vaccines [18], whereas VigiBase® collects worldwide reports on vaccines and drugs, thus making these archives act as complementary approaches [19].
VAERS transmits its vaccine adverse event reports to the VigiBase, in order to contribute to the global pharmacovigilance effort along with other countries that employ passive vaccine safety monitoring systems [18], thus possible duplicates between the two databases may exist.
2.2. Data Source
Established in 1990, the VAERS is co-managed by the Centers for Disease Control and Prevention and the US Food and Drug Administration (FDA); it collects and analyzes reports of AEs following immunization (AEFI) for vaccines licensed in the US, receiving approximately 28,000 reports of AEFI annually.
AEFI may be any unfavorable or unintended sign, abnormal laboratory finding, symptom, or disease that occurs following or during the administration of a vaccine. AEs are temporally associated events that may either be caused by a vaccine or be coincidental to it, i.e., not necessarily related to the vaccination [20]. VAERS may be used to detect unexpected and rare patterns of AEFI, unlikely to arise in pivotal trials because of the limited number of patients involved [21]. Health-care professionals, vaccine manufacturers, and consumers (patients, parents, and caregivers) can submit reports of AEs to VAERS.
VigiBase® is one of the largest and most comprehensive pharmacovigilance databases, maintained by the Uppsala Monitoring Centre in Sweden, and containing over 20 million of Individual Case Safety Reports from 110 countries over the five continents. VigiBase® collects reports of AEs for authorized drugs, vaccines, and food supplements, submitted from healthcare professionals, pharmaceutical companies, and patients.
For each vaccine/drug, the characterization of the vaccine/drug role indicated by the primary reporter (i.e., the original source of the information) includes the following three categories: suspect, concomitant, and interacting. All spontaneous reports should have at least one suspect vaccine/drug, namely involved, presumably, in the occurrence of AEFI. If the reporter indicates a suspected interaction, all interacting vaccines/drugs are considered to be suspect vaccines/drugs.
In both databases, AEs are codified through the Medical Dictionary for Regulatory Activities (MedDRA) terminology, and described and organized in terms of Preferred Terms (PTs).
2.3. Data Extraction and Analysis
A multi-step approach was followed for data extraction in each database:(1) Reports for individuals receiving any type of vaccine against the influenza virus categorized as suspect AEFI submitted to VAERS (from July 1990 to September 2020) and VigiBase® (from inception to October 2020) were selected.
(2) Cases of myocarditis or pericarditis were extracted through specific PTs and lowest level terms, in line with previous studies on the influenza vaccination [4] and the potential immune-related basis of cardiotoxicity documented for ICIs by recent pharmacovigilance analyses [9,10]: myocarditis, pericarditis, immune-mediated myocarditis, and myopericarditis.
(3) Reports recording AEs of interest were finally assessed for co-reported drugs/vaccines of interest.
In VigiBase, retained reports (refer to point 2) with ICIs, namely PD-1 inhibitors (nivolumab, pembrolizumab, and cemiplimab), PD-L1 inhibitors (atezolizumab, avelumab, and durvalumab), and CTLA-4 inhibitors (ipilimumab and tremelimumab), were evaluated by extracting the following data: demographic features (age, gender, weight, year, and reporter country), reporter qualification, comorbidities, concomitant medications (including dose and route of administration when available), latency, degree of seriousness, outcome, and management of the AE. The same approach was applied to identify cases of interest reported for vaccines against the influenza virus, both as suspect alone or concomitant to ICI exposure.
In VAERS, for each report of interest with the influenza vaccines, the following data were extracted: demographic features (age, gender, year, and reporter country), type of vaccine against the influenza virus, medical history, concomitant drugs or administered vaccines, laboratory data, AEs codified as PTs, latency, AE degree of seriousness, outcome, and narratives, when available.
According to WHO criteria, a serious AE is any untoward medical occurrence that, no matter the dose, results as fatal, causing a life-threatening event, requiring hospitalization of the patient, causing serious/permanent disability, causing congenital abnormalities, or other clinically relevant conditions [22].
Co-reported medications and comorbidities known to cause myocarditis or pericarditis (i.e., potential confounders) were further characterized according to the lists proposed by Adler et al. [6], Caforio et al. [7], and Butany et al. [8].
2.4. Causality Assessment and Evaluation of Drug–Vaccine Interaction
The probability of interaction when the influenza vaccine and ICIs are co-reported was evaluated by applying the established WHO criteria for causality assessment [20], as well as the Drug Interaction Probability Scale (DIPS) [23].
The following items were accounted for in the AEFI causality assessment: temporal relationship, alternate explanations, proof of association, prior evidence, population-based evidence, and biological plausibility [20]. Cases without adequate information were classified as “unclassifiable”; cases with adequate information were categorized as: (1) “consistent with a causal relationship”, when the available evidence supported a causal relationship between the vaccine and the AEFI in the individual, but it did not rule out the possibility that the AEFI may have been caused by a factor other than the vaccine; (2) “inconsistent with a causal association”, when the available evidence did not support a causal relationship between vaccine administration and the reported AEFI in the individual; and (3) “indeterminate”, when the temporal relationship was consistent but the available evidence insufficient to support or rule out a causal relationship in the individual.
The DIPS is a 10-item tool specifically developed to assess the likelihood of drug–drug interactions [23]. ICIs were considered as the objective drugs (i.e., the one affected by the presence of another vaccine/drug), while the influenza vaccine was considered as the precipitant agent (i.e., the one causing a change on the object drug). To avoid overemphasis on the role of the vaccine, the answer to the second question was always “unknown” (knowledge on the mechanism of the interaction is hypothesized and literature data are very scarce/uncertain); in addition, questions 5, 6, and 10 were not assessable/applicable (dechallenge, rechallenge, and dose adjustments are unfeasible for vaccines considering the peculiarities of their administration), as previously performed [3]. The final summary score could reach 10 points. Higher total scores correspond to a higher likelihood of drug–vaccine interaction (i.e., >8 = highly probable; 5–8 = probable; 2–4 = possible; <2 = doubtful).
3. Results
3.1. Demographic and Clinical Data
Over the observed period, out of a total of 712,776 AEFI, 191 (0.03%) reports of MP mentioning the influenza vaccine as suspect were collected within the VAERS.
The clinical and demographic characteristics are provided in Table 1. The reports included 124 men (64.9%) and 62 women (in five cases gender was not reported), aged between 1 and 88 years (mean age 44.5 years). Pericarditis were reported in 117 cases (61.3%), followed by myocarditis (81 cases; 42.4%) and MP (7 cases; 3.7%). No cases of immune-mediated myocarditis were retrieved.
The median onset was seven days; in 34.0% of reports, the AEFI of interest occurred in the first 3 days after the administration of the influenza vaccine. Comorbidities potentially implicated in the occurrence of the AEFI of interest were retrieved in six cases (3.1%), with ulcerative colitis and systemic lupus erythematosus being the most represented. Other vaccines were concomitantly administered in 59 cases (30.9%), accounting for a mean number of 3.1 vaccines per patient.
In 141 cases (73.8%), the report was classified as serious, and 16 fatal cases (8.4%) were found. Recovery occurred in 31.4% of cases.
In the VigiBase®, 246,864 reports mentioning the influenza vaccine as a suspect agent were found, and myocarditis/pericarditis were reported in 399 cases (0.16%; Table 1).
The cases showed a mean age of 46.7 years, with a male preponderance (65.9%). Reports were largely submitted from US (45.9%) and Europe (45.1%). Pericarditis was reported in 225 cases (56.4%), followed by myocarditis (193 cases; 48.4%) and myopericarditis (29; 7.3%). No cases of immune-mediated myocarditis were found.
Median onset was five days, and in 29.8% of reports, AEs of interest occurred in the first three days after the administration of the influenza vaccine. Comorbidities potentially implicated in the occurrence of myocarditis/pericarditis were retrieved in two patients (0.5%) affected by ulcerative colitis. Other vaccines were concomitantly administered in 87 cases (21.8%), accounting for a mean number of 2.5 vaccines per patient.
In 303 cases (76.0%), the report was classified as serious, and 28 fatal cases (7.0%) were found. Recovering occurred in 41.1% of cases.
3.2. Co-Reported Medications and Detection of Cases with ICI Administration
Overall, concomitant medications were found in 49 (25.7%) and 57 (14.3%) cases with the influenza vaccine in VAERS and VigiBase®, respectively (Table 1). In 14 (7.3%) and 13 (3.3%) cases, five or more concomitant drugs were reported in VAERS and VigiBase®, respectively.
Concomitant medications potentially implicated in the occurrence of myocarditis/pericarditis were retrieved in 21 (11.0%) and 24 (6.0%) cases in VAERS and VigiBase®, respectively, with hydrochlorothiazide being the most frequent in both databases (in six and five cases, respectively).
Only six cases (one classified as serious, where Guillain-Barré syndrome was recorded) with the concomitant use of ICIs and the influenza vaccine were found in VAERS (Table S1), but no cases of myocarditis/pericarditis. In VigiBase®, two cases of myocarditis reporting the concomitant administration of ICIs and the influenza vaccine both mentioned as suspect agents were retrieved. A third case of myocarditis in which the influenza vaccine was classified as a concomitant agent was detected (Table 2).
The three cases were classified as serious (causing prolonged hospitalization), included two men and one woman, aged 67–77 years, and affected by lung or renal carcinoma. Nivolumab, pembrolizumab, and ipilimumab/nivolumab combination therapy were reported as the ICI regimen. In two cases ICI was withdrawn, while recovering occurred in only one case.
3.3. Causality Assessment and Evaluation of Drug–Vaccine Interaction
These three cases showed an unclassifiable causality assessment due to the lack of data concerning the latency and time window of increased risk (Table 2).
By applying the adapted DIPS algorithm, one report was categorized as possible (due to the lack of underlying diseases or co-reported agents known to cause or precipitate myocarditis, and to the detection of troponin increase) and two as doubtful (only the absence of underlying diseases or co-reported agents known to cause or precipitate myocarditis were recognized; Table S2).
4. Discussion
To the best of our knowledge, this is the first real-world study investigating the potential interactions between influenza vaccines and ICIs resulting in myocarditis or pericarditis in cancer patients, by assessing spontaneous reports submitted to the VAERS and VigiBase®. This global post-marketing safety study stems from recent conflicting real-world evidence surrounding the possible exacerbation of irAEs with influenza vaccines in patients treated with ICIs [14,15,24,25,26,27,28,29], thus joining in the wider debate on the bidirectional relationship between immunotherapy and the influenza vaccination, potentially affecting the clinical and humoral efficacy of the vaccine, performance of ICIs, and safety [14].
Four major findings emerged from our analysis: (a) myocarditis and pericarditis represented a very rare AEFI (with a non-negligible proportion of death, approximately 8–9%), based on the low reporting frequency retrieved in both SRSs (<0.1–0.2% of overall AEs), also considering the influenza vaccination coverage rates (estimated at about 25% per year in Europe [30,31]) and the relevant million doses distributed worldwide; (b) the reporting of myocarditis in patients concomitantly receiving influenza vaccines and ICIs is limited to only three out of a total of 1465 cases of myocarditis/pericarditis found with influenza vaccines or ICIs (considered as suspect agents) in the two databases; (c) these cases were unclassifiable for causality assessment with a doubtful probability of drug–vaccine interaction (according to the adapted DIPS algorithm), thus suggesting that the vaccine is not directly involved in the occurrence of myocarditis (and in one of the three cases, influenza vaccine was reported only as concomitant and not as suspect or interacting agent); and (d) no other cardiovascular AEs were found in patients concomitantly receiving influenza vaccination and ICIs, as well as no other irAEs were reported, except for a single case of Guillain-Barré syndrome, a condition already associated with both ICIs and the influenza vaccine [32,33,34].
Theoretically, a possible pharmacodynamic interaction between influenza vaccines and ICIs leading to the exacerbation of irAEs (including MP), could be supposed. The blockade of a PD-1/PD-L1 pathway together with the vaccination (particularly in conjunction with a strong vaccine adjuvant) could enhance one or more of the mechanisms associated with irAEs onset (infiltration of central memory T cells into the tissues, cross-presentation of shared antigens, and exacerbation of previously subclinical auto-immune syndromes) [24].
Our specific focus on the myo-pericardium stems from the peculiar clinical features of myocarditis in terms of severity and mortality compared with other irAEs, usually requiring immunotherapy discontinuation [9,10,11,12,13], as reported in two out of our three cases. Although, in all three cases, no underlying diseases or other agents known to cause or precipitate myocarditis were recorded, the lack of data concerning latency and solid literature studies allows for minimizing, if not completely excluding, the clinically relevant contribution of a potential drug–vaccine interaction in our cases.
Furthermore, the only study investigating the association between influenza vaccine and the development of myocarditis among patients on ICIs found that the administration of the vaccine was not associated with an increased risk of subsequent myocarditis [15]. Additionally, myocarditis cases in which the influenza vaccine was administered showed lower troponin levels at presentation and a lower risk of major adverse cardiac events at follow-up compared with non-vaccinate patients developing myocarditis with ICIs [15], thus suggesting a protective role for the influenza vaccine in this setting.
ICIs caused a paradigm shift in cancer treatment, and are currently used as first-line agents in the management of non-small cell lung cancer, melanoma, and renal carcinoma [35]. Considering their evolving role and expected increasing uptake, the assessment of cardiovascular safety is of paramount importance. Likewise, the safety of influenza vaccines represents an important issue, given the high morbidity and mortality rates caused by influenza in cancer patients [36]. Notably, the development of influenza infection may also, albeit rarely, be associated itself with an increased risk of myocarditis and major adverse cardiovascular events [37,38]. Therefore, the suggested protective role of the influenza vaccine on cardiovascular outcome [15] cannot be overlooked.
Collectively, our findings provide a reassuring message in terms of cardiovascular safety for cancer patients treated with ICIs and requiring the influenza vaccination. Of note, less than 20% of patients affected by malignancies received the influenza vaccine, with a gradual decline in the last decade [39]. We support and promote the achievement of an optimal vaccination coverage rate in cancer patients for several reasons, including the following: (a) direct association with a lower mortality and infection-related outcomes in immunosuppressed adults [1]; (b) a better overall survival recently reported in patients treated with ICIs receiving influenza vaccination [40]; and (c) the current COVID-19 pandemic, to reduce the strain on the healthcare system while protecting vulnerable subjects from the dramatic impact of a possible co-infection [41]. Cancer patients receiving immunotherapy are at high risk of severe events as a result of COVID-19 systemic involvement, including pneumonitis and myocarditis [42], and a recent systematic review found no significant increase in the risk of infection or in the illness severity or lethality of COVID-19 in subjects receiving the influenza vaccine, with some studies reporting a significantly inverse association [43]. Therefore, the implementation of measures aimed at raising influenza vaccination coverage in frail patients is strongly recommended.
We acknowledge the limitations of our study, mainly inherent to the nature of SRSs data. VAERS and VigiBase® are subject to reporting bias, including under- and over-reporting of adverse events, although there are not clues for major distortions, considering that serious events such as MP are less prone to under-reporting, and no specific warnings were posted by regulatory agencies, thus minimizing the existence and impact of a stimulated reporting [3,18]. We recognize the potential occurrence of subclinical myocarditis, which may be under-diagnosed/under-detected, and is thus likely to be under-reported. Furthermore, the quality and completeness of the reports collected in both databases are variable, and many records lack valid medical diagnoses, thus making the assessment of causality challenging. Additionally, DIPS was not specifically developed to assess drug–vaccine interactions, although we implemented an adapted version in order to the better focus on the possible precipitating role of the influenza vaccine.
Notwithstanding these limitations, pharmacovigilance assessment represents an invaluable opportunity to monitor vaccine safety and identify novel rare signals, potentially arising from drug–vaccine interactions, both from a local and international perspective. Furthermore, our findings are consistent between the two databases, thus supporting the lack of evidence of a clinically relevant drug–vaccine interaction. The identification of myocarditis with ICIs, in line with previous findings [9,10,11], further corroborates the ability of our post-marketing approach to identify actual true-positive associations.
In conclusion, the paucity of cases coupled with a lack of certainty in terms of causality assessment and doubtful probability make the risk of myocarditis and pericarditis by interaction between influenza vaccines and ICIs in cancer patients negligible from both clinical and epidemiological standpoints. Our findings support the cardiovascular safety of influenza vaccines in subjects treated with immunotherapy, thereby emphasizing the importance of a flu vaccination in this population, especially in the current COVID-19 era.
Acknowledgments
We would like to thank Annette Rudolph for data extraction from VigiBase®. Authors at the University of Bologna are supported by institutional research funds (Ricerca Fondamentale Orientata). No sources of funding were received for the preparation of this article.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2076-393X/9/1/19/s1. Table S1: Case-by-case assessment of reports recorded in VAERS in which influenza vaccine and immune checkpoint inhibitors (ICIs) were concomitantly used. Table S2: Application of the adapted version of Drug Interaction Probability Scale in cases of myocarditis/pericarditis in which immune checkpoint inhibitors (ICIs) and influenza vaccine were concomitantly administered.
Click here for additional data file.
Author Contributions
M.G.: methodology, investigation, formal analysis, and writing—original draft. E.R.: conceptualization, methodology, formal analysis, and writing—reviewing and editing. U.M.: writing—reviewing and editing. A.A.: writing—reviewing and editing. E.P.: conceptualization, methodology, formal analysis, and writing—reviewing and editing. I.D.: conceptualization and writing—reviewing and editing. All authors have read and agreed to the published version of the manuscript.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Institutional Review Board Statement
Under current legislation, institutional review board approval is not required when performing analysis of the publicly available VAERS and VigiBase databases, because it contains anonymized data that cannot allow patients’ identification.
Informed Consent Statement
Patient consent was waived due to VAERS and VigiBase databases contain anonymized data that cannot allow patients’ identification.
Data Availability Statement
Data supporting the findings of this study were derived from the following resource available in the public domains: https://wonder.cdc.gov/vaers.html and http://www.vigiaccess.org/.
Conflicts of Interest
M.G., E.R., E.P., U.M., and I.D. have no conflicts of interest relevant to the content of the present work. A.A. reports grants and personal fees from BMS, as well as grants from MSD, Roche, Astra Zeneca, Eli-Lilly, Takeda, and Bayer, outside of the submitted work.
vaccines-09-00019-t001_Table 1Table 1 Demographic and clinical feature of cases of myocarditis/pericarditis reported with influenza vaccine as suspect in Vaccine Adverse Event Reporting System (VAERS) and the World Health Organization’s (WHO) global Individual Case Safety Report database (VigiBase®).
Demographic Features VAERS VigiBase
Overall number of cases 191 399
Proportion of cases (based on overall number of reports with the flu vaccine) 0.03% (712,776) 0.16% (246,864)
Age (mean) 44.5 ± 22.9 46.7 ± 22.3
Sex
Female 62 (32.5%) 131 (32.8%)
Male 124 (64.9%) 263 (65.9%)
Not specified 5 (2.6%) 5 (1.3%)
Reporter country
US 109 (57.1%) 183 (45.9%)
Non-US 60 (31.4%) -
Europe - 180 (45.1%)
Asia - 10 (2.5%)
Oceania - 19 (4.8%)
America (except US) - 7 (1.7%)
Not specified 22 (11.5%) -
Reported symptoms (preferred terms) *
Myocarditis 81 (42.4%) 193 (48.4%)
Pericarditis 117 (61.3%) 225 (56.4%)
Myopericarditis 7 (3.7%) 29 (7.3%)
Immune-mediated myocarditis 0 (0.0%) 0 (0.0%)
Co-medications
Overall number of cases 49 (25.7%) 57 (14.3%)
≥5 concomitant drugs 14 (7.3%) 13 (3.3%)
1–4 concomitant drugs 35 (18.4%) 44 (11.0%)
No concomitant drugs 142 (74.3%) 342 (85.7%)
Co-medications potentially implicated in the occurrence of myocarditis/pericarditis **
Number of cases 21 (11.0%) § 24 (6.0%) #
Immune checkpoint inhibitors (ICIs) None 2
Hydrochlorothiazide 6 5
Indomethacin 2 2
Glipizide 2 -
Clonazepam 2 -
Alprazolam 2 -
Furosemide 1 1
Bendroflumethiazide 1 2
Mesalazine 1 2
Colchicine 1 1
Doxycycline 1 2
Cotrimoxazole 1 1
Lorazepam 1 -
Amoxicillin 1 1
Isosorbide dinitrate 1 2
Tetracycline - 2
Spironolactone - 1
Cefuroxime - 1
Heparin - 1
Bromazepam - 1
Comorbidities potentially implicated in occurrence of myocarditis/pericarditis **
Number of cases 6 (3.1%) 2 (0.5%)
Ulcerative colitis 2 2
Systemic lupus erythematosus 2 -
Juvenile rheumatoid arthritis 1 -
Insulin-dependent diabetes mellitus 1 -
Onset (days; median) 7 (1.5–13) 5 (1–12)
≤3 days 65 (34.0%) 119 (29.8%)
4–7 days 19 (10.0%) 50 (12.5%)
8–14 days 35 (18.4%) 61 (15.3%)
≥15 days 36 (18.8%) 56 (14.0%)
Not specified 36 (18.8%) 113 (28.4%)
Seriousness
Serious 141 (73.8%) 303 (76.0%)
Non-serious 50 (26.2%) 48 (12.0%)
Not specified - 48 (12.0%)
Seriousness criteria *
Congenital anomaly 0 (0.0%) 0 (0.0%)
Death 16 (8.4%) 28 (7.0%)
Hospitalization 125 (65.5%) 222 (55.6%)
Life-threatening 30 (15.7%) 46 (11.5%)
Permanent disability 12 (6.3%) 12 (3.0%)
Other outcomes 30 (15.7%) 60 (15.0%)
Median time of hospitalization (days) 3 (2–4) NA
Recovering
Recovered 60 (31.4%) 164 (41.1%)
Not recovered 64 (33.5%) 61 (15.3%)
Not specified 67 (35.1%) 174 (43.6%)
Concomitant other vaccines
Overall number of cases 59 (30.9%) 87 (21.8%)
Mean number of vaccines per patient 3.1 ± 1.4 2.5 ± 1.7
* One case may exhibit more than one seriousness criteria. ** According to 2015 the European Society of Cardiology (ESC) guidelines for the diagnosis and management of pericardial diseases [6], Caforio et al. [7] and Butany et al. [8]. § In one case, the concomitant use of glipizide and indomethacin, and colchicine and indomethacin. # In one case, concomitant use of amoxicillin and tetracycline, hydrochlorothiazide and cotrimoxazole, and bromazepam and heparin. Flu vaccine types (VAERS): FLU 3 (trivalent injected): 69 patients (36.1%); FLUX SEASONAL (influenza virus vaccine, no brand name): 62 (32.5%); FLU 4 (quadrivalent injected): 20 (10.5%); FLUN 3 (trivalent intranasal spray): 19 (9.9%); FLUN 4 (quadrivalent intranasal spray): 7 (3.7%); FLU H1N1 (monovalent injected): 5 (2.6%); FLUA 3 (trivalent adjuvant injected): 3 (1.6%); FLUN H1N1 (monovalent intranasal spray): 2 (1.1%); FLUX H1N1 (monovalent unknown manufacturer): 2 (1.1%); FLUC 4 (quadrivalent cell-culture-derived injected): 2 (1.1%); FLUC 3 (trivalent cell-culture-derived injected): 1 (0.5%). One patient received both FLUX SEASONAL and FLUX (H1N1).
vaccines-09-00019-t002_Table 2Table 2 Case-by-case assessment of reports concerning myocarditis or pericarditis in which the influenza vaccine and immune checkpoint inhibitors (ICIs) were concomitantly used.
Case ID Drugs/Role Dose Year Age/Sex Reporter Country Reporter Qualification Reactions Seriousness Outcome Concomitant Medications Comorbidities Management Causality Assessment Adapted DIPS Score
#1 Nivolumab (suspect)
Influenza vaccine(suspect) 3 mg/kg every 2 weeks IV- 2018 70/F Japan Physician Myocarditis Serious
(life-threatening; prolonged hospitalization; other outcomes) Recovered Ursodeoxycholic acid 200 mg/day
Bezafibrate
200 mg/day
Calcitriol
0.5 mcg/day NSCLC
Liver disorder
Hyperlipidemia
Osteoporosis Nivolumab withdrawn Unclassifiable (data on latency and time window of increased risk are lacking) Synergistic effect between influenza vaccine and ICIs cannot be excluded 1
Doubtful
#2 Pembrolizumab
(suspect)
Influenza vaccine (suspect) NA
IV
0.5 mL
IM 2018 67/M US Pharmacist Myocarditis,
stress, cardiomyopathy,
weight decreased,
headache,
cardiac failure, congestive,
cerebral infarction,
confusional state, and
dyspnoea Serious
(life-threatening; prolonged hospitalization) NA NA Lung neoplasm malignant NA Unclassifiable
(data on latency and time window of increased risk are lacking)
Synergistic effect between influenza vaccine and ICIs cannot be excluded 1
Doubtful
#3 Ipilimumab
(suspect)
Nivolumab
(suspect)
Influenza vaccine (concomitant) 80 mg every 3 weeks IV
240 mg every 3 weeks IV- 2019 77/M Canada Physician Myocarditis,
pulmonary hypertension,
dyspnoea chest discomfort asthenia, troponin increased c-reactive protein, increased diastolic dysfunction, oedema, peripheral urticaria, and pruritus Serious
(prolonged hospitalization; other outcomes) NA NA Metastatic renal cell carcinoma Ipilimumab and nivolumab withdrawn Unclassifiable
(data on latency and time window of increased risk are lacking)
Synergistic effect between influenza vaccine and ICIs cannot be excluded 2
Possible
US—United States of America; NSCLC—non-small cell lung cancer; NA—not available; IV—intravenous; IM—intramuscular; DIPS—drug-interaction probability scale. | 200 MILLIGRAM, QD | DrugDosageText | CC BY | 33406694 | 18,811,294 | 2021-01-04 |
What was the dosage of drug 'CALCITRIOL'? | Influenza Vaccination and Myo-Pericarditis in Patients Receiving Immune Checkpoint Inhibitors: Investigating the Likelihood of Interaction through the Vaccine Adverse Event Reporting System and VigiBase.
BACKGROUND
Evidence on whether the influenza vaccine could exacerbate immune-related adverse events, including myopericarditis (MP), in patients treated with immune checkpoint inhibitors (ICIs), is still conflicting. We explored this issue through a global real-world approach.
METHODS
We queried the Vaccine Adverse Event Reporting System (VAERS) and VigiBase to retrieve cases of MP in which the influenza vaccine and ICIs were recorded as suspect and were concomitantly reported. For the included cases, causality assessment and Drug Interaction Probability Scale (DIPS) algorithms were applied.
RESULTS
There were 191 and 399 reports of MP with the influenza vaccine that were retrieved (VAERS and VigiBase, respectively). No case of MP reporting the concomitant use of ICIs and the influenza vaccine was found in VAERS, while three cases of myocarditis were retrieved in VigiBase. All of the cases were unclassifiable for a causality assessment because of the lack of data concerning latency. According to the DIPS, one report was categorized as possible and two as doubtful.
CONCLUSIONS
The paucity of cases coupled with the doubtful causality assessment make the potential interaction between influenza vaccines and ICIs in cancer patients negligible from clinical and epidemiological standpoints. These findings support the cardiovascular safety of the influenza vaccination, which remains strongly recommended in cancer patients, especially in the current COVID-19 era.
1. Introduction
The safety of vaccines and medications is a current global safety issue. The annual vaccination against the influenza virus is the primary means of preventing influenza and its complications in high-risk subjects, including adult cancer patients, as described by observational studies, suggesting lower mortality and infection-related outcomes with influenza vaccination [1]. However, in the recent past, potential pharmacokinetic interactions have been proposed, considering that vaccines can influence the drug metabolism via inflammatory cytokines [2]. Therefore, potential interactions between influenza vaccines and drugs used for chronic diseases (e.g., immunosuppressive agents) cannot be excluded [3]. Moreover, cases of myo-pericarditis (MP) after immunization, although rarely, are reported [4,5].
Myocarditis and pericarditis represent serious and life-threatening inflammatory diseases involving myocardium and pericardium, potentially associated with the use of several drugs and vaccines [6,7,8]. In particular, cases of MP were described with the smallpox vaccine in early 2000 and, more recently, very rarely are reported after influenza immunization [4,5]. Immune checkpoint inhibitors (ICIs), such as anti-PD1, anti-PDL1, and anti-CTLA4 monoclonal antibodies, are approved as first-line agents in the management of melanoma and non-small cell lung cancer. They may cause a variegate spectrum of cardiovascular events, including MP, with a higher mortality compared with other immune-related adverse events (irAEs) [9,10,11,12,13]. In a summary of the product characteristics of the different ICIs, pericarditis and myocarditis are reported as uncommon (≥1/1000 to <1/100) and rare (≥1/10,000 to <1/1000, respectively) AEs. Notably, the detection of myocarditis with ICIs requires the permanent discontinuation of treatment, no matter the severity.
Consequently, the question arises as to whether pharmacokinetic and pharmacodynamic interactions occur in patients receiving the influenza vaccination (recommended both by oncologists and cardiologists) and ICIs, possibly causing or exacerbating irAEs such MP. Although no cases of myocarditis have been reported, evidence on whether the influenza vaccine exacerbates irAEs is still conflicting and poorly investigated [14]. Only a retrospective study investigated the clinical features of myocarditis with ICIs in patients receiving the influenza vaccine; reduced myocardial injury and a lower risk of major adverse cardiac events among recipients of the influenza vaccine was found compared with not vaccinated patients [15].
In the recent past, analysis of the spontaneous reporting systems (SRSs) has attracted considerable interest among clinicians for the accurate and timely characterization of drug- and vaccine-related risks occurring in the real world, where comorbidities and polypharmacotherapy exist. By offering a global epidemiological perspective, these pharmacovigilance studies have been pursued to test the hypothesis of potential associations, including refusing the likelihood of interactions [3,16,17], especially for rare, unexpected, and delayed AEs, such as MP.
In this study, we investigated the likelihood of interaction between the influenza vaccination and ICIs by analyzing spontaneous reports of MP collected from the Vaccine Adverse Event Reporting System (VAERS; P.O. Box 1100; Rockville, MD 20849-1100) and the World Health Organization’s (WHO) global Individual Case Safety Report database (VigiBase®; Uppsala Monitoring Centre Box, 1051 SE-751 40, Uppsala, Sweden).
2. Materials and Methods
2.1. Study Conception and Design
The study was conceived as an observational retrospective analysis of spontaneous reports of MP collected from the VAERS and the VigiBase® to (a) characterize relevant clinical features; (b) highlight the concomitant use of agents known to cause MP, including ICIs; and (c) assess the causality and probability of interaction between the influenza vaccine and ICIs.
VAERS is a national system to monitor the safety of US-licensed vaccines [18], whereas VigiBase® collects worldwide reports on vaccines and drugs, thus making these archives act as complementary approaches [19].
VAERS transmits its vaccine adverse event reports to the VigiBase, in order to contribute to the global pharmacovigilance effort along with other countries that employ passive vaccine safety monitoring systems [18], thus possible duplicates between the two databases may exist.
2.2. Data Source
Established in 1990, the VAERS is co-managed by the Centers for Disease Control and Prevention and the US Food and Drug Administration (FDA); it collects and analyzes reports of AEs following immunization (AEFI) for vaccines licensed in the US, receiving approximately 28,000 reports of AEFI annually.
AEFI may be any unfavorable or unintended sign, abnormal laboratory finding, symptom, or disease that occurs following or during the administration of a vaccine. AEs are temporally associated events that may either be caused by a vaccine or be coincidental to it, i.e., not necessarily related to the vaccination [20]. VAERS may be used to detect unexpected and rare patterns of AEFI, unlikely to arise in pivotal trials because of the limited number of patients involved [21]. Health-care professionals, vaccine manufacturers, and consumers (patients, parents, and caregivers) can submit reports of AEs to VAERS.
VigiBase® is one of the largest and most comprehensive pharmacovigilance databases, maintained by the Uppsala Monitoring Centre in Sweden, and containing over 20 million of Individual Case Safety Reports from 110 countries over the five continents. VigiBase® collects reports of AEs for authorized drugs, vaccines, and food supplements, submitted from healthcare professionals, pharmaceutical companies, and patients.
For each vaccine/drug, the characterization of the vaccine/drug role indicated by the primary reporter (i.e., the original source of the information) includes the following three categories: suspect, concomitant, and interacting. All spontaneous reports should have at least one suspect vaccine/drug, namely involved, presumably, in the occurrence of AEFI. If the reporter indicates a suspected interaction, all interacting vaccines/drugs are considered to be suspect vaccines/drugs.
In both databases, AEs are codified through the Medical Dictionary for Regulatory Activities (MedDRA) terminology, and described and organized in terms of Preferred Terms (PTs).
2.3. Data Extraction and Analysis
A multi-step approach was followed for data extraction in each database:(1) Reports for individuals receiving any type of vaccine against the influenza virus categorized as suspect AEFI submitted to VAERS (from July 1990 to September 2020) and VigiBase® (from inception to October 2020) were selected.
(2) Cases of myocarditis or pericarditis were extracted through specific PTs and lowest level terms, in line with previous studies on the influenza vaccination [4] and the potential immune-related basis of cardiotoxicity documented for ICIs by recent pharmacovigilance analyses [9,10]: myocarditis, pericarditis, immune-mediated myocarditis, and myopericarditis.
(3) Reports recording AEs of interest were finally assessed for co-reported drugs/vaccines of interest.
In VigiBase, retained reports (refer to point 2) with ICIs, namely PD-1 inhibitors (nivolumab, pembrolizumab, and cemiplimab), PD-L1 inhibitors (atezolizumab, avelumab, and durvalumab), and CTLA-4 inhibitors (ipilimumab and tremelimumab), were evaluated by extracting the following data: demographic features (age, gender, weight, year, and reporter country), reporter qualification, comorbidities, concomitant medications (including dose and route of administration when available), latency, degree of seriousness, outcome, and management of the AE. The same approach was applied to identify cases of interest reported for vaccines against the influenza virus, both as suspect alone or concomitant to ICI exposure.
In VAERS, for each report of interest with the influenza vaccines, the following data were extracted: demographic features (age, gender, year, and reporter country), type of vaccine against the influenza virus, medical history, concomitant drugs or administered vaccines, laboratory data, AEs codified as PTs, latency, AE degree of seriousness, outcome, and narratives, when available.
According to WHO criteria, a serious AE is any untoward medical occurrence that, no matter the dose, results as fatal, causing a life-threatening event, requiring hospitalization of the patient, causing serious/permanent disability, causing congenital abnormalities, or other clinically relevant conditions [22].
Co-reported medications and comorbidities known to cause myocarditis or pericarditis (i.e., potential confounders) were further characterized according to the lists proposed by Adler et al. [6], Caforio et al. [7], and Butany et al. [8].
2.4. Causality Assessment and Evaluation of Drug–Vaccine Interaction
The probability of interaction when the influenza vaccine and ICIs are co-reported was evaluated by applying the established WHO criteria for causality assessment [20], as well as the Drug Interaction Probability Scale (DIPS) [23].
The following items were accounted for in the AEFI causality assessment: temporal relationship, alternate explanations, proof of association, prior evidence, population-based evidence, and biological plausibility [20]. Cases without adequate information were classified as “unclassifiable”; cases with adequate information were categorized as: (1) “consistent with a causal relationship”, when the available evidence supported a causal relationship between the vaccine and the AEFI in the individual, but it did not rule out the possibility that the AEFI may have been caused by a factor other than the vaccine; (2) “inconsistent with a causal association”, when the available evidence did not support a causal relationship between vaccine administration and the reported AEFI in the individual; and (3) “indeterminate”, when the temporal relationship was consistent but the available evidence insufficient to support or rule out a causal relationship in the individual.
The DIPS is a 10-item tool specifically developed to assess the likelihood of drug–drug interactions [23]. ICIs were considered as the objective drugs (i.e., the one affected by the presence of another vaccine/drug), while the influenza vaccine was considered as the precipitant agent (i.e., the one causing a change on the object drug). To avoid overemphasis on the role of the vaccine, the answer to the second question was always “unknown” (knowledge on the mechanism of the interaction is hypothesized and literature data are very scarce/uncertain); in addition, questions 5, 6, and 10 were not assessable/applicable (dechallenge, rechallenge, and dose adjustments are unfeasible for vaccines considering the peculiarities of their administration), as previously performed [3]. The final summary score could reach 10 points. Higher total scores correspond to a higher likelihood of drug–vaccine interaction (i.e., >8 = highly probable; 5–8 = probable; 2–4 = possible; <2 = doubtful).
3. Results
3.1. Demographic and Clinical Data
Over the observed period, out of a total of 712,776 AEFI, 191 (0.03%) reports of MP mentioning the influenza vaccine as suspect were collected within the VAERS.
The clinical and demographic characteristics are provided in Table 1. The reports included 124 men (64.9%) and 62 women (in five cases gender was not reported), aged between 1 and 88 years (mean age 44.5 years). Pericarditis were reported in 117 cases (61.3%), followed by myocarditis (81 cases; 42.4%) and MP (7 cases; 3.7%). No cases of immune-mediated myocarditis were retrieved.
The median onset was seven days; in 34.0% of reports, the AEFI of interest occurred in the first 3 days after the administration of the influenza vaccine. Comorbidities potentially implicated in the occurrence of the AEFI of interest were retrieved in six cases (3.1%), with ulcerative colitis and systemic lupus erythematosus being the most represented. Other vaccines were concomitantly administered in 59 cases (30.9%), accounting for a mean number of 3.1 vaccines per patient.
In 141 cases (73.8%), the report was classified as serious, and 16 fatal cases (8.4%) were found. Recovery occurred in 31.4% of cases.
In the VigiBase®, 246,864 reports mentioning the influenza vaccine as a suspect agent were found, and myocarditis/pericarditis were reported in 399 cases (0.16%; Table 1).
The cases showed a mean age of 46.7 years, with a male preponderance (65.9%). Reports were largely submitted from US (45.9%) and Europe (45.1%). Pericarditis was reported in 225 cases (56.4%), followed by myocarditis (193 cases; 48.4%) and myopericarditis (29; 7.3%). No cases of immune-mediated myocarditis were found.
Median onset was five days, and in 29.8% of reports, AEs of interest occurred in the first three days after the administration of the influenza vaccine. Comorbidities potentially implicated in the occurrence of myocarditis/pericarditis were retrieved in two patients (0.5%) affected by ulcerative colitis. Other vaccines were concomitantly administered in 87 cases (21.8%), accounting for a mean number of 2.5 vaccines per patient.
In 303 cases (76.0%), the report was classified as serious, and 28 fatal cases (7.0%) were found. Recovering occurred in 41.1% of cases.
3.2. Co-Reported Medications and Detection of Cases with ICI Administration
Overall, concomitant medications were found in 49 (25.7%) and 57 (14.3%) cases with the influenza vaccine in VAERS and VigiBase®, respectively (Table 1). In 14 (7.3%) and 13 (3.3%) cases, five or more concomitant drugs were reported in VAERS and VigiBase®, respectively.
Concomitant medications potentially implicated in the occurrence of myocarditis/pericarditis were retrieved in 21 (11.0%) and 24 (6.0%) cases in VAERS and VigiBase®, respectively, with hydrochlorothiazide being the most frequent in both databases (in six and five cases, respectively).
Only six cases (one classified as serious, where Guillain-Barré syndrome was recorded) with the concomitant use of ICIs and the influenza vaccine were found in VAERS (Table S1), but no cases of myocarditis/pericarditis. In VigiBase®, two cases of myocarditis reporting the concomitant administration of ICIs and the influenza vaccine both mentioned as suspect agents were retrieved. A third case of myocarditis in which the influenza vaccine was classified as a concomitant agent was detected (Table 2).
The three cases were classified as serious (causing prolonged hospitalization), included two men and one woman, aged 67–77 years, and affected by lung or renal carcinoma. Nivolumab, pembrolizumab, and ipilimumab/nivolumab combination therapy were reported as the ICI regimen. In two cases ICI was withdrawn, while recovering occurred in only one case.
3.3. Causality Assessment and Evaluation of Drug–Vaccine Interaction
These three cases showed an unclassifiable causality assessment due to the lack of data concerning the latency and time window of increased risk (Table 2).
By applying the adapted DIPS algorithm, one report was categorized as possible (due to the lack of underlying diseases or co-reported agents known to cause or precipitate myocarditis, and to the detection of troponin increase) and two as doubtful (only the absence of underlying diseases or co-reported agents known to cause or precipitate myocarditis were recognized; Table S2).
4. Discussion
To the best of our knowledge, this is the first real-world study investigating the potential interactions between influenza vaccines and ICIs resulting in myocarditis or pericarditis in cancer patients, by assessing spontaneous reports submitted to the VAERS and VigiBase®. This global post-marketing safety study stems from recent conflicting real-world evidence surrounding the possible exacerbation of irAEs with influenza vaccines in patients treated with ICIs [14,15,24,25,26,27,28,29], thus joining in the wider debate on the bidirectional relationship between immunotherapy and the influenza vaccination, potentially affecting the clinical and humoral efficacy of the vaccine, performance of ICIs, and safety [14].
Four major findings emerged from our analysis: (a) myocarditis and pericarditis represented a very rare AEFI (with a non-negligible proportion of death, approximately 8–9%), based on the low reporting frequency retrieved in both SRSs (<0.1–0.2% of overall AEs), also considering the influenza vaccination coverage rates (estimated at about 25% per year in Europe [30,31]) and the relevant million doses distributed worldwide; (b) the reporting of myocarditis in patients concomitantly receiving influenza vaccines and ICIs is limited to only three out of a total of 1465 cases of myocarditis/pericarditis found with influenza vaccines or ICIs (considered as suspect agents) in the two databases; (c) these cases were unclassifiable for causality assessment with a doubtful probability of drug–vaccine interaction (according to the adapted DIPS algorithm), thus suggesting that the vaccine is not directly involved in the occurrence of myocarditis (and in one of the three cases, influenza vaccine was reported only as concomitant and not as suspect or interacting agent); and (d) no other cardiovascular AEs were found in patients concomitantly receiving influenza vaccination and ICIs, as well as no other irAEs were reported, except for a single case of Guillain-Barré syndrome, a condition already associated with both ICIs and the influenza vaccine [32,33,34].
Theoretically, a possible pharmacodynamic interaction between influenza vaccines and ICIs leading to the exacerbation of irAEs (including MP), could be supposed. The blockade of a PD-1/PD-L1 pathway together with the vaccination (particularly in conjunction with a strong vaccine adjuvant) could enhance one or more of the mechanisms associated with irAEs onset (infiltration of central memory T cells into the tissues, cross-presentation of shared antigens, and exacerbation of previously subclinical auto-immune syndromes) [24].
