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ITP after COVID-19 Vaccination at the Salisbury VA Healthcare System: Case Studies
Background
An association between vaccines and the rare development of immune thrombocytopenic purpura (ITP) has been reported in the literature. More recently, there have been a few case reports published describing patients developing ITP shortly after COVID- 19 vaccination, but this has not been reported specifically in the Veteran population. The SVAHCS has three cases of Veterans diagnosed with new or relapsed ITP within two months of receiving the second COVID-19 vaccine (all Pfizer brand). The treatment(s) and current outcome for each patient is summarized below.
Case Reports
Case 1 is a 78-year-old male Veteran who received his second COVID-19 vaccine on 2/10/21. Patient was diagnosed with ITP 4/27/21, hospitalized multiple times and treated with pulse dexamethasone, prednisone taper, rituximab IV weekly and romiplostim injections. Currently, patient has a thrombocytosis and romiplostim injections are on hold. Case 2 is a 90-yearold male Veteran who received his second COVID-19 vaccine on 3/16/21. Patient was diagnosed on 5/3/21 and treated with pulse dexamethasone, prednisone taper and rituximab IV weekly. Platelet count is currently normal. Case 3 is a 75-year-old male Veteran who received his second COVID-19 vaccine on 2/1/21. He has a history of ITP diagnosed 12/12/14 that has been well controlled with weekly romiplostim injections until 4/9/21. Patient was hospitalized and treated with pulse dexamethasone and prednisone taper. Upon discharge, therapy was changed from romiplostim to fostamatinib. Currently, platelet count recovered and is stable.
Conclusions
The two Veterans with de novo ITP exhibited resistant disease and had prolonged treatment courses, taking approximately a month to recover their platelet counts. In contrast, the Veteran with relapsed ITP exhibited a faster recovery period of approximately two weeks. In the safety trials conducted for the Pfizer COVID-19 vaccine, participants received vaccination or placebo and had a follow-up for an average of two months which may explain why ITP was not reported as a possible association until after marketing. After treating the above cases, the SVAHCS plans to use thrombopoietin receptor agonists (TPO-RAs) earlier in the treatment of ITP that may be associated with the COVID-19 vaccine as this has recently been recommended in case reports from the general population.
Background
An association between vaccines and the rare development of immune thrombocytopenic purpura (ITP) has been reported in the literature. More recently, there have been a few case reports published describing patients developing ITP shortly after COVID- 19 vaccination, but this has not been reported specifically in the Veteran population. The SVAHCS has three cases of Veterans diagnosed with new or relapsed ITP within two months of receiving the second COVID-19 vaccine (all Pfizer brand). The treatment(s) and current outcome for each patient is summarized below.
Case Reports
Case 1 is a 78-year-old male Veteran who received his second COVID-19 vaccine on 2/10/21. Patient was diagnosed with ITP 4/27/21, hospitalized multiple times and treated with pulse dexamethasone, prednisone taper, rituximab IV weekly and romiplostim injections. Currently, patient has a thrombocytosis and romiplostim injections are on hold. Case 2 is a 90-yearold male Veteran who received his second COVID-19 vaccine on 3/16/21. Patient was diagnosed on 5/3/21 and treated with pulse dexamethasone, prednisone taper and rituximab IV weekly. Platelet count is currently normal. Case 3 is a 75-year-old male Veteran who received his second COVID-19 vaccine on 2/1/21. He has a history of ITP diagnosed 12/12/14 that has been well controlled with weekly romiplostim injections until 4/9/21. Patient was hospitalized and treated with pulse dexamethasone and prednisone taper. Upon discharge, therapy was changed from romiplostim to fostamatinib. Currently, platelet count recovered and is stable.