Our specific focus on the myo-pericardium stems from the peculiar clinical features of myocarditis in terms of severity and mortality compared with other irAEs, usually requiring immunotherapy discontinuation [9,10,11,12,13], as reported in two out of our three cases. Although, in all three cases, no underlying diseases or other agents known to cause or precipitate myocarditis were recorded, the lack of data concerning latency and solid literature studies allows for minimizing, if not completely excluding, the clinically relevant contribution of a potential drug–vaccine interaction in our cases.
Furthermore, the only study investigating the association between influenza vaccine and the development of myocarditis among patients on ICIs found that the administration of the vaccine was not associated with an increased risk of subsequent myocarditis [15]. Additionally, myocarditis cases in which the influenza vaccine was administered showed lower troponin levels at presentation and a lower risk of major adverse cardiac events at follow-up compared with non-vaccinate patients developing myocarditis with ICIs [15], thus suggesting a protective role for the influenza vaccine in this setting.
ICIs caused a paradigm shift in cancer treatment, and are currently used as first-line agents in the management of non-small cell lung cancer, melanoma, and renal carcinoma [35]. Considering their evolving role and expected increasing uptake, the assessment of cardiovascular safety is of paramount importance. Likewise, the safety of influenza vaccines represents an important issue, given the high morbidity and mortality rates caused by influenza in cancer patients [36]. Notably, the development of influenza infection may also, albeit rarely, be associated itself with an increased risk of myocarditis and major adverse cardiovascular events [37,38]. Therefore, the suggested protective role of the influenza vaccine on cardiovascular outcome [15] cannot be overlooked.
Collectively, our findings provide a reassuring message in terms of cardiovascular safety for cancer patients treated with ICIs and requiring the influenza vaccination. Of note, less than 20% of patients affected by malignancies received the influenza vaccine, with a gradual decline in the last decade [39]. We support and promote the achievement of an optimal vaccination coverage rate in cancer patients for several reasons, including the following: (a) direct association with a lower mortality and infection-related outcomes in immunosuppressed adults [1]; (b) a better overall survival recently reported in patients treated with ICIs receiving influenza vaccination [40]; and (c) the current COVID-19 pandemic, to reduce the strain on the healthcare system while protecting vulnerable subjects from the dramatic impact of a possible co-infection [41]. Cancer patients receiving immunotherapy are at high risk of severe events as a result of COVID-19 systemic involvement, including pneumonitis and myocarditis [42], and a recent systematic review found no significant increase in the risk of infection or in the illness severity or lethality of COVID-19 in subjects receiving the influenza vaccine, with some studies reporting a significantly inverse association [43]. Therefore, the implementation of measures aimed at raising influenza vaccination coverage in frail patients is strongly recommended.
We acknowledge the limitations of our study, mainly inherent to the nature of SRSs data. VAERS and VigiBase® are subject to reporting bias, including under- and over-reporting of adverse events, although there are not clues for major distortions, considering that serious events such as MP are less prone to under-reporting, and no specific warnings were posted by regulatory agencies, thus minimizing the existence and impact of a stimulated reporting [3,18]. We recognize the potential occurrence of subclinical myocarditis, which may be under-diagnosed/under-detected, and is thus likely to be under-reported. Furthermore, the quality and completeness of the reports collected in both databases are variable, and many records lack valid medical diagnoses, thus making the assessment of causality challenging. Additionally, DIPS was not specifically developed to assess drug–vaccine interactions, although we implemented an adapted version in order to the better focus on the possible precipitating role of the influenza vaccine.
Notwithstanding these limitations, pharmacovigilance assessment represents an invaluable opportunity to monitor vaccine safety and identify novel rare signals, potentially arising from drug–vaccine interactions, both from a local and international perspective. Furthermore, our findings are consistent between the two databases, thus supporting the lack of evidence of a clinically relevant drug–vaccine interaction. The identification of myocarditis with ICIs, in line with previous findings [9,10,11], further corroborates the ability of our post-marketing approach to identify actual true-positive associations.
In conclusion, the paucity of cases coupled with a lack of certainty in terms of causality assessment and doubtful probability make the risk of myocarditis and pericarditis by interaction between influenza vaccines and ICIs in cancer patients negligible from both clinical and epidemiological standpoints. Our findings support the cardiovascular safety of influenza vaccines in subjects treated with immunotherapy, thereby emphasizing the importance of a flu vaccination in this population, especially in the current COVID-19 era.
Acknowledgments
We would like to thank Annette Rudolph for data extraction from VigiBase®. Authors at the University of Bologna are supported by institutional research funds (Ricerca Fondamentale Orientata). No sources of funding were received for the preparation of this article.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2076-393X/9/1/19/s1. Table S1: Case-by-case assessment of reports recorded in VAERS in which influenza vaccine and immune checkpoint inhibitors (ICIs) were concomitantly used. Table S2: Application of the adapted version of Drug Interaction Probability Scale in cases of myocarditis/pericarditis in which immune checkpoint inhibitors (ICIs) and influenza vaccine were concomitantly administered.
Click here for additional data file.
Author Contributions
M.G.: methodology, investigation, formal analysis, and writing—original draft. E.R.: conceptualization, methodology, formal analysis, and writing—reviewing and editing. U.M.: writing—reviewing and editing. A.A.: writing—reviewing and editing. E.P.: conceptualization, methodology, formal analysis, and writing—reviewing and editing. I.D.: conceptualization and writing—reviewing and editing. All authors have read and agreed to the published version of the manuscript.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Institutional Review Board Statement
Under current legislation, institutional review board approval is not required when performing analysis of the publicly available VAERS and VigiBase databases, because it contains anonymized data that cannot allow patients’ identification.
Informed Consent Statement
Patient consent was waived due to VAERS and VigiBase databases contain anonymized data that cannot allow patients’ identification.
Data Availability Statement
Data supporting the findings of this study were derived from the following resource available in the public domains: https://wonder.cdc.gov/vaers.html and http://www.vigiaccess.org/.
Conflicts of Interest
M.G., E.R., E.P., U.M., and I.D. have no conflicts of interest relevant to the content of the present work. A.A. reports grants and personal fees from BMS, as well as grants from MSD, Roche, Astra Zeneca, Eli-Lilly, Takeda, and Bayer, outside of the submitted work.
vaccines-09-00019-t001_Table 1Table 1 Demographic and clinical feature of cases of myocarditis/pericarditis reported with influenza vaccine as suspect in Vaccine Adverse Event Reporting System (VAERS) and the World Health Organization’s (WHO) global Individual Case Safety Report database (VigiBase®).
Demographic Features VAERS VigiBase
Overall number of cases 191 399
Proportion of cases (based on overall number of reports with the flu vaccine) 0.03% (712,776) 0.16% (246,864)
Age (mean) 44.5 ± 22.9 46.7 ± 22.3
Sex
Female 62 (32.5%) 131 (32.8%)
Male 124 (64.9%) 263 (65.9%)
Not specified 5 (2.6%) 5 (1.3%)
Reporter country
US 109 (57.1%) 183 (45.9%)
Non-US 60 (31.4%) -
Europe - 180 (45.1%)
Asia - 10 (2.5%)
Oceania - 19 (4.8%)
America (except US) - 7 (1.7%)
Not specified 22 (11.5%) -
Reported symptoms (preferred terms) *
Myocarditis 81 (42.4%) 193 (48.4%)
Pericarditis 117 (61.3%) 225 (56.4%)
Myopericarditis 7 (3.7%) 29 (7.3%)
Immune-mediated myocarditis 0 (0.0%) 0 (0.0%)
Co-medications
Overall number of cases 49 (25.7%) 57 (14.3%)
≥5 concomitant drugs 14 (7.3%) 13 (3.3%)
1–4 concomitant drugs 35 (18.4%) 44 (11.0%)
No concomitant drugs 142 (74.3%) 342 (85.7%)
Co-medications potentially implicated in the occurrence of myocarditis/pericarditis **
Number of cases 21 (11.0%) § 24 (6.0%) #
Immune checkpoint inhibitors (ICIs) None 2
Hydrochlorothiazide 6 5
Indomethacin 2 2
Glipizide 2 -
Clonazepam 2 -
Alprazolam 2 -
Furosemide 1 1
Bendroflumethiazide 1 2
Mesalazine 1 2
Colchicine 1 1
Doxycycline 1 2
Cotrimoxazole 1 1
Lorazepam 1 -
Amoxicillin 1 1
Isosorbide dinitrate 1 2
Tetracycline - 2
Spironolactone - 1
Cefuroxime - 1
Heparin - 1
Bromazepam - 1
Comorbidities potentially implicated in occurrence of myocarditis/pericarditis **
Number of cases 6 (3.1%) 2 (0.5%)
Ulcerative colitis 2 2
Systemic lupus erythematosus 2 -
Juvenile rheumatoid arthritis 1 -
Insulin-dependent diabetes mellitus 1 -
Onset (days; median) 7 (1.5–13) 5 (1–12)
≤3 days 65 (34.0%) 119 (29.8%)
4–7 days 19 (10.0%) 50 (12.5%)
8–14 days 35 (18.4%) 61 (15.3%)
≥15 days 36 (18.8%) 56 (14.0%)
Not specified 36 (18.8%) 113 (28.4%)
Seriousness
Serious 141 (73.8%) 303 (76.0%)
Non-serious 50 (26.2%) 48 (12.0%)
Not specified - 48 (12.0%)
Seriousness criteria *
Congenital anomaly 0 (0.0%) 0 (0.0%)
Death 16 (8.4%) 28 (7.0%)
Hospitalization 125 (65.5%) 222 (55.6%)
Life-threatening 30 (15.7%) 46 (11.5%)
Permanent disability 12 (6.3%) 12 (3.0%)
Other outcomes 30 (15.7%) 60 (15.0%)
Median time of hospitalization (days) 3 (2–4) NA
Recovering
Recovered 60 (31.4%) 164 (41.1%)
Not recovered 64 (33.5%) 61 (15.3%)
Not specified 67 (35.1%) 174 (43.6%)
Concomitant other vaccines
Overall number of cases 59 (30.9%) 87 (21.8%)
Mean number of vaccines per patient 3.1 ± 1.4 2.5 ± 1.7
* One case may exhibit more than one seriousness criteria. ** According to 2015 the European Society of Cardiology (ESC) guidelines for the diagnosis and management of pericardial diseases [6], Caforio et al. [7] and Butany et al. [8]. § In one case, the concomitant use of glipizide and indomethacin, and colchicine and indomethacin. # In one case, concomitant use of amoxicillin and tetracycline, hydrochlorothiazide and cotrimoxazole, and bromazepam and heparin. Flu vaccine types (VAERS): FLU 3 (trivalent injected): 69 patients (36.1%); FLUX SEASONAL (influenza virus vaccine, no brand name): 62 (32.5%); FLU 4 (quadrivalent injected): 20 (10.5%); FLUN 3 (trivalent intranasal spray): 19 (9.9%); FLUN 4 (quadrivalent intranasal spray): 7 (3.7%); FLU H1N1 (monovalent injected): 5 (2.6%); FLUA 3 (trivalent adjuvant injected): 3 (1.6%); FLUN H1N1 (monovalent intranasal spray): 2 (1.1%); FLUX H1N1 (monovalent unknown manufacturer): 2 (1.1%); FLUC 4 (quadrivalent cell-culture-derived injected): 2 (1.1%); FLUC 3 (trivalent cell-culture-derived injected): 1 (0.5%). One patient received both FLUX SEASONAL and FLUX (H1N1).
vaccines-09-00019-t002_Table 2Table 2 Case-by-case assessment of reports concerning myocarditis or pericarditis in which the influenza vaccine and immune checkpoint inhibitors (ICIs) were concomitantly used.
Case ID Drugs/Role Dose Year Age/Sex Reporter Country Reporter Qualification Reactions Seriousness Outcome Concomitant Medications Comorbidities Management Causality Assessment Adapted DIPS Score
#1 Nivolumab (suspect)
Influenza vaccine(suspect) 3 mg/kg every 2 weeks IV- 2018 70/F Japan Physician Myocarditis Serious
(life-threatening; prolonged hospitalization; other outcomes) Recovered Ursodeoxycholic acid 200 mg/day
Bezafibrate
200 mg/day
Calcitriol
0.5 mcg/day NSCLC
Liver disorder
Hyperlipidemia
Osteoporosis Nivolumab withdrawn Unclassifiable (data on latency and time window of increased risk are lacking) Synergistic effect between influenza vaccine and ICIs cannot be excluded 1
Doubtful
#2 Pembrolizumab
(suspect)
Influenza vaccine (suspect) NA
IV
0.5 mL
IM 2018 67/M US Pharmacist Myocarditis,
stress, cardiomyopathy,
weight decreased,
headache,
cardiac failure, congestive,
cerebral infarction,
confusional state, and
dyspnoea Serious
(life-threatening; prolonged hospitalization) NA NA Lung neoplasm malignant NA Unclassifiable
(data on latency and time window of increased risk are lacking)
Synergistic effect between influenza vaccine and ICIs cannot be excluded 1
Doubtful
#3 Ipilimumab
(suspect)
Nivolumab
(suspect)
Influenza vaccine (concomitant) 80 mg every 3 weeks IV
240 mg every 3 weeks IV- 2019 77/M Canada Physician Myocarditis,
pulmonary hypertension,
dyspnoea chest discomfort asthenia, troponin increased c-reactive protein, increased diastolic dysfunction, oedema, peripheral urticaria, and pruritus Serious
(prolonged hospitalization; other outcomes) NA NA Metastatic renal cell carcinoma Ipilimumab and nivolumab withdrawn Unclassifiable
(data on latency and time window of increased risk are lacking)
Synergistic effect between influenza vaccine and ICIs cannot be excluded 2
Possible
US—United States of America; NSCLC—non-small cell lung cancer; NA—not available; IV—intravenous; IM—intramuscular; DIPS—drug-interaction probability scale. | 0.5 MICROGRAM, QD | DrugDosageText | CC BY | 33406694 | 18,811,294 | 2021-01-04 |
What was the dosage of drug 'URSODIOL'? | Influenza Vaccination and Myo-Pericarditis in Patients Receiving Immune Checkpoint Inhibitors: Investigating the Likelihood of Interaction through the Vaccine Adverse Event Reporting System and VigiBase.
BACKGROUND
Evidence on whether the influenza vaccine could exacerbate immune-related adverse events, including myopericarditis (MP), in patients treated with immune checkpoint inhibitors (ICIs), is still conflicting. We explored this issue through a global real-world approach.
METHODS
We queried the Vaccine Adverse Event Reporting System (VAERS) and VigiBase to retrieve cases of MP in which the influenza vaccine and ICIs were recorded as suspect and were concomitantly reported. For the included cases, causality assessment and Drug Interaction Probability Scale (DIPS) algorithms were applied.
RESULTS
There were 191 and 399 reports of MP with the influenza vaccine that were retrieved (VAERS and VigiBase, respectively). No case of MP reporting the concomitant use of ICIs and the influenza vaccine was found in VAERS, while three cases of myocarditis were retrieved in VigiBase. All of the cases were unclassifiable for a causality assessment because of the lack of data concerning latency. According to the DIPS, one report was categorized as possible and two as doubtful.
CONCLUSIONS
The paucity of cases coupled with the doubtful causality assessment make the potential interaction between influenza vaccines and ICIs in cancer patients negligible from clinical and epidemiological standpoints. These findings support the cardiovascular safety of the influenza vaccination, which remains strongly recommended in cancer patients, especially in the current COVID-19 era.
1. Introduction
The safety of vaccines and medications is a current global safety issue. The annual vaccination against the influenza virus is the primary means of preventing influenza and its complications in high-risk subjects, including adult cancer patients, as described by observational studies, suggesting lower mortality and infection-related outcomes with influenza vaccination [1]. However, in the recent past, potential pharmacokinetic interactions have been proposed, considering that vaccines can influence the drug metabolism via inflammatory cytokines [2]. Therefore, potential interactions between influenza vaccines and drugs used for chronic diseases (e.g., immunosuppressive agents) cannot be excluded [3]. Moreover, cases of myo-pericarditis (MP) after immunization, although rarely, are reported [4,5].
Myocarditis and pericarditis represent serious and life-threatening inflammatory diseases involving myocardium and pericardium, potentially associated with the use of several drugs and vaccines [6,7,8]. In particular, cases of MP were described with the smallpox vaccine in early 2000 and, more recently, very rarely are reported after influenza immunization [4,5]. Immune checkpoint inhibitors (ICIs), such as anti-PD1, anti-PDL1, and anti-CTLA4 monoclonal antibodies, are approved as first-line agents in the management of melanoma and non-small cell lung cancer. They may cause a variegate spectrum of cardiovascular events, including MP, with a higher mortality compared with other immune-related adverse events (irAEs) [9,10,11,12,13]. In a summary of the product characteristics of the different ICIs, pericarditis and myocarditis are reported as uncommon (≥1/1000 to <1/100) and rare (≥1/10,000 to <1/1000, respectively) AEs. Notably, the detection of myocarditis with ICIs requires the permanent discontinuation of treatment, no matter the severity.
Consequently, the question arises as to whether pharmacokinetic and pharmacodynamic interactions occur in patients receiving the influenza vaccination (recommended both by oncologists and cardiologists) and ICIs, possibly causing or exacerbating irAEs such MP. Although no cases of myocarditis have been reported, evidence on whether the influenza vaccine exacerbates irAEs is still conflicting and poorly investigated [14]. Only a retrospective study investigated the clinical features of myocarditis with ICIs in patients receiving the influenza vaccine; reduced myocardial injury and a lower risk of major adverse cardiac events among recipients of the influenza vaccine was found compared with not vaccinated patients [15].
In the recent past, analysis of the spontaneous reporting systems (SRSs) has attracted considerable interest among clinicians for the accurate and timely characterization of drug- and vaccine-related risks occurring in the real world, where comorbidities and polypharmacotherapy exist. By offering a global epidemiological perspective, these pharmacovigilance studies have been pursued to test the hypothesis of potential associations, including refusing the likelihood of interactions [3,16,17], especially for rare, unexpected, and delayed AEs, such as MP.
In this study, we investigated the likelihood of interaction between the influenza vaccination and ICIs by analyzing spontaneous reports of MP collected from the Vaccine Adverse Event Reporting System (VAERS; P.O. Box 1100; Rockville, MD 20849-1100) and the World Health Organization’s (WHO) global Individual Case Safety Report database (VigiBase®; Uppsala Monitoring Centre Box, 1051 SE-751 40, Uppsala, Sweden).
2. Materials and Methods
2.1. Study Conception and Design
The study was conceived as an observational retrospective analysis of spontaneous reports of MP collected from the VAERS and the VigiBase® to (a) characterize relevant clinical features; (b) highlight the concomitant use of agents known to cause MP, including ICIs; and (c) assess the causality and probability of interaction between the influenza vaccine and ICIs.
VAERS is a national system to monitor the safety of US-licensed vaccines [18], whereas VigiBase® collects worldwide reports on vaccines and drugs, thus making these archives act as complementary approaches [19].
VAERS transmits its vaccine adverse event reports to the VigiBase, in order to contribute to the global pharmacovigilance effort along with other countries that employ passive vaccine safety monitoring systems [18], thus possible duplicates between the two databases may exist.
2.2. Data Source
Established in 1990, the VAERS is co-managed by the Centers for Disease Control and Prevention and the US Food and Drug Administration (FDA); it collects and analyzes reports of AEs following immunization (AEFI) for vaccines licensed in the US, receiving approximately 28,000 reports of AEFI annually.
AEFI may be any unfavorable or unintended sign, abnormal laboratory finding, symptom, or disease that occurs following or during the administration of a vaccine. AEs are temporally associated events that may either be caused by a vaccine or be coincidental to it, i.e., not necessarily related to the vaccination [20]. VAERS may be used to detect unexpected and rare patterns of AEFI, unlikely to arise in pivotal trials because of the limited number of patients involved [21]. Health-care professionals, vaccine manufacturers, and consumers (patients, parents, and caregivers) can submit reports of AEs to VAERS.
VigiBase® is one of the largest and most comprehensive pharmacovigilance databases, maintained by the Uppsala Monitoring Centre in Sweden, and containing over 20 million of Individual Case Safety Reports from 110 countries over the five continents. VigiBase® collects reports of AEs for authorized drugs, vaccines, and food supplements, submitted from healthcare professionals, pharmaceutical companies, and patients.
For each vaccine/drug, the characterization of the vaccine/drug role indicated by the primary reporter (i.e., the original source of the information) includes the following three categories: suspect, concomitant, and interacting. All spontaneous reports should have at least one suspect vaccine/drug, namely involved, presumably, in the occurrence of AEFI. If the reporter indicates a suspected interaction, all interacting vaccines/drugs are considered to be suspect vaccines/drugs.
In both databases, AEs are codified through the Medical Dictionary for Regulatory Activities (MedDRA) terminology, and described and organized in terms of Preferred Terms (PTs).
2.3. Data Extraction and Analysis
A multi-step approach was followed for data extraction in each database:(1) Reports for individuals receiving any type of vaccine against the influenza virus categorized as suspect AEFI submitted to VAERS (from July 1990 to September 2020) and VigiBase® (from inception to October 2020) were selected.
(2) Cases of myocarditis or pericarditis were extracted through specific PTs and lowest level terms, in line with previous studies on the influenza vaccination [4] and the potential immune-related basis of cardiotoxicity documented for ICIs by recent pharmacovigilance analyses [9,10]: myocarditis, pericarditis, immune-mediated myocarditis, and myopericarditis.
(3) Reports recording AEs of interest were finally assessed for co-reported drugs/vaccines of interest.
In VigiBase, retained reports (refer to point 2) with ICIs, namely PD-1 inhibitors (nivolumab, pembrolizumab, and cemiplimab), PD-L1 inhibitors (atezolizumab, avelumab, and durvalumab), and CTLA-4 inhibitors (ipilimumab and tremelimumab), were evaluated by extracting the following data: demographic features (age, gender, weight, year, and reporter country), reporter qualification, comorbidities, concomitant medications (including dose and route of administration when available), latency, degree of seriousness, outcome, and management of the AE. The same approach was applied to identify cases of interest reported for vaccines against the influenza virus, both as suspect alone or concomitant to ICI exposure.
In VAERS, for each report of interest with the influenza vaccines, the following data were extracted: demographic features (age, gender, year, and reporter country), type of vaccine against the influenza virus, medical history, concomitant drugs or administered vaccines, laboratory data, AEs codified as PTs, latency, AE degree of seriousness, outcome, and narratives, when available.
According to WHO criteria, a serious AE is any untoward medical occurrence that, no matter the dose, results as fatal, causing a life-threatening event, requiring hospitalization of the patient, causing serious/permanent disability, causing congenital abnormalities, or other clinically relevant conditions [22].
Co-reported medications and comorbidities known to cause myocarditis or pericarditis (i.e., potential confounders) were further characterized according to the lists proposed by Adler et al. [6], Caforio et al. [7], and Butany et al. [8].
2.4. Causality Assessment and Evaluation of Drug–Vaccine Interaction
The probability of interaction when the influenza vaccine and ICIs are co-reported was evaluated by applying the established WHO criteria for causality assessment [20], as well as the Drug Interaction Probability Scale (DIPS) [23].
The following items were accounted for in the AEFI causality assessment: temporal relationship, alternate explanations, proof of association, prior evidence, population-based evidence, and biological plausibility [20]. Cases without adequate information were classified as “unclassifiable”; cases with adequate information were categorized as: (1) “consistent with a causal relationship”, when the available evidence supported a causal relationship between the vaccine and the AEFI in the individual, but it did not rule out the possibility that the AEFI may have been caused by a factor other than the vaccine; (2) “inconsistent with a causal association”, when the available evidence did not support a causal relationship between vaccine administration and the reported AEFI in the individual; and (3) “indeterminate”, when the temporal relationship was consistent but the available evidence insufficient to support or rule out a causal relationship in the individual.
The DIPS is a 10-item tool specifically developed to assess the likelihood of drug–drug interactions [23]. ICIs were considered as the objective drugs (i.e., the one affected by the presence of another vaccine/drug), while the influenza vaccine was considered as the precipitant agent (i.e., the one causing a change on the object drug). To avoid overemphasis on the role of the vaccine, the answer to the second question was always “unknown” (knowledge on the mechanism of the interaction is hypothesized and literature data are very scarce/uncertain); in addition, questions 5, 6, and 10 were not assessable/applicable (dechallenge, rechallenge, and dose adjustments are unfeasible for vaccines considering the peculiarities of their administration), as previously performed [3]. The final summary score could reach 10 points. Higher total scores correspond to a higher likelihood of drug–vaccine interaction (i.e., >8 = highly probable; 5–8 = probable; 2–4 = possible; <2 = doubtful).
3. Results
3.1. Demographic and Clinical Data
Over the observed period, out of a total of 712,776 AEFI, 191 (0.03%) reports of MP mentioning the influenza vaccine as suspect were collected within the VAERS.
The clinical and demographic characteristics are provided in Table 1. The reports included 124 men (64.9%) and 62 women (in five cases gender was not reported), aged between 1 and 88 years (mean age 44.5 years). Pericarditis were reported in 117 cases (61.3%), followed by myocarditis (81 cases; 42.4%) and MP (7 cases; 3.7%). No cases of immune-mediated myocarditis were retrieved.
The median onset was seven days; in 34.0% of reports, the AEFI of interest occurred in the first 3 days after the administration of the influenza vaccine. Comorbidities potentially implicated in the occurrence of the AEFI of interest were retrieved in six cases (3.1%), with ulcerative colitis and systemic lupus erythematosus being the most represented. Other vaccines were concomitantly administered in 59 cases (30.9%), accounting for a mean number of 3.1 vaccines per patient.
In 141 cases (73.8%), the report was classified as serious, and 16 fatal cases (8.4%) were found. Recovery occurred in 31.4% of cases.
In the VigiBase®, 246,864 reports mentioning the influenza vaccine as a suspect agent were found, and myocarditis/pericarditis were reported in 399 cases (0.16%; Table 1).
The cases showed a mean age of 46.7 years, with a male preponderance (65.9%). Reports were largely submitted from US (45.9%) and Europe (45.1%). Pericarditis was reported in 225 cases (56.4%), followed by myocarditis (193 cases; 48.4%) and myopericarditis (29; 7.3%). No cases of immune-mediated myocarditis were found.
Median onset was five days, and in 29.8% of reports, AEs of interest occurred in the first three days after the administration of the influenza vaccine. Comorbidities potentially implicated in the occurrence of myocarditis/pericarditis were retrieved in two patients (0.5%) affected by ulcerative colitis. Other vaccines were concomitantly administered in 87 cases (21.8%), accounting for a mean number of 2.5 vaccines per patient.
In 303 cases (76.0%), the report was classified as serious, and 28 fatal cases (7.0%) were found. Recovering occurred in 41.1% of cases.
3.2. Co-Reported Medications and Detection of Cases with ICI Administration
Overall, concomitant medications were found in 49 (25.7%) and 57 (14.3%) cases with the influenza vaccine in VAERS and VigiBase®, respectively (Table 1). In 14 (7.3%) and 13 (3.3%) cases, five or more concomitant drugs were reported in VAERS and VigiBase®, respectively.
Concomitant medications potentially implicated in the occurrence of myocarditis/pericarditis were retrieved in 21 (11.0%) and 24 (6.0%) cases in VAERS and VigiBase®, respectively, with hydrochlorothiazide being the most frequent in both databases (in six and five cases, respectively).
Only six cases (one classified as serious, where Guillain-Barré syndrome was recorded) with the concomitant use of ICIs and the influenza vaccine were found in VAERS (Table S1), but no cases of myocarditis/pericarditis. In VigiBase®, two cases of myocarditis reporting the concomitant administration of ICIs and the influenza vaccine both mentioned as suspect agents were retrieved. A third case of myocarditis in which the influenza vaccine was classified as a concomitant agent was detected (Table 2).
The three cases were classified as serious (causing prolonged hospitalization), included two men and one woman, aged 67–77 years, and affected by lung or renal carcinoma. Nivolumab, pembrolizumab, and ipilimumab/nivolumab combination therapy were reported as the ICI regimen. In two cases ICI was withdrawn, while recovering occurred in only one case.
3.3. Causality Assessment and Evaluation of Drug–Vaccine Interaction
These three cases showed an unclassifiable causality assessment due to the lack of data concerning the latency and time window of increased risk (Table 2).
By applying the adapted DIPS algorithm, one report was categorized as possible (due to the lack of underlying diseases or co-reported agents known to cause or precipitate myocarditis, and to the detection of troponin increase) and two as doubtful (only the absence of underlying diseases or co-reported agents known to cause or precipitate myocarditis were recognized; Table S2).
4. Discussion
To the best of our knowledge, this is the first real-world study investigating the potential interactions between influenza vaccines and ICIs resulting in myocarditis or pericarditis in cancer patients, by assessing spontaneous reports submitted to the VAERS and VigiBase®. This global post-marketing safety study stems from recent conflicting real-world evidence surrounding the possible exacerbation of irAEs with influenza vaccines in patients treated with ICIs [14,15,24,25,26,27,28,29], thus joining in the wider debate on the bidirectional relationship between immunotherapy and the influenza vaccination, potentially affecting the clinical and humoral efficacy of the vaccine, performance of ICIs, and safety [14].
Four major findings emerged from our analysis: (a) myocarditis and pericarditis represented a very rare AEFI (with a non-negligible proportion of death, approximately 8–9%), based on the low reporting frequency retrieved in both SRSs (<0.1–0.2% of overall AEs), also considering the influenza vaccination coverage rates (estimated at about 25% per year in Europe [30,31]) and the relevant million doses distributed worldwide; (b) the reporting of myocarditis in patients concomitantly receiving influenza vaccines and ICIs is limited to only three out of a total of 1465 cases of myocarditis/pericarditis found with influenza vaccines or ICIs (considered as suspect agents) in the two databases; (c) these cases were unclassifiable for causality assessment with a doubtful probability of drug–vaccine interaction (according to the adapted DIPS algorithm), thus suggesting that the vaccine is not directly involved in the occurrence of myocarditis (and in one of the three cases, influenza vaccine was reported only as concomitant and not as suspect or interacting agent); and (d) no other cardiovascular AEs were found in patients concomitantly receiving influenza vaccination and ICIs, as well as no other irAEs were reported, except for a single case of Guillain-Barré syndrome, a condition already associated with both ICIs and the influenza vaccine [32,33,34].
Theoretically, a possible pharmacodynamic interaction between influenza vaccines and ICIs leading to the exacerbation of irAEs (including MP), could be supposed. The blockade of a PD-1/PD-L1 pathway together with the vaccination (particularly in conjunction with a strong vaccine adjuvant) could enhance one or more of the mechanisms associated with irAEs onset (infiltration of central memory T cells into the tissues, cross-presentation of shared antigens, and exacerbation of previously subclinical auto-immune syndromes) [24].
Our specific focus on the myo-pericardium stems from the peculiar clinical features of myocarditis in terms of severity and mortality compared with other irAEs, usually requiring immunotherapy discontinuation [9,10,11,12,13], as reported in two out of our three cases. Although, in all three cases, no underlying diseases or other agents known to cause or precipitate myocarditis were recorded, the lack of data concerning latency and solid literature studies allows for minimizing, if not completely excluding, the clinically relevant contribution of a potential drug–vaccine interaction in our cases.
Furthermore, the only study investigating the association between influenza vaccine and the development of myocarditis among patients on ICIs found that the administration of the vaccine was not associated with an increased risk of subsequent myocarditis [15]. Additionally, myocarditis cases in which the influenza vaccine was administered showed lower troponin levels at presentation and a lower risk of major adverse cardiac events at follow-up compared with non-vaccinate patients developing myocarditis with ICIs [15], thus suggesting a protective role for the influenza vaccine in this setting.
ICIs caused a paradigm shift in cancer treatment, and are currently used as first-line agents in the management of non-small cell lung cancer, melanoma, and renal carcinoma [35]. Considering their evolving role and expected increasing uptake, the assessment of cardiovascular safety is of paramount importance. Likewise, the safety of influenza vaccines represents an important issue, given the high morbidity and mortality rates caused by influenza in cancer patients [36]. Notably, the development of influenza infection may also, albeit rarely, be associated itself with an increased risk of myocarditis and major adverse cardiovascular events [37,38]. Therefore, the suggested protective role of the influenza vaccine on cardiovascular outcome [15] cannot be overlooked.
Collectively, our findings provide a reassuring message in terms of cardiovascular safety for cancer patients treated with ICIs and requiring the influenza vaccination. Of note, less than 20% of patients affected by malignancies received the influenza vaccine, with a gradual decline in the last decade [39]. We support and promote the achievement of an optimal vaccination coverage rate in cancer patients for several reasons, including the following: (a) direct association with a lower mortality and infection-related outcomes in immunosuppressed adults [1]; (b) a better overall survival recently reported in patients treated with ICIs receiving influenza vaccination [40]; and (c) the current COVID-19 pandemic, to reduce the strain on the healthcare system while protecting vulnerable subjects from the dramatic impact of a possible co-infection [41]. Cancer patients receiving immunotherapy are at high risk of severe events as a result of COVID-19 systemic involvement, including pneumonitis and myocarditis [42], and a recent systematic review found no significant increase in the risk of infection or in the illness severity or lethality of COVID-19 in subjects receiving the influenza vaccine, with some studies reporting a significantly inverse association [43]. Therefore, the implementation of measures aimed at raising influenza vaccination coverage in frail patients is strongly recommended.
We acknowledge the limitations of our study, mainly inherent to the nature of SRSs data. VAERS and VigiBase® are subject to reporting bias, including under- and over-reporting of adverse events, although there are not clues for major distortions, considering that serious events such as MP are less prone to under-reporting, and no specific warnings were posted by regulatory agencies, thus minimizing the existence and impact of a stimulated reporting [3,18]. We recognize the potential occurrence of subclinical myocarditis, which may be under-diagnosed/under-detected, and is thus likely to be under-reported. Furthermore, the quality and completeness of the reports collected in both databases are variable, and many records lack valid medical diagnoses, thus making the assessment of causality challenging. Additionally, DIPS was not specifically developed to assess drug–vaccine interactions, although we implemented an adapted version in order to the better focus on the possible precipitating role of the influenza vaccine.
Notwithstanding these limitations, pharmacovigilance assessment represents an invaluable opportunity to monitor vaccine safety and identify novel rare signals, potentially arising from drug–vaccine interactions, both from a local and international perspective. Furthermore, our findings are consistent between the two databases, thus supporting the lack of evidence of a clinically relevant drug–vaccine interaction. The identification of myocarditis with ICIs, in line with previous findings [9,10,11], further corroborates the ability of our post-marketing approach to identify actual true-positive associations.
In conclusion, the paucity of cases coupled with a lack of certainty in terms of causality assessment and doubtful probability make the risk of myocarditis and pericarditis by interaction between influenza vaccines and ICIs in cancer patients negligible from both clinical and epidemiological standpoints. Our findings support the cardiovascular safety of influenza vaccines in subjects treated with immunotherapy, thereby emphasizing the importance of a flu vaccination in this population, especially in the current COVID-19 era.
Acknowledgments
We would like to thank Annette Rudolph for data extraction from VigiBase®. Authors at the University of Bologna are supported by institutional research funds (Ricerca Fondamentale Orientata). No sources of funding were received for the preparation of this article.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2076-393X/9/1/19/s1. Table S1: Case-by-case assessment of reports recorded in VAERS in which influenza vaccine and immune checkpoint inhibitors (ICIs) were concomitantly used. Table S2: Application of the adapted version of Drug Interaction Probability Scale in cases of myocarditis/pericarditis in which immune checkpoint inhibitors (ICIs) and influenza vaccine were concomitantly administered.
Click here for additional data file.
Author Contributions
M.G.: methodology, investigation, formal analysis, and writing—original draft. E.R.: conceptualization, methodology, formal analysis, and writing—reviewing and editing. U.M.: writing—reviewing and editing. A.A.: writing—reviewing and editing. E.P.: conceptualization, methodology, formal analysis, and writing—reviewing and editing. I.D.: conceptualization and writing—reviewing and editing. All authors have read and agreed to the published version of the manuscript.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Institutional Review Board Statement
Under current legislation, institutional review board approval is not required when performing analysis of the publicly available VAERS and VigiBase databases, because it contains anonymized data that cannot allow patients’ identification.
Informed Consent Statement
Patient consent was waived due to VAERS and VigiBase databases contain anonymized data that cannot allow patients’ identification.
Data Availability Statement
Data supporting the findings of this study were derived from the following resource available in the public domains: https://wonder.cdc.gov/vaers.html and http://www.vigiaccess.org/.
Conflicts of Interest
M.G., E.R., E.P., U.M., and I.D. have no conflicts of interest relevant to the content of the present work. A.A. reports grants and personal fees from BMS, as well as grants from MSD, Roche, Astra Zeneca, Eli-Lilly, Takeda, and Bayer, outside of the submitted work.
vaccines-09-00019-t001_Table 1Table 1 Demographic and clinical feature of cases of myocarditis/pericarditis reported with influenza vaccine as suspect in Vaccine Adverse Event Reporting System (VAERS) and the World Health Organization’s (WHO) global Individual Case Safety Report database (VigiBase®).
Demographic Features VAERS VigiBase
Overall number of cases 191 399
Proportion of cases (based on overall number of reports with the flu vaccine) 0.03% (712,776) 0.16% (246,864)
Age (mean) 44.5 ± 22.9 46.7 ± 22.3
Sex
Female 62 (32.5%) 131 (32.8%)
Male 124 (64.9%) 263 (65.9%)
Not specified 5 (2.6%) 5 (1.3%)
Reporter country
US 109 (57.1%) 183 (45.9%)
Non-US 60 (31.4%) -
Europe - 180 (45.1%)
Asia - 10 (2.5%)
Oceania - 19 (4.8%)
America (except US) - 7 (1.7%)
Not specified 22 (11.5%) -
Reported symptoms (preferred terms) *
Myocarditis 81 (42.4%) 193 (48.4%)
Pericarditis 117 (61.3%) 225 (56.4%)
Myopericarditis 7 (3.7%) 29 (7.3%)
Immune-mediated myocarditis 0 (0.0%) 0 (0.0%)
Co-medications
Overall number of cases 49 (25.7%) 57 (14.3%)
≥5 concomitant drugs 14 (7.3%) 13 (3.3%)
1–4 concomitant drugs 35 (18.4%) 44 (11.0%)
No concomitant drugs 142 (74.3%) 342 (85.7%)
Co-medications potentially implicated in the occurrence of myocarditis/pericarditis **
Number of cases 21 (11.0%) § 24 (6.0%) #
Immune checkpoint inhibitors (ICIs) None 2
Hydrochlorothiazide 6 5
Indomethacin 2 2
Glipizide 2 -
Clonazepam 2 -
Alprazolam 2 -
Furosemide 1 1
Bendroflumethiazide 1 2
Mesalazine 1 2
Colchicine 1 1
Doxycycline 1 2
Cotrimoxazole 1 1
Lorazepam 1 -
Amoxicillin 1 1
Isosorbide dinitrate 1 2
Tetracycline - 2
Spironolactone - 1
Cefuroxime - 1
Heparin - 1
Bromazepam - 1
Comorbidities potentially implicated in occurrence of myocarditis/pericarditis **
Number of cases 6 (3.1%) 2 (0.5%)
Ulcerative colitis 2 2
Systemic lupus erythematosus 2 -
Juvenile rheumatoid arthritis 1 -
Insulin-dependent diabetes mellitus 1 -
Onset (days; median) 7 (1.5–13) 5 (1–12)
≤3 days 65 (34.0%) 119 (29.8%)
4–7 days 19 (10.0%) 50 (12.5%)
8–14 days 35 (18.4%) 61 (15.3%)
≥15 days 36 (18.8%) 56 (14.0%)
Not specified 36 (18.8%) 113 (28.4%)
Seriousness
Serious 141 (73.8%) 303 (76.0%)
Non-serious 50 (26.2%) 48 (12.0%)
Not specified - 48 (12.0%)
Seriousness criteria *
Congenital anomaly 0 (0.0%) 0 (0.0%)
Death 16 (8.4%) 28 (7.0%)
Hospitalization 125 (65.5%) 222 (55.6%)
Life-threatening 30 (15.7%) 46 (11.5%)
Permanent disability 12 (6.3%) 12 (3.0%)
Other outcomes 30 (15.7%) 60 (15.0%)
Median time of hospitalization (days) 3 (2–4) NA
Recovering
Recovered 60 (31.4%) 164 (41.1%)
Not recovered 64 (33.5%) 61 (15.3%)
Not specified 67 (35.1%) 174 (43.6%)
Concomitant other vaccines
Overall number of cases 59 (30.9%) 87 (21.8%)
Mean number of vaccines per patient 3.1 ± 1.4 2.5 ± 1.7
* One case may exhibit more than one seriousness criteria. ** According to 2015 the European Society of Cardiology (ESC) guidelines for the diagnosis and management of pericardial diseases [6], Caforio et al. [7] and Butany et al. [8]. § In one case, the concomitant use of glipizide and indomethacin, and colchicine and indomethacin. # In one case, concomitant use of amoxicillin and tetracycline, hydrochlorothiazide and cotrimoxazole, and bromazepam and heparin. Flu vaccine types (VAERS): FLU 3 (trivalent injected): 69 patients (36.1%); FLUX SEASONAL (influenza virus vaccine, no brand name): 62 (32.5%); FLU 4 (quadrivalent injected): 20 (10.5%); FLUN 3 (trivalent intranasal spray): 19 (9.9%); FLUN 4 (quadrivalent intranasal spray): 7 (3.7%); FLU H1N1 (monovalent injected): 5 (2.6%); FLUA 3 (trivalent adjuvant injected): 3 (1.6%); FLUN H1N1 (monovalent intranasal spray): 2 (1.1%); FLUX H1N1 (monovalent unknown manufacturer): 2 (1.1%); FLUC 4 (quadrivalent cell-culture-derived injected): 2 (1.1%); FLUC 3 (trivalent cell-culture-derived injected): 1 (0.5%). One patient received both FLUX SEASONAL and FLUX (H1N1).
vaccines-09-00019-t002_Table 2Table 2 Case-by-case assessment of reports concerning myocarditis or pericarditis in which the influenza vaccine and immune checkpoint inhibitors (ICIs) were concomitantly used.
Case ID Drugs/Role Dose Year Age/Sex Reporter Country Reporter Qualification Reactions Seriousness Outcome Concomitant Medications Comorbidities Management Causality Assessment Adapted DIPS Score
#1 Nivolumab (suspect)
Influenza vaccine(suspect) 3 mg/kg every 2 weeks IV- 2018 70/F Japan Physician Myocarditis Serious
(life-threatening; prolonged hospitalization; other outcomes) Recovered Ursodeoxycholic acid 200 mg/day
Bezafibrate
200 mg/day
Calcitriol
0.5 mcg/day NSCLC
Liver disorder
Hyperlipidemia
Osteoporosis Nivolumab withdrawn Unclassifiable (data on latency and time window of increased risk are lacking) Synergistic effect between influenza vaccine and ICIs cannot be excluded 1
Doubtful
#2 Pembrolizumab
(suspect)
Influenza vaccine (suspect) NA
IV
0.5 mL
IM 2018 67/M US Pharmacist Myocarditis,
stress, cardiomyopathy,
weight decreased,
headache,
cardiac failure, congestive,
cerebral infarction,
confusional state, and
dyspnoea Serious
(life-threatening; prolonged hospitalization) NA NA Lung neoplasm malignant NA Unclassifiable
(data on latency and time window of increased risk are lacking)
Synergistic effect between influenza vaccine and ICIs cannot be excluded 1
Doubtful
#3 Ipilimumab
(suspect)
Nivolumab
(suspect)
Influenza vaccine (concomitant) 80 mg every 3 weeks IV
240 mg every 3 weeks IV- 2019 77/M Canada Physician Myocarditis,
pulmonary hypertension,
dyspnoea chest discomfort asthenia, troponin increased c-reactive protein, increased diastolic dysfunction, oedema, peripheral urticaria, and pruritus Serious
(prolonged hospitalization; other outcomes) NA NA Metastatic renal cell carcinoma Ipilimumab and nivolumab withdrawn Unclassifiable
(data on latency and time window of increased risk are lacking)
Synergistic effect between influenza vaccine and ICIs cannot be excluded 2
Possible
US—United States of America; NSCLC—non-small cell lung cancer; NA—not available; IV—intravenous; IM—intramuscular; DIPS—drug-interaction probability scale. | 200 MILLIGRAM, QD | DrugDosageText | CC BY | 33406694 | 18,811,294 | 2021-01-04 |
What was the outcome of reaction 'Myocarditis'? | Influenza Vaccination and Myo-Pericarditis in Patients Receiving Immune Checkpoint Inhibitors: Investigating the Likelihood of Interaction through the Vaccine Adverse Event Reporting System and VigiBase.
BACKGROUND
Evidence on whether the influenza vaccine could exacerbate immune-related adverse events, including myopericarditis (MP), in patients treated with immune checkpoint inhibitors (ICIs), is still conflicting. We explored this issue through a global real-world approach.
METHODS
We queried the Vaccine Adverse Event Reporting System (VAERS) and VigiBase to retrieve cases of MP in which the influenza vaccine and ICIs were recorded as suspect and were concomitantly reported. For the included cases, causality assessment and Drug Interaction Probability Scale (DIPS) algorithms were applied.
RESULTS
There were 191 and 399 reports of MP with the influenza vaccine that were retrieved (VAERS and VigiBase, respectively). No case of MP reporting the concomitant use of ICIs and the influenza vaccine was found in VAERS, while three cases of myocarditis were retrieved in VigiBase. All of the cases were unclassifiable for a causality assessment because of the lack of data concerning latency. According to the DIPS, one report was categorized as possible and two as doubtful.
CONCLUSIONS
The paucity of cases coupled with the doubtful causality assessment make the potential interaction between influenza vaccines and ICIs in cancer patients negligible from clinical and epidemiological standpoints. These findings support the cardiovascular safety of the influenza vaccination, which remains strongly recommended in cancer patients, especially in the current COVID-19 era.
1. Introduction
The safety of vaccines and medications is a current global safety issue. The annual vaccination against the influenza virus is the primary means of preventing influenza and its complications in high-risk subjects, including adult cancer patients, as described by observational studies, suggesting lower mortality and infection-related outcomes with influenza vaccination [1]. However, in the recent past, potential pharmacokinetic interactions have been proposed, considering that vaccines can influence the drug metabolism via inflammatory cytokines [2]. Therefore, potential interactions between influenza vaccines and drugs used for chronic diseases (e.g., immunosuppressive agents) cannot be excluded [3]. Moreover, cases of myo-pericarditis (MP) after immunization, although rarely, are reported [4,5].
Myocarditis and pericarditis represent serious and life-threatening inflammatory diseases involving myocardium and pericardium, potentially associated with the use of several drugs and vaccines [6,7,8]. In particular, cases of MP were described with the smallpox vaccine in early 2000 and, more recently, very rarely are reported after influenza immunization [4,5]. Immune checkpoint inhibitors (ICIs), such as anti-PD1, anti-PDL1, and anti-CTLA4 monoclonal antibodies, are approved as first-line agents in the management of melanoma and non-small cell lung cancer. They may cause a variegate spectrum of cardiovascular events, including MP, with a higher mortality compared with other immune-related adverse events (irAEs) [9,10,11,12,13]. In a summary of the product characteristics of the different ICIs, pericarditis and myocarditis are reported as uncommon (≥1/1000 to <1/100) and rare (≥1/10,000 to <1/1000, respectively) AEs. Notably, the detection of myocarditis with ICIs requires the permanent discontinuation of treatment, no matter the severity.
Consequently, the question arises as to whether pharmacokinetic and pharmacodynamic interactions occur in patients receiving the influenza vaccination (recommended both by oncologists and cardiologists) and ICIs, possibly causing or exacerbating irAEs such MP. Although no cases of myocarditis have been reported, evidence on whether the influenza vaccine exacerbates irAEs is still conflicting and poorly investigated [14]. Only a retrospective study investigated the clinical features of myocarditis with ICIs in patients receiving the influenza vaccine; reduced myocardial injury and a lower risk of major adverse cardiac events among recipients of the influenza vaccine was found compared with not vaccinated patients [15].
In the recent past, analysis of the spontaneous reporting systems (SRSs) has attracted considerable interest among clinicians for the accurate and timely characterization of drug- and vaccine-related risks occurring in the real world, where comorbidities and polypharmacotherapy exist. By offering a global epidemiological perspective, these pharmacovigilance studies have been pursued to test the hypothesis of potential associations, including refusing the likelihood of interactions [3,16,17], especially for rare, unexpected, and delayed AEs, such as MP.
In this study, we investigated the likelihood of interaction between the influenza vaccination and ICIs by analyzing spontaneous reports of MP collected from the Vaccine Adverse Event Reporting System (VAERS; P.O. Box 1100; Rockville, MD 20849-1100) and the World Health Organization’s (WHO) global Individual Case Safety Report database (VigiBase®; Uppsala Monitoring Centre Box, 1051 SE-751 40, Uppsala, Sweden).
2. Materials and Methods
2.1. Study Conception and Design
The study was conceived as an observational retrospective analysis of spontaneous reports of MP collected from the VAERS and the VigiBase® to (a) characterize relevant clinical features; (b) highlight the concomitant use of agents known to cause MP, including ICIs; and (c) assess the causality and probability of interaction between the influenza vaccine and ICIs.
VAERS is a national system to monitor the safety of US-licensed vaccines [18], whereas VigiBase® collects worldwide reports on vaccines and drugs, thus making these archives act as complementary approaches [19].
VAERS transmits its vaccine adverse event reports to the VigiBase, in order to contribute to the global pharmacovigilance effort along with other countries that employ passive vaccine safety monitoring systems [18], thus possible duplicates between the two databases may exist.
2.2. Data Source
Established in 1990, the VAERS is co-managed by the Centers for Disease Control and Prevention and the US Food and Drug Administration (FDA); it collects and analyzes reports of AEs following immunization (AEFI) for vaccines licensed in the US, receiving approximately 28,000 reports of AEFI annually.
AEFI may be any unfavorable or unintended sign, abnormal laboratory finding, symptom, or disease that occurs following or during the administration of a vaccine. AEs are temporally associated events that may either be caused by a vaccine or be coincidental to it, i.e., not necessarily related to the vaccination [20]. VAERS may be used to detect unexpected and rare patterns of AEFI, unlikely to arise in pivotal trials because of the limited number of patients involved [21]. Health-care professionals, vaccine manufacturers, and consumers (patients, parents, and caregivers) can submit reports of AEs to VAERS.
VigiBase® is one of the largest and most comprehensive pharmacovigilance databases, maintained by the Uppsala Monitoring Centre in Sweden, and containing over 20 million of Individual Case Safety Reports from 110 countries over the five continents. VigiBase® collects reports of AEs for authorized drugs, vaccines, and food supplements, submitted from healthcare professionals, pharmaceutical companies, and patients.
For each vaccine/drug, the characterization of the vaccine/drug role indicated by the primary reporter (i.e., the original source of the information) includes the following three categories: suspect, concomitant, and interacting. All spontaneous reports should have at least one suspect vaccine/drug, namely involved, presumably, in the occurrence of AEFI. If the reporter indicates a suspected interaction, all interacting vaccines/drugs are considered to be suspect vaccines/drugs.
In both databases, AEs are codified through the Medical Dictionary for Regulatory Activities (MedDRA) terminology, and described and organized in terms of Preferred Terms (PTs).
2.3. Data Extraction and Analysis
A multi-step approach was followed for data extraction in each database:(1) Reports for individuals receiving any type of vaccine against the influenza virus categorized as suspect AEFI submitted to VAERS (from July 1990 to September 2020) and VigiBase® (from inception to October 2020) were selected.
(2) Cases of myocarditis or pericarditis were extracted through specific PTs and lowest level terms, in line with previous studies on the influenza vaccination [4] and the potential immune-related basis of cardiotoxicity documented for ICIs by recent pharmacovigilance analyses [9,10]: myocarditis, pericarditis, immune-mediated myocarditis, and myopericarditis.
(3) Reports recording AEs of interest were finally assessed for co-reported drugs/vaccines of interest.
In VigiBase, retained reports (refer to point 2) with ICIs, namely PD-1 inhibitors (nivolumab, pembrolizumab, and cemiplimab), PD-L1 inhibitors (atezolizumab, avelumab, and durvalumab), and CTLA-4 inhibitors (ipilimumab and tremelimumab), were evaluated by extracting the following data: demographic features (age, gender, weight, year, and reporter country), reporter qualification, comorbidities, concomitant medications (including dose and route of administration when available), latency, degree of seriousness, outcome, and management of the AE. The same approach was applied to identify cases of interest reported for vaccines against the influenza virus, both as suspect alone or concomitant to ICI exposure.
In VAERS, for each report of interest with the influenza vaccines, the following data were extracted: demographic features (age, gender, year, and reporter country), type of vaccine against the influenza virus, medical history, concomitant drugs or administered vaccines, laboratory data, AEs codified as PTs, latency, AE degree of seriousness, outcome, and narratives, when available.
According to WHO criteria, a serious AE is any untoward medical occurrence that, no matter the dose, results as fatal, causing a life-threatening event, requiring hospitalization of the patient, causing serious/permanent disability, causing congenital abnormalities, or other clinically relevant conditions [22].
Co-reported medications and comorbidities known to cause myocarditis or pericarditis (i.e., potential confounders) were further characterized according to the lists proposed by Adler et al. [6], Caforio et al. [7], and Butany et al. [8].
2.4. Causality Assessment and Evaluation of Drug–Vaccine Interaction
The probability of interaction when the influenza vaccine and ICIs are co-reported was evaluated by applying the established WHO criteria for causality assessment [20], as well as the Drug Interaction Probability Scale (DIPS) [23].
The following items were accounted for in the AEFI causality assessment: temporal relationship, alternate explanations, proof of association, prior evidence, population-based evidence, and biological plausibility [20]. Cases without adequate information were classified as “unclassifiable”; cases with adequate information were categorized as: (1) “consistent with a causal relationship”, when the available evidence supported a causal relationship between the vaccine and the AEFI in the individual, but it did not rule out the possibility that the AEFI may have been caused by a factor other than the vaccine; (2) “inconsistent with a causal association”, when the available evidence did not support a causal relationship between vaccine administration and the reported AEFI in the individual; and (3) “indeterminate”, when the temporal relationship was consistent but the available evidence insufficient to support or rule out a causal relationship in the individual.
The DIPS is a 10-item tool specifically developed to assess the likelihood of drug–drug interactions [23]. ICIs were considered as the objective drugs (i.e., the one affected by the presence of another vaccine/drug), while the influenza vaccine was considered as the precipitant agent (i.e., the one causing a change on the object drug). To avoid overemphasis on the role of the vaccine, the answer to the second question was always “unknown” (knowledge on the mechanism of the interaction is hypothesized and literature data are very scarce/uncertain); in addition, questions 5, 6, and 10 were not assessable/applicable (dechallenge, rechallenge, and dose adjustments are unfeasible for vaccines considering the peculiarities of their administration), as previously performed [3]. The final summary score could reach 10 points. Higher total scores correspond to a higher likelihood of drug–vaccine interaction (i.e., >8 = highly probable; 5–8 = probable; 2–4 = possible; <2 = doubtful).
3. Results
3.1. Demographic and Clinical Data
Over the observed period, out of a total of 712,776 AEFI, 191 (0.03%) reports of MP mentioning the influenza vaccine as suspect were collected within the VAERS.
The clinical and demographic characteristics are provided in Table 1. The reports included 124 men (64.9%) and 62 women (in five cases gender was not reported), aged between 1 and 88 years (mean age 44.5 years). Pericarditis were reported in 117 cases (61.3%), followed by myocarditis (81 cases; 42.4%) and MP (7 cases; 3.7%). No cases of immune-mediated myocarditis were retrieved.
The median onset was seven days; in 34.0% of reports, the AEFI of interest occurred in the first 3 days after the administration of the influenza vaccine. Comorbidities potentially implicated in the occurrence of the AEFI of interest were retrieved in six cases (3.1%), with ulcerative colitis and systemic lupus erythematosus being the most represented. Other vaccines were concomitantly administered in 59 cases (30.9%), accounting for a mean number of 3.1 vaccines per patient.
In 141 cases (73.8%), the report was classified as serious, and 16 fatal cases (8.4%) were found. Recovery occurred in 31.4% of cases.
In the VigiBase®, 246,864 reports mentioning the influenza vaccine as a suspect agent were found, and myocarditis/pericarditis were reported in 399 cases (0.16%; Table 1).
The cases showed a mean age of 46.7 years, with a male preponderance (65.9%). Reports were largely submitted from US (45.9%) and Europe (45.1%). Pericarditis was reported in 225 cases (56.4%), followed by myocarditis (193 cases; 48.4%) and myopericarditis (29; 7.3%). No cases of immune-mediated myocarditis were found.
Median onset was five days, and in 29.8% of reports, AEs of interest occurred in the first three days after the administration of the influenza vaccine. Comorbidities potentially implicated in the occurrence of myocarditis/pericarditis were retrieved in two patients (0.5%) affected by ulcerative colitis. Other vaccines were concomitantly administered in 87 cases (21.8%), accounting for a mean number of 2.5 vaccines per patient.
In 303 cases (76.0%), the report was classified as serious, and 28 fatal cases (7.0%) were found. Recovering occurred in 41.1% of cases.
3.2. Co-Reported Medications and Detection of Cases with ICI Administration
Overall, concomitant medications were found in 49 (25.7%) and 57 (14.3%) cases with the influenza vaccine in VAERS and VigiBase®, respectively (Table 1). In 14 (7.3%) and 13 (3.3%) cases, five or more concomitant drugs were reported in VAERS and VigiBase®, respectively.
Concomitant medications potentially implicated in the occurrence of myocarditis/pericarditis were retrieved in 21 (11.0%) and 24 (6.0%) cases in VAERS and VigiBase®, respectively, with hydrochlorothiazide being the most frequent in both databases (in six and five cases, respectively).
Only six cases (one classified as serious, where Guillain-Barré syndrome was recorded) with the concomitant use of ICIs and the influenza vaccine were found in VAERS (Table S1), but no cases of myocarditis/pericarditis. In VigiBase®, two cases of myocarditis reporting the concomitant administration of ICIs and the influenza vaccine both mentioned as suspect agents were retrieved. A third case of myocarditis in which the influenza vaccine was classified as a concomitant agent was detected (Table 2).
The three cases were classified as serious (causing prolonged hospitalization), included two men and one woman, aged 67–77 years, and affected by lung or renal carcinoma. Nivolumab, pembrolizumab, and ipilimumab/nivolumab combination therapy were reported as the ICI regimen. In two cases ICI was withdrawn, while recovering occurred in only one case.
3.3. Causality Assessment and Evaluation of Drug–Vaccine Interaction
These three cases showed an unclassifiable causality assessment due to the lack of data concerning the latency and time window of increased risk (Table 2).
By applying the adapted DIPS algorithm, one report was categorized as possible (due to the lack of underlying diseases or co-reported agents known to cause or precipitate myocarditis, and to the detection of troponin increase) and two as doubtful (only the absence of underlying diseases or co-reported agents known to cause or precipitate myocarditis were recognized; Table S2).
4. Discussion
To the best of our knowledge, this is the first real-world study investigating the potential interactions between influenza vaccines and ICIs resulting in myocarditis or pericarditis in cancer patients, by assessing spontaneous reports submitted to the VAERS and VigiBase®. This global post-marketing safety study stems from recent conflicting real-world evidence surrounding the possible exacerbation of irAEs with influenza vaccines in patients treated with ICIs [14,15,24,25,26,27,28,29], thus joining in the wider debate on the bidirectional relationship between immunotherapy and the influenza vaccination, potentially affecting the clinical and humoral efficacy of the vaccine, performance of ICIs, and safety [14].
Four major findings emerged from our analysis: (a) myocarditis and pericarditis represented a very rare AEFI (with a non-negligible proportion of death, approximately 8–9%), based on the low reporting frequency retrieved in both SRSs (<0.1–0.2% of overall AEs), also considering the influenza vaccination coverage rates (estimated at about 25% per year in Europe [30,31]) and the relevant million doses distributed worldwide; (b) the reporting of myocarditis in patients concomitantly receiving influenza vaccines and ICIs is limited to only three out of a total of 1465 cases of myocarditis/pericarditis found with influenza vaccines or ICIs (considered as suspect agents) in the two databases; (c) these cases were unclassifiable for causality assessment with a doubtful probability of drug–vaccine interaction (according to the adapted DIPS algorithm), thus suggesting that the vaccine is not directly involved in the occurrence of myocarditis (and in one of the three cases, influenza vaccine was reported only as concomitant and not as suspect or interacting agent); and (d) no other cardiovascular AEs were found in patients concomitantly receiving influenza vaccination and ICIs, as well as no other irAEs were reported, except for a single case of Guillain-Barré syndrome, a condition already associated with both ICIs and the influenza vaccine [32,33,34].
Theoretically, a possible pharmacodynamic interaction between influenza vaccines and ICIs leading to the exacerbation of irAEs (including MP), could be supposed. The blockade of a PD-1/PD-L1 pathway together with the vaccination (particularly in conjunction with a strong vaccine adjuvant) could enhance one or more of the mechanisms associated with irAEs onset (infiltration of central memory T cells into the tissues, cross-presentation of shared antigens, and exacerbation of previously subclinical auto-immune syndromes) [24].
Our specific focus on the myo-pericardium stems from the peculiar clinical features of myocarditis in terms of severity and mortality compared with other irAEs, usually requiring immunotherapy discontinuation [9,10,11,12,13], as reported in two out of our three cases. Although, in all three cases, no underlying diseases or other agents known to cause or precipitate myocarditis were recorded, the lack of data concerning latency and solid literature studies allows for minimizing, if not completely excluding, the clinically relevant contribution of a potential drug–vaccine interaction in our cases.
Furthermore, the only study investigating the association between influenza vaccine and the development of myocarditis among patients on ICIs found that the administration of the vaccine was not associated with an increased risk of subsequent myocarditis [15]. Additionally, myocarditis cases in which the influenza vaccine was administered showed lower troponin levels at presentation and a lower risk of major adverse cardiac events at follow-up compared with non-vaccinate patients developing myocarditis with ICIs [15], thus suggesting a protective role for the influenza vaccine in this setting.
ICIs caused a paradigm shift in cancer treatment, and are currently used as first-line agents in the management of non-small cell lung cancer, melanoma, and renal carcinoma [35]. Considering their evolving role and expected increasing uptake, the assessment of cardiovascular safety is of paramount importance. Likewise, the safety of influenza vaccines represents an important issue, given the high morbidity and mortality rates caused by influenza in cancer patients [36]. Notably, the development of influenza infection may also, albeit rarely, be associated itself with an increased risk of myocarditis and major adverse cardiovascular events [37,38]. Therefore, the suggested protective role of the influenza vaccine on cardiovascular outcome [15] cannot be overlooked.
Collectively, our findings provide a reassuring message in terms of cardiovascular safety for cancer patients treated with ICIs and requiring the influenza vaccination. Of note, less than 20% of patients affected by malignancies received the influenza vaccine, with a gradual decline in the last decade [39]. We support and promote the achievement of an optimal vaccination coverage rate in cancer patients for several reasons, including the following: (a) direct association with a lower mortality and infection-related outcomes in immunosuppressed adults [1]; (b) a better overall survival recently reported in patients treated with ICIs receiving influenza vaccination [40]; and (c) the current COVID-19 pandemic, to reduce the strain on the healthcare system while protecting vulnerable subjects from the dramatic impact of a possible co-infection [41]. Cancer patients receiving immunotherapy are at high risk of severe events as a result of COVID-19 systemic involvement, including pneumonitis and myocarditis [42], and a recent systematic review found no significant increase in the risk of infection or in the illness severity or lethality of COVID-19 in subjects receiving the influenza vaccine, with some studies reporting a significantly inverse association [43]. Therefore, the implementation of measures aimed at raising influenza vaccination coverage in frail patients is strongly recommended.
We acknowledge the limitations of our study, mainly inherent to the nature of SRSs data. VAERS and VigiBase® are subject to reporting bias, including under- and over-reporting of adverse events, although there are not clues for major distortions, considering that serious events such as MP are less prone to under-reporting, and no specific warnings were posted by regulatory agencies, thus minimizing the existence and impact of a stimulated reporting [3,18]. We recognize the potential occurrence of subclinical myocarditis, which may be under-diagnosed/under-detected, and is thus likely to be under-reported. Furthermore, the quality and completeness of the reports collected in both databases are variable, and many records lack valid medical diagnoses, thus making the assessment of causality challenging. Additionally, DIPS was not specifically developed to assess drug–vaccine interactions, although we implemented an adapted version in order to the better focus on the possible precipitating role of the influenza vaccine.
Notwithstanding these limitations, pharmacovigilance assessment represents an invaluable opportunity to monitor vaccine safety and identify novel rare signals, potentially arising from drug–vaccine interactions, both from a local and international perspective. Furthermore, our findings are consistent between the two databases, thus supporting the lack of evidence of a clinically relevant drug–vaccine interaction. The identification of myocarditis with ICIs, in line with previous findings [9,10,11], further corroborates the ability of our post-marketing approach to identify actual true-positive associations.
In conclusion, the paucity of cases coupled with a lack of certainty in terms of causality assessment and doubtful probability make the risk of myocarditis and pericarditis by interaction between influenza vaccines and ICIs in cancer patients negligible from both clinical and epidemiological standpoints. Our findings support the cardiovascular safety of influenza vaccines in subjects treated with immunotherapy, thereby emphasizing the importance of a flu vaccination in this population, especially in the current COVID-19 era.
Acknowledgments
We would like to thank Annette Rudolph for data extraction from VigiBase®. Authors at the University of Bologna are supported by institutional research funds (Ricerca Fondamentale Orientata). No sources of funding were received for the preparation of this article.
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Supplementary Materials
The following are available online at https://www.mdpi.com/2076-393X/9/1/19/s1. Table S1: Case-by-case assessment of reports recorded in VAERS in which influenza vaccine and immune checkpoint inhibitors (ICIs) were concomitantly used. Table S2: Application of the adapted version of Drug Interaction Probability Scale in cases of myocarditis/pericarditis in which immune checkpoint inhibitors (ICIs) and influenza vaccine were concomitantly administered.
Click here for additional data file.
Author Contributions
M.G.: methodology, investigation, formal analysis, and writing—original draft. E.R.: conceptualization, methodology, formal analysis, and writing—reviewing and editing. U.M.: writing—reviewing and editing. A.A.: writing—reviewing and editing. E.P.: conceptualization, methodology, formal analysis, and writing—reviewing and editing. I.D.: conceptualization and writing—reviewing and editing. All authors have read and agreed to the published version of the manuscript.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Institutional Review Board Statement
Under current legislation, institutional review board approval is not required when performing analysis of the publicly available VAERS and VigiBase databases, because it contains anonymized data that cannot allow patients’ identification.
Informed Consent Statement
Patient consent was waived due to VAERS and VigiBase databases contain anonymized data that cannot allow patients’ identification.
Data Availability Statement
Data supporting the findings of this study were derived from the following resource available in the public domains: https://wonder.cdc.gov/vaers.html and http://www.vigiaccess.org/.
Conflicts of Interest
M.G., E.R., E.P., U.M., and I.D. have no conflicts of interest relevant to the content of the present work. A.A. reports grants and personal fees from BMS, as well as grants from MSD, Roche, Astra Zeneca, Eli-Lilly, Takeda, and Bayer, outside of the submitted work.
vaccines-09-00019-t001_Table 1Table 1 Demographic and clinical feature of cases of myocarditis/pericarditis reported with influenza vaccine as suspect in Vaccine Adverse Event Reporting System (VAERS) and the World Health Organization’s (WHO) global Individual Case Safety Report database (VigiBase®).
Demographic Features VAERS VigiBase
Overall number of cases 191 399
Proportion of cases (based on overall number of reports with the flu vaccine) 0.03% (712,776) 0.16% (246,864)
Age (mean) 44.5 ± 22.9 46.7 ± 22.3
Sex
Female 62 (32.5%) 131 (32.8%)
Male 124 (64.9%) 263 (65.9%)
Not specified 5 (2.6%) 5 (1.3%)
Reporter country
US 109 (57.1%) 183 (45.9%)
Non-US 60 (31.4%) -
Europe - 180 (45.1%)
Asia - 10 (2.5%)
Oceania - 19 (4.8%)
America (except US) - 7 (1.7%)
Not specified 22 (11.5%) -
Reported symptoms (preferred terms) *
Myocarditis 81 (42.4%) 193 (48.4%)
Pericarditis 117 (61.3%) 225 (56.4%)
Myopericarditis 7 (3.7%) 29 (7.3%)
Immune-mediated myocarditis 0 (0.0%) 0 (0.0%)
Co-medications
Overall number of cases 49 (25.7%) 57 (14.3%)
≥5 concomitant drugs 14 (7.3%) 13 (3.3%)
1–4 concomitant drugs 35 (18.4%) 44 (11.0%)
No concomitant drugs 142 (74.3%) 342 (85.7%)
Co-medications potentially implicated in the occurrence of myocarditis/pericarditis **
Number of cases 21 (11.0%) § 24 (6.0%) #
Immune checkpoint inhibitors (ICIs) None 2
Hydrochlorothiazide 6 5
Indomethacin 2 2
Glipizide 2 -
Clonazepam 2 -
Alprazolam 2 -
Furosemide 1 1
Bendroflumethiazide 1 2
Mesalazine 1 2
Colchicine 1 1
Doxycycline 1 2
Cotrimoxazole 1 1
Lorazepam 1 -
Amoxicillin 1 1
Isosorbide dinitrate 1 2
Tetracycline - 2
Spironolactone - 1
Cefuroxime - 1
Heparin - 1
Bromazepam - 1
Comorbidities potentially implicated in occurrence of myocarditis/pericarditis **
Number of cases 6 (3.1%) 2 (0.5%)
Ulcerative colitis 2 2
Systemic lupus erythematosus 2 -
Juvenile rheumatoid arthritis 1 -
Insulin-dependent diabetes mellitus 1 -
Onset (days; median) 7 (1.5–13) 5 (1–12)
≤3 days 65 (34.0%) 119 (29.8%)
4–7 days 19 (10.0%) 50 (12.5%)
8–14 days 35 (18.4%) 61 (15.3%)
≥15 days 36 (18.8%) 56 (14.0%)
Not specified 36 (18.8%) 113 (28.4%)
Seriousness
Serious 141 (73.8%) 303 (76.0%)
Non-serious 50 (26.2%) 48 (12.0%)
Not specified - 48 (12.0%)
Seriousness criteria *
Congenital anomaly 0 (0.0%) 0 (0.0%)
Death 16 (8.4%) 28 (7.0%)
Hospitalization 125 (65.5%) 222 (55.6%)
Life-threatening 30 (15.7%) 46 (11.5%)
Permanent disability 12 (6.3%) 12 (3.0%)
Other outcomes 30 (15.7%) 60 (15.0%)
Median time of hospitalization (days) 3 (2–4) NA
Recovering
Recovered 60 (31.4%) 164 (41.1%)
Not recovered 64 (33.5%) 61 (15.3%)
Not specified 67 (35.1%) 174 (43.6%)
Concomitant other vaccines
Overall number of cases 59 (30.9%) 87 (21.8%)
Mean number of vaccines per patient 3.1 ± 1.4 2.5 ± 1.7
* One case may exhibit more than one seriousness criteria. ** According to 2015 the European Society of Cardiology (ESC) guidelines for the diagnosis and management of pericardial diseases [6], Caforio et al. [7] and Butany et al. [8]. § In one case, the concomitant use of glipizide and indomethacin, and colchicine and indomethacin. # In one case, concomitant use of amoxicillin and tetracycline, hydrochlorothiazide and cotrimoxazole, and bromazepam and heparin. Flu vaccine types (VAERS): FLU 3 (trivalent injected): 69 patients (36.1%); FLUX SEASONAL (influenza virus vaccine, no brand name): 62 (32.5%); FLU 4 (quadrivalent injected): 20 (10.5%); FLUN 3 (trivalent intranasal spray): 19 (9.9%); FLUN 4 (quadrivalent intranasal spray): 7 (3.7%); FLU H1N1 (monovalent injected): 5 (2.6%); FLUA 3 (trivalent adjuvant injected): 3 (1.6%); FLUN H1N1 (monovalent intranasal spray): 2 (1.1%); FLUX H1N1 (monovalent unknown manufacturer): 2 (1.1%); FLUC 4 (quadrivalent cell-culture-derived injected): 2 (1.1%); FLUC 3 (trivalent cell-culture-derived injected): 1 (0.5%). One patient received both FLUX SEASONAL and FLUX (H1N1).
vaccines-09-00019-t002_Table 2Table 2 Case-by-case assessment of reports concerning myocarditis or pericarditis in which the influenza vaccine and immune checkpoint inhibitors (ICIs) were concomitantly used.
Case ID Drugs/Role Dose Year Age/Sex Reporter Country Reporter Qualification Reactions Seriousness Outcome Concomitant Medications Comorbidities Management Causality Assessment Adapted DIPS Score
#1 Nivolumab (suspect)
Influenza vaccine(suspect) 3 mg/kg every 2 weeks IV- 2018 70/F Japan Physician Myocarditis Serious
(life-threatening; prolonged hospitalization; other outcomes) Recovered Ursodeoxycholic acid 200 mg/day
Bezafibrate
200 mg/day
Calcitriol
0.5 mcg/day NSCLC
Liver disorder
Hyperlipidemia
Osteoporosis Nivolumab withdrawn Unclassifiable (data on latency and time window of increased risk are lacking) Synergistic effect between influenza vaccine and ICIs cannot be excluded 1
Doubtful
#2 Pembrolizumab
(suspect)
Influenza vaccine (suspect) NA
IV
0.5 mL
IM 2018 67/M US Pharmacist Myocarditis,
stress, cardiomyopathy,
weight decreased,
headache,
cardiac failure, congestive,
cerebral infarction,
confusional state, and
dyspnoea Serious
(life-threatening; prolonged hospitalization) NA NA Lung neoplasm malignant NA Unclassifiable
(data on latency and time window of increased risk are lacking)
Synergistic effect between influenza vaccine and ICIs cannot be excluded 1
Doubtful
#3 Ipilimumab
(suspect)
Nivolumab
(suspect)
Influenza vaccine (concomitant) 80 mg every 3 weeks IV
240 mg every 3 weeks IV- 2019 77/M Canada Physician Myocarditis,
pulmonary hypertension,
dyspnoea chest discomfort asthenia, troponin increased c-reactive protein, increased diastolic dysfunction, oedema, peripheral urticaria, and pruritus Serious
(prolonged hospitalization; other outcomes) NA NA Metastatic renal cell carcinoma Ipilimumab and nivolumab withdrawn Unclassifiable
(data on latency and time window of increased risk are lacking)
Synergistic effect between influenza vaccine and ICIs cannot be excluded 2
Possible
US—United States of America; NSCLC—non-small cell lung cancer; NA—not available; IV—intravenous; IM—intramuscular; DIPS—drug-interaction probability scale. | Recovered | ReactionOutcome | CC BY | 33406694 | 18,811,294 | 2021-01-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anaphylactic reaction'. | Circulatory collapse during wound closure in spine surgery with an unknown cause: a possible adverse effect of topical application of vancomycin?
Vancomycin (VCM) is effective in fighting Gram-positive bacteria related severe infections, and topical application of VCM powder is widely used in orthopedic surgery to prevent wound infection. However, VCM could lead to infusion rate-dependent antibody-and complement-independent anaphylaxis reaction by inducing direct release of histamine.
We retrospectively analyzed seven cases of severe hypotension and shock during wound closure or immediately after orthopedic surgery with unidentifiable reasons. We found that these cases were all associated with local application of VCM powder during wound closure process. Two patients experienced sudden cardiac arrest. Most of the cases (6/7) with circulatory collapse were discharged without severe sequelae. While one case with application of 3 g VCM developed cardiac arrest and remained in a coma due to hypoxic-hypoxic encephalopathy. The clinical presentations and the time of the shock onset were considered to be related with a VCM induced anaphylaxis reaction. However, as this was a retrospective study, and there was no laboratory examination performed, the conclusion was made upon differential diagnosis based on clinical manifestations and the timing of the shock.
Local application of VCM may not be as safe as was once believed and may lead to a related anaphylaxis. As VCM induced infusion-rate dependent, non-IgE mediated anaphylaxis is characterized by delayed occurrence, severe hypotension and even circulatory collapse, surgeons and anesthesiologists should be extra vigilant during and after VCM application.
Background
Shock is defined as a state of insufficient perfusion and oxygen delivery to the tissues. The pathophysiology of shock could be simplified to three major components: cardiac function (the pump), intravascular volume (the tank), and systemic vascular resistance (the pipes) [1]. Whatever the causes of shock may be, if the impaired perfusion and oxygen delivery is not recognized and reversed, the circulatory collapse may progress into organ dysfunction and failure, tissue necrosis and even death. It is urgent to identify the causes of shock and take immediate measures. However, in critical situations, it is hard to rapidly distinguish the culprit during complex clinical situations. Here we present 7 cases (Table 1) of unidentifiable causes of shock during wound closure or shortly after spine surgery, and discuss the possible reasons.
Table 1 Summary of clinical presentations of seven patients with circulatory collapse and unknown etiologies during or shortly after wound closure in spine surgery
Case Demographic information Initial signs/symptoms of shock and management Hemoglobin value (g/L),
fluid resuscitation and blood product infusion VCM administration
and Postoperative sequelae
1 Female; 68-yr; 160 cm/60 kg
BMI: 23.4
Diagnosis:
Lumbar stenosis (L3-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Hypertension
History of retina surgery
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
ABP: 30/20 mmHg
SpO2: undetectable
ECG: tarchycardia with elevated ST segment
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for 45 min. Fluid resuscitation and blood transfusion.
Preoperative HGB value: 124
Intraoperative minimum value of HGB: 73
Blood loss: 600 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 3450 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 210 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
Proceeded with surgery and the patient was extubated uneventfully.
2 Male; 74-yr; 171 cm/67 kg
BMI: 23.9
Diagnosis:
lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
ECG: tachycardia with ST segment depression
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min) for 4 h.
Preoperative HGB value:135
Intraoperative minimum value of HGB: 79
Blood loss: 600 ml
Urine: 1950 ml
Fluid and blood product infusion:
Crystalloid: 6300 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Plasma: 800 ml
Infused autologous blood: 254 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions).
Postoperative imaging: intracranial minor hemorrhage at subdural and subarachnoid space.
The patient was discharged from hospital without neurological deficit.
3 Male; 63-yr; 169 cm/70 kg
BMI: 24.5
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Lacunar infarction;
Bilateral carotid atherosclerotic plaque formation
Time of occurrence:
50 min after initiation of wound closure and 20 min post-extubation in the PACU.
Signs and symptoms:
NBP: 60/25 mmHg
SpO2: 96%
HR:sudden elevation from 60 to 90 bpm
Postoperative agitation
Skin and airway symptoms: none.
Management:
Boluses of ephedrine, phenylephrine and fluid resuscitation.
Preoperative HGB value: 176
Intraoperative minimum value of HGB:123
Blood loss: 800 ml
Urine: 800 ml
Fluid and blood product infusion:
Crystalloid: 2350 ml
Colloid: 1000 ml
PRBC infusion: 400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis.
Postoperative sequelae:
Uneventful.
4 Female; 70-yr; 160 cm/65 kg
BMI:25.4
Diagnosis:
Lumbar stenosis (L4-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Hypertension
Diabetes Mellitus
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
Persistent tachycardia
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine for treating severe hypotension and esmolol for tachycardia
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 150
Intraoperative minimum value of HGB: 92
Blood loss: 1500 ml
Urine: 1800 ml
Fluid and blood product infusion:
Crystalloid: 3100 ml
Colloid: 1500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 450 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery and transferred to ICU due to tachycardia after sufficient fluid resuscitation.
Recovered uneventfully.
5 Female;48-yr; 170 cm/75 kg
BMI: 26.0
Diagnosis:
Thoracic spinal canal stenosis (T6-T11)
Surgery:
Posterior decompression, fixation and fusion of thoracic spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 40/30 mmHg to undetectable
HR: 120 bpm to 40 bpm
SpO2: undetectable
Cardiac arrest
Skin and airway symptoms: none.
Management:
Extracardiac compression
Boluses of noradrenaline (200 μg) and adrenaline (1 g)
Continuous infusion of noradrenaline (0.02–0.08 μg/kg/min) for 50 min
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 132
Intraoperative minimum value of HGB: 74
Blood loss: 2500 ml
Urine: 1300 ml
Fluid and blood product infusion:
Crystalloid: 4000 ml
Colloid: 500 ml
PRBC infusion: 2400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery, and discharged from hospital uneventfully.
6 Male; 66-yr; 175 cm/ 80 kg
BMI: 26.1
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Carotid artery stenosis
Diabetes Mellitus
Time of occurrence:
Sudden cardiac arrest 10 min after extubation (approximately 45 min after initiation of wound closure) with full recovery from anesthesia and without any discomfort complaint.
Signs and symptoms:
Cardiac arrest and persistent VF
Skin and airway symptoms: none.
Management:
Continuous CPR
Persistent VF was treated with repeated defibrillation
Boluses of adrenaline (a total of 6 mg) and amiodarone.
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 143
Intraoperative minimum value of HGB: 78
Blood loss: 1000 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 4400 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 600 ml
VCM administration:
Topical spraying of vancomycin (3 g) on the dura mater and into the mascularis.
Postoperative sequelae:
The patient was reintubated and transferred to ICU after ROSC. The patient was diagnosed as hypoxic encephalopathy and remained in a coma state. Tracheotomy was performed 2 weeks after surgery, and the patient was transferred to a nursing home for rehabilitation 1 month after orthopedic surgery.
7 Female; 43-yr; 155 cm / 54 kg
BMI: 22.4
Diagnosis:
Thoracic kyphosis (T7-T8)
Surgery:
Osteotomy for kyphosis of thoracic spine (T7-T8).
Medical and allergy history:
nil relevant.
Time of occurrence:
subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
HR:tachycardia
NBP: 60/30 mmHg
SpO2 82%
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine and ephedrine;
Continuous infusion of noradrenaline (0.05–0.1 μg/kg/min)
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 138
Intraoperative minimum value of HGB: 95
Blood loss: 1200 ml
Urine: 1900 ml
Fluid and blood product infusion:
Crystalloid: 4700 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 470 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was transferred to ICU for optimal monitoring and recovered uneventfully.
Abbreviations: NBP Non-invasive blood pressure; ABP Arterial blood pressure; (NBP is noted when ABP is not available.) VF Ventricular fibrillation; CPR Cardiopulmonary Resuscitation; HGB Hemoglobin; VCM Vancomycin; PRBC Packed red blood cell; ROSC Return of spontaneous circulation
Case presentation
The first case we encountered was a 68-yr female with past medical history of hypertension and surgical treated retina detachment, who underwent posterior decompression, fixation and fusion of lumbar spine due to lumbar stenosis (L3-S1). The operation was uneventful until sudden circulatory collapse occurred during the process of rinsing mascularis and superficial fascia layer whilst closing the wound. A sudden drop in arterial blood pressure (ABP) (130/60 mmHg to 30/20 mmHg), increased HR (60 bpm to 100 bpm) with elevated ST-segment and significant decrease of PetCO2 (31 mmHg to 16 mmHg) were noticed, with undetectable pulse oximetry read. The patient was turned to supine position immediately and managed with boluses (40–100 μg) and a continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for approximately 45 min. The circulation was gradually stabilized. No rash, erythema, or bronchospasm were noted. The bilateral breath sounds were equal and the airway pressure remained normal. We continued treatments of fluid resuscitation and blood transfusion with corticosteroid and ice cap to prevent hypoxic-ischemic encephalopathy. Intraoperative emergency consultations and immediate examinations of 12-lead ECG, point-of-care transthoracic echocardiography (TTE), and full panel laboratory tests were performed. However, these results did not support the causes of sudden cardiac dysfunction (the pump) including mechanical obstruction (pericardial tamponade and massive pulmonary embolus), acute myocardial infarction, acute valvular insufficiency, and arrhythmia. Vascular catastrophes were excluded and there were no signs of sepsis. We also examined the intravascular volume function (the tank) by performing the TTE, and ruled out intraperitoneal major hemorrhage which we once encountered (caused by inadvertent piercing of iliac artery when placing probe during lumbar surgery) by examination of abdominal ultrasound and hemoglobin level; Volume status was evaluated by measuring CVP, urine output, infused fluid volume; Surgical blood loss was reviewed to exclude hemorrhage shock and hypovolemia. As no special medications were given except anesthetic maintenance drugs, and no signs of mottled skin or bronchospasm were noticed, anaphylaxis was not considered at that time. After restoring circulatory stability, the surgery preceded uneventfully. The patient was discharged from hospital 7 days later.