Conclusions
The two Veterans with de novo ITP exhibited resistant disease and had prolonged treatment courses, taking approximately a month to recover their platelet counts. In contrast, the Veteran with relapsed ITP exhibited a faster recovery period of approximately two weeks. In the safety trials conducted for the Pfizer COVID-19 vaccine, participants received vaccination or placebo and had a follow-up for an average of two months which may explain why ITP was not reported as a possible association until after marketing. After treating the above cases, the SVAHCS plans to use thrombopoietin receptor agonists (TPO-RAs) earlier in the treatment of ITP that may be associated with the COVID-19 vaccine as this has recently been recommended in case reports from the general population.
Background
An association between vaccines and the rare development of immune thrombocytopenic purpura (ITP) has been reported in the literature. More recently, there have been a few case reports published describing patients developing ITP shortly after COVID- 19 vaccination, but this has not been reported specifically in the Veteran population. The SVAHCS has three cases of Veterans diagnosed with new or relapsed ITP within two months of receiving the second COVID-19 vaccine (all Pfizer brand). The treatment(s) and current outcome for each patient is summarized below.
Case Reports
Case 1 is a 78-year-old male Veteran who received his second COVID-19 vaccine on 2/10/21. Patient was diagnosed with ITP 4/27/21, hospitalized multiple times and treated with pulse dexamethasone, prednisone taper, rituximab IV weekly and romiplostim injections. Currently, patient has a thrombocytosis and romiplostim injections are on hold. Case 2 is a 90-yearold male Veteran who received his second COVID-19 vaccine on 3/16/21. Patient was diagnosed on 5/3/21 and treated with pulse dexamethasone, prednisone taper and rituximab IV weekly. Platelet count is currently normal. Case 3 is a 75-year-old male Veteran who received his second COVID-19 vaccine on 2/1/21. He has a history of ITP diagnosed 12/12/14 that has been well controlled with weekly romiplostim injections until 4/9/21. Patient was hospitalized and treated with pulse dexamethasone and prednisone taper. Upon discharge, therapy was changed from romiplostim to fostamatinib. Currently, platelet count recovered and is stable.
Conclusions
The two Veterans with de novo ITP exhibited resistant disease and had prolonged treatment courses, taking approximately a month to recover their platelet counts. In contrast, the Veteran with relapsed ITP exhibited a faster recovery period of approximately two weeks. In the safety trials conducted for the Pfizer COVID-19 vaccine, participants received vaccination or placebo and had a follow-up for an average of two months which may explain why ITP was not reported as a possible association until after marketing. After treating the above cases, the SVAHCS plans to use thrombopoietin receptor agonists (TPO-RAs) earlier in the treatment of ITP that may be associated with the COVID-19 vaccine as this has recently been recommended in case reports from the general population.
Evans’ Syndrome in Undiagnosed Small Lymphocytic Lymphoma: Case Report and Literature Review
Background
Evans’ syndrome is a rare entity characterized by concomitant or sequential multilineage cytopenia particularly autoimmune hemolytic anemia, ITP and very rarely autoimmune neutropenia. Although more common in young adults, it can occur in elderly usually associated with malignancies like CLL.
Case Report
A 74 years old Veteran presented with complaints of fatigue and worsening dyspnea on exertion. His physical exam was unremarkable except jaundice. His labs were significant for macrocytic anemia with Hemoglobin of 7.4g/dl compared to 11.7g/dl 6 months prior, MCV 106.9 fL, LDH 809U/L, indirect bilirubin 4.1mg/dl, absolute reticulocyte 0.16M/uL, Haptoglobin <15mg/dl and Positive DAT. Platelets were mildly decreased at 111K/ul. No lymphocytosis was noted. Initially, the hemolysis was thought to be cephalosporin- related given that the patient had taken cephalexin recently for cellulitis. As part of the workup for anemia, the patient underwent EGD and colonoscopy which was initially unrevealing. However, random biopsies from the descending colon and terminal ileum returned with a small lymphocytic infiltrate consistent with SLL/CLL. Cytogenetics showed trisomy-12 which is associated with intermediate prognosis for CLL. PET scan done subsequently revealed only a reactive marrow and an enlarged 15.8cm non-hypermetabolic spleen. This veteran having anemia, positive DAT, thrombocytopenia, and splenomegaly got diagnosed with Evans’s syndrome. This syndrome was the initial manifestation of his underlying CLL. We started the patient on a prednisone taper for 4 weeks to which anemia and thrombocytopenia barely responded, ultimately Rituximab 375mg/m2 x4 weekly doses was started which led to complete resolution of anemia and thrombocytopenia. We closely followed the patient and monitored CBC and hemolytic markers. The patient relapsed in two years which was subsequently managed with another course of Rituximab 375mg/m2 x4 weekly doses.