It was intriguing that within 1 month, another case of circulatory collapse happened during wound closure in spine surgery performed by the same orthopedic surgeon. The intraoperative clinical manifestations were very similar to the previous one. Hemodynamic resuscitation were initiated immediately with repeated boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min). After stabilizing the circulation 4 h later, the patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions after full recovery from anesthesia). Postoperative imaging revealed intracranial micro hemorrhagic foci in the subdural and subarachnoid space. The patient was discharged from hospital without any neurological sequelae.
With further exploration and analysis of the similarities of these two cases, we found that local application of vancomycin (VCM) powder was used in these two patients to prevent postoperative surgical site infections (SSIs) during wound closure (0.5 g VCM loaded with bone debris into the cage and another 0.5 g sprayed on the dura mater and into the mascularis). Ramamani Mariappan reported a case of circulatory collapse after topical application of vancomycin powder during spine surgery, which exhibited almost the same clinical course as ours [2]. It was speculated that the rapid absorption of VCM applied to the surgical wound caused an anaphylaxis reaction and circulatory collapse. The reaction occurred approximately 30 min after the application and persisted for 6 h. The serum tryptase level was not elevated, suggesting that VCM caused a direct histamine release, which is in keeping with our current understanding. A similar case reported a 74-year-old woman who underwent a primary total knee replacement presented with red man syndrome in the PACU 45 min after release of tourniquet following the use of VCM-loaded bone cement. The patient remained fully conscious despite a sudden drop in blood pressure to 47/34 mmHg [3]. Therefore, local application of VCM may pose the risk of causing severe circulatory adverse effect.
Similar circulatory collapse cases in spine surgery without definitive causes during wound closure or shortly after surgery, though rare, were encountered in our institution. Therefore we retrospectively analyzed these cases for the past 2 years, and asked the anesthesiologists and orthopedic surgeons in charge for further information. A total of 7 cases were collected (Table 1). There were 3 males and 4 females, the median age was 66 y (43–74 y), and the averaged BMI was 24.39 ± 1.51 (22.3–26.1). It was interesting to note that these cases were all associated with topical application of VCM powder (Table 1). In these 7 cases, the onset time of severe circulatory fluctuation was 30 min in 5 cases, 50 min in one case (applied with 1 g of VCM), and approximately 45 min in another case (locally applied 3 g of VCM), respectively. Most of the cases (6/7) with severe circulatory fluctuation were corrected without severe sequelae. While in one case in which 3 g of VCM was applied on the dura mater and into the mascularis during wound closure, sudden cardiac arrest happened shortly after the patient had fully recovered from the anesthetic, following surgery and extubation in the OR. CPR was initiated immediately. The patient was reintubated and ventilated mechanically. The persistent VF was treated with continuous chest compressions and repeated defibrillation, with boluses of adrenaline (a total of 6 mg) and amiodarone. After 50 min of continuous CPR, with fluid resuscitation and blood transfusion, the patient was transferred to ICU following the return of spontaneous circulation and reverting into sinus rhythm. However, the patient remained in a comatose state due to hypoxic-hypoxic encephalopathy, and tracheotomy was performed 2 weeks later.
Discussion and conclusion
Vancomycin and anaphylaxis reaction
“International Consensus on (ICON) Anaphylaxis” define anaphylaxis as “a serious, generalized or systemic, allergic or hypersensitivity reaction that can be life threatening or fatal” [4]. It has been demonstrated that there exists IgE-dependent and three IgE-independent mechanisms in anaphylaxis pathophysiology [5]. VCM could directly activate mast cells to release histamine and other mediators through an IgE-independent mechanism that is calcium-, phospholipase C–, and phospholipase A2–dependent but otherwise unknown [5, 6]. Vancomycin-induced direct histamine release is also infusion rate dependent [7]. This IgE-independent anaphylaxis reaction generally disappears within 20 mins, but may linger for hours. The most common manifestation is a sudden drop in blood pressure, which is related to the negative inotropic effect and the vasodilator action stimulated by the histamine release. Alteration in vascular tone is also a common feature of anaphylactic shock [8]. Richter J and colleagues demonstrated in rats that VCM could directly influence the vascular tonus, affecting the microcirculation [9].
The VCM reactions studied in the pediatric population revealed that non-IgE mediated reaction accounts for the vast majority of reactions (92%; prevalence, 5.4–5.8%), whereas possible IgE-mediated vancomycin reactions were exceedingly rare (prevalence, 0.0–0.37%) [7]. For adults, the reported incidence of non-IgE mediated reaction varies between 3.7 and 47% in infected patients and 90% in healthy volunteers [2]. Elevated serum mast cell tryptase is a valuable indicator for diagnosing Ig-E mediated anaphylactic reaction. However, it is not useful in determining a non-IgE mediated anaphylactic reaction caused by histamine release [2]. Detection of histamine concentration in clinical blood specimens is difficult due to its extremely short half-life, and histamine is not a mast cell specific product [10]. As this study is retrospective in nature, and our hospital does not perform examination of serum tryptase and histamine concentration, we could not differentiate whether the adverse effects were caused by VCM induced IgE-mediated or non-IgE mediated reaction.
Topical application of vancomycin powder and surgical site infections
VCM is effective in fighting Gram-positive bacteria related severe infections [11]. While the actual utility of local application of VCM is controversial. After the first reported topical application of VCM by orthopedic surgeons to reduce postoperative surgical site infections (SSIs) rate [12], a large number of meta-analyses, retrospective cohort studies, and randomized controlled trials were published to assess the power of this method in preventing SSIs. Recent findings from large-scale propensity score matched analyses, meta analyses, RCTs studies, and observational studies of spine surgeries and knee arthroplasties all demonstrated that the intrawound VCM powder application may not decrease SSIs, but may increase postoperative complications [13–19].
VCM is an antibiotic that was considered safe in local application and has been widely used in hospitals. However, dose recommendations, dilutions, monitoring, infusion types and rates are still controversial [20]. There’s no defined time or situation during surgery when local VCM should be applied. Some may load VCM powder with bone debris into the cage, or apply VCM powder directly onto the dura mater or after closure of the fascia, whereas other studies reported that VCM powder was applied in the subfascial layer [2, 13]. However, intrawound absorption rate of VCM powder is uncontrollable as this depends on multiple factors, such as the extent and degree of tissue/muscle damaged by surgical manipulation, anatomic location where VCM powder is placed (mixed with bone debris, or between muscularis layers that are abundant with blood supply), and the surgeon’s suturing maneuvers (the flushing saline would leak from upper layer into the layer where VCM powder is deposited). These factors all pose potential risk of causing rapid drug dissolution and accelerated absorption into the circulatory system. Moreover, individual’s adverse reactions to VCM varied. These incidental events may be accidentally linked and lead to severe outcome. Since intravenous administration of VCM could lead to adverse effects, it is theoretically possible that local application of VCM powder may cause similar clinical manifestation.
Topical application of VCM was intended to achieve the effect of providing high local concentrations while avoiding high systemic levels and the risk of bacterial resistance. The serum concentration level peaks at 30 min and then declines to baseline at 6 h [2]. This may explain the delayed and unpredictable occurrence of anaphylaxis reactions after local application of VCM powder, due to the uncertainty of the drug absorption rate and individual reaction differences. The instructed therapeutic dosage of VCM is 30 mg/kg/day which should be fractioned in 2 or 3 doses. Moreover, the infusion rate should be within 10 mg/min, and last for more than 60 min. For elderly patients, this dosage should be reduced [21, 22]. Although the most commonly used dose of intrawound VCM is 1 g, some authors reported that they altered the dose according to the length of the incision [23]. VCM is not the first-choice antibiotic as its adverse effects are frequently reported including hypotension and tachycardia, phlebitis, nephrotoxicity, ototoxicity, hypersensitivity reactions, red man syndrome, neutropenia, chills, fever, interstitial nephritis, etc. [13]. As VCM induced adverse reactions are dose and infusion-rate dependent, doctors should be highly vigilant to over-dosing which might bring disastrous results.
Other issues related to shock
In this case series, the typical signs of erythema and redness (red man syndrome) have not appeared, which resemble the previous case reported by Mariappan R and colleagues [2]. The lack of skin flushing may be the result of reduced perfusion due to circulatory shock or the adverse effect of VCM mainly manifested as severe alteration of vascular tonus [8, 9]. In our experience, a rapid but low dose intravenous infusion of VCM induced anaphylaxis reaction was not necessarily associated with skin manifestations. Whether this is related to racial differences or rapid absorption of low dose VCM was not known. However, the clinical features of hypotension, tachycadia and low oxygenation were notable.
For this case series, as there is no definitive laboratory examination or gold standard to help reach a definitive diagnosis of VCM induced anaphylaxis reaction, the conclusions were made upon differential diagnosis based on clinical manifestations and the timing of the shock. Other possible causes or contributing factors for the development of severe hypotension and shock need to be considered. For example, restrictive fluid therapy during surgical procedure and restrictive blood transfusion strategy leading to hypovolemia and hypotension, complicated with unseen bleeding from surgical site and other compounding factors such as hypoproteinemia and unaltered anesthetic depth during wound closure.
Another issue needs to be addressed is that there’s a notable decrease in hemoglobin (HGB) concentration in all cases when severe hypotension occurred. However, the hemorrhagic shock induced by surgical blood loss was ruled out. We speculate that this might be due to the infusion of large amounts of fluid during resuscitation. It is reported that the administration of 500 ml of fluids may acutely decrease the HGB concentration by about 1 g/dl, or about 8%, by “dilutional anemia” [24]. In septic shock patients, approximately 30% decrease of hematocrit was commonly observed in patients receiving large amounts of fluids during resuscitation, which further indicates more blood transfusion [25]. In the current study, the HGB concentrations were all measured after the initiation of fluid resuscitation and this may at least partially explained the sharp decrease of the HGB level (Table 1). When severe hypotension with unknown causes occur, initial management is to infuse large amounts of fluid with vaso-constrictive drugs. The iatrogenic hemodilution related blood transfusion may result in dilutional coagulopathy and increase surgical bleeding. This then leads to a decreased HGB level below the acceptable transfusion threshold, leading to further blood transfusion in the absence of significant blood loss [26]. This is especially true when in the scenario of the existence of suspected hemorrhagic shock.
In conclusion, local application of VCM powder during wound closure could cause delayed occurrence of severe hypotension and shock in spine surgery. Hemodynamic changes may be under-emphasized and under-reported as in most cases, this hemodynamic reaction is easy to correct and normally wouldn’t cause serious consequences. However, the actual occurrence is not rare and this might be confused with hypovolemia or anesthetic induced hypotension. Surgeons and anesthesiologists should be highly aware of VCM induced IgE-independent anaphylaxis reactions. The differential diagnosis of anaphylactic shock must be taken into consideration in patients with acute hypotension during or immediately after wound closure. Prompt laboratory analysis of serum tryptase and histamine concentration could help differentiate the causes. Moreover, since controversies still exist in the actual effect of intrawound application of VCM powder to reduce SSIs in spine surgery, local application of this drug should be used with caution.
Abbreviations
VCMVancomycin
ABPArterial blood pressure
TTETransthoracic echocardiography
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
We sincerely thank our colleagues from anesthesia (Dr. XW, Dr. CW, Dr. WL, Dr. JY, Dr. YW, Dr. CN, Dr. CX, Dr. YT, Dr. HW, Dr. HT, Dr. WW, Dr. YT, Dr. XJ, HL, Dr. HW, Dr. HZ, Dr. YW, and Dr. BW) and surgical department (Dr. YD, Dr. YL, Dr. FZ, Dr. QQ, and Dr. ZC) for providing and verifying the cases.
The authors have completed the CARE reporting checklist.
Authors’ contributions
Guarantor of integrity of entire study: XZ, WZ, ML, XG. Literature research: XZ, WZ. Case study and follow-up: XZ, WZ. Manuscript preparation: XZ, WZ. Manuscript editing and revision: ML, XG. Manuscript final version approval: ML, XG. All authors have read and approved the manuscript.
Funding
This work was supported by the Clinical Key Project of Peking University Third Hospital, Grants No. BYSY2017001.
The role of the funder: study design, decision to submit the manuscript for publication.
Availability of data and materials
All data generated or analyzed during this study are included in this published article. More detailed information could be find in Table 1.
Ethics approval and consent to participate
This case was performed according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Peking University Third Hospital. All the authors listed in the manuscript consent to participate the study. The consent for publication from patient or their relatives were collected retrospectively.
Consent for publication
As this is a retrospective case study, written informed consent to publish this manuscript were collected from patients or their relatives retrospectively. The proof of consent to publish from study participants can be requested at any time.
Competing interests
The author(s) declare no competing interests. | VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33407142 | 18,839,984 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac arrest'. | Circulatory collapse during wound closure in spine surgery with an unknown cause: a possible adverse effect of topical application of vancomycin?
Vancomycin (VCM) is effective in fighting Gram-positive bacteria related severe infections, and topical application of VCM powder is widely used in orthopedic surgery to prevent wound infection. However, VCM could lead to infusion rate-dependent antibody-and complement-independent anaphylaxis reaction by inducing direct release of histamine.
We retrospectively analyzed seven cases of severe hypotension and shock during wound closure or immediately after orthopedic surgery with unidentifiable reasons. We found that these cases were all associated with local application of VCM powder during wound closure process. Two patients experienced sudden cardiac arrest. Most of the cases (6/7) with circulatory collapse were discharged without severe sequelae. While one case with application of 3 g VCM developed cardiac arrest and remained in a coma due to hypoxic-hypoxic encephalopathy. The clinical presentations and the time of the shock onset were considered to be related with a VCM induced anaphylaxis reaction. However, as this was a retrospective study, and there was no laboratory examination performed, the conclusion was made upon differential diagnosis based on clinical manifestations and the timing of the shock.
Local application of VCM may not be as safe as was once believed and may lead to a related anaphylaxis. As VCM induced infusion-rate dependent, non-IgE mediated anaphylaxis is characterized by delayed occurrence, severe hypotension and even circulatory collapse, surgeons and anesthesiologists should be extra vigilant during and after VCM application.
Background
Shock is defined as a state of insufficient perfusion and oxygen delivery to the tissues. The pathophysiology of shock could be simplified to three major components: cardiac function (the pump), intravascular volume (the tank), and systemic vascular resistance (the pipes) [1]. Whatever the causes of shock may be, if the impaired perfusion and oxygen delivery is not recognized and reversed, the circulatory collapse may progress into organ dysfunction and failure, tissue necrosis and even death. It is urgent to identify the causes of shock and take immediate measures. However, in critical situations, it is hard to rapidly distinguish the culprit during complex clinical situations. Here we present 7 cases (Table 1) of unidentifiable causes of shock during wound closure or shortly after spine surgery, and discuss the possible reasons.
Table 1 Summary of clinical presentations of seven patients with circulatory collapse and unknown etiologies during or shortly after wound closure in spine surgery
Case Demographic information Initial signs/symptoms of shock and management Hemoglobin value (g/L),
fluid resuscitation and blood product infusion VCM administration
and Postoperative sequelae
1 Female; 68-yr; 160 cm/60 kg
BMI: 23.4
Diagnosis:
Lumbar stenosis (L3-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Hypertension
History of retina surgery
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
ABP: 30/20 mmHg
SpO2: undetectable
ECG: tarchycardia with elevated ST segment
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for 45 min. Fluid resuscitation and blood transfusion.
Preoperative HGB value: 124
Intraoperative minimum value of HGB: 73
Blood loss: 600 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 3450 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 210 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
Proceeded with surgery and the patient was extubated uneventfully.
2 Male; 74-yr; 171 cm/67 kg
BMI: 23.9
Diagnosis:
lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
ECG: tachycardia with ST segment depression
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min) for 4 h.
Preoperative HGB value:135
Intraoperative minimum value of HGB: 79
Blood loss: 600 ml
Urine: 1950 ml
Fluid and blood product infusion:
Crystalloid: 6300 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Plasma: 800 ml
Infused autologous blood: 254 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions).
Postoperative imaging: intracranial minor hemorrhage at subdural and subarachnoid space.
The patient was discharged from hospital without neurological deficit.
3 Male; 63-yr; 169 cm/70 kg
BMI: 24.5
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Lacunar infarction;
Bilateral carotid atherosclerotic plaque formation
Time of occurrence:
50 min after initiation of wound closure and 20 min post-extubation in the PACU.
Signs and symptoms:
NBP: 60/25 mmHg
SpO2: 96%
HR:sudden elevation from 60 to 90 bpm
Postoperative agitation
Skin and airway symptoms: none.
Management:
Boluses of ephedrine, phenylephrine and fluid resuscitation.
Preoperative HGB value: 176
Intraoperative minimum value of HGB:123
Blood loss: 800 ml
Urine: 800 ml
Fluid and blood product infusion:
Crystalloid: 2350 ml
Colloid: 1000 ml
PRBC infusion: 400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis.
Postoperative sequelae:
Uneventful.
4 Female; 70-yr; 160 cm/65 kg
BMI:25.4
Diagnosis:
Lumbar stenosis (L4-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Hypertension
Diabetes Mellitus
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
Persistent tachycardia
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine for treating severe hypotension and esmolol for tachycardia
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 150
Intraoperative minimum value of HGB: 92
Blood loss: 1500 ml
Urine: 1800 ml
Fluid and blood product infusion:
Crystalloid: 3100 ml
Colloid: 1500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 450 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery and transferred to ICU due to tachycardia after sufficient fluid resuscitation.
Recovered uneventfully.
5 Female;48-yr; 170 cm/75 kg
BMI: 26.0
Diagnosis:
Thoracic spinal canal stenosis (T6-T11)
Surgery:
Posterior decompression, fixation and fusion of thoracic spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 40/30 mmHg to undetectable
HR: 120 bpm to 40 bpm
SpO2: undetectable
Cardiac arrest
Skin and airway symptoms: none.
Management:
Extracardiac compression
Boluses of noradrenaline (200 μg) and adrenaline (1 g)
Continuous infusion of noradrenaline (0.02–0.08 μg/kg/min) for 50 min
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 132
Intraoperative minimum value of HGB: 74
Blood loss: 2500 ml
Urine: 1300 ml
Fluid and blood product infusion:
Crystalloid: 4000 ml
Colloid: 500 ml
PRBC infusion: 2400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery, and discharged from hospital uneventfully.
6 Male; 66-yr; 175 cm/ 80 kg
BMI: 26.1
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Carotid artery stenosis
Diabetes Mellitus
Time of occurrence:
Sudden cardiac arrest 10 min after extubation (approximately 45 min after initiation of wound closure) with full recovery from anesthesia and without any discomfort complaint.
Signs and symptoms:
Cardiac arrest and persistent VF
Skin and airway symptoms: none.
Management:
Continuous CPR
Persistent VF was treated with repeated defibrillation
Boluses of adrenaline (a total of 6 mg) and amiodarone.
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 143
Intraoperative minimum value of HGB: 78
Blood loss: 1000 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 4400 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 600 ml
VCM administration:
Topical spraying of vancomycin (3 g) on the dura mater and into the mascularis.
Postoperative sequelae:
The patient was reintubated and transferred to ICU after ROSC. The patient was diagnosed as hypoxic encephalopathy and remained in a coma state. Tracheotomy was performed 2 weeks after surgery, and the patient was transferred to a nursing home for rehabilitation 1 month after orthopedic surgery.
7 Female; 43-yr; 155 cm / 54 kg
BMI: 22.4
Diagnosis:
Thoracic kyphosis (T7-T8)
Surgery:
Osteotomy for kyphosis of thoracic spine (T7-T8).
Medical and allergy history:
nil relevant.
Time of occurrence:
subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
HR:tachycardia
NBP: 60/30 mmHg
SpO2 82%
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine and ephedrine;
Continuous infusion of noradrenaline (0.05–0.1 μg/kg/min)
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 138
Intraoperative minimum value of HGB: 95
Blood loss: 1200 ml
Urine: 1900 ml
Fluid and blood product infusion:
Crystalloid: 4700 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 470 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was transferred to ICU for optimal monitoring and recovered uneventfully.
Abbreviations: NBP Non-invasive blood pressure; ABP Arterial blood pressure; (NBP is noted when ABP is not available.) VF Ventricular fibrillation; CPR Cardiopulmonary Resuscitation; HGB Hemoglobin; VCM Vancomycin; PRBC Packed red blood cell; ROSC Return of spontaneous circulation
Case presentation
The first case we encountered was a 68-yr female with past medical history of hypertension and surgical treated retina detachment, who underwent posterior decompression, fixation and fusion of lumbar spine due to lumbar stenosis (L3-S1). The operation was uneventful until sudden circulatory collapse occurred during the process of rinsing mascularis and superficial fascia layer whilst closing the wound. A sudden drop in arterial blood pressure (ABP) (130/60 mmHg to 30/20 mmHg), increased HR (60 bpm to 100 bpm) with elevated ST-segment and significant decrease of PetCO2 (31 mmHg to 16 mmHg) were noticed, with undetectable pulse oximetry read. The patient was turned to supine position immediately and managed with boluses (40–100 μg) and a continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for approximately 45 min. The circulation was gradually stabilized. No rash, erythema, or bronchospasm were noted. The bilateral breath sounds were equal and the airway pressure remained normal. We continued treatments of fluid resuscitation and blood transfusion with corticosteroid and ice cap to prevent hypoxic-ischemic encephalopathy. Intraoperative emergency consultations and immediate examinations of 12-lead ECG, point-of-care transthoracic echocardiography (TTE), and full panel laboratory tests were performed. However, these results did not support the causes of sudden cardiac dysfunction (the pump) including mechanical obstruction (pericardial tamponade and massive pulmonary embolus), acute myocardial infarction, acute valvular insufficiency, and arrhythmia. Vascular catastrophes were excluded and there were no signs of sepsis. We also examined the intravascular volume function (the tank) by performing the TTE, and ruled out intraperitoneal major hemorrhage which we once encountered (caused by inadvertent piercing of iliac artery when placing probe during lumbar surgery) by examination of abdominal ultrasound and hemoglobin level; Volume status was evaluated by measuring CVP, urine output, infused fluid volume; Surgical blood loss was reviewed to exclude hemorrhage shock and hypovolemia. As no special medications were given except anesthetic maintenance drugs, and no signs of mottled skin or bronchospasm were noticed, anaphylaxis was not considered at that time. After restoring circulatory stability, the surgery preceded uneventfully. The patient was discharged from hospital 7 days later.
It was intriguing that within 1 month, another case of circulatory collapse happened during wound closure in spine surgery performed by the same orthopedic surgeon. The intraoperative clinical manifestations were very similar to the previous one. Hemodynamic resuscitation were initiated immediately with repeated boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min). After stabilizing the circulation 4 h later, the patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions after full recovery from anesthesia). Postoperative imaging revealed intracranial micro hemorrhagic foci in the subdural and subarachnoid space. The patient was discharged from hospital without any neurological sequelae.
With further exploration and analysis of the similarities of these two cases, we found that local application of vancomycin (VCM) powder was used in these two patients to prevent postoperative surgical site infections (SSIs) during wound closure (0.5 g VCM loaded with bone debris into the cage and another 0.5 g sprayed on the dura mater and into the mascularis). Ramamani Mariappan reported a case of circulatory collapse after topical application of vancomycin powder during spine surgery, which exhibited almost the same clinical course as ours [2]. It was speculated that the rapid absorption of VCM applied to the surgical wound caused an anaphylaxis reaction and circulatory collapse. The reaction occurred approximately 30 min after the application and persisted for 6 h. The serum tryptase level was not elevated, suggesting that VCM caused a direct histamine release, which is in keeping with our current understanding. A similar case reported a 74-year-old woman who underwent a primary total knee replacement presented with red man syndrome in the PACU 45 min after release of tourniquet following the use of VCM-loaded bone cement. The patient remained fully conscious despite a sudden drop in blood pressure to 47/34 mmHg [3]. Therefore, local application of VCM may pose the risk of causing severe circulatory adverse effect.
Similar circulatory collapse cases in spine surgery without definitive causes during wound closure or shortly after surgery, though rare, were encountered in our institution. Therefore we retrospectively analyzed these cases for the past 2 years, and asked the anesthesiologists and orthopedic surgeons in charge for further information. A total of 7 cases were collected (Table 1). There were 3 males and 4 females, the median age was 66 y (43–74 y), and the averaged BMI was 24.39 ± 1.51 (22.3–26.1). It was interesting to note that these cases were all associated with topical application of VCM powder (Table 1). In these 7 cases, the onset time of severe circulatory fluctuation was 30 min in 5 cases, 50 min in one case (applied with 1 g of VCM), and approximately 45 min in another case (locally applied 3 g of VCM), respectively. Most of the cases (6/7) with severe circulatory fluctuation were corrected without severe sequelae. While in one case in which 3 g of VCM was applied on the dura mater and into the mascularis during wound closure, sudden cardiac arrest happened shortly after the patient had fully recovered from the anesthetic, following surgery and extubation in the OR. CPR was initiated immediately. The patient was reintubated and ventilated mechanically. The persistent VF was treated with continuous chest compressions and repeated defibrillation, with boluses of adrenaline (a total of 6 mg) and amiodarone. After 50 min of continuous CPR, with fluid resuscitation and blood transfusion, the patient was transferred to ICU following the return of spontaneous circulation and reverting into sinus rhythm. However, the patient remained in a comatose state due to hypoxic-hypoxic encephalopathy, and tracheotomy was performed 2 weeks later.
Discussion and conclusion
Vancomycin and anaphylaxis reaction
“International Consensus on (ICON) Anaphylaxis” define anaphylaxis as “a serious, generalized or systemic, allergic or hypersensitivity reaction that can be life threatening or fatal” [4]. It has been demonstrated that there exists IgE-dependent and three IgE-independent mechanisms in anaphylaxis pathophysiology [5]. VCM could directly activate mast cells to release histamine and other mediators through an IgE-independent mechanism that is calcium-, phospholipase C–, and phospholipase A2–dependent but otherwise unknown [5, 6]. Vancomycin-induced direct histamine release is also infusion rate dependent [7]. This IgE-independent anaphylaxis reaction generally disappears within 20 mins, but may linger for hours. The most common manifestation is a sudden drop in blood pressure, which is related to the negative inotropic effect and the vasodilator action stimulated by the histamine release. Alteration in vascular tone is also a common feature of anaphylactic shock [8]. Richter J and colleagues demonstrated in rats that VCM could directly influence the vascular tonus, affecting the microcirculation [9].
The VCM reactions studied in the pediatric population revealed that non-IgE mediated reaction accounts for the vast majority of reactions (92%; prevalence, 5.4–5.8%), whereas possible IgE-mediated vancomycin reactions were exceedingly rare (prevalence, 0.0–0.37%) [7]. For adults, the reported incidence of non-IgE mediated reaction varies between 3.7 and 47% in infected patients and 90% in healthy volunteers [2]. Elevated serum mast cell tryptase is a valuable indicator for diagnosing Ig-E mediated anaphylactic reaction. However, it is not useful in determining a non-IgE mediated anaphylactic reaction caused by histamine release [2]. Detection of histamine concentration in clinical blood specimens is difficult due to its extremely short half-life, and histamine is not a mast cell specific product [10]. As this study is retrospective in nature, and our hospital does not perform examination of serum tryptase and histamine concentration, we could not differentiate whether the adverse effects were caused by VCM induced IgE-mediated or non-IgE mediated reaction.
Topical application of vancomycin powder and surgical site infections
VCM is effective in fighting Gram-positive bacteria related severe infections [11]. While the actual utility of local application of VCM is controversial. After the first reported topical application of VCM by orthopedic surgeons to reduce postoperative surgical site infections (SSIs) rate [12], a large number of meta-analyses, retrospective cohort studies, and randomized controlled trials were published to assess the power of this method in preventing SSIs. Recent findings from large-scale propensity score matched analyses, meta analyses, RCTs studies, and observational studies of spine surgeries and knee arthroplasties all demonstrated that the intrawound VCM powder application may not decrease SSIs, but may increase postoperative complications [13–19].
VCM is an antibiotic that was considered safe in local application and has been widely used in hospitals. However, dose recommendations, dilutions, monitoring, infusion types and rates are still controversial [20]. There’s no defined time or situation during surgery when local VCM should be applied. Some may load VCM powder with bone debris into the cage, or apply VCM powder directly onto the dura mater or after closure of the fascia, whereas other studies reported that VCM powder was applied in the subfascial layer [2, 13]. However, intrawound absorption rate of VCM powder is uncontrollable as this depends on multiple factors, such as the extent and degree of tissue/muscle damaged by surgical manipulation, anatomic location where VCM powder is placed (mixed with bone debris, or between muscularis layers that are abundant with blood supply), and the surgeon’s suturing maneuvers (the flushing saline would leak from upper layer into the layer where VCM powder is deposited). These factors all pose potential risk of causing rapid drug dissolution and accelerated absorption into the circulatory system. Moreover, individual’s adverse reactions to VCM varied. These incidental events may be accidentally linked and lead to severe outcome. Since intravenous administration of VCM could lead to adverse effects, it is theoretically possible that local application of VCM powder may cause similar clinical manifestation.
Topical application of VCM was intended to achieve the effect of providing high local concentrations while avoiding high systemic levels and the risk of bacterial resistance. The serum concentration level peaks at 30 min and then declines to baseline at 6 h [2]. This may explain the delayed and unpredictable occurrence of anaphylaxis reactions after local application of VCM powder, due to the uncertainty of the drug absorption rate and individual reaction differences. The instructed therapeutic dosage of VCM is 30 mg/kg/day which should be fractioned in 2 or 3 doses. Moreover, the infusion rate should be within 10 mg/min, and last for more than 60 min. For elderly patients, this dosage should be reduced [21, 22]. Although the most commonly used dose of intrawound VCM is 1 g, some authors reported that they altered the dose according to the length of the incision [23]. VCM is not the first-choice antibiotic as its adverse effects are frequently reported including hypotension and tachycardia, phlebitis, nephrotoxicity, ototoxicity, hypersensitivity reactions, red man syndrome, neutropenia, chills, fever, interstitial nephritis, etc. [13]. As VCM induced adverse reactions are dose and infusion-rate dependent, doctors should be highly vigilant to over-dosing which might bring disastrous results.
Other issues related to shock
In this case series, the typical signs of erythema and redness (red man syndrome) have not appeared, which resemble the previous case reported by Mariappan R and colleagues [2]. The lack of skin flushing may be the result of reduced perfusion due to circulatory shock or the adverse effect of VCM mainly manifested as severe alteration of vascular tonus [8, 9]. In our experience, a rapid but low dose intravenous infusion of VCM induced anaphylaxis reaction was not necessarily associated with skin manifestations. Whether this is related to racial differences or rapid absorption of low dose VCM was not known. However, the clinical features of hypotension, tachycadia and low oxygenation were notable.
For this case series, as there is no definitive laboratory examination or gold standard to help reach a definitive diagnosis of VCM induced anaphylaxis reaction, the conclusions were made upon differential diagnosis based on clinical manifestations and the timing of the shock. Other possible causes or contributing factors for the development of severe hypotension and shock need to be considered. For example, restrictive fluid therapy during surgical procedure and restrictive blood transfusion strategy leading to hypovolemia and hypotension, complicated with unseen bleeding from surgical site and other compounding factors such as hypoproteinemia and unaltered anesthetic depth during wound closure.
Another issue needs to be addressed is that there’s a notable decrease in hemoglobin (HGB) concentration in all cases when severe hypotension occurred. However, the hemorrhagic shock induced by surgical blood loss was ruled out. We speculate that this might be due to the infusion of large amounts of fluid during resuscitation. It is reported that the administration of 500 ml of fluids may acutely decrease the HGB concentration by about 1 g/dl, or about 8%, by “dilutional anemia” [24]. In septic shock patients, approximately 30% decrease of hematocrit was commonly observed in patients receiving large amounts of fluids during resuscitation, which further indicates more blood transfusion [25]. In the current study, the HGB concentrations were all measured after the initiation of fluid resuscitation and this may at least partially explained the sharp decrease of the HGB level (Table 1). When severe hypotension with unknown causes occur, initial management is to infuse large amounts of fluid with vaso-constrictive drugs. The iatrogenic hemodilution related blood transfusion may result in dilutional coagulopathy and increase surgical bleeding. This then leads to a decreased HGB level below the acceptable transfusion threshold, leading to further blood transfusion in the absence of significant blood loss [26]. This is especially true when in the scenario of the existence of suspected hemorrhagic shock.
In conclusion, local application of VCM powder during wound closure could cause delayed occurrence of severe hypotension and shock in spine surgery. Hemodynamic changes may be under-emphasized and under-reported as in most cases, this hemodynamic reaction is easy to correct and normally wouldn’t cause serious consequences. However, the actual occurrence is not rare and this might be confused with hypovolemia or anesthetic induced hypotension. Surgeons and anesthesiologists should be highly aware of VCM induced IgE-independent anaphylaxis reactions. The differential diagnosis of anaphylactic shock must be taken into consideration in patients with acute hypotension during or immediately after wound closure. Prompt laboratory analysis of serum tryptase and histamine concentration could help differentiate the causes. Moreover, since controversies still exist in the actual effect of intrawound application of VCM powder to reduce SSIs in spine surgery, local application of this drug should be used with caution.
Abbreviations
VCMVancomycin
ABPArterial blood pressure
TTETransthoracic echocardiography
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
We sincerely thank our colleagues from anesthesia (Dr. XW, Dr. CW, Dr. WL, Dr. JY, Dr. YW, Dr. CN, Dr. CX, Dr. YT, Dr. HW, Dr. HT, Dr. WW, Dr. YT, Dr. XJ, HL, Dr. HW, Dr. HZ, Dr. YW, and Dr. BW) and surgical department (Dr. YD, Dr. YL, Dr. FZ, Dr. QQ, and Dr. ZC) for providing and verifying the cases.
The authors have completed the CARE reporting checklist.
Authors’ contributions
Guarantor of integrity of entire study: XZ, WZ, ML, XG. Literature research: XZ, WZ. Case study and follow-up: XZ, WZ. Manuscript preparation: XZ, WZ. Manuscript editing and revision: ML, XG. Manuscript final version approval: ML, XG. All authors have read and approved the manuscript.
Funding
This work was supported by the Clinical Key Project of Peking University Third Hospital, Grants No. BYSY2017001.
The role of the funder: study design, decision to submit the manuscript for publication.
Availability of data and materials
All data generated or analyzed during this study are included in this published article. More detailed information could be find in Table 1.
Ethics approval and consent to participate
This case was performed according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Peking University Third Hospital. All the authors listed in the manuscript consent to participate the study. The consent for publication from patient or their relatives were collected retrospectively.
Consent for publication
As this is a retrospective case study, written informed consent to publish this manuscript were collected from patients or their relatives retrospectively. The proof of consent to publish from study participants can be requested at any time.
Competing interests
The author(s) declare no competing interests. | VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33407142 | 18,839,984 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Circulatory collapse'. | Circulatory collapse during wound closure in spine surgery with an unknown cause: a possible adverse effect of topical application of vancomycin?
Vancomycin (VCM) is effective in fighting Gram-positive bacteria related severe infections, and topical application of VCM powder is widely used in orthopedic surgery to prevent wound infection. However, VCM could lead to infusion rate-dependent antibody-and complement-independent anaphylaxis reaction by inducing direct release of histamine.
We retrospectively analyzed seven cases of severe hypotension and shock during wound closure or immediately after orthopedic surgery with unidentifiable reasons. We found that these cases were all associated with local application of VCM powder during wound closure process. Two patients experienced sudden cardiac arrest. Most of the cases (6/7) with circulatory collapse were discharged without severe sequelae. While one case with application of 3 g VCM developed cardiac arrest and remained in a coma due to hypoxic-hypoxic encephalopathy. The clinical presentations and the time of the shock onset were considered to be related with a VCM induced anaphylaxis reaction. However, as this was a retrospective study, and there was no laboratory examination performed, the conclusion was made upon differential diagnosis based on clinical manifestations and the timing of the shock.
Local application of VCM may not be as safe as was once believed and may lead to a related anaphylaxis. As VCM induced infusion-rate dependent, non-IgE mediated anaphylaxis is characterized by delayed occurrence, severe hypotension and even circulatory collapse, surgeons and anesthesiologists should be extra vigilant during and after VCM application.
Background
Shock is defined as a state of insufficient perfusion and oxygen delivery to the tissues. The pathophysiology of shock could be simplified to three major components: cardiac function (the pump), intravascular volume (the tank), and systemic vascular resistance (the pipes) [1]. Whatever the causes of shock may be, if the impaired perfusion and oxygen delivery is not recognized and reversed, the circulatory collapse may progress into organ dysfunction and failure, tissue necrosis and even death. It is urgent to identify the causes of shock and take immediate measures. However, in critical situations, it is hard to rapidly distinguish the culprit during complex clinical situations. Here we present 7 cases (Table 1) of unidentifiable causes of shock during wound closure or shortly after spine surgery, and discuss the possible reasons.
Table 1 Summary of clinical presentations of seven patients with circulatory collapse and unknown etiologies during or shortly after wound closure in spine surgery
Case Demographic information Initial signs/symptoms of shock and management Hemoglobin value (g/L),
fluid resuscitation and blood product infusion VCM administration
and Postoperative sequelae
1 Female; 68-yr; 160 cm/60 kg
BMI: 23.4
Diagnosis:
Lumbar stenosis (L3-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Hypertension
History of retina surgery
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
ABP: 30/20 mmHg
SpO2: undetectable
ECG: tarchycardia with elevated ST segment
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for 45 min. Fluid resuscitation and blood transfusion.
Preoperative HGB value: 124
Intraoperative minimum value of HGB: 73
Blood loss: 600 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 3450 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 210 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
Proceeded with surgery and the patient was extubated uneventfully.
2 Male; 74-yr; 171 cm/67 kg
BMI: 23.9
Diagnosis:
lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
ECG: tachycardia with ST segment depression
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min) for 4 h.
Preoperative HGB value:135
Intraoperative minimum value of HGB: 79
Blood loss: 600 ml
Urine: 1950 ml
Fluid and blood product infusion:
Crystalloid: 6300 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Plasma: 800 ml
Infused autologous blood: 254 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions).
Postoperative imaging: intracranial minor hemorrhage at subdural and subarachnoid space.
The patient was discharged from hospital without neurological deficit.
3 Male; 63-yr; 169 cm/70 kg
BMI: 24.5
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Lacunar infarction;
Bilateral carotid atherosclerotic plaque formation
Time of occurrence:
50 min after initiation of wound closure and 20 min post-extubation in the PACU.
Signs and symptoms:
NBP: 60/25 mmHg
SpO2: 96%
HR:sudden elevation from 60 to 90 bpm
Postoperative agitation
Skin and airway symptoms: none.
Management:
Boluses of ephedrine, phenylephrine and fluid resuscitation.
Preoperative HGB value: 176
Intraoperative minimum value of HGB:123
Blood loss: 800 ml
Urine: 800 ml
Fluid and blood product infusion:
Crystalloid: 2350 ml
Colloid: 1000 ml
PRBC infusion: 400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis.
Postoperative sequelae:
Uneventful.
4 Female; 70-yr; 160 cm/65 kg
BMI:25.4
Diagnosis:
Lumbar stenosis (L4-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Hypertension
Diabetes Mellitus
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
Persistent tachycardia
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine for treating severe hypotension and esmolol for tachycardia
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 150
Intraoperative minimum value of HGB: 92
Blood loss: 1500 ml
Urine: 1800 ml
Fluid and blood product infusion:
Crystalloid: 3100 ml
Colloid: 1500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 450 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery and transferred to ICU due to tachycardia after sufficient fluid resuscitation.
Recovered uneventfully.
5 Female;48-yr; 170 cm/75 kg
BMI: 26.0
Diagnosis:
Thoracic spinal canal stenosis (T6-T11)
Surgery:
Posterior decompression, fixation and fusion of thoracic spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 40/30 mmHg to undetectable
HR: 120 bpm to 40 bpm
SpO2: undetectable
Cardiac arrest
Skin and airway symptoms: none.
Management:
Extracardiac compression
Boluses of noradrenaline (200 μg) and adrenaline (1 g)
Continuous infusion of noradrenaline (0.02–0.08 μg/kg/min) for 50 min
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 132
Intraoperative minimum value of HGB: 74
Blood loss: 2500 ml
Urine: 1300 ml
Fluid and blood product infusion:
Crystalloid: 4000 ml
Colloid: 500 ml
PRBC infusion: 2400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery, and discharged from hospital uneventfully.
6 Male; 66-yr; 175 cm/ 80 kg
BMI: 26.1
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Carotid artery stenosis
Diabetes Mellitus
Time of occurrence:
Sudden cardiac arrest 10 min after extubation (approximately 45 min after initiation of wound closure) with full recovery from anesthesia and without any discomfort complaint.
Signs and symptoms:
Cardiac arrest and persistent VF
Skin and airway symptoms: none.
Management:
Continuous CPR
Persistent VF was treated with repeated defibrillation
Boluses of adrenaline (a total of 6 mg) and amiodarone.
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 143
Intraoperative minimum value of HGB: 78
Blood loss: 1000 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 4400 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 600 ml
VCM administration:
Topical spraying of vancomycin (3 g) on the dura mater and into the mascularis.
Postoperative sequelae:
The patient was reintubated and transferred to ICU after ROSC. The patient was diagnosed as hypoxic encephalopathy and remained in a coma state. Tracheotomy was performed 2 weeks after surgery, and the patient was transferred to a nursing home for rehabilitation 1 month after orthopedic surgery.
7 Female; 43-yr; 155 cm / 54 kg
BMI: 22.4
Diagnosis:
Thoracic kyphosis (T7-T8)
Surgery:
Osteotomy for kyphosis of thoracic spine (T7-T8).
Medical and allergy history:
nil relevant.
Time of occurrence:
subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
HR:tachycardia
NBP: 60/30 mmHg
SpO2 82%
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine and ephedrine;
Continuous infusion of noradrenaline (0.05–0.1 μg/kg/min)
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 138
Intraoperative minimum value of HGB: 95
Blood loss: 1200 ml
Urine: 1900 ml
Fluid and blood product infusion:
Crystalloid: 4700 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 470 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was transferred to ICU for optimal monitoring and recovered uneventfully.
Abbreviations: NBP Non-invasive blood pressure; ABP Arterial blood pressure; (NBP is noted when ABP is not available.) VF Ventricular fibrillation; CPR Cardiopulmonary Resuscitation; HGB Hemoglobin; VCM Vancomycin; PRBC Packed red blood cell; ROSC Return of spontaneous circulation
Case presentation
The first case we encountered was a 68-yr female with past medical history of hypertension and surgical treated retina detachment, who underwent posterior decompression, fixation and fusion of lumbar spine due to lumbar stenosis (L3-S1). The operation was uneventful until sudden circulatory collapse occurred during the process of rinsing mascularis and superficial fascia layer whilst closing the wound. A sudden drop in arterial blood pressure (ABP) (130/60 mmHg to 30/20 mmHg), increased HR (60 bpm to 100 bpm) with elevated ST-segment and significant decrease of PetCO2 (31 mmHg to 16 mmHg) were noticed, with undetectable pulse oximetry read. The patient was turned to supine position immediately and managed with boluses (40–100 μg) and a continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for approximately 45 min. The circulation was gradually stabilized. No rash, erythema, or bronchospasm were noted. The bilateral breath sounds were equal and the airway pressure remained normal. We continued treatments of fluid resuscitation and blood transfusion with corticosteroid and ice cap to prevent hypoxic-ischemic encephalopathy. Intraoperative emergency consultations and immediate examinations of 12-lead ECG, point-of-care transthoracic echocardiography (TTE), and full panel laboratory tests were performed. However, these results did not support the causes of sudden cardiac dysfunction (the pump) including mechanical obstruction (pericardial tamponade and massive pulmonary embolus), acute myocardial infarction, acute valvular insufficiency, and arrhythmia. Vascular catastrophes were excluded and there were no signs of sepsis. We also examined the intravascular volume function (the tank) by performing the TTE, and ruled out intraperitoneal major hemorrhage which we once encountered (caused by inadvertent piercing of iliac artery when placing probe during lumbar surgery) by examination of abdominal ultrasound and hemoglobin level; Volume status was evaluated by measuring CVP, urine output, infused fluid volume; Surgical blood loss was reviewed to exclude hemorrhage shock and hypovolemia. As no special medications were given except anesthetic maintenance drugs, and no signs of mottled skin or bronchospasm were noticed, anaphylaxis was not considered at that time. After restoring circulatory stability, the surgery preceded uneventfully. The patient was discharged from hospital 7 days later.
It was intriguing that within 1 month, another case of circulatory collapse happened during wound closure in spine surgery performed by the same orthopedic surgeon. The intraoperative clinical manifestations were very similar to the previous one. Hemodynamic resuscitation were initiated immediately with repeated boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min). After stabilizing the circulation 4 h later, the patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions after full recovery from anesthesia). Postoperative imaging revealed intracranial micro hemorrhagic foci in the subdural and subarachnoid space. The patient was discharged from hospital without any neurological sequelae.
With further exploration and analysis of the similarities of these two cases, we found that local application of vancomycin (VCM) powder was used in these two patients to prevent postoperative surgical site infections (SSIs) during wound closure (0.5 g VCM loaded with bone debris into the cage and another 0.5 g sprayed on the dura mater and into the mascularis). Ramamani Mariappan reported a case of circulatory collapse after topical application of vancomycin powder during spine surgery, which exhibited almost the same clinical course as ours [2]. It was speculated that the rapid absorption of VCM applied to the surgical wound caused an anaphylaxis reaction and circulatory collapse. The reaction occurred approximately 30 min after the application and persisted for 6 h. The serum tryptase level was not elevated, suggesting that VCM caused a direct histamine release, which is in keeping with our current understanding. A similar case reported a 74-year-old woman who underwent a primary total knee replacement presented with red man syndrome in the PACU 45 min after release of tourniquet following the use of VCM-loaded bone cement. The patient remained fully conscious despite a sudden drop in blood pressure to 47/34 mmHg [3]. Therefore, local application of VCM may pose the risk of causing severe circulatory adverse effect.
Similar circulatory collapse cases in spine surgery without definitive causes during wound closure or shortly after surgery, though rare, were encountered in our institution. Therefore we retrospectively analyzed these cases for the past 2 years, and asked the anesthesiologists and orthopedic surgeons in charge for further information. A total of 7 cases were collected (Table 1). There were 3 males and 4 females, the median age was 66 y (43–74 y), and the averaged BMI was 24.39 ± 1.51 (22.3–26.1). It was interesting to note that these cases were all associated with topical application of VCM powder (Table 1). In these 7 cases, the onset time of severe circulatory fluctuation was 30 min in 5 cases, 50 min in one case (applied with 1 g of VCM), and approximately 45 min in another case (locally applied 3 g of VCM), respectively. Most of the cases (6/7) with severe circulatory fluctuation were corrected without severe sequelae. While in one case in which 3 g of VCM was applied on the dura mater and into the mascularis during wound closure, sudden cardiac arrest happened shortly after the patient had fully recovered from the anesthetic, following surgery and extubation in the OR. CPR was initiated immediately. The patient was reintubated and ventilated mechanically. The persistent VF was treated with continuous chest compressions and repeated defibrillation, with boluses of adrenaline (a total of 6 mg) and amiodarone. After 50 min of continuous CPR, with fluid resuscitation and blood transfusion, the patient was transferred to ICU following the return of spontaneous circulation and reverting into sinus rhythm. However, the patient remained in a comatose state due to hypoxic-hypoxic encephalopathy, and tracheotomy was performed 2 weeks later.
Discussion and conclusion
Vancomycin and anaphylaxis reaction
“International Consensus on (ICON) Anaphylaxis” define anaphylaxis as “a serious, generalized or systemic, allergic or hypersensitivity reaction that can be life threatening or fatal” [4]. It has been demonstrated that there exists IgE-dependent and three IgE-independent mechanisms in anaphylaxis pathophysiology [5]. VCM could directly activate mast cells to release histamine and other mediators through an IgE-independent mechanism that is calcium-, phospholipase C–, and phospholipase A2–dependent but otherwise unknown [5, 6]. Vancomycin-induced direct histamine release is also infusion rate dependent [7]. This IgE-independent anaphylaxis reaction generally disappears within 20 mins, but may linger for hours. The most common manifestation is a sudden drop in blood pressure, which is related to the negative inotropic effect and the vasodilator action stimulated by the histamine release. Alteration in vascular tone is also a common feature of anaphylactic shock [8]. Richter J and colleagues demonstrated in rats that VCM could directly influence the vascular tonus, affecting the microcirculation [9].
The VCM reactions studied in the pediatric population revealed that non-IgE mediated reaction accounts for the vast majority of reactions (92%; prevalence, 5.4–5.8%), whereas possible IgE-mediated vancomycin reactions were exceedingly rare (prevalence, 0.0–0.37%) [7]. For adults, the reported incidence of non-IgE mediated reaction varies between 3.7 and 47% in infected patients and 90% in healthy volunteers [2]. Elevated serum mast cell tryptase is a valuable indicator for diagnosing Ig-E mediated anaphylactic reaction. However, it is not useful in determining a non-IgE mediated anaphylactic reaction caused by histamine release [2]. Detection of histamine concentration in clinical blood specimens is difficult due to its extremely short half-life, and histamine is not a mast cell specific product [10]. As this study is retrospective in nature, and our hospital does not perform examination of serum tryptase and histamine concentration, we could not differentiate whether the adverse effects were caused by VCM induced IgE-mediated or non-IgE mediated reaction.
Topical application of vancomycin powder and surgical site infections
VCM is effective in fighting Gram-positive bacteria related severe infections [11]. While the actual utility of local application of VCM is controversial. After the first reported topical application of VCM by orthopedic surgeons to reduce postoperative surgical site infections (SSIs) rate [12], a large number of meta-analyses, retrospective cohort studies, and randomized controlled trials were published to assess the power of this method in preventing SSIs. Recent findings from large-scale propensity score matched analyses, meta analyses, RCTs studies, and observational studies of spine surgeries and knee arthroplasties all demonstrated that the intrawound VCM powder application may not decrease SSIs, but may increase postoperative complications [13–19].
VCM is an antibiotic that was considered safe in local application and has been widely used in hospitals. However, dose recommendations, dilutions, monitoring, infusion types and rates are still controversial [20]. There’s no defined time or situation during surgery when local VCM should be applied. Some may load VCM powder with bone debris into the cage, or apply VCM powder directly onto the dura mater or after closure of the fascia, whereas other studies reported that VCM powder was applied in the subfascial layer [2, 13]. However, intrawound absorption rate of VCM powder is uncontrollable as this depends on multiple factors, such as the extent and degree of tissue/muscle damaged by surgical manipulation, anatomic location where VCM powder is placed (mixed with bone debris, or between muscularis layers that are abundant with blood supply), and the surgeon’s suturing maneuvers (the flushing saline would leak from upper layer into the layer where VCM powder is deposited). These factors all pose potential risk of causing rapid drug dissolution and accelerated absorption into the circulatory system. Moreover, individual’s adverse reactions to VCM varied. These incidental events may be accidentally linked and lead to severe outcome. Since intravenous administration of VCM could lead to adverse effects, it is theoretically possible that local application of VCM powder may cause similar clinical manifestation.
Topical application of VCM was intended to achieve the effect of providing high local concentrations while avoiding high systemic levels and the risk of bacterial resistance. The serum concentration level peaks at 30 min and then declines to baseline at 6 h [2]. This may explain the delayed and unpredictable occurrence of anaphylaxis reactions after local application of VCM powder, due to the uncertainty of the drug absorption rate and individual reaction differences. The instructed therapeutic dosage of VCM is 30 mg/kg/day which should be fractioned in 2 or 3 doses. Moreover, the infusion rate should be within 10 mg/min, and last for more than 60 min. For elderly patients, this dosage should be reduced [21, 22]. Although the most commonly used dose of intrawound VCM is 1 g, some authors reported that they altered the dose according to the length of the incision [23]. VCM is not the first-choice antibiotic as its adverse effects are frequently reported including hypotension and tachycardia, phlebitis, nephrotoxicity, ototoxicity, hypersensitivity reactions, red man syndrome, neutropenia, chills, fever, interstitial nephritis, etc. [13]. As VCM induced adverse reactions are dose and infusion-rate dependent, doctors should be highly vigilant to over-dosing which might bring disastrous results.
Other issues related to shock
In this case series, the typical signs of erythema and redness (red man syndrome) have not appeared, which resemble the previous case reported by Mariappan R and colleagues [2]. The lack of skin flushing may be the result of reduced perfusion due to circulatory shock or the adverse effect of VCM mainly manifested as severe alteration of vascular tonus [8, 9]. In our experience, a rapid but low dose intravenous infusion of VCM induced anaphylaxis reaction was not necessarily associated with skin manifestations. Whether this is related to racial differences or rapid absorption of low dose VCM was not known. However, the clinical features of hypotension, tachycadia and low oxygenation were notable.
For this case series, as there is no definitive laboratory examination or gold standard to help reach a definitive diagnosis of VCM induced anaphylaxis reaction, the conclusions were made upon differential diagnosis based on clinical manifestations and the timing of the shock. Other possible causes or contributing factors for the development of severe hypotension and shock need to be considered. For example, restrictive fluid therapy during surgical procedure and restrictive blood transfusion strategy leading to hypovolemia and hypotension, complicated with unseen bleeding from surgical site and other compounding factors such as hypoproteinemia and unaltered anesthetic depth during wound closure.
Another issue needs to be addressed is that there’s a notable decrease in hemoglobin (HGB) concentration in all cases when severe hypotension occurred. However, the hemorrhagic shock induced by surgical blood loss was ruled out. We speculate that this might be due to the infusion of large amounts of fluid during resuscitation. It is reported that the administration of 500 ml of fluids may acutely decrease the HGB concentration by about 1 g/dl, or about 8%, by “dilutional anemia” [24]. In septic shock patients, approximately 30% decrease of hematocrit was commonly observed in patients receiving large amounts of fluids during resuscitation, which further indicates more blood transfusion [25]. In the current study, the HGB concentrations were all measured after the initiation of fluid resuscitation and this may at least partially explained the sharp decrease of the HGB level (Table 1). When severe hypotension with unknown causes occur, initial management is to infuse large amounts of fluid with vaso-constrictive drugs. The iatrogenic hemodilution related blood transfusion may result in dilutional coagulopathy and increase surgical bleeding. This then leads to a decreased HGB level below the acceptable transfusion threshold, leading to further blood transfusion in the absence of significant blood loss [26]. This is especially true when in the scenario of the existence of suspected hemorrhagic shock.
In conclusion, local application of VCM powder during wound closure could cause delayed occurrence of severe hypotension and shock in spine surgery. Hemodynamic changes may be under-emphasized and under-reported as in most cases, this hemodynamic reaction is easy to correct and normally wouldn’t cause serious consequences. However, the actual occurrence is not rare and this might be confused with hypovolemia or anesthetic induced hypotension. Surgeons and anesthesiologists should be highly aware of VCM induced IgE-independent anaphylaxis reactions. The differential diagnosis of anaphylactic shock must be taken into consideration in patients with acute hypotension during or immediately after wound closure. Prompt laboratory analysis of serum tryptase and histamine concentration could help differentiate the causes. Moreover, since controversies still exist in the actual effect of intrawound application of VCM powder to reduce SSIs in spine surgery, local application of this drug should be used with caution.
Abbreviations
VCMVancomycin
ABPArterial blood pressure
TTETransthoracic echocardiography
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
We sincerely thank our colleagues from anesthesia (Dr. XW, Dr. CW, Dr. WL, Dr. JY, Dr. YW, Dr. CN, Dr. CX, Dr. YT, Dr. HW, Dr. HT, Dr. WW, Dr. YT, Dr. XJ, HL, Dr. HW, Dr. HZ, Dr. YW, and Dr. BW) and surgical department (Dr. YD, Dr. YL, Dr. FZ, Dr. QQ, and Dr. ZC) for providing and verifying the cases.
The authors have completed the CARE reporting checklist.
Authors’ contributions
Guarantor of integrity of entire study: XZ, WZ, ML, XG. Literature research: XZ, WZ. Case study and follow-up: XZ, WZ. Manuscript preparation: XZ, WZ. Manuscript editing and revision: ML, XG. Manuscript final version approval: ML, XG. All authors have read and approved the manuscript.
Funding
This work was supported by the Clinical Key Project of Peking University Third Hospital, Grants No. BYSY2017001.
The role of the funder: study design, decision to submit the manuscript for publication.
Availability of data and materials
All data generated or analyzed during this study are included in this published article. More detailed information could be find in Table 1.
Ethics approval and consent to participate
This case was performed according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Peking University Third Hospital. All the authors listed in the manuscript consent to participate the study. The consent for publication from patient or their relatives were collected retrospectively.
Consent for publication
As this is a retrospective case study, written informed consent to publish this manuscript were collected from patients or their relatives retrospectively. The proof of consent to publish from study participants can be requested at any time.
Competing interests
The author(s) declare no competing interests. | VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33407142 | 18,839,984 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Coma'. | Circulatory collapse during wound closure in spine surgery with an unknown cause: a possible adverse effect of topical application of vancomycin?
Vancomycin (VCM) is effective in fighting Gram-positive bacteria related severe infections, and topical application of VCM powder is widely used in orthopedic surgery to prevent wound infection. However, VCM could lead to infusion rate-dependent antibody-and complement-independent anaphylaxis reaction by inducing direct release of histamine.
We retrospectively analyzed seven cases of severe hypotension and shock during wound closure or immediately after orthopedic surgery with unidentifiable reasons. We found that these cases were all associated with local application of VCM powder during wound closure process. Two patients experienced sudden cardiac arrest. Most of the cases (6/7) with circulatory collapse were discharged without severe sequelae. While one case with application of 3 g VCM developed cardiac arrest and remained in a coma due to hypoxic-hypoxic encephalopathy. The clinical presentations and the time of the shock onset were considered to be related with a VCM induced anaphylaxis reaction. However, as this was a retrospective study, and there was no laboratory examination performed, the conclusion was made upon differential diagnosis based on clinical manifestations and the timing of the shock.
Local application of VCM may not be as safe as was once believed and may lead to a related anaphylaxis. As VCM induced infusion-rate dependent, non-IgE mediated anaphylaxis is characterized by delayed occurrence, severe hypotension and even circulatory collapse, surgeons and anesthesiologists should be extra vigilant during and after VCM application.
Background
Shock is defined as a state of insufficient perfusion and oxygen delivery to the tissues. The pathophysiology of shock could be simplified to three major components: cardiac function (the pump), intravascular volume (the tank), and systemic vascular resistance (the pipes) [1]. Whatever the causes of shock may be, if the impaired perfusion and oxygen delivery is not recognized and reversed, the circulatory collapse may progress into organ dysfunction and failure, tissue necrosis and even death. It is urgent to identify the causes of shock and take immediate measures. However, in critical situations, it is hard to rapidly distinguish the culprit during complex clinical situations. Here we present 7 cases (Table 1) of unidentifiable causes of shock during wound closure or shortly after spine surgery, and discuss the possible reasons.
Table 1 Summary of clinical presentations of seven patients with circulatory collapse and unknown etiologies during or shortly after wound closure in spine surgery
Case Demographic information Initial signs/symptoms of shock and management Hemoglobin value (g/L),
fluid resuscitation and blood product infusion VCM administration
and Postoperative sequelae
1 Female; 68-yr; 160 cm/60 kg
BMI: 23.4
Diagnosis:
Lumbar stenosis (L3-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Hypertension
History of retina surgery
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
ABP: 30/20 mmHg
SpO2: undetectable
ECG: tarchycardia with elevated ST segment
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for 45 min. Fluid resuscitation and blood transfusion.
Preoperative HGB value: 124
Intraoperative minimum value of HGB: 73
Blood loss: 600 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 3450 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 210 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
Proceeded with surgery and the patient was extubated uneventfully.
2 Male; 74-yr; 171 cm/67 kg
BMI: 23.9
Diagnosis:
lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
ECG: tachycardia with ST segment depression
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min) for 4 h.
Preoperative HGB value:135
Intraoperative minimum value of HGB: 79
Blood loss: 600 ml
Urine: 1950 ml
Fluid and blood product infusion:
Crystalloid: 6300 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Plasma: 800 ml
Infused autologous blood: 254 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions).
Postoperative imaging: intracranial minor hemorrhage at subdural and subarachnoid space.
The patient was discharged from hospital without neurological deficit.
3 Male; 63-yr; 169 cm/70 kg
BMI: 24.5
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Lacunar infarction;
Bilateral carotid atherosclerotic plaque formation
Time of occurrence:
50 min after initiation of wound closure and 20 min post-extubation in the PACU.
Signs and symptoms:
NBP: 60/25 mmHg
SpO2: 96%
HR:sudden elevation from 60 to 90 bpm
Postoperative agitation
Skin and airway symptoms: none.
Management:
Boluses of ephedrine, phenylephrine and fluid resuscitation.
Preoperative HGB value: 176
Intraoperative minimum value of HGB:123
Blood loss: 800 ml
Urine: 800 ml
Fluid and blood product infusion:
Crystalloid: 2350 ml
Colloid: 1000 ml
PRBC infusion: 400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis.
Postoperative sequelae:
Uneventful.
4 Female; 70-yr; 160 cm/65 kg
BMI:25.4
Diagnosis:
Lumbar stenosis (L4-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Hypertension
Diabetes Mellitus
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
Persistent tachycardia
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine for treating severe hypotension and esmolol for tachycardia
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 150
Intraoperative minimum value of HGB: 92
Blood loss: 1500 ml
Urine: 1800 ml
Fluid and blood product infusion:
Crystalloid: 3100 ml
Colloid: 1500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 450 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery and transferred to ICU due to tachycardia after sufficient fluid resuscitation.
Recovered uneventfully.
5 Female;48-yr; 170 cm/75 kg
BMI: 26.0
Diagnosis:
Thoracic spinal canal stenosis (T6-T11)
Surgery:
Posterior decompression, fixation and fusion of thoracic spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 40/30 mmHg to undetectable
HR: 120 bpm to 40 bpm
SpO2: undetectable
Cardiac arrest
Skin and airway symptoms: none.
Management:
Extracardiac compression
Boluses of noradrenaline (200 μg) and adrenaline (1 g)
Continuous infusion of noradrenaline (0.02–0.08 μg/kg/min) for 50 min
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 132
Intraoperative minimum value of HGB: 74
Blood loss: 2500 ml
Urine: 1300 ml
Fluid and blood product infusion:
Crystalloid: 4000 ml
Colloid: 500 ml
PRBC infusion: 2400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery, and discharged from hospital uneventfully.
6 Male; 66-yr; 175 cm/ 80 kg
BMI: 26.1
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Carotid artery stenosis
Diabetes Mellitus
Time of occurrence:
Sudden cardiac arrest 10 min after extubation (approximately 45 min after initiation of wound closure) with full recovery from anesthesia and without any discomfort complaint.
Signs and symptoms:
Cardiac arrest and persistent VF
Skin and airway symptoms: none.
Management:
Continuous CPR
Persistent VF was treated with repeated defibrillation
Boluses of adrenaline (a total of 6 mg) and amiodarone.
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 143
Intraoperative minimum value of HGB: 78
Blood loss: 1000 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 4400 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 600 ml
VCM administration:
Topical spraying of vancomycin (3 g) on the dura mater and into the mascularis.
Postoperative sequelae:
The patient was reintubated and transferred to ICU after ROSC. The patient was diagnosed as hypoxic encephalopathy and remained in a coma state. Tracheotomy was performed 2 weeks after surgery, and the patient was transferred to a nursing home for rehabilitation 1 month after orthopedic surgery.
7 Female; 43-yr; 155 cm / 54 kg
BMI: 22.4
Diagnosis:
Thoracic kyphosis (T7-T8)
Surgery:
Osteotomy for kyphosis of thoracic spine (T7-T8).
Medical and allergy history:
nil relevant.
Time of occurrence:
subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
HR:tachycardia
NBP: 60/30 mmHg
SpO2 82%
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine and ephedrine;
Continuous infusion of noradrenaline (0.05–0.1 μg/kg/min)
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 138
Intraoperative minimum value of HGB: 95
Blood loss: 1200 ml
Urine: 1900 ml
Fluid and blood product infusion:
Crystalloid: 4700 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 470 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was transferred to ICU for optimal monitoring and recovered uneventfully.
Abbreviations: NBP Non-invasive blood pressure; ABP Arterial blood pressure; (NBP is noted when ABP is not available.) VF Ventricular fibrillation; CPR Cardiopulmonary Resuscitation; HGB Hemoglobin; VCM Vancomycin; PRBC Packed red blood cell; ROSC Return of spontaneous circulation
Case presentation
The first case we encountered was a 68-yr female with past medical history of hypertension and surgical treated retina detachment, who underwent posterior decompression, fixation and fusion of lumbar spine due to lumbar stenosis (L3-S1). The operation was uneventful until sudden circulatory collapse occurred during the process of rinsing mascularis and superficial fascia layer whilst closing the wound. A sudden drop in arterial blood pressure (ABP) (130/60 mmHg to 30/20 mmHg), increased HR (60 bpm to 100 bpm) with elevated ST-segment and significant decrease of PetCO2 (31 mmHg to 16 mmHg) were noticed, with undetectable pulse oximetry read. The patient was turned to supine position immediately and managed with boluses (40–100 μg) and a continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for approximately 45 min. The circulation was gradually stabilized. No rash, erythema, or bronchospasm were noted. The bilateral breath sounds were equal and the airway pressure remained normal. We continued treatments of fluid resuscitation and blood transfusion with corticosteroid and ice cap to prevent hypoxic-ischemic encephalopathy. Intraoperative emergency consultations and immediate examinations of 12-lead ECG, point-of-care transthoracic echocardiography (TTE), and full panel laboratory tests were performed. However, these results did not support the causes of sudden cardiac dysfunction (the pump) including mechanical obstruction (pericardial tamponade and massive pulmonary embolus), acute myocardial infarction, acute valvular insufficiency, and arrhythmia. Vascular catastrophes were excluded and there were no signs of sepsis. We also examined the intravascular volume function (the tank) by performing the TTE, and ruled out intraperitoneal major hemorrhage which we once encountered (caused by inadvertent piercing of iliac artery when placing probe during lumbar surgery) by examination of abdominal ultrasound and hemoglobin level; Volume status was evaluated by measuring CVP, urine output, infused fluid volume; Surgical blood loss was reviewed to exclude hemorrhage shock and hypovolemia. As no special medications were given except anesthetic maintenance drugs, and no signs of mottled skin or bronchospasm were noticed, anaphylaxis was not considered at that time. After restoring circulatory stability, the surgery preceded uneventfully. The patient was discharged from hospital 7 days later.
It was intriguing that within 1 month, another case of circulatory collapse happened during wound closure in spine surgery performed by the same orthopedic surgeon. The intraoperative clinical manifestations were very similar to the previous one. Hemodynamic resuscitation were initiated immediately with repeated boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min). After stabilizing the circulation 4 h later, the patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions after full recovery from anesthesia). Postoperative imaging revealed intracranial micro hemorrhagic foci in the subdural and subarachnoid space. The patient was discharged from hospital without any neurological sequelae.
With further exploration and analysis of the similarities of these two cases, we found that local application of vancomycin (VCM) powder was used in these two patients to prevent postoperative surgical site infections (SSIs) during wound closure (0.5 g VCM loaded with bone debris into the cage and another 0.5 g sprayed on the dura mater and into the mascularis). Ramamani Mariappan reported a case of circulatory collapse after topical application of vancomycin powder during spine surgery, which exhibited almost the same clinical course as ours [2]. It was speculated that the rapid absorption of VCM applied to the surgical wound caused an anaphylaxis reaction and circulatory collapse. The reaction occurred approximately 30 min after the application and persisted for 6 h. The serum tryptase level was not elevated, suggesting that VCM caused a direct histamine release, which is in keeping with our current understanding. A similar case reported a 74-year-old woman who underwent a primary total knee replacement presented with red man syndrome in the PACU 45 min after release of tourniquet following the use of VCM-loaded bone cement. The patient remained fully conscious despite a sudden drop in blood pressure to 47/34 mmHg [3]. Therefore, local application of VCM may pose the risk of causing severe circulatory adverse effect.
Similar circulatory collapse cases in spine surgery without definitive causes during wound closure or shortly after surgery, though rare, were encountered in our institution. Therefore we retrospectively analyzed these cases for the past 2 years, and asked the anesthesiologists and orthopedic surgeons in charge for further information. A total of 7 cases were collected (Table 1). There were 3 males and 4 females, the median age was 66 y (43–74 y), and the averaged BMI was 24.39 ± 1.51 (22.3–26.1). It was interesting to note that these cases were all associated with topical application of VCM powder (Table 1). In these 7 cases, the onset time of severe circulatory fluctuation was 30 min in 5 cases, 50 min in one case (applied with 1 g of VCM), and approximately 45 min in another case (locally applied 3 g of VCM), respectively. Most of the cases (6/7) with severe circulatory fluctuation were corrected without severe sequelae. While in one case in which 3 g of VCM was applied on the dura mater and into the mascularis during wound closure, sudden cardiac arrest happened shortly after the patient had fully recovered from the anesthetic, following surgery and extubation in the OR. CPR was initiated immediately. The patient was reintubated and ventilated mechanically. The persistent VF was treated with continuous chest compressions and repeated defibrillation, with boluses of adrenaline (a total of 6 mg) and amiodarone. After 50 min of continuous CPR, with fluid resuscitation and blood transfusion, the patient was transferred to ICU following the return of spontaneous circulation and reverting into sinus rhythm. However, the patient remained in a comatose state due to hypoxic-hypoxic encephalopathy, and tracheotomy was performed 2 weeks later.
Discussion and conclusion
Vancomycin and anaphylaxis reaction
“International Consensus on (ICON) Anaphylaxis” define anaphylaxis as “a serious, generalized or systemic, allergic or hypersensitivity reaction that can be life threatening or fatal” [4]. It has been demonstrated that there exists IgE-dependent and three IgE-independent mechanisms in anaphylaxis pathophysiology [5]. VCM could directly activate mast cells to release histamine and other mediators through an IgE-independent mechanism that is calcium-, phospholipase C–, and phospholipase A2–dependent but otherwise unknown [5, 6]. Vancomycin-induced direct histamine release is also infusion rate dependent [7]. This IgE-independent anaphylaxis reaction generally disappears within 20 mins, but may linger for hours. The most common manifestation is a sudden drop in blood pressure, which is related to the negative inotropic effect and the vasodilator action stimulated by the histamine release. Alteration in vascular tone is also a common feature of anaphylactic shock [8]. Richter J and colleagues demonstrated in rats that VCM could directly influence the vascular tonus, affecting the microcirculation [9].
The VCM reactions studied in the pediatric population revealed that non-IgE mediated reaction accounts for the vast majority of reactions (92%; prevalence, 5.4–5.8%), whereas possible IgE-mediated vancomycin reactions were exceedingly rare (prevalence, 0.0–0.37%) [7]. For adults, the reported incidence of non-IgE mediated reaction varies between 3.7 and 47% in infected patients and 90% in healthy volunteers [2]. Elevated serum mast cell tryptase is a valuable indicator for diagnosing Ig-E mediated anaphylactic reaction. However, it is not useful in determining a non-IgE mediated anaphylactic reaction caused by histamine release [2]. Detection of histamine concentration in clinical blood specimens is difficult due to its extremely short half-life, and histamine is not a mast cell specific product [10]. As this study is retrospective in nature, and our hospital does not perform examination of serum tryptase and histamine concentration, we could not differentiate whether the adverse effects were caused by VCM induced IgE-mediated or non-IgE mediated reaction.
Topical application of vancomycin powder and surgical site infections
VCM is effective in fighting Gram-positive bacteria related severe infections [11]. While the actual utility of local application of VCM is controversial. After the first reported topical application of VCM by orthopedic surgeons to reduce postoperative surgical site infections (SSIs) rate [12], a large number of meta-analyses, retrospective cohort studies, and randomized controlled trials were published to assess the power of this method in preventing SSIs. Recent findings from large-scale propensity score matched analyses, meta analyses, RCTs studies, and observational studies of spine surgeries and knee arthroplasties all demonstrated that the intrawound VCM powder application may not decrease SSIs, but may increase postoperative complications [13–19].
VCM is an antibiotic that was considered safe in local application and has been widely used in hospitals. However, dose recommendations, dilutions, monitoring, infusion types and rates are still controversial [20]. There’s no defined time or situation during surgery when local VCM should be applied. Some may load VCM powder with bone debris into the cage, or apply VCM powder directly onto the dura mater or after closure of the fascia, whereas other studies reported that VCM powder was applied in the subfascial layer [2, 13]. However, intrawound absorption rate of VCM powder is uncontrollable as this depends on multiple factors, such as the extent and degree of tissue/muscle damaged by surgical manipulation, anatomic location where VCM powder is placed (mixed with bone debris, or between muscularis layers that are abundant with blood supply), and the surgeon’s suturing maneuvers (the flushing saline would leak from upper layer into the layer where VCM powder is deposited). These factors all pose potential risk of causing rapid drug dissolution and accelerated absorption into the circulatory system. Moreover, individual’s adverse reactions to VCM varied. These incidental events may be accidentally linked and lead to severe outcome. Since intravenous administration of VCM could lead to adverse effects, it is theoretically possible that local application of VCM powder may cause similar clinical manifestation.
Topical application of VCM was intended to achieve the effect of providing high local concentrations while avoiding high systemic levels and the risk of bacterial resistance. The serum concentration level peaks at 30 min and then declines to baseline at 6 h [2]. This may explain the delayed and unpredictable occurrence of anaphylaxis reactions after local application of VCM powder, due to the uncertainty of the drug absorption rate and individual reaction differences. The instructed therapeutic dosage of VCM is 30 mg/kg/day which should be fractioned in 2 or 3 doses. Moreover, the infusion rate should be within 10 mg/min, and last for more than 60 min. For elderly patients, this dosage should be reduced [21, 22]. Although the most commonly used dose of intrawound VCM is 1 g, some authors reported that they altered the dose according to the length of the incision [23]. VCM is not the first-choice antibiotic as its adverse effects are frequently reported including hypotension and tachycardia, phlebitis, nephrotoxicity, ototoxicity, hypersensitivity reactions, red man syndrome, neutropenia, chills, fever, interstitial nephritis, etc. [13]. As VCM induced adverse reactions are dose and infusion-rate dependent, doctors should be highly vigilant to over-dosing which might bring disastrous results.
Other issues related to shock
In this case series, the typical signs of erythema and redness (red man syndrome) have not appeared, which resemble the previous case reported by Mariappan R and colleagues [2]. The lack of skin flushing may be the result of reduced perfusion due to circulatory shock or the adverse effect of VCM mainly manifested as severe alteration of vascular tonus [8, 9]. In our experience, a rapid but low dose intravenous infusion of VCM induced anaphylaxis reaction was not necessarily associated with skin manifestations. Whether this is related to racial differences or rapid absorption of low dose VCM was not known. However, the clinical features of hypotension, tachycadia and low oxygenation were notable.
For this case series, as there is no definitive laboratory examination or gold standard to help reach a definitive diagnosis of VCM induced anaphylaxis reaction, the conclusions were made upon differential diagnosis based on clinical manifestations and the timing of the shock. Other possible causes or contributing factors for the development of severe hypotension and shock need to be considered. For example, restrictive fluid therapy during surgical procedure and restrictive blood transfusion strategy leading to hypovolemia and hypotension, complicated with unseen bleeding from surgical site and other compounding factors such as hypoproteinemia and unaltered anesthetic depth during wound closure.
Another issue needs to be addressed is that there’s a notable decrease in hemoglobin (HGB) concentration in all cases when severe hypotension occurred. However, the hemorrhagic shock induced by surgical blood loss was ruled out. We speculate that this might be due to the infusion of large amounts of fluid during resuscitation. It is reported that the administration of 500 ml of fluids may acutely decrease the HGB concentration by about 1 g/dl, or about 8%, by “dilutional anemia” [24]. In septic shock patients, approximately 30% decrease of hematocrit was commonly observed in patients receiving large amounts of fluids during resuscitation, which further indicates more blood transfusion [25]. In the current study, the HGB concentrations were all measured after the initiation of fluid resuscitation and this may at least partially explained the sharp decrease of the HGB level (Table 1). When severe hypotension with unknown causes occur, initial management is to infuse large amounts of fluid with vaso-constrictive drugs. The iatrogenic hemodilution related blood transfusion may result in dilutional coagulopathy and increase surgical bleeding. This then leads to a decreased HGB level below the acceptable transfusion threshold, leading to further blood transfusion in the absence of significant blood loss [26]. This is especially true when in the scenario of the existence of suspected hemorrhagic shock.
In conclusion, local application of VCM powder during wound closure could cause delayed occurrence of severe hypotension and shock in spine surgery. Hemodynamic changes may be under-emphasized and under-reported as in most cases, this hemodynamic reaction is easy to correct and normally wouldn’t cause serious consequences. However, the actual occurrence is not rare and this might be confused with hypovolemia or anesthetic induced hypotension. Surgeons and anesthesiologists should be highly aware of VCM induced IgE-independent anaphylaxis reactions. The differential diagnosis of anaphylactic shock must be taken into consideration in patients with acute hypotension during or immediately after wound closure. Prompt laboratory analysis of serum tryptase and histamine concentration could help differentiate the causes. Moreover, since controversies still exist in the actual effect of intrawound application of VCM powder to reduce SSIs in spine surgery, local application of this drug should be used with caution.
Abbreviations
VCMVancomycin
ABPArterial blood pressure
TTETransthoracic echocardiography
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
We sincerely thank our colleagues from anesthesia (Dr. XW, Dr. CW, Dr. WL, Dr. JY, Dr. YW, Dr. CN, Dr. CX, Dr. YT, Dr. HW, Dr. HT, Dr. WW, Dr. YT, Dr. XJ, HL, Dr. HW, Dr. HZ, Dr. YW, and Dr. BW) and surgical department (Dr. YD, Dr. YL, Dr. FZ, Dr. QQ, and Dr. ZC) for providing and verifying the cases.
The authors have completed the CARE reporting checklist.
Authors’ contributions
Guarantor of integrity of entire study: XZ, WZ, ML, XG. Literature research: XZ, WZ. Case study and follow-up: XZ, WZ. Manuscript preparation: XZ, WZ. Manuscript editing and revision: ML, XG. Manuscript final version approval: ML, XG. All authors have read and approved the manuscript.
Funding
This work was supported by the Clinical Key Project of Peking University Third Hospital, Grants No. BYSY2017001.
The role of the funder: study design, decision to submit the manuscript for publication.
Availability of data and materials
All data generated or analyzed during this study are included in this published article. More detailed information could be find in Table 1.
Ethics approval and consent to participate
This case was performed according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Peking University Third Hospital. All the authors listed in the manuscript consent to participate the study. The consent for publication from patient or their relatives were collected retrospectively.
Consent for publication
As this is a retrospective case study, written informed consent to publish this manuscript were collected from patients or their relatives retrospectively. The proof of consent to publish from study participants can be requested at any time.
Competing interests
The author(s) declare no competing interests. | VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33407142 | 18,839,984 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemorrhage intracranial'. | Circulatory collapse during wound closure in spine surgery with an unknown cause: a possible adverse effect of topical application of vancomycin?
Vancomycin (VCM) is effective in fighting Gram-positive bacteria related severe infections, and topical application of VCM powder is widely used in orthopedic surgery to prevent wound infection. However, VCM could lead to infusion rate-dependent antibody-and complement-independent anaphylaxis reaction by inducing direct release of histamine.
We retrospectively analyzed seven cases of severe hypotension and shock during wound closure or immediately after orthopedic surgery with unidentifiable reasons. We found that these cases were all associated with local application of VCM powder during wound closure process. Two patients experienced sudden cardiac arrest. Most of the cases (6/7) with circulatory collapse were discharged without severe sequelae. While one case with application of 3 g VCM developed cardiac arrest and remained in a coma due to hypoxic-hypoxic encephalopathy. The clinical presentations and the time of the shock onset were considered to be related with a VCM induced anaphylaxis reaction. However, as this was a retrospective study, and there was no laboratory examination performed, the conclusion was made upon differential diagnosis based on clinical manifestations and the timing of the shock.
Local application of VCM may not be as safe as was once believed and may lead to a related anaphylaxis. As VCM induced infusion-rate dependent, non-IgE mediated anaphylaxis is characterized by delayed occurrence, severe hypotension and even circulatory collapse, surgeons and anesthesiologists should be extra vigilant during and after VCM application.
Background
Shock is defined as a state of insufficient perfusion and oxygen delivery to the tissues. The pathophysiology of shock could be simplified to three major components: cardiac function (the pump), intravascular volume (the tank), and systemic vascular resistance (the pipes) [1]. Whatever the causes of shock may be, if the impaired perfusion and oxygen delivery is not recognized and reversed, the circulatory collapse may progress into organ dysfunction and failure, tissue necrosis and even death. It is urgent to identify the causes of shock and take immediate measures. However, in critical situations, it is hard to rapidly distinguish the culprit during complex clinical situations. Here we present 7 cases (Table 1) of unidentifiable causes of shock during wound closure or shortly after spine surgery, and discuss the possible reasons.
Table 1 Summary of clinical presentations of seven patients with circulatory collapse and unknown etiologies during or shortly after wound closure in spine surgery
Case Demographic information Initial signs/symptoms of shock and management Hemoglobin value (g/L),
fluid resuscitation and blood product infusion VCM administration
and Postoperative sequelae
1 Female; 68-yr; 160 cm/60 kg
BMI: 23.4
Diagnosis:
Lumbar stenosis (L3-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Hypertension
History of retina surgery
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
ABP: 30/20 mmHg
SpO2: undetectable
ECG: tarchycardia with elevated ST segment
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for 45 min. Fluid resuscitation and blood transfusion.
Preoperative HGB value: 124
Intraoperative minimum value of HGB: 73
Blood loss: 600 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 3450 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 210 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
Proceeded with surgery and the patient was extubated uneventfully.
2 Male; 74-yr; 171 cm/67 kg
BMI: 23.9
Diagnosis:
lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
ECG: tachycardia with ST segment depression
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min) for 4 h.
Preoperative HGB value:135
Intraoperative minimum value of HGB: 79
Blood loss: 600 ml
Urine: 1950 ml
Fluid and blood product infusion:
Crystalloid: 6300 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Plasma: 800 ml
Infused autologous blood: 254 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions).
Postoperative imaging: intracranial minor hemorrhage at subdural and subarachnoid space.
The patient was discharged from hospital without neurological deficit.
3 Male; 63-yr; 169 cm/70 kg
BMI: 24.5
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Lacunar infarction;
Bilateral carotid atherosclerotic plaque formation
Time of occurrence:
50 min after initiation of wound closure and 20 min post-extubation in the PACU.
Signs and symptoms:
NBP: 60/25 mmHg
SpO2: 96%
HR:sudden elevation from 60 to 90 bpm
Postoperative agitation
Skin and airway symptoms: none.
Management:
Boluses of ephedrine, phenylephrine and fluid resuscitation.
Preoperative HGB value: 176
Intraoperative minimum value of HGB:123
Blood loss: 800 ml
Urine: 800 ml
Fluid and blood product infusion:
Crystalloid: 2350 ml
Colloid: 1000 ml
PRBC infusion: 400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis.
Postoperative sequelae:
Uneventful.
4 Female; 70-yr; 160 cm/65 kg
BMI:25.4
Diagnosis:
Lumbar stenosis (L4-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Hypertension
Diabetes Mellitus
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
Persistent tachycardia
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine for treating severe hypotension and esmolol for tachycardia
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 150
Intraoperative minimum value of HGB: 92
Blood loss: 1500 ml
Urine: 1800 ml
Fluid and blood product infusion:
Crystalloid: 3100 ml
Colloid: 1500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 450 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery and transferred to ICU due to tachycardia after sufficient fluid resuscitation.
Recovered uneventfully.
5 Female;48-yr; 170 cm/75 kg
BMI: 26.0
Diagnosis:
Thoracic spinal canal stenosis (T6-T11)
Surgery:
Posterior decompression, fixation and fusion of thoracic spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 40/30 mmHg to undetectable
HR: 120 bpm to 40 bpm
SpO2: undetectable
Cardiac arrest
Skin and airway symptoms: none.
Management:
Extracardiac compression
Boluses of noradrenaline (200 μg) and adrenaline (1 g)
Continuous infusion of noradrenaline (0.02–0.08 μg/kg/min) for 50 min
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 132
Intraoperative minimum value of HGB: 74
Blood loss: 2500 ml
Urine: 1300 ml
Fluid and blood product infusion:
Crystalloid: 4000 ml
Colloid: 500 ml
PRBC infusion: 2400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery, and discharged from hospital uneventfully.
6 Male; 66-yr; 175 cm/ 80 kg
BMI: 26.1
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Carotid artery stenosis
Diabetes Mellitus
Time of occurrence:
Sudden cardiac arrest 10 min after extubation (approximately 45 min after initiation of wound closure) with full recovery from anesthesia and without any discomfort complaint.
Signs and symptoms:
Cardiac arrest and persistent VF
Skin and airway symptoms: none.