Conclusions
This case report aims to call attention to this relatively rare entity which is difficult to treat and often associated with frequent relapses. Though rare, physicians should maintain high suspicion for this syndrome in patients with multi-lineage cytopenia which are usually not even responding well to the common treatment for cytopenia. Furthermore, there is room for improvement in Evans’ syndrome management since mortality remains higher in these patients than in those with isolated autoimmuce cytopenias.
Background
Evans’ syndrome is a rare entity characterized by concomitant or sequential multilineage cytopenia particularly autoimmune hemolytic anemia, ITP and very rarely autoimmune neutropenia. Although more common in young adults, it can occur in elderly usually associated with malignancies like CLL.
Case Report
A 74 years old Veteran presented with complaints of fatigue and worsening dyspnea on exertion. His physical exam was unremarkable except jaundice. His labs were significant for macrocytic anemia with Hemoglobin of 7.4g/dl compared to 11.7g/dl 6 months prior, MCV 106.9 fL, LDH 809U/L, indirect bilirubin 4.1mg/dl, absolute reticulocyte 0.16M/uL, Haptoglobin <15mg/dl and Positive DAT. Platelets were mildly decreased at 111K/ul. No lymphocytosis was noted. Initially, the hemolysis was thought to be cephalosporin- related given that the patient had taken cephalexin recently for cellulitis. As part of the workup for anemia, the patient underwent EGD and colonoscopy which was initially unrevealing. However, random biopsies from the descending colon and terminal ileum returned with a small lymphocytic infiltrate consistent with SLL/CLL. Cytogenetics showed trisomy-12 which is associated with intermediate prognosis for CLL. PET scan done subsequently revealed only a reactive marrow and an enlarged 15.8cm non-hypermetabolic spleen. This veteran having anemia, positive DAT, thrombocytopenia, and splenomegaly got diagnosed with Evans’s syndrome. This syndrome was the initial manifestation of his underlying CLL. We started the patient on a prednisone taper for 4 weeks to which anemia and thrombocytopenia barely responded, ultimately Rituximab 375mg/m2 x4 weekly doses was started which led to complete resolution of anemia and thrombocytopenia. We closely followed the patient and monitored CBC and hemolytic markers. The patient relapsed in two years which was subsequently managed with another course of Rituximab 375mg/m2 x4 weekly doses.
Conclusions
This case report aims to call attention to this relatively rare entity which is difficult to treat and often associated with frequent relapses. Though rare, physicians should maintain high suspicion for this syndrome in patients with multi-lineage cytopenia which are usually not even responding well to the common treatment for cytopenia. Furthermore, there is room for improvement in Evans’ syndrome management since mortality remains higher in these patients than in those with isolated autoimmuce cytopenias.
Background
Evans’ syndrome is a rare entity characterized by concomitant or sequential multilineage cytopenia particularly autoimmune hemolytic anemia, ITP and very rarely autoimmune neutropenia. Although more common in young adults, it can occur in elderly usually associated with malignancies like CLL.