Management:
Continuous CPR
Persistent VF was treated with repeated defibrillation
Boluses of adrenaline (a total of 6 mg) and amiodarone.
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 143
Intraoperative minimum value of HGB: 78
Blood loss: 1000 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 4400 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 600 ml
VCM administration:
Topical spraying of vancomycin (3 g) on the dura mater and into the mascularis.
Postoperative sequelae:
The patient was reintubated and transferred to ICU after ROSC. The patient was diagnosed as hypoxic encephalopathy and remained in a coma state. Tracheotomy was performed 2 weeks after surgery, and the patient was transferred to a nursing home for rehabilitation 1 month after orthopedic surgery.
7 Female; 43-yr; 155 cm / 54 kg
BMI: 22.4
Diagnosis:
Thoracic kyphosis (T7-T8)
Surgery:
Osteotomy for kyphosis of thoracic spine (T7-T8).
Medical and allergy history:
nil relevant.
Time of occurrence:
subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
HR:tachycardia
NBP: 60/30 mmHg
SpO2 82%
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine and ephedrine;
Continuous infusion of noradrenaline (0.05–0.1 μg/kg/min)
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 138
Intraoperative minimum value of HGB: 95
Blood loss: 1200 ml
Urine: 1900 ml
Fluid and blood product infusion:
Crystalloid: 4700 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 470 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was transferred to ICU for optimal monitoring and recovered uneventfully.
Abbreviations: NBP Non-invasive blood pressure; ABP Arterial blood pressure; (NBP is noted when ABP is not available.) VF Ventricular fibrillation; CPR Cardiopulmonary Resuscitation; HGB Hemoglobin; VCM Vancomycin; PRBC Packed red blood cell; ROSC Return of spontaneous circulation
Case presentation
The first case we encountered was a 68-yr female with past medical history of hypertension and surgical treated retina detachment, who underwent posterior decompression, fixation and fusion of lumbar spine due to lumbar stenosis (L3-S1). The operation was uneventful until sudden circulatory collapse occurred during the process of rinsing mascularis and superficial fascia layer whilst closing the wound. A sudden drop in arterial blood pressure (ABP) (130/60 mmHg to 30/20 mmHg), increased HR (60 bpm to 100 bpm) with elevated ST-segment and significant decrease of PetCO2 (31 mmHg to 16 mmHg) were noticed, with undetectable pulse oximetry read. The patient was turned to supine position immediately and managed with boluses (40–100 μg) and a continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for approximately 45 min. The circulation was gradually stabilized. No rash, erythema, or bronchospasm were noted. The bilateral breath sounds were equal and the airway pressure remained normal. We continued treatments of fluid resuscitation and blood transfusion with corticosteroid and ice cap to prevent hypoxic-ischemic encephalopathy. Intraoperative emergency consultations and immediate examinations of 12-lead ECG, point-of-care transthoracic echocardiography (TTE), and full panel laboratory tests were performed. However, these results did not support the causes of sudden cardiac dysfunction (the pump) including mechanical obstruction (pericardial tamponade and massive pulmonary embolus), acute myocardial infarction, acute valvular insufficiency, and arrhythmia. Vascular catastrophes were excluded and there were no signs of sepsis. We also examined the intravascular volume function (the tank) by performing the TTE, and ruled out intraperitoneal major hemorrhage which we once encountered (caused by inadvertent piercing of iliac artery when placing probe during lumbar surgery) by examination of abdominal ultrasound and hemoglobin level; Volume status was evaluated by measuring CVP, urine output, infused fluid volume; Surgical blood loss was reviewed to exclude hemorrhage shock and hypovolemia. As no special medications were given except anesthetic maintenance drugs, and no signs of mottled skin or bronchospasm were noticed, anaphylaxis was not considered at that time. After restoring circulatory stability, the surgery preceded uneventfully. The patient was discharged from hospital 7 days later.
It was intriguing that within 1 month, another case of circulatory collapse happened during wound closure in spine surgery performed by the same orthopedic surgeon. The intraoperative clinical manifestations were very similar to the previous one. Hemodynamic resuscitation were initiated immediately with repeated boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min). After stabilizing the circulation 4 h later, the patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions after full recovery from anesthesia). Postoperative imaging revealed intracranial micro hemorrhagic foci in the subdural and subarachnoid space. The patient was discharged from hospital without any neurological sequelae.
With further exploration and analysis of the similarities of these two cases, we found that local application of vancomycin (VCM) powder was used in these two patients to prevent postoperative surgical site infections (SSIs) during wound closure (0.5 g VCM loaded with bone debris into the cage and another 0.5 g sprayed on the dura mater and into the mascularis). Ramamani Mariappan reported a case of circulatory collapse after topical application of vancomycin powder during spine surgery, which exhibited almost the same clinical course as ours [2]. It was speculated that the rapid absorption of VCM applied to the surgical wound caused an anaphylaxis reaction and circulatory collapse. The reaction occurred approximately 30 min after the application and persisted for 6 h. The serum tryptase level was not elevated, suggesting that VCM caused a direct histamine release, which is in keeping with our current understanding. A similar case reported a 74-year-old woman who underwent a primary total knee replacement presented with red man syndrome in the PACU 45 min after release of tourniquet following the use of VCM-loaded bone cement. The patient remained fully conscious despite a sudden drop in blood pressure to 47/34 mmHg [3]. Therefore, local application of VCM may pose the risk of causing severe circulatory adverse effect.
Similar circulatory collapse cases in spine surgery without definitive causes during wound closure or shortly after surgery, though rare, were encountered in our institution. Therefore we retrospectively analyzed these cases for the past 2 years, and asked the anesthesiologists and orthopedic surgeons in charge for further information. A total of 7 cases were collected (Table 1). There were 3 males and 4 females, the median age was 66 y (43–74 y), and the averaged BMI was 24.39 ± 1.51 (22.3–26.1). It was interesting to note that these cases were all associated with topical application of VCM powder (Table 1). In these 7 cases, the onset time of severe circulatory fluctuation was 30 min in 5 cases, 50 min in one case (applied with 1 g of VCM), and approximately 45 min in another case (locally applied 3 g of VCM), respectively. Most of the cases (6/7) with severe circulatory fluctuation were corrected without severe sequelae. While in one case in which 3 g of VCM was applied on the dura mater and into the mascularis during wound closure, sudden cardiac arrest happened shortly after the patient had fully recovered from the anesthetic, following surgery and extubation in the OR. CPR was initiated immediately. The patient was reintubated and ventilated mechanically. The persistent VF was treated with continuous chest compressions and repeated defibrillation, with boluses of adrenaline (a total of 6 mg) and amiodarone. After 50 min of continuous CPR, with fluid resuscitation and blood transfusion, the patient was transferred to ICU following the return of spontaneous circulation and reverting into sinus rhythm. However, the patient remained in a comatose state due to hypoxic-hypoxic encephalopathy, and tracheotomy was performed 2 weeks later.
Discussion and conclusion
Vancomycin and anaphylaxis reaction
“International Consensus on (ICON) Anaphylaxis” define anaphylaxis as “a serious, generalized or systemic, allergic or hypersensitivity reaction that can be life threatening or fatal” [4]. It has been demonstrated that there exists IgE-dependent and three IgE-independent mechanisms in anaphylaxis pathophysiology [5]. VCM could directly activate mast cells to release histamine and other mediators through an IgE-independent mechanism that is calcium-, phospholipase C–, and phospholipase A2–dependent but otherwise unknown [5, 6]. Vancomycin-induced direct histamine release is also infusion rate dependent [7]. This IgE-independent anaphylaxis reaction generally disappears within 20 mins, but may linger for hours. The most common manifestation is a sudden drop in blood pressure, which is related to the negative inotropic effect and the vasodilator action stimulated by the histamine release. Alteration in vascular tone is also a common feature of anaphylactic shock [8]. Richter J and colleagues demonstrated in rats that VCM could directly influence the vascular tonus, affecting the microcirculation [9].
The VCM reactions studied in the pediatric population revealed that non-IgE mediated reaction accounts for the vast majority of reactions (92%; prevalence, 5.4–5.8%), whereas possible IgE-mediated vancomycin reactions were exceedingly rare (prevalence, 0.0–0.37%) [7]. For adults, the reported incidence of non-IgE mediated reaction varies between 3.7 and 47% in infected patients and 90% in healthy volunteers [2]. Elevated serum mast cell tryptase is a valuable indicator for diagnosing Ig-E mediated anaphylactic reaction. However, it is not useful in determining a non-IgE mediated anaphylactic reaction caused by histamine release [2]. Detection of histamine concentration in clinical blood specimens is difficult due to its extremely short half-life, and histamine is not a mast cell specific product [10]. As this study is retrospective in nature, and our hospital does not perform examination of serum tryptase and histamine concentration, we could not differentiate whether the adverse effects were caused by VCM induced IgE-mediated or non-IgE mediated reaction.
Topical application of vancomycin powder and surgical site infections
VCM is effective in fighting Gram-positive bacteria related severe infections [11]. While the actual utility of local application of VCM is controversial. After the first reported topical application of VCM by orthopedic surgeons to reduce postoperative surgical site infections (SSIs) rate [12], a large number of meta-analyses, retrospective cohort studies, and randomized controlled trials were published to assess the power of this method in preventing SSIs. Recent findings from large-scale propensity score matched analyses, meta analyses, RCTs studies, and observational studies of spine surgeries and knee arthroplasties all demonstrated that the intrawound VCM powder application may not decrease SSIs, but may increase postoperative complications [13–19].
VCM is an antibiotic that was considered safe in local application and has been widely used in hospitals. However, dose recommendations, dilutions, monitoring, infusion types and rates are still controversial [20]. There’s no defined time or situation during surgery when local VCM should be applied. Some may load VCM powder with bone debris into the cage, or apply VCM powder directly onto the dura mater or after closure of the fascia, whereas other studies reported that VCM powder was applied in the subfascial layer [2, 13]. However, intrawound absorption rate of VCM powder is uncontrollable as this depends on multiple factors, such as the extent and degree of tissue/muscle damaged by surgical manipulation, anatomic location where VCM powder is placed (mixed with bone debris, or between muscularis layers that are abundant with blood supply), and the surgeon’s suturing maneuvers (the flushing saline would leak from upper layer into the layer where VCM powder is deposited). These factors all pose potential risk of causing rapid drug dissolution and accelerated absorption into the circulatory system. Moreover, individual’s adverse reactions to VCM varied. These incidental events may be accidentally linked and lead to severe outcome. Since intravenous administration of VCM could lead to adverse effects, it is theoretically possible that local application of VCM powder may cause similar clinical manifestation.
Topical application of VCM was intended to achieve the effect of providing high local concentrations while avoiding high systemic levels and the risk of bacterial resistance. The serum concentration level peaks at 30 min and then declines to baseline at 6 h [2]. This may explain the delayed and unpredictable occurrence of anaphylaxis reactions after local application of VCM powder, due to the uncertainty of the drug absorption rate and individual reaction differences. The instructed therapeutic dosage of VCM is 30 mg/kg/day which should be fractioned in 2 or 3 doses. Moreover, the infusion rate should be within 10 mg/min, and last for more than 60 min. For elderly patients, this dosage should be reduced [21, 22]. Although the most commonly used dose of intrawound VCM is 1 g, some authors reported that they altered the dose according to the length of the incision [23]. VCM is not the first-choice antibiotic as its adverse effects are frequently reported including hypotension and tachycardia, phlebitis, nephrotoxicity, ototoxicity, hypersensitivity reactions, red man syndrome, neutropenia, chills, fever, interstitial nephritis, etc. [13]. As VCM induced adverse reactions are dose and infusion-rate dependent, doctors should be highly vigilant to over-dosing which might bring disastrous results.
Other issues related to shock
In this case series, the typical signs of erythema and redness (red man syndrome) have not appeared, which resemble the previous case reported by Mariappan R and colleagues [2]. The lack of skin flushing may be the result of reduced perfusion due to circulatory shock or the adverse effect of VCM mainly manifested as severe alteration of vascular tonus [8, 9]. In our experience, a rapid but low dose intravenous infusion of VCM induced anaphylaxis reaction was not necessarily associated with skin manifestations. Whether this is related to racial differences or rapid absorption of low dose VCM was not known. However, the clinical features of hypotension, tachycadia and low oxygenation were notable.
For this case series, as there is no definitive laboratory examination or gold standard to help reach a definitive diagnosis of VCM induced anaphylaxis reaction, the conclusions were made upon differential diagnosis based on clinical manifestations and the timing of the shock. Other possible causes or contributing factors for the development of severe hypotension and shock need to be considered. For example, restrictive fluid therapy during surgical procedure and restrictive blood transfusion strategy leading to hypovolemia and hypotension, complicated with unseen bleeding from surgical site and other compounding factors such as hypoproteinemia and unaltered anesthetic depth during wound closure.
Another issue needs to be addressed is that there’s a notable decrease in hemoglobin (HGB) concentration in all cases when severe hypotension occurred. However, the hemorrhagic shock induced by surgical blood loss was ruled out. We speculate that this might be due to the infusion of large amounts of fluid during resuscitation. It is reported that the administration of 500 ml of fluids may acutely decrease the HGB concentration by about 1 g/dl, or about 8%, by “dilutional anemia” [24]. In septic shock patients, approximately 30% decrease of hematocrit was commonly observed in patients receiving large amounts of fluids during resuscitation, which further indicates more blood transfusion [25]. In the current study, the HGB concentrations were all measured after the initiation of fluid resuscitation and this may at least partially explained the sharp decrease of the HGB level (Table 1). When severe hypotension with unknown causes occur, initial management is to infuse large amounts of fluid with vaso-constrictive drugs. The iatrogenic hemodilution related blood transfusion may result in dilutional coagulopathy and increase surgical bleeding. This then leads to a decreased HGB level below the acceptable transfusion threshold, leading to further blood transfusion in the absence of significant blood loss [26]. This is especially true when in the scenario of the existence of suspected hemorrhagic shock.
In conclusion, local application of VCM powder during wound closure could cause delayed occurrence of severe hypotension and shock in spine surgery. Hemodynamic changes may be under-emphasized and under-reported as in most cases, this hemodynamic reaction is easy to correct and normally wouldn’t cause serious consequences. However, the actual occurrence is not rare and this might be confused with hypovolemia or anesthetic induced hypotension. Surgeons and anesthesiologists should be highly aware of VCM induced IgE-independent anaphylaxis reactions. The differential diagnosis of anaphylactic shock must be taken into consideration in patients with acute hypotension during or immediately after wound closure. Prompt laboratory analysis of serum tryptase and histamine concentration could help differentiate the causes. Moreover, since controversies still exist in the actual effect of intrawound application of VCM powder to reduce SSIs in spine surgery, local application of this drug should be used with caution.
Abbreviations
VCMVancomycin
ABPArterial blood pressure
TTETransthoracic echocardiography
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
We sincerely thank our colleagues from anesthesia (Dr. XW, Dr. CW, Dr. WL, Dr. JY, Dr. YW, Dr. CN, Dr. CX, Dr. YT, Dr. HW, Dr. HT, Dr. WW, Dr. YT, Dr. XJ, HL, Dr. HW, Dr. HZ, Dr. YW, and Dr. BW) and surgical department (Dr. YD, Dr. YL, Dr. FZ, Dr. QQ, and Dr. ZC) for providing and verifying the cases.
The authors have completed the CARE reporting checklist.
Authors’ contributions
Guarantor of integrity of entire study: XZ, WZ, ML, XG. Literature research: XZ, WZ. Case study and follow-up: XZ, WZ. Manuscript preparation: XZ, WZ. Manuscript editing and revision: ML, XG. Manuscript final version approval: ML, XG. All authors have read and approved the manuscript.
Funding
This work was supported by the Clinical Key Project of Peking University Third Hospital, Grants No. BYSY2017001.
The role of the funder: study design, decision to submit the manuscript for publication.
Availability of data and materials
All data generated or analyzed during this study are included in this published article. More detailed information could be find in Table 1.
Ethics approval and consent to participate
This case was performed according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Peking University Third Hospital. All the authors listed in the manuscript consent to participate the study. The consent for publication from patient or their relatives were collected retrospectively.
Consent for publication
As this is a retrospective case study, written informed consent to publish this manuscript were collected from patients or their relatives retrospectively. The proof of consent to publish from study participants can be requested at any time.
Competing interests
The author(s) declare no competing interests. | VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33407142 | 18,822,543 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypoxic-ischaemic encephalopathy'. | Circulatory collapse during wound closure in spine surgery with an unknown cause: a possible adverse effect of topical application of vancomycin?
Vancomycin (VCM) is effective in fighting Gram-positive bacteria related severe infections, and topical application of VCM powder is widely used in orthopedic surgery to prevent wound infection. However, VCM could lead to infusion rate-dependent antibody-and complement-independent anaphylaxis reaction by inducing direct release of histamine.
We retrospectively analyzed seven cases of severe hypotension and shock during wound closure or immediately after orthopedic surgery with unidentifiable reasons. We found that these cases were all associated with local application of VCM powder during wound closure process. Two patients experienced sudden cardiac arrest. Most of the cases (6/7) with circulatory collapse were discharged without severe sequelae. While one case with application of 3 g VCM developed cardiac arrest and remained in a coma due to hypoxic-hypoxic encephalopathy. The clinical presentations and the time of the shock onset were considered to be related with a VCM induced anaphylaxis reaction. However, as this was a retrospective study, and there was no laboratory examination performed, the conclusion was made upon differential diagnosis based on clinical manifestations and the timing of the shock.
Local application of VCM may not be as safe as was once believed and may lead to a related anaphylaxis. As VCM induced infusion-rate dependent, non-IgE mediated anaphylaxis is characterized by delayed occurrence, severe hypotension and even circulatory collapse, surgeons and anesthesiologists should be extra vigilant during and after VCM application.
Background
Shock is defined as a state of insufficient perfusion and oxygen delivery to the tissues. The pathophysiology of shock could be simplified to three major components: cardiac function (the pump), intravascular volume (the tank), and systemic vascular resistance (the pipes) [1]. Whatever the causes of shock may be, if the impaired perfusion and oxygen delivery is not recognized and reversed, the circulatory collapse may progress into organ dysfunction and failure, tissue necrosis and even death. It is urgent to identify the causes of shock and take immediate measures. However, in critical situations, it is hard to rapidly distinguish the culprit during complex clinical situations. Here we present 7 cases (Table 1) of unidentifiable causes of shock during wound closure or shortly after spine surgery, and discuss the possible reasons.
Table 1 Summary of clinical presentations of seven patients with circulatory collapse and unknown etiologies during or shortly after wound closure in spine surgery
Case Demographic information Initial signs/symptoms of shock and management Hemoglobin value (g/L),
fluid resuscitation and blood product infusion VCM administration
and Postoperative sequelae
1 Female; 68-yr; 160 cm/60 kg
BMI: 23.4
Diagnosis:
Lumbar stenosis (L3-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Hypertension
History of retina surgery
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
ABP: 30/20 mmHg
SpO2: undetectable
ECG: tarchycardia with elevated ST segment
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for 45 min. Fluid resuscitation and blood transfusion.
Preoperative HGB value: 124
Intraoperative minimum value of HGB: 73
Blood loss: 600 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 3450 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 210 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
Proceeded with surgery and the patient was extubated uneventfully.
2 Male; 74-yr; 171 cm/67 kg
BMI: 23.9
Diagnosis:
lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
ECG: tachycardia with ST segment depression
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min) for 4 h.
Preoperative HGB value:135
Intraoperative minimum value of HGB: 79
Blood loss: 600 ml
Urine: 1950 ml
Fluid and blood product infusion:
Crystalloid: 6300 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Plasma: 800 ml
Infused autologous blood: 254 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions).
Postoperative imaging: intracranial minor hemorrhage at subdural and subarachnoid space.
The patient was discharged from hospital without neurological deficit.
3 Male; 63-yr; 169 cm/70 kg
BMI: 24.5
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Lacunar infarction;
Bilateral carotid atherosclerotic plaque formation
Time of occurrence:
50 min after initiation of wound closure and 20 min post-extubation in the PACU.
Signs and symptoms:
NBP: 60/25 mmHg
SpO2: 96%
HR:sudden elevation from 60 to 90 bpm
Postoperative agitation
Skin and airway symptoms: none.
Management:
Boluses of ephedrine, phenylephrine and fluid resuscitation.
Preoperative HGB value: 176
Intraoperative minimum value of HGB:123
Blood loss: 800 ml
Urine: 800 ml
Fluid and blood product infusion:
Crystalloid: 2350 ml
Colloid: 1000 ml
PRBC infusion: 400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis.
Postoperative sequelae:
Uneventful.
4 Female; 70-yr; 160 cm/65 kg
BMI:25.4
Diagnosis:
Lumbar stenosis (L4-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Hypertension
Diabetes Mellitus
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
Persistent tachycardia
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine for treating severe hypotension and esmolol for tachycardia
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 150
Intraoperative minimum value of HGB: 92
Blood loss: 1500 ml
Urine: 1800 ml
Fluid and blood product infusion:
Crystalloid: 3100 ml
Colloid: 1500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 450 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery and transferred to ICU due to tachycardia after sufficient fluid resuscitation.
Recovered uneventfully.
5 Female;48-yr; 170 cm/75 kg
BMI: 26.0
Diagnosis:
Thoracic spinal canal stenosis (T6-T11)
Surgery:
Posterior decompression, fixation and fusion of thoracic spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 40/30 mmHg to undetectable
HR: 120 bpm to 40 bpm
SpO2: undetectable
Cardiac arrest
Skin and airway symptoms: none.
Management:
Extracardiac compression
Boluses of noradrenaline (200 μg) and adrenaline (1 g)
Continuous infusion of noradrenaline (0.02–0.08 μg/kg/min) for 50 min
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 132
Intraoperative minimum value of HGB: 74
Blood loss: 2500 ml
Urine: 1300 ml
Fluid and blood product infusion:
Crystalloid: 4000 ml
Colloid: 500 ml
PRBC infusion: 2400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery, and discharged from hospital uneventfully.
6 Male; 66-yr; 175 cm/ 80 kg
BMI: 26.1
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Carotid artery stenosis
Diabetes Mellitus
Time of occurrence:
Sudden cardiac arrest 10 min after extubation (approximately 45 min after initiation of wound closure) with full recovery from anesthesia and without any discomfort complaint.
Signs and symptoms:
Cardiac arrest and persistent VF
Skin and airway symptoms: none.
Management:
Continuous CPR
Persistent VF was treated with repeated defibrillation
Boluses of adrenaline (a total of 6 mg) and amiodarone.
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 143
Intraoperative minimum value of HGB: 78
Blood loss: 1000 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 4400 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 600 ml
VCM administration:
Topical spraying of vancomycin (3 g) on the dura mater and into the mascularis.
Postoperative sequelae:
The patient was reintubated and transferred to ICU after ROSC. The patient was diagnosed as hypoxic encephalopathy and remained in a coma state. Tracheotomy was performed 2 weeks after surgery, and the patient was transferred to a nursing home for rehabilitation 1 month after orthopedic surgery.
7 Female; 43-yr; 155 cm / 54 kg
BMI: 22.4
Diagnosis:
Thoracic kyphosis (T7-T8)
Surgery:
Osteotomy for kyphosis of thoracic spine (T7-T8).
Medical and allergy history:
nil relevant.
Time of occurrence:
subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
HR:tachycardia
NBP: 60/30 mmHg
SpO2 82%
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine and ephedrine;
Continuous infusion of noradrenaline (0.05–0.1 μg/kg/min)
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 138
Intraoperative minimum value of HGB: 95
Blood loss: 1200 ml
Urine: 1900 ml
Fluid and blood product infusion:
Crystalloid: 4700 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 470 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was transferred to ICU for optimal monitoring and recovered uneventfully.
Abbreviations: NBP Non-invasive blood pressure; ABP Arterial blood pressure; (NBP is noted when ABP is not available.) VF Ventricular fibrillation; CPR Cardiopulmonary Resuscitation; HGB Hemoglobin; VCM Vancomycin; PRBC Packed red blood cell; ROSC Return of spontaneous circulation
Case presentation
The first case we encountered was a 68-yr female with past medical history of hypertension and surgical treated retina detachment, who underwent posterior decompression, fixation and fusion of lumbar spine due to lumbar stenosis (L3-S1). The operation was uneventful until sudden circulatory collapse occurred during the process of rinsing mascularis and superficial fascia layer whilst closing the wound. A sudden drop in arterial blood pressure (ABP) (130/60 mmHg to 30/20 mmHg), increased HR (60 bpm to 100 bpm) with elevated ST-segment and significant decrease of PetCO2 (31 mmHg to 16 mmHg) were noticed, with undetectable pulse oximetry read. The patient was turned to supine position immediately and managed with boluses (40–100 μg) and a continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for approximately 45 min. The circulation was gradually stabilized. No rash, erythema, or bronchospasm were noted. The bilateral breath sounds were equal and the airway pressure remained normal. We continued treatments of fluid resuscitation and blood transfusion with corticosteroid and ice cap to prevent hypoxic-ischemic encephalopathy. Intraoperative emergency consultations and immediate examinations of 12-lead ECG, point-of-care transthoracic echocardiography (TTE), and full panel laboratory tests were performed. However, these results did not support the causes of sudden cardiac dysfunction (the pump) including mechanical obstruction (pericardial tamponade and massive pulmonary embolus), acute myocardial infarction, acute valvular insufficiency, and arrhythmia. Vascular catastrophes were excluded and there were no signs of sepsis. We also examined the intravascular volume function (the tank) by performing the TTE, and ruled out intraperitoneal major hemorrhage which we once encountered (caused by inadvertent piercing of iliac artery when placing probe during lumbar surgery) by examination of abdominal ultrasound and hemoglobin level; Volume status was evaluated by measuring CVP, urine output, infused fluid volume; Surgical blood loss was reviewed to exclude hemorrhage shock and hypovolemia. As no special medications were given except anesthetic maintenance drugs, and no signs of mottled skin or bronchospasm were noticed, anaphylaxis was not considered at that time. After restoring circulatory stability, the surgery preceded uneventfully. The patient was discharged from hospital 7 days later.
It was intriguing that within 1 month, another case of circulatory collapse happened during wound closure in spine surgery performed by the same orthopedic surgeon. The intraoperative clinical manifestations were very similar to the previous one. Hemodynamic resuscitation were initiated immediately with repeated boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min). After stabilizing the circulation 4 h later, the patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions after full recovery from anesthesia). Postoperative imaging revealed intracranial micro hemorrhagic foci in the subdural and subarachnoid space. The patient was discharged from hospital without any neurological sequelae.
With further exploration and analysis of the similarities of these two cases, we found that local application of vancomycin (VCM) powder was used in these two patients to prevent postoperative surgical site infections (SSIs) during wound closure (0.5 g VCM loaded with bone debris into the cage and another 0.5 g sprayed on the dura mater and into the mascularis). Ramamani Mariappan reported a case of circulatory collapse after topical application of vancomycin powder during spine surgery, which exhibited almost the same clinical course as ours [2]. It was speculated that the rapid absorption of VCM applied to the surgical wound caused an anaphylaxis reaction and circulatory collapse. The reaction occurred approximately 30 min after the application and persisted for 6 h. The serum tryptase level was not elevated, suggesting that VCM caused a direct histamine release, which is in keeping with our current understanding. A similar case reported a 74-year-old woman who underwent a primary total knee replacement presented with red man syndrome in the PACU 45 min after release of tourniquet following the use of VCM-loaded bone cement. The patient remained fully conscious despite a sudden drop in blood pressure to 47/34 mmHg [3]. Therefore, local application of VCM may pose the risk of causing severe circulatory adverse effect.
Similar circulatory collapse cases in spine surgery without definitive causes during wound closure or shortly after surgery, though rare, were encountered in our institution. Therefore we retrospectively analyzed these cases for the past 2 years, and asked the anesthesiologists and orthopedic surgeons in charge for further information. A total of 7 cases were collected (Table 1). There were 3 males and 4 females, the median age was 66 y (43–74 y), and the averaged BMI was 24.39 ± 1.51 (22.3–26.1). It was interesting to note that these cases were all associated with topical application of VCM powder (Table 1). In these 7 cases, the onset time of severe circulatory fluctuation was 30 min in 5 cases, 50 min in one case (applied with 1 g of VCM), and approximately 45 min in another case (locally applied 3 g of VCM), respectively. Most of the cases (6/7) with severe circulatory fluctuation were corrected without severe sequelae. While in one case in which 3 g of VCM was applied on the dura mater and into the mascularis during wound closure, sudden cardiac arrest happened shortly after the patient had fully recovered from the anesthetic, following surgery and extubation in the OR. CPR was initiated immediately. The patient was reintubated and ventilated mechanically. The persistent VF was treated with continuous chest compressions and repeated defibrillation, with boluses of adrenaline (a total of 6 mg) and amiodarone. After 50 min of continuous CPR, with fluid resuscitation and blood transfusion, the patient was transferred to ICU following the return of spontaneous circulation and reverting into sinus rhythm. However, the patient remained in a comatose state due to hypoxic-hypoxic encephalopathy, and tracheotomy was performed 2 weeks later.
Discussion and conclusion
Vancomycin and anaphylaxis reaction
“International Consensus on (ICON) Anaphylaxis” define anaphylaxis as “a serious, generalized or systemic, allergic or hypersensitivity reaction that can be life threatening or fatal” [4]. It has been demonstrated that there exists IgE-dependent and three IgE-independent mechanisms in anaphylaxis pathophysiology [5]. VCM could directly activate mast cells to release histamine and other mediators through an IgE-independent mechanism that is calcium-, phospholipase C–, and phospholipase A2–dependent but otherwise unknown [5, 6]. Vancomycin-induced direct histamine release is also infusion rate dependent [7]. This IgE-independent anaphylaxis reaction generally disappears within 20 mins, but may linger for hours. The most common manifestation is a sudden drop in blood pressure, which is related to the negative inotropic effect and the vasodilator action stimulated by the histamine release. Alteration in vascular tone is also a common feature of anaphylactic shock [8]. Richter J and colleagues demonstrated in rats that VCM could directly influence the vascular tonus, affecting the microcirculation [9].
The VCM reactions studied in the pediatric population revealed that non-IgE mediated reaction accounts for the vast majority of reactions (92%; prevalence, 5.4–5.8%), whereas possible IgE-mediated vancomycin reactions were exceedingly rare (prevalence, 0.0–0.37%) [7]. For adults, the reported incidence of non-IgE mediated reaction varies between 3.7 and 47% in infected patients and 90% in healthy volunteers [2]. Elevated serum mast cell tryptase is a valuable indicator for diagnosing Ig-E mediated anaphylactic reaction. However, it is not useful in determining a non-IgE mediated anaphylactic reaction caused by histamine release [2]. Detection of histamine concentration in clinical blood specimens is difficult due to its extremely short half-life, and histamine is not a mast cell specific product [10]. As this study is retrospective in nature, and our hospital does not perform examination of serum tryptase and histamine concentration, we could not differentiate whether the adverse effects were caused by VCM induced IgE-mediated or non-IgE mediated reaction.
Topical application of vancomycin powder and surgical site infections
VCM is effective in fighting Gram-positive bacteria related severe infections [11]. While the actual utility of local application of VCM is controversial. After the first reported topical application of VCM by orthopedic surgeons to reduce postoperative surgical site infections (SSIs) rate [12], a large number of meta-analyses, retrospective cohort studies, and randomized controlled trials were published to assess the power of this method in preventing SSIs. Recent findings from large-scale propensity score matched analyses, meta analyses, RCTs studies, and observational studies of spine surgeries and knee arthroplasties all demonstrated that the intrawound VCM powder application may not decrease SSIs, but may increase postoperative complications [13–19].
VCM is an antibiotic that was considered safe in local application and has been widely used in hospitals. However, dose recommendations, dilutions, monitoring, infusion types and rates are still controversial [20]. There’s no defined time or situation during surgery when local VCM should be applied. Some may load VCM powder with bone debris into the cage, or apply VCM powder directly onto the dura mater or after closure of the fascia, whereas other studies reported that VCM powder was applied in the subfascial layer [2, 13]. However, intrawound absorption rate of VCM powder is uncontrollable as this depends on multiple factors, such as the extent and degree of tissue/muscle damaged by surgical manipulation, anatomic location where VCM powder is placed (mixed with bone debris, or between muscularis layers that are abundant with blood supply), and the surgeon’s suturing maneuvers (the flushing saline would leak from upper layer into the layer where VCM powder is deposited). These factors all pose potential risk of causing rapid drug dissolution and accelerated absorption into the circulatory system. Moreover, individual’s adverse reactions to VCM varied. These incidental events may be accidentally linked and lead to severe outcome. Since intravenous administration of VCM could lead to adverse effects, it is theoretically possible that local application of VCM powder may cause similar clinical manifestation.
Topical application of VCM was intended to achieve the effect of providing high local concentrations while avoiding high systemic levels and the risk of bacterial resistance. The serum concentration level peaks at 30 min and then declines to baseline at 6 h [2]. This may explain the delayed and unpredictable occurrence of anaphylaxis reactions after local application of VCM powder, due to the uncertainty of the drug absorption rate and individual reaction differences. The instructed therapeutic dosage of VCM is 30 mg/kg/day which should be fractioned in 2 or 3 doses. Moreover, the infusion rate should be within 10 mg/min, and last for more than 60 min. For elderly patients, this dosage should be reduced [21, 22]. Although the most commonly used dose of intrawound VCM is 1 g, some authors reported that they altered the dose according to the length of the incision [23]. VCM is not the first-choice antibiotic as its adverse effects are frequently reported including hypotension and tachycardia, phlebitis, nephrotoxicity, ototoxicity, hypersensitivity reactions, red man syndrome, neutropenia, chills, fever, interstitial nephritis, etc. [13]. As VCM induced adverse reactions are dose and infusion-rate dependent, doctors should be highly vigilant to over-dosing which might bring disastrous results.
Other issues related to shock
In this case series, the typical signs of erythema and redness (red man syndrome) have not appeared, which resemble the previous case reported by Mariappan R and colleagues [2]. The lack of skin flushing may be the result of reduced perfusion due to circulatory shock or the adverse effect of VCM mainly manifested as severe alteration of vascular tonus [8, 9]. In our experience, a rapid but low dose intravenous infusion of VCM induced anaphylaxis reaction was not necessarily associated with skin manifestations. Whether this is related to racial differences or rapid absorption of low dose VCM was not known. However, the clinical features of hypotension, tachycadia and low oxygenation were notable.
For this case series, as there is no definitive laboratory examination or gold standard to help reach a definitive diagnosis of VCM induced anaphylaxis reaction, the conclusions were made upon differential diagnosis based on clinical manifestations and the timing of the shock. Other possible causes or contributing factors for the development of severe hypotension and shock need to be considered. For example, restrictive fluid therapy during surgical procedure and restrictive blood transfusion strategy leading to hypovolemia and hypotension, complicated with unseen bleeding from surgical site and other compounding factors such as hypoproteinemia and unaltered anesthetic depth during wound closure.
Another issue needs to be addressed is that there’s a notable decrease in hemoglobin (HGB) concentration in all cases when severe hypotension occurred. However, the hemorrhagic shock induced by surgical blood loss was ruled out. We speculate that this might be due to the infusion of large amounts of fluid during resuscitation. It is reported that the administration of 500 ml of fluids may acutely decrease the HGB concentration by about 1 g/dl, or about 8%, by “dilutional anemia” [24]. In septic shock patients, approximately 30% decrease of hematocrit was commonly observed in patients receiving large amounts of fluids during resuscitation, which further indicates more blood transfusion [25]. In the current study, the HGB concentrations were all measured after the initiation of fluid resuscitation and this may at least partially explained the sharp decrease of the HGB level (Table 1). When severe hypotension with unknown causes occur, initial management is to infuse large amounts of fluid with vaso-constrictive drugs. The iatrogenic hemodilution related blood transfusion may result in dilutional coagulopathy and increase surgical bleeding. This then leads to a decreased HGB level below the acceptable transfusion threshold, leading to further blood transfusion in the absence of significant blood loss [26]. This is especially true when in the scenario of the existence of suspected hemorrhagic shock.
In conclusion, local application of VCM powder during wound closure could cause delayed occurrence of severe hypotension and shock in spine surgery. Hemodynamic changes may be under-emphasized and under-reported as in most cases, this hemodynamic reaction is easy to correct and normally wouldn’t cause serious consequences. However, the actual occurrence is not rare and this might be confused with hypovolemia or anesthetic induced hypotension. Surgeons and anesthesiologists should be highly aware of VCM induced IgE-independent anaphylaxis reactions. The differential diagnosis of anaphylactic shock must be taken into consideration in patients with acute hypotension during or immediately after wound closure. Prompt laboratory analysis of serum tryptase and histamine concentration could help differentiate the causes. Moreover, since controversies still exist in the actual effect of intrawound application of VCM powder to reduce SSIs in spine surgery, local application of this drug should be used with caution.
Abbreviations
VCMVancomycin
ABPArterial blood pressure
TTETransthoracic echocardiography
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
We sincerely thank our colleagues from anesthesia (Dr. XW, Dr. CW, Dr. WL, Dr. JY, Dr. YW, Dr. CN, Dr. CX, Dr. YT, Dr. HW, Dr. HT, Dr. WW, Dr. YT, Dr. XJ, HL, Dr. HW, Dr. HZ, Dr. YW, and Dr. BW) and surgical department (Dr. YD, Dr. YL, Dr. FZ, Dr. QQ, and Dr. ZC) for providing and verifying the cases.
The authors have completed the CARE reporting checklist.
Authors’ contributions
Guarantor of integrity of entire study: XZ, WZ, ML, XG. Literature research: XZ, WZ. Case study and follow-up: XZ, WZ. Manuscript preparation: XZ, WZ. Manuscript editing and revision: ML, XG. Manuscript final version approval: ML, XG. All authors have read and approved the manuscript.
Funding
This work was supported by the Clinical Key Project of Peking University Third Hospital, Grants No. BYSY2017001.
The role of the funder: study design, decision to submit the manuscript for publication.
Availability of data and materials
All data generated or analyzed during this study are included in this published article. More detailed information could be find in Table 1.
Ethics approval and consent to participate
This case was performed according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Peking University Third Hospital. All the authors listed in the manuscript consent to participate the study. The consent for publication from patient or their relatives were collected retrospectively.
Consent for publication
As this is a retrospective case study, written informed consent to publish this manuscript were collected from patients or their relatives retrospectively. The proof of consent to publish from study participants can be requested at any time.
Competing interests
The author(s) declare no competing interests. | VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33407142 | 18,839,984 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ventricular fibrillation'. | Circulatory collapse during wound closure in spine surgery with an unknown cause: a possible adverse effect of topical application of vancomycin?
Vancomycin (VCM) is effective in fighting Gram-positive bacteria related severe infections, and topical application of VCM powder is widely used in orthopedic surgery to prevent wound infection. However, VCM could lead to infusion rate-dependent antibody-and complement-independent anaphylaxis reaction by inducing direct release of histamine.
We retrospectively analyzed seven cases of severe hypotension and shock during wound closure or immediately after orthopedic surgery with unidentifiable reasons. We found that these cases were all associated with local application of VCM powder during wound closure process. Two patients experienced sudden cardiac arrest. Most of the cases (6/7) with circulatory collapse were discharged without severe sequelae. While one case with application of 3 g VCM developed cardiac arrest and remained in a coma due to hypoxic-hypoxic encephalopathy. The clinical presentations and the time of the shock onset were considered to be related with a VCM induced anaphylaxis reaction. However, as this was a retrospective study, and there was no laboratory examination performed, the conclusion was made upon differential diagnosis based on clinical manifestations and the timing of the shock.
Local application of VCM may not be as safe as was once believed and may lead to a related anaphylaxis. As VCM induced infusion-rate dependent, non-IgE mediated anaphylaxis is characterized by delayed occurrence, severe hypotension and even circulatory collapse, surgeons and anesthesiologists should be extra vigilant during and after VCM application.
Background
Shock is defined as a state of insufficient perfusion and oxygen delivery to the tissues. The pathophysiology of shock could be simplified to three major components: cardiac function (the pump), intravascular volume (the tank), and systemic vascular resistance (the pipes) [1]. Whatever the causes of shock may be, if the impaired perfusion and oxygen delivery is not recognized and reversed, the circulatory collapse may progress into organ dysfunction and failure, tissue necrosis and even death. It is urgent to identify the causes of shock and take immediate measures. However, in critical situations, it is hard to rapidly distinguish the culprit during complex clinical situations. Here we present 7 cases (Table 1) of unidentifiable causes of shock during wound closure or shortly after spine surgery, and discuss the possible reasons.
Table 1 Summary of clinical presentations of seven patients with circulatory collapse and unknown etiologies during or shortly after wound closure in spine surgery
Case Demographic information Initial signs/symptoms of shock and management Hemoglobin value (g/L),
fluid resuscitation and blood product infusion VCM administration
and Postoperative sequelae
1 Female; 68-yr; 160 cm/60 kg
BMI: 23.4
Diagnosis:
Lumbar stenosis (L3-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Hypertension
History of retina surgery
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
ABP: 30/20 mmHg
SpO2: undetectable
ECG: tarchycardia with elevated ST segment
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for 45 min. Fluid resuscitation and blood transfusion.
Preoperative HGB value: 124
Intraoperative minimum value of HGB: 73
Blood loss: 600 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 3450 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 210 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
Proceeded with surgery and the patient was extubated uneventfully.
2 Male; 74-yr; 171 cm/67 kg
BMI: 23.9
Diagnosis:
lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
ECG: tachycardia with ST segment depression
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min) for 4 h.
Preoperative HGB value:135
Intraoperative minimum value of HGB: 79
Blood loss: 600 ml
Urine: 1950 ml
Fluid and blood product infusion:
Crystalloid: 6300 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Plasma: 800 ml
Infused autologous blood: 254 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions).
Postoperative imaging: intracranial minor hemorrhage at subdural and subarachnoid space.
The patient was discharged from hospital without neurological deficit.
3 Male; 63-yr; 169 cm/70 kg
BMI: 24.5
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Lacunar infarction;
Bilateral carotid atherosclerotic plaque formation
Time of occurrence:
50 min after initiation of wound closure and 20 min post-extubation in the PACU.
Signs and symptoms:
NBP: 60/25 mmHg
SpO2: 96%
HR:sudden elevation from 60 to 90 bpm
Postoperative agitation
Skin and airway symptoms: none.
Management:
Boluses of ephedrine, phenylephrine and fluid resuscitation.
Preoperative HGB value: 176
Intraoperative minimum value of HGB:123
Blood loss: 800 ml
Urine: 800 ml
Fluid and blood product infusion:
Crystalloid: 2350 ml
Colloid: 1000 ml
PRBC infusion: 400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis.
Postoperative sequelae:
Uneventful.
4 Female; 70-yr; 160 cm/65 kg
BMI:25.4
Diagnosis:
Lumbar stenosis (L4-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Hypertension
Diabetes Mellitus
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
Persistent tachycardia
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine for treating severe hypotension and esmolol for tachycardia
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 150
Intraoperative minimum value of HGB: 92
Blood loss: 1500 ml
Urine: 1800 ml
Fluid and blood product infusion:
Crystalloid: 3100 ml
Colloid: 1500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 450 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery and transferred to ICU due to tachycardia after sufficient fluid resuscitation.
Recovered uneventfully.
5 Female;48-yr; 170 cm/75 kg
BMI: 26.0
Diagnosis:
Thoracic spinal canal stenosis (T6-T11)
Surgery:
Posterior decompression, fixation and fusion of thoracic spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 40/30 mmHg to undetectable
HR: 120 bpm to 40 bpm
SpO2: undetectable
Cardiac arrest
Skin and airway symptoms: none.
Management:
Extracardiac compression
Boluses of noradrenaline (200 μg) and adrenaline (1 g)
Continuous infusion of noradrenaline (0.02–0.08 μg/kg/min) for 50 min
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 132
Intraoperative minimum value of HGB: 74
Blood loss: 2500 ml
Urine: 1300 ml
Fluid and blood product infusion:
Crystalloid: 4000 ml
Colloid: 500 ml
PRBC infusion: 2400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery, and discharged from hospital uneventfully.
6 Male; 66-yr; 175 cm/ 80 kg
BMI: 26.1
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Carotid artery stenosis
Diabetes Mellitus
Time of occurrence:
Sudden cardiac arrest 10 min after extubation (approximately 45 min after initiation of wound closure) with full recovery from anesthesia and without any discomfort complaint.
Signs and symptoms:
Cardiac arrest and persistent VF
Skin and airway symptoms: none.
Management:
Continuous CPR
Persistent VF was treated with repeated defibrillation
Boluses of adrenaline (a total of 6 mg) and amiodarone.
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 143
Intraoperative minimum value of HGB: 78
Blood loss: 1000 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 4400 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 600 ml
VCM administration:
Topical spraying of vancomycin (3 g) on the dura mater and into the mascularis.
Postoperative sequelae:
The patient was reintubated and transferred to ICU after ROSC. The patient was diagnosed as hypoxic encephalopathy and remained in a coma state. Tracheotomy was performed 2 weeks after surgery, and the patient was transferred to a nursing home for rehabilitation 1 month after orthopedic surgery.
7 Female; 43-yr; 155 cm / 54 kg
BMI: 22.4
Diagnosis:
Thoracic kyphosis (T7-T8)
Surgery:
Osteotomy for kyphosis of thoracic spine (T7-T8).
Medical and allergy history:
nil relevant.
Time of occurrence:
subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
HR:tachycardia
NBP: 60/30 mmHg
SpO2 82%
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine and ephedrine;
Continuous infusion of noradrenaline (0.05–0.1 μg/kg/min)
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 138
Intraoperative minimum value of HGB: 95
Blood loss: 1200 ml
Urine: 1900 ml
Fluid and blood product infusion:
Crystalloid: 4700 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 470 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was transferred to ICU for optimal monitoring and recovered uneventfully.
Abbreviations: NBP Non-invasive blood pressure; ABP Arterial blood pressure; (NBP is noted when ABP is not available.) VF Ventricular fibrillation; CPR Cardiopulmonary Resuscitation; HGB Hemoglobin; VCM Vancomycin; PRBC Packed red blood cell; ROSC Return of spontaneous circulation
Case presentation
The first case we encountered was a 68-yr female with past medical history of hypertension and surgical treated retina detachment, who underwent posterior decompression, fixation and fusion of lumbar spine due to lumbar stenosis (L3-S1). The operation was uneventful until sudden circulatory collapse occurred during the process of rinsing mascularis and superficial fascia layer whilst closing the wound. A sudden drop in arterial blood pressure (ABP) (130/60 mmHg to 30/20 mmHg), increased HR (60 bpm to 100 bpm) with elevated ST-segment and significant decrease of PetCO2 (31 mmHg to 16 mmHg) were noticed, with undetectable pulse oximetry read. The patient was turned to supine position immediately and managed with boluses (40–100 μg) and a continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for approximately 45 min. The circulation was gradually stabilized. No rash, erythema, or bronchospasm were noted. The bilateral breath sounds were equal and the airway pressure remained normal. We continued treatments of fluid resuscitation and blood transfusion with corticosteroid and ice cap to prevent hypoxic-ischemic encephalopathy. Intraoperative emergency consultations and immediate examinations of 12-lead ECG, point-of-care transthoracic echocardiography (TTE), and full panel laboratory tests were performed. However, these results did not support the causes of sudden cardiac dysfunction (the pump) including mechanical obstruction (pericardial tamponade and massive pulmonary embolus), acute myocardial infarction, acute valvular insufficiency, and arrhythmia. Vascular catastrophes were excluded and there were no signs of sepsis. We also examined the intravascular volume function (the tank) by performing the TTE, and ruled out intraperitoneal major hemorrhage which we once encountered (caused by inadvertent piercing of iliac artery when placing probe during lumbar surgery) by examination of abdominal ultrasound and hemoglobin level; Volume status was evaluated by measuring CVP, urine output, infused fluid volume; Surgical blood loss was reviewed to exclude hemorrhage shock and hypovolemia. As no special medications were given except anesthetic maintenance drugs, and no signs of mottled skin or bronchospasm were noticed, anaphylaxis was not considered at that time. After restoring circulatory stability, the surgery preceded uneventfully. The patient was discharged from hospital 7 days later.
It was intriguing that within 1 month, another case of circulatory collapse happened during wound closure in spine surgery performed by the same orthopedic surgeon. The intraoperative clinical manifestations were very similar to the previous one. Hemodynamic resuscitation were initiated immediately with repeated boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min). After stabilizing the circulation 4 h later, the patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions after full recovery from anesthesia). Postoperative imaging revealed intracranial micro hemorrhagic foci in the subdural and subarachnoid space. The patient was discharged from hospital without any neurological sequelae.
With further exploration and analysis of the similarities of these two cases, we found that local application of vancomycin (VCM) powder was used in these two patients to prevent postoperative surgical site infections (SSIs) during wound closure (0.5 g VCM loaded with bone debris into the cage and another 0.5 g sprayed on the dura mater and into the mascularis). Ramamani Mariappan reported a case of circulatory collapse after topical application of vancomycin powder during spine surgery, which exhibited almost the same clinical course as ours [2]. It was speculated that the rapid absorption of VCM applied to the surgical wound caused an anaphylaxis reaction and circulatory collapse. The reaction occurred approximately 30 min after the application and persisted for 6 h. The serum tryptase level was not elevated, suggesting that VCM caused a direct histamine release, which is in keeping with our current understanding. A similar case reported a 74-year-old woman who underwent a primary total knee replacement presented with red man syndrome in the PACU 45 min after release of tourniquet following the use of VCM-loaded bone cement. The patient remained fully conscious despite a sudden drop in blood pressure to 47/34 mmHg [3]. Therefore, local application of VCM may pose the risk of causing severe circulatory adverse effect.
Similar circulatory collapse cases in spine surgery without definitive causes during wound closure or shortly after surgery, though rare, were encountered in our institution. Therefore we retrospectively analyzed these cases for the past 2 years, and asked the anesthesiologists and orthopedic surgeons in charge for further information. A total of 7 cases were collected (Table 1). There were 3 males and 4 females, the median age was 66 y (43–74 y), and the averaged BMI was 24.39 ± 1.51 (22.3–26.1). It was interesting to note that these cases were all associated with topical application of VCM powder (Table 1). In these 7 cases, the onset time of severe circulatory fluctuation was 30 min in 5 cases, 50 min in one case (applied with 1 g of VCM), and approximately 45 min in another case (locally applied 3 g of VCM), respectively. Most of the cases (6/7) with severe circulatory fluctuation were corrected without severe sequelae. While in one case in which 3 g of VCM was applied on the dura mater and into the mascularis during wound closure, sudden cardiac arrest happened shortly after the patient had fully recovered from the anesthetic, following surgery and extubation in the OR. CPR was initiated immediately. The patient was reintubated and ventilated mechanically. The persistent VF was treated with continuous chest compressions and repeated defibrillation, with boluses of adrenaline (a total of 6 mg) and amiodarone. After 50 min of continuous CPR, with fluid resuscitation and blood transfusion, the patient was transferred to ICU following the return of spontaneous circulation and reverting into sinus rhythm. However, the patient remained in a comatose state due to hypoxic-hypoxic encephalopathy, and tracheotomy was performed 2 weeks later.
Discussion and conclusion
Vancomycin and anaphylaxis reaction
“International Consensus on (ICON) Anaphylaxis” define anaphylaxis as “a serious, generalized or systemic, allergic or hypersensitivity reaction that can be life threatening or fatal” [4]. It has been demonstrated that there exists IgE-dependent and three IgE-independent mechanisms in anaphylaxis pathophysiology [5]. VCM could directly activate mast cells to release histamine and other mediators through an IgE-independent mechanism that is calcium-, phospholipase C–, and phospholipase A2–dependent but otherwise unknown [5, 6]. Vancomycin-induced direct histamine release is also infusion rate dependent [7]. This IgE-independent anaphylaxis reaction generally disappears within 20 mins, but may linger for hours. The most common manifestation is a sudden drop in blood pressure, which is related to the negative inotropic effect and the vasodilator action stimulated by the histamine release. Alteration in vascular tone is also a common feature of anaphylactic shock [8]. Richter J and colleagues demonstrated in rats that VCM could directly influence the vascular tonus, affecting the microcirculation [9].
The VCM reactions studied in the pediatric population revealed that non-IgE mediated reaction accounts for the vast majority of reactions (92%; prevalence, 5.4–5.8%), whereas possible IgE-mediated vancomycin reactions were exceedingly rare (prevalence, 0.0–0.37%) [7]. For adults, the reported incidence of non-IgE mediated reaction varies between 3.7 and 47% in infected patients and 90% in healthy volunteers [2]. Elevated serum mast cell tryptase is a valuable indicator for diagnosing Ig-E mediated anaphylactic reaction. However, it is not useful in determining a non-IgE mediated anaphylactic reaction caused by histamine release [2]. Detection of histamine concentration in clinical blood specimens is difficult due to its extremely short half-life, and histamine is not a mast cell specific product [10]. As this study is retrospective in nature, and our hospital does not perform examination of serum tryptase and histamine concentration, we could not differentiate whether the adverse effects were caused by VCM induced IgE-mediated or non-IgE mediated reaction.
Topical application of vancomycin powder and surgical site infections
VCM is effective in fighting Gram-positive bacteria related severe infections [11]. While the actual utility of local application of VCM is controversial. After the first reported topical application of VCM by orthopedic surgeons to reduce postoperative surgical site infections (SSIs) rate [12], a large number of meta-analyses, retrospective cohort studies, and randomized controlled trials were published to assess the power of this method in preventing SSIs. Recent findings from large-scale propensity score matched analyses, meta analyses, RCTs studies, and observational studies of spine surgeries and knee arthroplasties all demonstrated that the intrawound VCM powder application may not decrease SSIs, but may increase postoperative complications [13–19].
VCM is an antibiotic that was considered safe in local application and has been widely used in hospitals. However, dose recommendations, dilutions, monitoring, infusion types and rates are still controversial [20]. There’s no defined time or situation during surgery when local VCM should be applied. Some may load VCM powder with bone debris into the cage, or apply VCM powder directly onto the dura mater or after closure of the fascia, whereas other studies reported that VCM powder was applied in the subfascial layer [2, 13]. However, intrawound absorption rate of VCM powder is uncontrollable as this depends on multiple factors, such as the extent and degree of tissue/muscle damaged by surgical manipulation, anatomic location where VCM powder is placed (mixed with bone debris, or between muscularis layers that are abundant with blood supply), and the surgeon’s suturing maneuvers (the flushing saline would leak from upper layer into the layer where VCM powder is deposited). These factors all pose potential risk of causing rapid drug dissolution and accelerated absorption into the circulatory system. Moreover, individual’s adverse reactions to VCM varied. These incidental events may be accidentally linked and lead to severe outcome. Since intravenous administration of VCM could lead to adverse effects, it is theoretically possible that local application of VCM powder may cause similar clinical manifestation.
Topical application of VCM was intended to achieve the effect of providing high local concentrations while avoiding high systemic levels and the risk of bacterial resistance. The serum concentration level peaks at 30 min and then declines to baseline at 6 h [2]. This may explain the delayed and unpredictable occurrence of anaphylaxis reactions after local application of VCM powder, due to the uncertainty of the drug absorption rate and individual reaction differences. The instructed therapeutic dosage of VCM is 30 mg/kg/day which should be fractioned in 2 or 3 doses. Moreover, the infusion rate should be within 10 mg/min, and last for more than 60 min. For elderly patients, this dosage should be reduced [21, 22]. Although the most commonly used dose of intrawound VCM is 1 g, some authors reported that they altered the dose according to the length of the incision [23]. VCM is not the first-choice antibiotic as its adverse effects are frequently reported including hypotension and tachycardia, phlebitis, nephrotoxicity, ototoxicity, hypersensitivity reactions, red man syndrome, neutropenia, chills, fever, interstitial nephritis, etc. [13]. As VCM induced adverse reactions are dose and infusion-rate dependent, doctors should be highly vigilant to over-dosing which might bring disastrous results.
Other issues related to shock
In this case series, the typical signs of erythema and redness (red man syndrome) have not appeared, which resemble the previous case reported by Mariappan R and colleagues [2]. The lack of skin flushing may be the result of reduced perfusion due to circulatory shock or the adverse effect of VCM mainly manifested as severe alteration of vascular tonus [8, 9]. In our experience, a rapid but low dose intravenous infusion of VCM induced anaphylaxis reaction was not necessarily associated with skin manifestations. Whether this is related to racial differences or rapid absorption of low dose VCM was not known. However, the clinical features of hypotension, tachycadia and low oxygenation were notable.
For this case series, as there is no definitive laboratory examination or gold standard to help reach a definitive diagnosis of VCM induced anaphylaxis reaction, the conclusions were made upon differential diagnosis based on clinical manifestations and the timing of the shock. Other possible causes or contributing factors for the development of severe hypotension and shock need to be considered. For example, restrictive fluid therapy during surgical procedure and restrictive blood transfusion strategy leading to hypovolemia and hypotension, complicated with unseen bleeding from surgical site and other compounding factors such as hypoproteinemia and unaltered anesthetic depth during wound closure.
Another issue needs to be addressed is that there’s a notable decrease in hemoglobin (HGB) concentration in all cases when severe hypotension occurred. However, the hemorrhagic shock induced by surgical blood loss was ruled out. We speculate that this might be due to the infusion of large amounts of fluid during resuscitation. It is reported that the administration of 500 ml of fluids may acutely decrease the HGB concentration by about 1 g/dl, or about 8%, by “dilutional anemia” [24]. In septic shock patients, approximately 30% decrease of hematocrit was commonly observed in patients receiving large amounts of fluids during resuscitation, which further indicates more blood transfusion [25]. In the current study, the HGB concentrations were all measured after the initiation of fluid resuscitation and this may at least partially explained the sharp decrease of the HGB level (Table 1). When severe hypotension with unknown causes occur, initial management is to infuse large amounts of fluid with vaso-constrictive drugs. The iatrogenic hemodilution related blood transfusion may result in dilutional coagulopathy and increase surgical bleeding. This then leads to a decreased HGB level below the acceptable transfusion threshold, leading to further blood transfusion in the absence of significant blood loss [26]. This is especially true when in the scenario of the existence of suspected hemorrhagic shock.
In conclusion, local application of VCM powder during wound closure could cause delayed occurrence of severe hypotension and shock in spine surgery. Hemodynamic changes may be under-emphasized and under-reported as in most cases, this hemodynamic reaction is easy to correct and normally wouldn’t cause serious consequences. However, the actual occurrence is not rare and this might be confused with hypovolemia or anesthetic induced hypotension. Surgeons and anesthesiologists should be highly aware of VCM induced IgE-independent anaphylaxis reactions. The differential diagnosis of anaphylactic shock must be taken into consideration in patients with acute hypotension during or immediately after wound closure. Prompt laboratory analysis of serum tryptase and histamine concentration could help differentiate the causes. Moreover, since controversies still exist in the actual effect of intrawound application of VCM powder to reduce SSIs in spine surgery, local application of this drug should be used with caution.
Abbreviations
VCMVancomycin
ABPArterial blood pressure
TTETransthoracic echocardiography
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
We sincerely thank our colleagues from anesthesia (Dr. XW, Dr. CW, Dr. WL, Dr. JY, Dr. YW, Dr. CN, Dr. CX, Dr. YT, Dr. HW, Dr. HT, Dr. WW, Dr. YT, Dr. XJ, HL, Dr. HW, Dr. HZ, Dr. YW, and Dr. BW) and surgical department (Dr. YD, Dr. YL, Dr. FZ, Dr. QQ, and Dr. ZC) for providing and verifying the cases.
The authors have completed the CARE reporting checklist.
Authors’ contributions
Guarantor of integrity of entire study: XZ, WZ, ML, XG. Literature research: XZ, WZ. Case study and follow-up: XZ, WZ. Manuscript preparation: XZ, WZ. Manuscript editing and revision: ML, XG. Manuscript final version approval: ML, XG. All authors have read and approved the manuscript.
Funding
This work was supported by the Clinical Key Project of Peking University Third Hospital, Grants No. BYSY2017001.
The role of the funder: study design, decision to submit the manuscript for publication.
Availability of data and materials
All data generated or analyzed during this study are included in this published article. More detailed information could be find in Table 1.
Ethics approval and consent to participate
This case was performed according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Peking University Third Hospital. All the authors listed in the manuscript consent to participate the study. The consent for publication from patient or their relatives were collected retrospectively.
Consent for publication
As this is a retrospective case study, written informed consent to publish this manuscript were collected from patients or their relatives retrospectively. The proof of consent to publish from study participants can be requested at any time.
Competing interests
The author(s) declare no competing interests. | VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33407142 | 18,839,984 | 2021-01-06 |
What was the administration route of drug 'VANCOMYCIN HYDROCHLORIDE'? | Circulatory collapse during wound closure in spine surgery with an unknown cause: a possible adverse effect of topical application of vancomycin?
Vancomycin (VCM) is effective in fighting Gram-positive bacteria related severe infections, and topical application of VCM powder is widely used in orthopedic surgery to prevent wound infection. However, VCM could lead to infusion rate-dependent antibody-and complement-independent anaphylaxis reaction by inducing direct release of histamine.
We retrospectively analyzed seven cases of severe hypotension and shock during wound closure or immediately after orthopedic surgery with unidentifiable reasons. We found that these cases were all associated with local application of VCM powder during wound closure process. Two patients experienced sudden cardiac arrest. Most of the cases (6/7) with circulatory collapse were discharged without severe sequelae. While one case with application of 3 g VCM developed cardiac arrest and remained in a coma due to hypoxic-hypoxic encephalopathy. The clinical presentations and the time of the shock onset were considered to be related with a VCM induced anaphylaxis reaction. However, as this was a retrospective study, and there was no laboratory examination performed, the conclusion was made upon differential diagnosis based on clinical manifestations and the timing of the shock.
Local application of VCM may not be as safe as was once believed and may lead to a related anaphylaxis. As VCM induced infusion-rate dependent, non-IgE mediated anaphylaxis is characterized by delayed occurrence, severe hypotension and even circulatory collapse, surgeons and anesthesiologists should be extra vigilant during and after VCM application.
Background
Shock is defined as a state of insufficient perfusion and oxygen delivery to the tissues. The pathophysiology of shock could be simplified to three major components: cardiac function (the pump), intravascular volume (the tank), and systemic vascular resistance (the pipes) [1]. Whatever the causes of shock may be, if the impaired perfusion and oxygen delivery is not recognized and reversed, the circulatory collapse may progress into organ dysfunction and failure, tissue necrosis and even death. It is urgent to identify the causes of shock and take immediate measures. However, in critical situations, it is hard to rapidly distinguish the culprit during complex clinical situations. Here we present 7 cases (Table 1) of unidentifiable causes of shock during wound closure or shortly after spine surgery, and discuss the possible reasons.
Table 1 Summary of clinical presentations of seven patients with circulatory collapse and unknown etiologies during or shortly after wound closure in spine surgery
Case Demographic information Initial signs/symptoms of shock and management Hemoglobin value (g/L),
fluid resuscitation and blood product infusion VCM administration
and Postoperative sequelae
1 Female; 68-yr; 160 cm/60 kg
BMI: 23.4
Diagnosis:
Lumbar stenosis (L3-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Hypertension
History of retina surgery
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
ABP: 30/20 mmHg
SpO2: undetectable
ECG: tarchycardia with elevated ST segment
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for 45 min. Fluid resuscitation and blood transfusion.
Preoperative HGB value: 124
Intraoperative minimum value of HGB: 73
Blood loss: 600 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 3450 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 210 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
Proceeded with surgery and the patient was extubated uneventfully.
2 Male; 74-yr; 171 cm/67 kg
BMI: 23.9
Diagnosis:
lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
ECG: tachycardia with ST segment depression
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min) for 4 h.
Preoperative HGB value:135
Intraoperative minimum value of HGB: 79
Blood loss: 600 ml
Urine: 1950 ml
Fluid and blood product infusion:
Crystalloid: 6300 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Plasma: 800 ml
Infused autologous blood: 254 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions).
Postoperative imaging: intracranial minor hemorrhage at subdural and subarachnoid space.
The patient was discharged from hospital without neurological deficit.
3 Male; 63-yr; 169 cm/70 kg
BMI: 24.5
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Lacunar infarction;
Bilateral carotid atherosclerotic plaque formation
Time of occurrence:
50 min after initiation of wound closure and 20 min post-extubation in the PACU.
Signs and symptoms:
NBP: 60/25 mmHg
SpO2: 96%
HR:sudden elevation from 60 to 90 bpm
Postoperative agitation
Skin and airway symptoms: none.
Management:
Boluses of ephedrine, phenylephrine and fluid resuscitation.
Preoperative HGB value: 176
Intraoperative minimum value of HGB:123
Blood loss: 800 ml
Urine: 800 ml
Fluid and blood product infusion:
Crystalloid: 2350 ml
Colloid: 1000 ml
PRBC infusion: 400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis.
Postoperative sequelae:
Uneventful.
4 Female; 70-yr; 160 cm/65 kg
BMI:25.4
Diagnosis:
Lumbar stenosis (L4-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Hypertension
Diabetes Mellitus
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
Persistent tachycardia
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine for treating severe hypotension and esmolol for tachycardia
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 150
Intraoperative minimum value of HGB: 92
Blood loss: 1500 ml
Urine: 1800 ml
Fluid and blood product infusion:
Crystalloid: 3100 ml
Colloid: 1500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 450 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery and transferred to ICU due to tachycardia after sufficient fluid resuscitation.
Recovered uneventfully.
5 Female;48-yr; 170 cm/75 kg
BMI: 26.0
Diagnosis:
Thoracic spinal canal stenosis (T6-T11)
Surgery:
Posterior decompression, fixation and fusion of thoracic spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 40/30 mmHg to undetectable
HR: 120 bpm to 40 bpm
SpO2: undetectable
Cardiac arrest
Skin and airway symptoms: none.
Management:
Extracardiac compression
Boluses of noradrenaline (200 μg) and adrenaline (1 g)
Continuous infusion of noradrenaline (0.02–0.08 μg/kg/min) for 50 min
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 132
Intraoperative minimum value of HGB: 74
Blood loss: 2500 ml
Urine: 1300 ml
Fluid and blood product infusion:
Crystalloid: 4000 ml
Colloid: 500 ml
PRBC infusion: 2400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery, and discharged from hospital uneventfully.
6 Male; 66-yr; 175 cm/ 80 kg
BMI: 26.1
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Carotid artery stenosis
Diabetes Mellitus
Time of occurrence:
Sudden cardiac arrest 10 min after extubation (approximately 45 min after initiation of wound closure) with full recovery from anesthesia and without any discomfort complaint.
Signs and symptoms:
Cardiac arrest and persistent VF
Skin and airway symptoms: none.
Management:
Continuous CPR
Persistent VF was treated with repeated defibrillation
Boluses of adrenaline (a total of 6 mg) and amiodarone.
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 143
Intraoperative minimum value of HGB: 78
Blood loss: 1000 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 4400 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 600 ml
VCM administration:
Topical spraying of vancomycin (3 g) on the dura mater and into the mascularis.
Postoperative sequelae:
The patient was reintubated and transferred to ICU after ROSC. The patient was diagnosed as hypoxic encephalopathy and remained in a coma state. Tracheotomy was performed 2 weeks after surgery, and the patient was transferred to a nursing home for rehabilitation 1 month after orthopedic surgery.
7 Female; 43-yr; 155 cm / 54 kg
BMI: 22.4
Diagnosis:
Thoracic kyphosis (T7-T8)
Surgery:
Osteotomy for kyphosis of thoracic spine (T7-T8).
Medical and allergy history:
nil relevant.
Time of occurrence:
subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
HR:tachycardia
NBP: 60/30 mmHg
SpO2 82%
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine and ephedrine;
Continuous infusion of noradrenaline (0.05–0.1 μg/kg/min)
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 138
Intraoperative minimum value of HGB: 95
Blood loss: 1200 ml
Urine: 1900 ml
Fluid and blood product infusion:
Crystalloid: 4700 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 470 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was transferred to ICU for optimal monitoring and recovered uneventfully.
Abbreviations: NBP Non-invasive blood pressure; ABP Arterial blood pressure; (NBP is noted when ABP is not available.) VF Ventricular fibrillation; CPR Cardiopulmonary Resuscitation; HGB Hemoglobin; VCM Vancomycin; PRBC Packed red blood cell; ROSC Return of spontaneous circulation
Case presentation
The first case we encountered was a 68-yr female with past medical history of hypertension and surgical treated retina detachment, who underwent posterior decompression, fixation and fusion of lumbar spine due to lumbar stenosis (L3-S1). The operation was uneventful until sudden circulatory collapse occurred during the process of rinsing mascularis and superficial fascia layer whilst closing the wound. A sudden drop in arterial blood pressure (ABP) (130/60 mmHg to 30/20 mmHg), increased HR (60 bpm to 100 bpm) with elevated ST-segment and significant decrease of PetCO2 (31 mmHg to 16 mmHg) were noticed, with undetectable pulse oximetry read. The patient was turned to supine position immediately and managed with boluses (40–100 μg) and a continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for approximately 45 min. The circulation was gradually stabilized. No rash, erythema, or bronchospasm were noted. The bilateral breath sounds were equal and the airway pressure remained normal. We continued treatments of fluid resuscitation and blood transfusion with corticosteroid and ice cap to prevent hypoxic-ischemic encephalopathy. Intraoperative emergency consultations and immediate examinations of 12-lead ECG, point-of-care transthoracic echocardiography (TTE), and full panel laboratory tests were performed. However, these results did not support the causes of sudden cardiac dysfunction (the pump) including mechanical obstruction (pericardial tamponade and massive pulmonary embolus), acute myocardial infarction, acute valvular insufficiency, and arrhythmia. Vascular catastrophes were excluded and there were no signs of sepsis. We also examined the intravascular volume function (the tank) by performing the TTE, and ruled out intraperitoneal major hemorrhage which we once encountered (caused by inadvertent piercing of iliac artery when placing probe during lumbar surgery) by examination of abdominal ultrasound and hemoglobin level; Volume status was evaluated by measuring CVP, urine output, infused fluid volume; Surgical blood loss was reviewed to exclude hemorrhage shock and hypovolemia. As no special medications were given except anesthetic maintenance drugs, and no signs of mottled skin or bronchospasm were noticed, anaphylaxis was not considered at that time. After restoring circulatory stability, the surgery preceded uneventfully. The patient was discharged from hospital 7 days later.
It was intriguing that within 1 month, another case of circulatory collapse happened during wound closure in spine surgery performed by the same orthopedic surgeon. The intraoperative clinical manifestations were very similar to the previous one. Hemodynamic resuscitation were initiated immediately with repeated boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min). After stabilizing the circulation 4 h later, the patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions after full recovery from anesthesia). Postoperative imaging revealed intracranial micro hemorrhagic foci in the subdural and subarachnoid space. The patient was discharged from hospital without any neurological sequelae.
With further exploration and analysis of the similarities of these two cases, we found that local application of vancomycin (VCM) powder was used in these two patients to prevent postoperative surgical site infections (SSIs) during wound closure (0.5 g VCM loaded with bone debris into the cage and another 0.5 g sprayed on the dura mater and into the mascularis). Ramamani Mariappan reported a case of circulatory collapse after topical application of vancomycin powder during spine surgery, which exhibited almost the same clinical course as ours [2]. It was speculated that the rapid absorption of VCM applied to the surgical wound caused an anaphylaxis reaction and circulatory collapse. The reaction occurred approximately 30 min after the application and persisted for 6 h. The serum tryptase level was not elevated, suggesting that VCM caused a direct histamine release, which is in keeping with our current understanding. A similar case reported a 74-year-old woman who underwent a primary total knee replacement presented with red man syndrome in the PACU 45 min after release of tourniquet following the use of VCM-loaded bone cement. The patient remained fully conscious despite a sudden drop in blood pressure to 47/34 mmHg [3]. Therefore, local application of VCM may pose the risk of causing severe circulatory adverse effect.
Similar circulatory collapse cases in spine surgery without definitive causes during wound closure or shortly after surgery, though rare, were encountered in our institution. Therefore we retrospectively analyzed these cases for the past 2 years, and asked the anesthesiologists and orthopedic surgeons in charge for further information. A total of 7 cases were collected (Table 1). There were 3 males and 4 females, the median age was 66 y (43–74 y), and the averaged BMI was 24.39 ± 1.51 (22.3–26.1). It was interesting to note that these cases were all associated with topical application of VCM powder (Table 1). In these 7 cases, the onset time of severe circulatory fluctuation was 30 min in 5 cases, 50 min in one case (applied with 1 g of VCM), and approximately 45 min in another case (locally applied 3 g of VCM), respectively. Most of the cases (6/7) with severe circulatory fluctuation were corrected without severe sequelae. While in one case in which 3 g of VCM was applied on the dura mater and into the mascularis during wound closure, sudden cardiac arrest happened shortly after the patient had fully recovered from the anesthetic, following surgery and extubation in the OR. CPR was initiated immediately. The patient was reintubated and ventilated mechanically. The persistent VF was treated with continuous chest compressions and repeated defibrillation, with boluses of adrenaline (a total of 6 mg) and amiodarone. After 50 min of continuous CPR, with fluid resuscitation and blood transfusion, the patient was transferred to ICU following the return of spontaneous circulation and reverting into sinus rhythm. However, the patient remained in a comatose state due to hypoxic-hypoxic encephalopathy, and tracheotomy was performed 2 weeks later.
Discussion and conclusion
Vancomycin and anaphylaxis reaction
“International Consensus on (ICON) Anaphylaxis” define anaphylaxis as “a serious, generalized or systemic, allergic or hypersensitivity reaction that can be life threatening or fatal” [4]. It has been demonstrated that there exists IgE-dependent and three IgE-independent mechanisms in anaphylaxis pathophysiology [5]. VCM could directly activate mast cells to release histamine and other mediators through an IgE-independent mechanism that is calcium-, phospholipase C–, and phospholipase A2–dependent but otherwise unknown [5, 6]. Vancomycin-induced direct histamine release is also infusion rate dependent [7]. This IgE-independent anaphylaxis reaction generally disappears within 20 mins, but may linger for hours. The most common manifestation is a sudden drop in blood pressure, which is related to the negative inotropic effect and the vasodilator action stimulated by the histamine release. Alteration in vascular tone is also a common feature of anaphylactic shock [8]. Richter J and colleagues demonstrated in rats that VCM could directly influence the vascular tonus, affecting the microcirculation [9].
The VCM reactions studied in the pediatric population revealed that non-IgE mediated reaction accounts for the vast majority of reactions (92%; prevalence, 5.4–5.8%), whereas possible IgE-mediated vancomycin reactions were exceedingly rare (prevalence, 0.0–0.37%) [7]. For adults, the reported incidence of non-IgE mediated reaction varies between 3.7 and 47% in infected patients and 90% in healthy volunteers [2]. Elevated serum mast cell tryptase is a valuable indicator for diagnosing Ig-E mediated anaphylactic reaction. However, it is not useful in determining a non-IgE mediated anaphylactic reaction caused by histamine release [2]. Detection of histamine concentration in clinical blood specimens is difficult due to its extremely short half-life, and histamine is not a mast cell specific product [10]. As this study is retrospective in nature, and our hospital does not perform examination of serum tryptase and histamine concentration, we could not differentiate whether the adverse effects were caused by VCM induced IgE-mediated or non-IgE mediated reaction.
Topical application of vancomycin powder and surgical site infections
VCM is effective in fighting Gram-positive bacteria related severe infections [11]. While the actual utility of local application of VCM is controversial. After the first reported topical application of VCM by orthopedic surgeons to reduce postoperative surgical site infections (SSIs) rate [12], a large number of meta-analyses, retrospective cohort studies, and randomized controlled trials were published to assess the power of this method in preventing SSIs. Recent findings from large-scale propensity score matched analyses, meta analyses, RCTs studies, and observational studies of spine surgeries and knee arthroplasties all demonstrated that the intrawound VCM powder application may not decrease SSIs, but may increase postoperative complications [13–19].
VCM is an antibiotic that was considered safe in local application and has been widely used in hospitals. However, dose recommendations, dilutions, monitoring, infusion types and rates are still controversial [20]. There’s no defined time or situation during surgery when local VCM should be applied. Some may load VCM powder with bone debris into the cage, or apply VCM powder directly onto the dura mater or after closure of the fascia, whereas other studies reported that VCM powder was applied in the subfascial layer [2, 13]. However, intrawound absorption rate of VCM powder is uncontrollable as this depends on multiple factors, such as the extent and degree of tissue/muscle damaged by surgical manipulation, anatomic location where VCM powder is placed (mixed with bone debris, or between muscularis layers that are abundant with blood supply), and the surgeon’s suturing maneuvers (the flushing saline would leak from upper layer into the layer where VCM powder is deposited). These factors all pose potential risk of causing rapid drug dissolution and accelerated absorption into the circulatory system. Moreover, individual’s adverse reactions to VCM varied. These incidental events may be accidentally linked and lead to severe outcome. Since intravenous administration of VCM could lead to adverse effects, it is theoretically possible that local application of VCM powder may cause similar clinical manifestation.
Topical application of VCM was intended to achieve the effect of providing high local concentrations while avoiding high systemic levels and the risk of bacterial resistance. The serum concentration level peaks at 30 min and then declines to baseline at 6 h [2]. This may explain the delayed and unpredictable occurrence of anaphylaxis reactions after local application of VCM powder, due to the uncertainty of the drug absorption rate and individual reaction differences. The instructed therapeutic dosage of VCM is 30 mg/kg/day which should be fractioned in 2 or 3 doses. Moreover, the infusion rate should be within 10 mg/min, and last for more than 60 min. For elderly patients, this dosage should be reduced [21, 22]. Although the most commonly used dose of intrawound VCM is 1 g, some authors reported that they altered the dose according to the length of the incision [23]. VCM is not the first-choice antibiotic as its adverse effects are frequently reported including hypotension and tachycardia, phlebitis, nephrotoxicity, ototoxicity, hypersensitivity reactions, red man syndrome, neutropenia, chills, fever, interstitial nephritis, etc. [13]. As VCM induced adverse reactions are dose and infusion-rate dependent, doctors should be highly vigilant to over-dosing which might bring disastrous results.
Other issues related to shock
In this case series, the typical signs of erythema and redness (red man syndrome) have not appeared, which resemble the previous case reported by Mariappan R and colleagues [2]. The lack of skin flushing may be the result of reduced perfusion due to circulatory shock or the adverse effect of VCM mainly manifested as severe alteration of vascular tonus [8, 9]. In our experience, a rapid but low dose intravenous infusion of VCM induced anaphylaxis reaction was not necessarily associated with skin manifestations. Whether this is related to racial differences or rapid absorption of low dose VCM was not known. However, the clinical features of hypotension, tachycadia and low oxygenation were notable.
For this case series, as there is no definitive laboratory examination or gold standard to help reach a definitive diagnosis of VCM induced anaphylaxis reaction, the conclusions were made upon differential diagnosis based on clinical manifestations and the timing of the shock. Other possible causes or contributing factors for the development of severe hypotension and shock need to be considered. For example, restrictive fluid therapy during surgical procedure and restrictive blood transfusion strategy leading to hypovolemia and hypotension, complicated with unseen bleeding from surgical site and other compounding factors such as hypoproteinemia and unaltered anesthetic depth during wound closure.
Another issue needs to be addressed is that there’s a notable decrease in hemoglobin (HGB) concentration in all cases when severe hypotension occurred. However, the hemorrhagic shock induced by surgical blood loss was ruled out. We speculate that this might be due to the infusion of large amounts of fluid during resuscitation. It is reported that the administration of 500 ml of fluids may acutely decrease the HGB concentration by about 1 g/dl, or about 8%, by “dilutional anemia” [24]. In septic shock patients, approximately 30% decrease of hematocrit was commonly observed in patients receiving large amounts of fluids during resuscitation, which further indicates more blood transfusion [25]. In the current study, the HGB concentrations were all measured after the initiation of fluid resuscitation and this may at least partially explained the sharp decrease of the HGB level (Table 1). When severe hypotension with unknown causes occur, initial management is to infuse large amounts of fluid with vaso-constrictive drugs. The iatrogenic hemodilution related blood transfusion may result in dilutional coagulopathy and increase surgical bleeding. This then leads to a decreased HGB level below the acceptable transfusion threshold, leading to further blood transfusion in the absence of significant blood loss [26]. This is especially true when in the scenario of the existence of suspected hemorrhagic shock.
In conclusion, local application of VCM powder during wound closure could cause delayed occurrence of severe hypotension and shock in spine surgery. Hemodynamic changes may be under-emphasized and under-reported as in most cases, this hemodynamic reaction is easy to correct and normally wouldn’t cause serious consequences. However, the actual occurrence is not rare and this might be confused with hypovolemia or anesthetic induced hypotension. Surgeons and anesthesiologists should be highly aware of VCM induced IgE-independent anaphylaxis reactions. The differential diagnosis of anaphylactic shock must be taken into consideration in patients with acute hypotension during or immediately after wound closure. Prompt laboratory analysis of serum tryptase and histamine concentration could help differentiate the causes. Moreover, since controversies still exist in the actual effect of intrawound application of VCM powder to reduce SSIs in spine surgery, local application of this drug should be used with caution.
Abbreviations
VCMVancomycin
ABPArterial blood pressure
TTETransthoracic echocardiography
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
We sincerely thank our colleagues from anesthesia (Dr. XW, Dr. CW, Dr. WL, Dr. JY, Dr. YW, Dr. CN, Dr. CX, Dr. YT, Dr. HW, Dr. HT, Dr. WW, Dr. YT, Dr. XJ, HL, Dr. HW, Dr. HZ, Dr. YW, and Dr. BW) and surgical department (Dr. YD, Dr. YL, Dr. FZ, Dr. QQ, and Dr. ZC) for providing and verifying the cases.
The authors have completed the CARE reporting checklist.
Authors’ contributions
Guarantor of integrity of entire study: XZ, WZ, ML, XG. Literature research: XZ, WZ. Case study and follow-up: XZ, WZ. Manuscript preparation: XZ, WZ. Manuscript editing and revision: ML, XG. Manuscript final version approval: ML, XG. All authors have read and approved the manuscript.
Funding
This work was supported by the Clinical Key Project of Peking University Third Hospital, Grants No. BYSY2017001.
The role of the funder: study design, decision to submit the manuscript for publication.
Availability of data and materials
All data generated or analyzed during this study are included in this published article. More detailed information could be find in Table 1.
Ethics approval and consent to participate
This case was performed according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Peking University Third Hospital. All the authors listed in the manuscript consent to participate the study. The consent for publication from patient or their relatives were collected retrospectively.
Consent for publication
As this is a retrospective case study, written informed consent to publish this manuscript were collected from patients or their relatives retrospectively. The proof of consent to publish from study participants can be requested at any time.
Competing interests
The author(s) declare no competing interests. | Topical | DrugAdministrationRoute | CC BY | 33407142 | 18,839,984 | 2021-01-06 |
What was the outcome of reaction 'Anaphylactic reaction'? | Circulatory collapse during wound closure in spine surgery with an unknown cause: a possible adverse effect of topical application of vancomycin?
Vancomycin (VCM) is effective in fighting Gram-positive bacteria related severe infections, and topical application of VCM powder is widely used in orthopedic surgery to prevent wound infection. However, VCM could lead to infusion rate-dependent antibody-and complement-independent anaphylaxis reaction by inducing direct release of histamine.
We retrospectively analyzed seven cases of severe hypotension and shock during wound closure or immediately after orthopedic surgery with unidentifiable reasons. We found that these cases were all associated with local application of VCM powder during wound closure process. Two patients experienced sudden cardiac arrest. Most of the cases (6/7) with circulatory collapse were discharged without severe sequelae. While one case with application of 3 g VCM developed cardiac arrest and remained in a coma due to hypoxic-hypoxic encephalopathy. The clinical presentations and the time of the shock onset were considered to be related with a VCM induced anaphylaxis reaction. However, as this was a retrospective study, and there was no laboratory examination performed, the conclusion was made upon differential diagnosis based on clinical manifestations and the timing of the shock.
Local application of VCM may not be as safe as was once believed and may lead to a related anaphylaxis. As VCM induced infusion-rate dependent, non-IgE mediated anaphylaxis is characterized by delayed occurrence, severe hypotension and even circulatory collapse, surgeons and anesthesiologists should be extra vigilant during and after VCM application.
Background
Shock is defined as a state of insufficient perfusion and oxygen delivery to the tissues. The pathophysiology of shock could be simplified to three major components: cardiac function (the pump), intravascular volume (the tank), and systemic vascular resistance (the pipes) [1]. Whatever the causes of shock may be, if the impaired perfusion and oxygen delivery is not recognized and reversed, the circulatory collapse may progress into organ dysfunction and failure, tissue necrosis and even death. It is urgent to identify the causes of shock and take immediate measures. However, in critical situations, it is hard to rapidly distinguish the culprit during complex clinical situations. Here we present 7 cases (Table 1) of unidentifiable causes of shock during wound closure or shortly after spine surgery, and discuss the possible reasons.
Table 1 Summary of clinical presentations of seven patients with circulatory collapse and unknown etiologies during or shortly after wound closure in spine surgery
Case Demographic information Initial signs/symptoms of shock and management Hemoglobin value (g/L),
fluid resuscitation and blood product infusion VCM administration
and Postoperative sequelae
1 Female; 68-yr; 160 cm/60 kg
BMI: 23.4
Diagnosis:
Lumbar stenosis (L3-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Hypertension
History of retina surgery
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
ABP: 30/20 mmHg
SpO2: undetectable
ECG: tarchycardia with elevated ST segment
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for 45 min. Fluid resuscitation and blood transfusion.
Preoperative HGB value: 124
Intraoperative minimum value of HGB: 73
Blood loss: 600 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 3450 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 210 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
Proceeded with surgery and the patient was extubated uneventfully.
2 Male; 74-yr; 171 cm/67 kg
BMI: 23.9
Diagnosis:
lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
ECG: tachycardia with ST segment depression
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min) for 4 h.
Preoperative HGB value:135
Intraoperative minimum value of HGB: 79
Blood loss: 600 ml
Urine: 1950 ml
Fluid and blood product infusion:
Crystalloid: 6300 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Plasma: 800 ml
Infused autologous blood: 254 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions).
Postoperative imaging: intracranial minor hemorrhage at subdural and subarachnoid space.
The patient was discharged from hospital without neurological deficit.
3 Male; 63-yr; 169 cm/70 kg
BMI: 24.5
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Lacunar infarction;
Bilateral carotid atherosclerotic plaque formation
Time of occurrence:
50 min after initiation of wound closure and 20 min post-extubation in the PACU.
Signs and symptoms:
NBP: 60/25 mmHg
SpO2: 96%
HR:sudden elevation from 60 to 90 bpm
Postoperative agitation
Skin and airway symptoms: none.
Management:
Boluses of ephedrine, phenylephrine and fluid resuscitation.
Preoperative HGB value: 176
Intraoperative minimum value of HGB:123
Blood loss: 800 ml
Urine: 800 ml
Fluid and blood product infusion:
Crystalloid: 2350 ml
Colloid: 1000 ml
PRBC infusion: 400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis.
Postoperative sequelae:
Uneventful.
4 Female; 70-yr; 160 cm/65 kg
BMI:25.4
Diagnosis:
Lumbar stenosis (L4-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Hypertension
Diabetes Mellitus
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
Persistent tachycardia
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine for treating severe hypotension and esmolol for tachycardia
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 150
Intraoperative minimum value of HGB: 92
Blood loss: 1500 ml
Urine: 1800 ml
Fluid and blood product infusion:
Crystalloid: 3100 ml
Colloid: 1500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 450 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery and transferred to ICU due to tachycardia after sufficient fluid resuscitation.
Recovered uneventfully.
5 Female;48-yr; 170 cm/75 kg
BMI: 26.0
Diagnosis:
Thoracic spinal canal stenosis (T6-T11)
Surgery:
Posterior decompression, fixation and fusion of thoracic spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 40/30 mmHg to undetectable
HR: 120 bpm to 40 bpm
SpO2: undetectable
Cardiac arrest
Skin and airway symptoms: none.
Management:
Extracardiac compression
Boluses of noradrenaline (200 μg) and adrenaline (1 g)
Continuous infusion of noradrenaline (0.02–0.08 μg/kg/min) for 50 min
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 132
Intraoperative minimum value of HGB: 74
Blood loss: 2500 ml
Urine: 1300 ml
Fluid and blood product infusion:
Crystalloid: 4000 ml
Colloid: 500 ml
PRBC infusion: 2400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery, and discharged from hospital uneventfully.
6 Male; 66-yr; 175 cm/ 80 kg
BMI: 26.1
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Carotid artery stenosis
Diabetes Mellitus
Time of occurrence:
Sudden cardiac arrest 10 min after extubation (approximately 45 min after initiation of wound closure) with full recovery from anesthesia and without any discomfort complaint.
Signs and symptoms:
Cardiac arrest and persistent VF
Skin and airway symptoms: none.
Management:
Continuous CPR
Persistent VF was treated with repeated defibrillation
Boluses of adrenaline (a total of 6 mg) and amiodarone.
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 143
Intraoperative minimum value of HGB: 78
Blood loss: 1000 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 4400 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 600 ml
VCM administration:
Topical spraying of vancomycin (3 g) on the dura mater and into the mascularis.
Postoperative sequelae:
The patient was reintubated and transferred to ICU after ROSC. The patient was diagnosed as hypoxic encephalopathy and remained in a coma state. Tracheotomy was performed 2 weeks after surgery, and the patient was transferred to a nursing home for rehabilitation 1 month after orthopedic surgery.
7 Female; 43-yr; 155 cm / 54 kg
BMI: 22.4
Diagnosis:
Thoracic kyphosis (T7-T8)
Surgery:
Osteotomy for kyphosis of thoracic spine (T7-T8).
Medical and allergy history:
nil relevant.
Time of occurrence:
subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
HR:tachycardia
NBP: 60/30 mmHg
SpO2 82%
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine and ephedrine;
Continuous infusion of noradrenaline (0.05–0.1 μg/kg/min)
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 138
Intraoperative minimum value of HGB: 95
Blood loss: 1200 ml
Urine: 1900 ml
Fluid and blood product infusion:
Crystalloid: 4700 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 470 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was transferred to ICU for optimal monitoring and recovered uneventfully.
Abbreviations: NBP Non-invasive blood pressure; ABP Arterial blood pressure; (NBP is noted when ABP is not available.) VF Ventricular fibrillation; CPR Cardiopulmonary Resuscitation; HGB Hemoglobin; VCM Vancomycin; PRBC Packed red blood cell; ROSC Return of spontaneous circulation
Case presentation
The first case we encountered was a 68-yr female with past medical history of hypertension and surgical treated retina detachment, who underwent posterior decompression, fixation and fusion of lumbar spine due to lumbar stenosis (L3-S1). The operation was uneventful until sudden circulatory collapse occurred during the process of rinsing mascularis and superficial fascia layer whilst closing the wound. A sudden drop in arterial blood pressure (ABP) (130/60 mmHg to 30/20 mmHg), increased HR (60 bpm to 100 bpm) with elevated ST-segment and significant decrease of PetCO2 (31 mmHg to 16 mmHg) were noticed, with undetectable pulse oximetry read. The patient was turned to supine position immediately and managed with boluses (40–100 μg) and a continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for approximately 45 min. The circulation was gradually stabilized. No rash, erythema, or bronchospasm were noted. The bilateral breath sounds were equal and the airway pressure remained normal. We continued treatments of fluid resuscitation and blood transfusion with corticosteroid and ice cap to prevent hypoxic-ischemic encephalopathy. Intraoperative emergency consultations and immediate examinations of 12-lead ECG, point-of-care transthoracic echocardiography (TTE), and full panel laboratory tests were performed. However, these results did not support the causes of sudden cardiac dysfunction (the pump) including mechanical obstruction (pericardial tamponade and massive pulmonary embolus), acute myocardial infarction, acute valvular insufficiency, and arrhythmia. Vascular catastrophes were excluded and there were no signs of sepsis. We also examined the intravascular volume function (the tank) by performing the TTE, and ruled out intraperitoneal major hemorrhage which we once encountered (caused by inadvertent piercing of iliac artery when placing probe during lumbar surgery) by examination of abdominal ultrasound and hemoglobin level; Volume status was evaluated by measuring CVP, urine output, infused fluid volume; Surgical blood loss was reviewed to exclude hemorrhage shock and hypovolemia. As no special medications were given except anesthetic maintenance drugs, and no signs of mottled skin or bronchospasm were noticed, anaphylaxis was not considered at that time. After restoring circulatory stability, the surgery preceded uneventfully. The patient was discharged from hospital 7 days later.
It was intriguing that within 1 month, another case of circulatory collapse happened during wound closure in spine surgery performed by the same orthopedic surgeon. The intraoperative clinical manifestations were very similar to the previous one. Hemodynamic resuscitation were initiated immediately with repeated boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min). After stabilizing the circulation 4 h later, the patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions after full recovery from anesthesia). Postoperative imaging revealed intracranial micro hemorrhagic foci in the subdural and subarachnoid space. The patient was discharged from hospital without any neurological sequelae.
With further exploration and analysis of the similarities of these two cases, we found that local application of vancomycin (VCM) powder was used in these two patients to prevent postoperative surgical site infections (SSIs) during wound closure (0.5 g VCM loaded with bone debris into the cage and another 0.5 g sprayed on the dura mater and into the mascularis). Ramamani Mariappan reported a case of circulatory collapse after topical application of vancomycin powder during spine surgery, which exhibited almost the same clinical course as ours [2]. It was speculated that the rapid absorption of VCM applied to the surgical wound caused an anaphylaxis reaction and circulatory collapse. The reaction occurred approximately 30 min after the application and persisted for 6 h. The serum tryptase level was not elevated, suggesting that VCM caused a direct histamine release, which is in keeping with our current understanding. A similar case reported a 74-year-old woman who underwent a primary total knee replacement presented with red man syndrome in the PACU 45 min after release of tourniquet following the use of VCM-loaded bone cement. The patient remained fully conscious despite a sudden drop in blood pressure to 47/34 mmHg [3]. Therefore, local application of VCM may pose the risk of causing severe circulatory adverse effect.
Similar circulatory collapse cases in spine surgery without definitive causes during wound closure or shortly after surgery, though rare, were encountered in our institution. Therefore we retrospectively analyzed these cases for the past 2 years, and asked the anesthesiologists and orthopedic surgeons in charge for further information. A total of 7 cases were collected (Table 1). There were 3 males and 4 females, the median age was 66 y (43–74 y), and the averaged BMI was 24.39 ± 1.51 (22.3–26.1). It was interesting to note that these cases were all associated with topical application of VCM powder (Table 1). In these 7 cases, the onset time of severe circulatory fluctuation was 30 min in 5 cases, 50 min in one case (applied with 1 g of VCM), and approximately 45 min in another case (locally applied 3 g of VCM), respectively. Most of the cases (6/7) with severe circulatory fluctuation were corrected without severe sequelae. While in one case in which 3 g of VCM was applied on the dura mater and into the mascularis during wound closure, sudden cardiac arrest happened shortly after the patient had fully recovered from the anesthetic, following surgery and extubation in the OR. CPR was initiated immediately. The patient was reintubated and ventilated mechanically. The persistent VF was treated with continuous chest compressions and repeated defibrillation, with boluses of adrenaline (a total of 6 mg) and amiodarone. After 50 min of continuous CPR, with fluid resuscitation and blood transfusion, the patient was transferred to ICU following the return of spontaneous circulation and reverting into sinus rhythm. However, the patient remained in a comatose state due to hypoxic-hypoxic encephalopathy, and tracheotomy was performed 2 weeks later.
Discussion and conclusion
Vancomycin and anaphylaxis reaction
“International Consensus on (ICON) Anaphylaxis” define anaphylaxis as “a serious, generalized or systemic, allergic or hypersensitivity reaction that can be life threatening or fatal” [4]. It has been demonstrated that there exists IgE-dependent and three IgE-independent mechanisms in anaphylaxis pathophysiology [5]. VCM could directly activate mast cells to release histamine and other mediators through an IgE-independent mechanism that is calcium-, phospholipase C–, and phospholipase A2–dependent but otherwise unknown [5, 6]. Vancomycin-induced direct histamine release is also infusion rate dependent [7]. This IgE-independent anaphylaxis reaction generally disappears within 20 mins, but may linger for hours. The most common manifestation is a sudden drop in blood pressure, which is related to the negative inotropic effect and the vasodilator action stimulated by the histamine release. Alteration in vascular tone is also a common feature of anaphylactic shock [8]. Richter J and colleagues demonstrated in rats that VCM could directly influence the vascular tonus, affecting the microcirculation [9].
The VCM reactions studied in the pediatric population revealed that non-IgE mediated reaction accounts for the vast majority of reactions (92%; prevalence, 5.4–5.8%), whereas possible IgE-mediated vancomycin reactions were exceedingly rare (prevalence, 0.0–0.37%) [7]. For adults, the reported incidence of non-IgE mediated reaction varies between 3.7 and 47% in infected patients and 90% in healthy volunteers [2]. Elevated serum mast cell tryptase is a valuable indicator for diagnosing Ig-E mediated anaphylactic reaction. However, it is not useful in determining a non-IgE mediated anaphylactic reaction caused by histamine release [2]. Detection of histamine concentration in clinical blood specimens is difficult due to its extremely short half-life, and histamine is not a mast cell specific product [10]. As this study is retrospective in nature, and our hospital does not perform examination of serum tryptase and histamine concentration, we could not differentiate whether the adverse effects were caused by VCM induced IgE-mediated or non-IgE mediated reaction.
Topical application of vancomycin powder and surgical site infections
VCM is effective in fighting Gram-positive bacteria related severe infections [11]. While the actual utility of local application of VCM is controversial. After the first reported topical application of VCM by orthopedic surgeons to reduce postoperative surgical site infections (SSIs) rate [12], a large number of meta-analyses, retrospective cohort studies, and randomized controlled trials were published to assess the power of this method in preventing SSIs. Recent findings from large-scale propensity score matched analyses, meta analyses, RCTs studies, and observational studies of spine surgeries and knee arthroplasties all demonstrated that the intrawound VCM powder application may not decrease SSIs, but may increase postoperative complications [13–19].
VCM is an antibiotic that was considered safe in local application and has been widely used in hospitals. However, dose recommendations, dilutions, monitoring, infusion types and rates are still controversial [20]. There’s no defined time or situation during surgery when local VCM should be applied. Some may load VCM powder with bone debris into the cage, or apply VCM powder directly onto the dura mater or after closure of the fascia, whereas other studies reported that VCM powder was applied in the subfascial layer [2, 13]. However, intrawound absorption rate of VCM powder is uncontrollable as this depends on multiple factors, such as the extent and degree of tissue/muscle damaged by surgical manipulation, anatomic location where VCM powder is placed (mixed with bone debris, or between muscularis layers that are abundant with blood supply), and the surgeon’s suturing maneuvers (the flushing saline would leak from upper layer into the layer where VCM powder is deposited). These factors all pose potential risk of causing rapid drug dissolution and accelerated absorption into the circulatory system. Moreover, individual’s adverse reactions to VCM varied. These incidental events may be accidentally linked and lead to severe outcome. Since intravenous administration of VCM could lead to adverse effects, it is theoretically possible that local application of VCM powder may cause similar clinical manifestation.
Topical application of VCM was intended to achieve the effect of providing high local concentrations while avoiding high systemic levels and the risk of bacterial resistance. The serum concentration level peaks at 30 min and then declines to baseline at 6 h [2]. This may explain the delayed and unpredictable occurrence of anaphylaxis reactions after local application of VCM powder, due to the uncertainty of the drug absorption rate and individual reaction differences. The instructed therapeutic dosage of VCM is 30 mg/kg/day which should be fractioned in 2 or 3 doses. Moreover, the infusion rate should be within 10 mg/min, and last for more than 60 min. For elderly patients, this dosage should be reduced [21, 22]. Although the most commonly used dose of intrawound VCM is 1 g, some authors reported that they altered the dose according to the length of the incision [23]. VCM is not the first-choice antibiotic as its adverse effects are frequently reported including hypotension and tachycardia, phlebitis, nephrotoxicity, ototoxicity, hypersensitivity reactions, red man syndrome, neutropenia, chills, fever, interstitial nephritis, etc. [13]. As VCM induced adverse reactions are dose and infusion-rate dependent, doctors should be highly vigilant to over-dosing which might bring disastrous results.
Other issues related to shock
In this case series, the typical signs of erythema and redness (red man syndrome) have not appeared, which resemble the previous case reported by Mariappan R and colleagues [2]. The lack of skin flushing may be the result of reduced perfusion due to circulatory shock or the adverse effect of VCM mainly manifested as severe alteration of vascular tonus [8, 9]. In our experience, a rapid but low dose intravenous infusion of VCM induced anaphylaxis reaction was not necessarily associated with skin manifestations. Whether this is related to racial differences or rapid absorption of low dose VCM was not known. However, the clinical features of hypotension, tachycadia and low oxygenation were notable.
For this case series, as there is no definitive laboratory examination or gold standard to help reach a definitive diagnosis of VCM induced anaphylaxis reaction, the conclusions were made upon differential diagnosis based on clinical manifestations and the timing of the shock. Other possible causes or contributing factors for the development of severe hypotension and shock need to be considered. For example, restrictive fluid therapy during surgical procedure and restrictive blood transfusion strategy leading to hypovolemia and hypotension, complicated with unseen bleeding from surgical site and other compounding factors such as hypoproteinemia and unaltered anesthetic depth during wound closure.
Another issue needs to be addressed is that there’s a notable decrease in hemoglobin (HGB) concentration in all cases when severe hypotension occurred. However, the hemorrhagic shock induced by surgical blood loss was ruled out. We speculate that this might be due to the infusion of large amounts of fluid during resuscitation. It is reported that the administration of 500 ml of fluids may acutely decrease the HGB concentration by about 1 g/dl, or about 8%, by “dilutional anemia” [24]. In septic shock patients, approximately 30% decrease of hematocrit was commonly observed in patients receiving large amounts of fluids during resuscitation, which further indicates more blood transfusion [25]. In the current study, the HGB concentrations were all measured after the initiation of fluid resuscitation and this may at least partially explained the sharp decrease of the HGB level (Table 1). When severe hypotension with unknown causes occur, initial management is to infuse large amounts of fluid with vaso-constrictive drugs. The iatrogenic hemodilution related blood transfusion may result in dilutional coagulopathy and increase surgical bleeding. This then leads to a decreased HGB level below the acceptable transfusion threshold, leading to further blood transfusion in the absence of significant blood loss [26]. This is especially true when in the scenario of the existence of suspected hemorrhagic shock.
In conclusion, local application of VCM powder during wound closure could cause delayed occurrence of severe hypotension and shock in spine surgery. Hemodynamic changes may be under-emphasized and under-reported as in most cases, this hemodynamic reaction is easy to correct and normally wouldn’t cause serious consequences. However, the actual occurrence is not rare and this might be confused with hypovolemia or anesthetic induced hypotension. Surgeons and anesthesiologists should be highly aware of VCM induced IgE-independent anaphylaxis reactions. The differential diagnosis of anaphylactic shock must be taken into consideration in patients with acute hypotension during or immediately after wound closure. Prompt laboratory analysis of serum tryptase and histamine concentration could help differentiate the causes. Moreover, since controversies still exist in the actual effect of intrawound application of VCM powder to reduce SSIs in spine surgery, local application of this drug should be used with caution.
Abbreviations
VCMVancomycin
ABPArterial blood pressure
TTETransthoracic echocardiography
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
We sincerely thank our colleagues from anesthesia (Dr. XW, Dr. CW, Dr. WL, Dr. JY, Dr. YW, Dr. CN, Dr. CX, Dr. YT, Dr. HW, Dr. HT, Dr. WW, Dr. YT, Dr. XJ, HL, Dr. HW, Dr. HZ, Dr. YW, and Dr. BW) and surgical department (Dr. YD, Dr. YL, Dr. FZ, Dr. QQ, and Dr. ZC) for providing and verifying the cases.
The authors have completed the CARE reporting checklist.
Authors’ contributions
Guarantor of integrity of entire study: XZ, WZ, ML, XG. Literature research: XZ, WZ. Case study and follow-up: XZ, WZ. Manuscript preparation: XZ, WZ. Manuscript editing and revision: ML, XG. Manuscript final version approval: ML, XG. All authors have read and approved the manuscript.
Funding
This work was supported by the Clinical Key Project of Peking University Third Hospital, Grants No. BYSY2017001.
The role of the funder: study design, decision to submit the manuscript for publication.
Availability of data and materials
All data generated or analyzed during this study are included in this published article. More detailed information could be find in Table 1.
Ethics approval and consent to participate
This case was performed according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Peking University Third Hospital. All the authors listed in the manuscript consent to participate the study. The consent for publication from patient or their relatives were collected retrospectively.
Consent for publication
As this is a retrospective case study, written informed consent to publish this manuscript were collected from patients or their relatives retrospectively. The proof of consent to publish from study participants can be requested at any time.
Competing interests
The author(s) declare no competing interests. | Recovered | ReactionOutcome | CC BY | 33407142 | 18,839,984 | 2021-01-06 |
What was the outcome of reaction 'Cardiac arrest'? | Circulatory collapse during wound closure in spine surgery with an unknown cause: a possible adverse effect of topical application of vancomycin?
Vancomycin (VCM) is effective in fighting Gram-positive bacteria related severe infections, and topical application of VCM powder is widely used in orthopedic surgery to prevent wound infection. However, VCM could lead to infusion rate-dependent antibody-and complement-independent anaphylaxis reaction by inducing direct release of histamine.
We retrospectively analyzed seven cases of severe hypotension and shock during wound closure or immediately after orthopedic surgery with unidentifiable reasons. We found that these cases were all associated with local application of VCM powder during wound closure process. Two patients experienced sudden cardiac arrest. Most of the cases (6/7) with circulatory collapse were discharged without severe sequelae. While one case with application of 3 g VCM developed cardiac arrest and remained in a coma due to hypoxic-hypoxic encephalopathy. The clinical presentations and the time of the shock onset were considered to be related with a VCM induced anaphylaxis reaction. However, as this was a retrospective study, and there was no laboratory examination performed, the conclusion was made upon differential diagnosis based on clinical manifestations and the timing of the shock.
Local application of VCM may not be as safe as was once believed and may lead to a related anaphylaxis. As VCM induced infusion-rate dependent, non-IgE mediated anaphylaxis is characterized by delayed occurrence, severe hypotension and even circulatory collapse, surgeons and anesthesiologists should be extra vigilant during and after VCM application.
Background
Shock is defined as a state of insufficient perfusion and oxygen delivery to the tissues. The pathophysiology of shock could be simplified to three major components: cardiac function (the pump), intravascular volume (the tank), and systemic vascular resistance (the pipes) [1]. Whatever the causes of shock may be, if the impaired perfusion and oxygen delivery is not recognized and reversed, the circulatory collapse may progress into organ dysfunction and failure, tissue necrosis and even death. It is urgent to identify the causes of shock and take immediate measures. However, in critical situations, it is hard to rapidly distinguish the culprit during complex clinical situations. Here we present 7 cases (Table 1) of unidentifiable causes of shock during wound closure or shortly after spine surgery, and discuss the possible reasons.
Table 1 Summary of clinical presentations of seven patients with circulatory collapse and unknown etiologies during or shortly after wound closure in spine surgery
Case Demographic information Initial signs/symptoms of shock and management Hemoglobin value (g/L),
fluid resuscitation and blood product infusion VCM administration
and Postoperative sequelae
1 Female; 68-yr; 160 cm/60 kg
BMI: 23.4
Diagnosis:
Lumbar stenosis (L3-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Hypertension
History of retina surgery
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
ABP: 30/20 mmHg
SpO2: undetectable
ECG: tarchycardia with elevated ST segment
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for 45 min. Fluid resuscitation and blood transfusion.
Preoperative HGB value: 124
Intraoperative minimum value of HGB: 73
Blood loss: 600 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 3450 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 210 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
Proceeded with surgery and the patient was extubated uneventfully.
2 Male; 74-yr; 171 cm/67 kg
BMI: 23.9
Diagnosis:
lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
ECG: tachycardia with ST segment depression
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min) for 4 h.
Preoperative HGB value:135
Intraoperative minimum value of HGB: 79
Blood loss: 600 ml
Urine: 1950 ml
Fluid and blood product infusion:
Crystalloid: 6300 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Plasma: 800 ml
Infused autologous blood: 254 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions).
Postoperative imaging: intracranial minor hemorrhage at subdural and subarachnoid space.
The patient was discharged from hospital without neurological deficit.
3 Male; 63-yr; 169 cm/70 kg
BMI: 24.5
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Lacunar infarction;
Bilateral carotid atherosclerotic plaque formation
Time of occurrence:
50 min after initiation of wound closure and 20 min post-extubation in the PACU.
Signs and symptoms:
NBP: 60/25 mmHg
SpO2: 96%
HR:sudden elevation from 60 to 90 bpm
Postoperative agitation
Skin and airway symptoms: none.
Management:
Boluses of ephedrine, phenylephrine and fluid resuscitation.
Preoperative HGB value: 176
Intraoperative minimum value of HGB:123
Blood loss: 800 ml
Urine: 800 ml
Fluid and blood product infusion:
Crystalloid: 2350 ml
Colloid: 1000 ml
PRBC infusion: 400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis.
Postoperative sequelae:
Uneventful.
4 Female; 70-yr; 160 cm/65 kg
BMI:25.4
Diagnosis:
Lumbar stenosis (L4-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Hypertension
Diabetes Mellitus
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
Persistent tachycardia
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine for treating severe hypotension and esmolol for tachycardia
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 150
Intraoperative minimum value of HGB: 92
Blood loss: 1500 ml
Urine: 1800 ml
Fluid and blood product infusion:
Crystalloid: 3100 ml
Colloid: 1500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 450 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery and transferred to ICU due to tachycardia after sufficient fluid resuscitation.
Recovered uneventfully.
5 Female;48-yr; 170 cm/75 kg
BMI: 26.0
Diagnosis:
Thoracic spinal canal stenosis (T6-T11)
Surgery:
Posterior decompression, fixation and fusion of thoracic spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 40/30 mmHg to undetectable
HR: 120 bpm to 40 bpm
SpO2: undetectable
Cardiac arrest
Skin and airway symptoms: none.
Management:
Extracardiac compression
Boluses of noradrenaline (200 μg) and adrenaline (1 g)
Continuous infusion of noradrenaline (0.02–0.08 μg/kg/min) for 50 min
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 132
Intraoperative minimum value of HGB: 74
Blood loss: 2500 ml
Urine: 1300 ml
Fluid and blood product infusion:
Crystalloid: 4000 ml
Colloid: 500 ml
PRBC infusion: 2400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery, and discharged from hospital uneventfully.
6 Male; 66-yr; 175 cm/ 80 kg
BMI: 26.1
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Carotid artery stenosis
Diabetes Mellitus
Time of occurrence:
Sudden cardiac arrest 10 min after extubation (approximately 45 min after initiation of wound closure) with full recovery from anesthesia and without any discomfort complaint.
Signs and symptoms:
Cardiac arrest and persistent VF
Skin and airway symptoms: none.
Management:
Continuous CPR
Persistent VF was treated with repeated defibrillation
Boluses of adrenaline (a total of 6 mg) and amiodarone.
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 143
Intraoperative minimum value of HGB: 78
Blood loss: 1000 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 4400 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 600 ml
VCM administration:
Topical spraying of vancomycin (3 g) on the dura mater and into the mascularis.
Postoperative sequelae:
The patient was reintubated and transferred to ICU after ROSC. The patient was diagnosed as hypoxic encephalopathy and remained in a coma state. Tracheotomy was performed 2 weeks after surgery, and the patient was transferred to a nursing home for rehabilitation 1 month after orthopedic surgery.
7 Female; 43-yr; 155 cm / 54 kg
BMI: 22.4
Diagnosis:
Thoracic kyphosis (T7-T8)
Surgery:
Osteotomy for kyphosis of thoracic spine (T7-T8).
Medical and allergy history:
nil relevant.
Time of occurrence:
subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
HR:tachycardia
NBP: 60/30 mmHg
SpO2 82%
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine and ephedrine;
Continuous infusion of noradrenaline (0.05–0.1 μg/kg/min)
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 138
Intraoperative minimum value of HGB: 95
Blood loss: 1200 ml
Urine: 1900 ml
Fluid and blood product infusion:
Crystalloid: 4700 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 470 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was transferred to ICU for optimal monitoring and recovered uneventfully.
Abbreviations: NBP Non-invasive blood pressure; ABP Arterial blood pressure; (NBP is noted when ABP is not available.) VF Ventricular fibrillation; CPR Cardiopulmonary Resuscitation; HGB Hemoglobin; VCM Vancomycin; PRBC Packed red blood cell; ROSC Return of spontaneous circulation
Case presentation
The first case we encountered was a 68-yr female with past medical history of hypertension and surgical treated retina detachment, who underwent posterior decompression, fixation and fusion of lumbar spine due to lumbar stenosis (L3-S1). The operation was uneventful until sudden circulatory collapse occurred during the process of rinsing mascularis and superficial fascia layer whilst closing the wound. A sudden drop in arterial blood pressure (ABP) (130/60 mmHg to 30/20 mmHg), increased HR (60 bpm to 100 bpm) with elevated ST-segment and significant decrease of PetCO2 (31 mmHg to 16 mmHg) were noticed, with undetectable pulse oximetry read. The patient was turned to supine position immediately and managed with boluses (40–100 μg) and a continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for approximately 45 min. The circulation was gradually stabilized. No rash, erythema, or bronchospasm were noted. The bilateral breath sounds were equal and the airway pressure remained normal. We continued treatments of fluid resuscitation and blood transfusion with corticosteroid and ice cap to prevent hypoxic-ischemic encephalopathy. Intraoperative emergency consultations and immediate examinations of 12-lead ECG, point-of-care transthoracic echocardiography (TTE), and full panel laboratory tests were performed. However, these results did not support the causes of sudden cardiac dysfunction (the pump) including mechanical obstruction (pericardial tamponade and massive pulmonary embolus), acute myocardial infarction, acute valvular insufficiency, and arrhythmia. Vascular catastrophes were excluded and there were no signs of sepsis. We also examined the intravascular volume function (the tank) by performing the TTE, and ruled out intraperitoneal major hemorrhage which we once encountered (caused by inadvertent piercing of iliac artery when placing probe during lumbar surgery) by examination of abdominal ultrasound and hemoglobin level; Volume status was evaluated by measuring CVP, urine output, infused fluid volume; Surgical blood loss was reviewed to exclude hemorrhage shock and hypovolemia. As no special medications were given except anesthetic maintenance drugs, and no signs of mottled skin or bronchospasm were noticed, anaphylaxis was not considered at that time. After restoring circulatory stability, the surgery preceded uneventfully. The patient was discharged from hospital 7 days later.
It was intriguing that within 1 month, another case of circulatory collapse happened during wound closure in spine surgery performed by the same orthopedic surgeon. The intraoperative clinical manifestations were very similar to the previous one. Hemodynamic resuscitation were initiated immediately with repeated boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min). After stabilizing the circulation 4 h later, the patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions after full recovery from anesthesia). Postoperative imaging revealed intracranial micro hemorrhagic foci in the subdural and subarachnoid space. The patient was discharged from hospital without any neurological sequelae.
With further exploration and analysis of the similarities of these two cases, we found that local application of vancomycin (VCM) powder was used in these two patients to prevent postoperative surgical site infections (SSIs) during wound closure (0.5 g VCM loaded with bone debris into the cage and another 0.5 g sprayed on the dura mater and into the mascularis). Ramamani Mariappan reported a case of circulatory collapse after topical application of vancomycin powder during spine surgery, which exhibited almost the same clinical course as ours [2]. It was speculated that the rapid absorption of VCM applied to the surgical wound caused an anaphylaxis reaction and circulatory collapse. The reaction occurred approximately 30 min after the application and persisted for 6 h. The serum tryptase level was not elevated, suggesting that VCM caused a direct histamine release, which is in keeping with our current understanding. A similar case reported a 74-year-old woman who underwent a primary total knee replacement presented with red man syndrome in the PACU 45 min after release of tourniquet following the use of VCM-loaded bone cement. The patient remained fully conscious despite a sudden drop in blood pressure to 47/34 mmHg [3]. Therefore, local application of VCM may pose the risk of causing severe circulatory adverse effect.
Similar circulatory collapse cases in spine surgery without definitive causes during wound closure or shortly after surgery, though rare, were encountered in our institution. Therefore we retrospectively analyzed these cases for the past 2 years, and asked the anesthesiologists and orthopedic surgeons in charge for further information. A total of 7 cases were collected (Table 1). There were 3 males and 4 females, the median age was 66 y (43–74 y), and the averaged BMI was 24.39 ± 1.51 (22.3–26.1). It was interesting to note that these cases were all associated with topical application of VCM powder (Table 1). In these 7 cases, the onset time of severe circulatory fluctuation was 30 min in 5 cases, 50 min in one case (applied with 1 g of VCM), and approximately 45 min in another case (locally applied 3 g of VCM), respectively. Most of the cases (6/7) with severe circulatory fluctuation were corrected without severe sequelae. While in one case in which 3 g of VCM was applied on the dura mater and into the mascularis during wound closure, sudden cardiac arrest happened shortly after the patient had fully recovered from the anesthetic, following surgery and extubation in the OR. CPR was initiated immediately. The patient was reintubated and ventilated mechanically. The persistent VF was treated with continuous chest compressions and repeated defibrillation, with boluses of adrenaline (a total of 6 mg) and amiodarone. After 50 min of continuous CPR, with fluid resuscitation and blood transfusion, the patient was transferred to ICU following the return of spontaneous circulation and reverting into sinus rhythm. However, the patient remained in a comatose state due to hypoxic-hypoxic encephalopathy, and tracheotomy was performed 2 weeks later.
Discussion and conclusion
Vancomycin and anaphylaxis reaction
“International Consensus on (ICON) Anaphylaxis” define anaphylaxis as “a serious, generalized or systemic, allergic or hypersensitivity reaction that can be life threatening or fatal” [4]. It has been demonstrated that there exists IgE-dependent and three IgE-independent mechanisms in anaphylaxis pathophysiology [5]. VCM could directly activate mast cells to release histamine and other mediators through an IgE-independent mechanism that is calcium-, phospholipase C–, and phospholipase A2–dependent but otherwise unknown [5, 6]. Vancomycin-induced direct histamine release is also infusion rate dependent [7]. This IgE-independent anaphylaxis reaction generally disappears within 20 mins, but may linger for hours. The most common manifestation is a sudden drop in blood pressure, which is related to the negative inotropic effect and the vasodilator action stimulated by the histamine release. Alteration in vascular tone is also a common feature of anaphylactic shock [8]. Richter J and colleagues demonstrated in rats that VCM could directly influence the vascular tonus, affecting the microcirculation [9].
The VCM reactions studied in the pediatric population revealed that non-IgE mediated reaction accounts for the vast majority of reactions (92%; prevalence, 5.4–5.8%), whereas possible IgE-mediated vancomycin reactions were exceedingly rare (prevalence, 0.0–0.37%) [7]. For adults, the reported incidence of non-IgE mediated reaction varies between 3.7 and 47% in infected patients and 90% in healthy volunteers [2]. Elevated serum mast cell tryptase is a valuable indicator for diagnosing Ig-E mediated anaphylactic reaction. However, it is not useful in determining a non-IgE mediated anaphylactic reaction caused by histamine release [2]. Detection of histamine concentration in clinical blood specimens is difficult due to its extremely short half-life, and histamine is not a mast cell specific product [10]. As this study is retrospective in nature, and our hospital does not perform examination of serum tryptase and histamine concentration, we could not differentiate whether the adverse effects were caused by VCM induced IgE-mediated or non-IgE mediated reaction.
Topical application of vancomycin powder and surgical site infections
VCM is effective in fighting Gram-positive bacteria related severe infections [11]. While the actual utility of local application of VCM is controversial. After the first reported topical application of VCM by orthopedic surgeons to reduce postoperative surgical site infections (SSIs) rate [12], a large number of meta-analyses, retrospective cohort studies, and randomized controlled trials were published to assess the power of this method in preventing SSIs. Recent findings from large-scale propensity score matched analyses, meta analyses, RCTs studies, and observational studies of spine surgeries and knee arthroplasties all demonstrated that the intrawound VCM powder application may not decrease SSIs, but may increase postoperative complications [13–19].
VCM is an antibiotic that was considered safe in local application and has been widely used in hospitals. However, dose recommendations, dilutions, monitoring, infusion types and rates are still controversial [20]. There’s no defined time or situation during surgery when local VCM should be applied. Some may load VCM powder with bone debris into the cage, or apply VCM powder directly onto the dura mater or after closure of the fascia, whereas other studies reported that VCM powder was applied in the subfascial layer [2, 13]. However, intrawound absorption rate of VCM powder is uncontrollable as this depends on multiple factors, such as the extent and degree of tissue/muscle damaged by surgical manipulation, anatomic location where VCM powder is placed (mixed with bone debris, or between muscularis layers that are abundant with blood supply), and the surgeon’s suturing maneuvers (the flushing saline would leak from upper layer into the layer where VCM powder is deposited). These factors all pose potential risk of causing rapid drug dissolution and accelerated absorption into the circulatory system. Moreover, individual’s adverse reactions to VCM varied. These incidental events may be accidentally linked and lead to severe outcome. Since intravenous administration of VCM could lead to adverse effects, it is theoretically possible that local application of VCM powder may cause similar clinical manifestation.
Topical application of VCM was intended to achieve the effect of providing high local concentrations while avoiding high systemic levels and the risk of bacterial resistance. The serum concentration level peaks at 30 min and then declines to baseline at 6 h [2]. This may explain the delayed and unpredictable occurrence of anaphylaxis reactions after local application of VCM powder, due to the uncertainty of the drug absorption rate and individual reaction differences. The instructed therapeutic dosage of VCM is 30 mg/kg/day which should be fractioned in 2 or 3 doses. Moreover, the infusion rate should be within 10 mg/min, and last for more than 60 min. For elderly patients, this dosage should be reduced [21, 22]. Although the most commonly used dose of intrawound VCM is 1 g, some authors reported that they altered the dose according to the length of the incision [23]. VCM is not the first-choice antibiotic as its adverse effects are frequently reported including hypotension and tachycardia, phlebitis, nephrotoxicity, ototoxicity, hypersensitivity reactions, red man syndrome, neutropenia, chills, fever, interstitial nephritis, etc. [13]. As VCM induced adverse reactions are dose and infusion-rate dependent, doctors should be highly vigilant to over-dosing which might bring disastrous results.
Other issues related to shock
In this case series, the typical signs of erythema and redness (red man syndrome) have not appeared, which resemble the previous case reported by Mariappan R and colleagues [2]. The lack of skin flushing may be the result of reduced perfusion due to circulatory shock or the adverse effect of VCM mainly manifested as severe alteration of vascular tonus [8, 9]. In our experience, a rapid but low dose intravenous infusion of VCM induced anaphylaxis reaction was not necessarily associated with skin manifestations. Whether this is related to racial differences or rapid absorption of low dose VCM was not known. However, the clinical features of hypotension, tachycadia and low oxygenation were notable.
For this case series, as there is no definitive laboratory examination or gold standard to help reach a definitive diagnosis of VCM induced anaphylaxis reaction, the conclusions were made upon differential diagnosis based on clinical manifestations and the timing of the shock. Other possible causes or contributing factors for the development of severe hypotension and shock need to be considered. For example, restrictive fluid therapy during surgical procedure and restrictive blood transfusion strategy leading to hypovolemia and hypotension, complicated with unseen bleeding from surgical site and other compounding factors such as hypoproteinemia and unaltered anesthetic depth during wound closure.
Another issue needs to be addressed is that there’s a notable decrease in hemoglobin (HGB) concentration in all cases when severe hypotension occurred. However, the hemorrhagic shock induced by surgical blood loss was ruled out. We speculate that this might be due to the infusion of large amounts of fluid during resuscitation. It is reported that the administration of 500 ml of fluids may acutely decrease the HGB concentration by about 1 g/dl, or about 8%, by “dilutional anemia” [24]. In septic shock patients, approximately 30% decrease of hematocrit was commonly observed in patients receiving large amounts of fluids during resuscitation, which further indicates more blood transfusion [25]. In the current study, the HGB concentrations were all measured after the initiation of fluid resuscitation and this may at least partially explained the sharp decrease of the HGB level (Table 1). When severe hypotension with unknown causes occur, initial management is to infuse large amounts of fluid with vaso-constrictive drugs. The iatrogenic hemodilution related blood transfusion may result in dilutional coagulopathy and increase surgical bleeding. This then leads to a decreased HGB level below the acceptable transfusion threshold, leading to further blood transfusion in the absence of significant blood loss [26]. This is especially true when in the scenario of the existence of suspected hemorrhagic shock.
In conclusion, local application of VCM powder during wound closure could cause delayed occurrence of severe hypotension and shock in spine surgery. Hemodynamic changes may be under-emphasized and under-reported as in most cases, this hemodynamic reaction is easy to correct and normally wouldn’t cause serious consequences. However, the actual occurrence is not rare and this might be confused with hypovolemia or anesthetic induced hypotension. Surgeons and anesthesiologists should be highly aware of VCM induced IgE-independent anaphylaxis reactions. The differential diagnosis of anaphylactic shock must be taken into consideration in patients with acute hypotension during or immediately after wound closure. Prompt laboratory analysis of serum tryptase and histamine concentration could help differentiate the causes. Moreover, since controversies still exist in the actual effect of intrawound application of VCM powder to reduce SSIs in spine surgery, local application of this drug should be used with caution.
Abbreviations
VCMVancomycin
ABPArterial blood pressure
TTETransthoracic echocardiography
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We sincerely thank our colleagues from anesthesia (Dr. XW, Dr. CW, Dr. WL, Dr. JY, Dr. YW, Dr. CN, Dr. CX, Dr. YT, Dr. HW, Dr. HT, Dr. WW, Dr. YT, Dr. XJ, HL, Dr. HW, Dr. HZ, Dr. YW, and Dr. BW) and surgical department (Dr. YD, Dr. YL, Dr. FZ, Dr. QQ, and Dr. ZC) for providing and verifying the cases.
The authors have completed the CARE reporting checklist.
Authors’ contributions
Guarantor of integrity of entire study: XZ, WZ, ML, XG. Literature research: XZ, WZ. Case study and follow-up: XZ, WZ. Manuscript preparation: XZ, WZ. Manuscript editing and revision: ML, XG. Manuscript final version approval: ML, XG. All authors have read and approved the manuscript.
Funding
This work was supported by the Clinical Key Project of Peking University Third Hospital, Grants No. BYSY2017001.
The role of the funder: study design, decision to submit the manuscript for publication.
Availability of data and materials
All data generated or analyzed during this study are included in this published article. More detailed information could be find in Table 1.
Ethics approval and consent to participate
This case was performed according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Peking University Third Hospital. All the authors listed in the manuscript consent to participate the study. The consent for publication from patient or their relatives were collected retrospectively.
Consent for publication
As this is a retrospective case study, written informed consent to publish this manuscript were collected from patients or their relatives retrospectively. The proof of consent to publish from study participants can be requested at any time.
Competing interests
The author(s) declare no competing interests. | Recovered | ReactionOutcome | CC BY | 33407142 | 18,839,984 | 2021-01-06 |
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