Case Report
A 74 years old Veteran presented with complaints of fatigue and worsening dyspnea on exertion. His physical exam was unremarkable except jaundice. His labs were significant for macrocytic anemia with Hemoglobin of 7.4g/dl compared to 11.7g/dl 6 months prior, MCV 106.9 fL, LDH 809U/L, indirect bilirubin 4.1mg/dl, absolute reticulocyte 0.16M/uL, Haptoglobin <15mg/dl and Positive DAT. Platelets were mildly decreased at 111K/ul. No lymphocytosis was noted. Initially, the hemolysis was thought to be cephalosporin- related given that the patient had taken cephalexin recently for cellulitis. As part of the workup for anemia, the patient underwent EGD and colonoscopy which was initially unrevealing. However, random biopsies from the descending colon and terminal ileum returned with a small lymphocytic infiltrate consistent with SLL/CLL. Cytogenetics showed trisomy-12 which is associated with intermediate prognosis for CLL. PET scan done subsequently revealed only a reactive marrow and an enlarged 15.8cm non-hypermetabolic spleen. This veteran having anemia, positive DAT, thrombocytopenia, and splenomegaly got diagnosed with Evans’s syndrome. This syndrome was the initial manifestation of his underlying CLL. We started the patient on a prednisone taper for 4 weeks to which anemia and thrombocytopenia barely responded, ultimately Rituximab 375mg/m2 x4 weekly doses was started which led to complete resolution of anemia and thrombocytopenia. We closely followed the patient and monitored CBC and hemolytic markers. The patient relapsed in two years which was subsequently managed with another course of Rituximab 375mg/m2 x4 weekly doses.
Conclusions
This case report aims to call attention to this relatively rare entity which is difficult to treat and often associated with frequent relapses. Though rare, physicians should maintain high suspicion for this syndrome in patients with multi-lineage cytopenia which are usually not even responding well to the common treatment for cytopenia. Furthermore, there is room for improvement in Evans’ syndrome management since mortality remains higher in these patients than in those with isolated autoimmuce cytopenias.
Factors Associated with Survival and Epidemiology of Gastrointestinal Neuroendocrine Tumors in the US Department of Veteran Affairs
Introduction
Rectal carcinoid tumors are rare but the second most common carcinoid in the gastrointestinal tract. They are usually found incidentally during endoscopic or rectal examination. They do not often produce carcinoid syndrome like manifestations although they may manifest as rectal bleeding. Rectal carcinoid patients also have a higher morbidity for other cancers such as stomach, small intestine, or secondary lung cancer.
Methods
We retrospectively explored factors associated with survival in Veterans with rectal carcinoid tumors over a ten-year period from 2007-2017 using the National Veterans Affairs Cancer Cube Registry using specific histological ICD-03 coding. We identified 1110 cases of rectal carcinoid. Chi-squared tests were used for statistical analysis.
Results
Regarding age distribution in our cohort, there were 2.61% of patients ages 40-50 group, 14.0% in the 50-60 age group, 41.5% in the 60-70 age group, and 40.7% above ages 70. There was a higher proportion of rectal cancer in stage 1 compared to other stages (86.3%). The majority of diagnoses occur after age 50 (89.8%). A higher proportion of rectal carcinoid was identified in the 60-70 years category compared to <60 and >70 years old. In the general VA population, there are 80.2% White and 12.8% Black patients. We found a higher proportion of rectal carcinoid in Black patients (47.8%) over White patients (42.8%, p=0.02), which differs significantly from the racial makeup of the VA population (12.8% Black vs 80.3% White). Looking at survival time based on diagnosis, it is notable that 82.7% of individuals survive longer than 5 years when the diagnosis is made in ages 50-60 when compared to 68.7% when the diagnosis is made between ages 60-70 (p<0.001).
Conclusions
Our data is consistent with the SEER data in that the incidence and prevalence of rectal carcinoid are higher in Black patients compared to White patients. Further analysis into reasons for this racial disparity may prove beneficial to our understanding of this malignancy in the Veteran population. Further research is needed to determine whether diagnosis at a younger age offers a survival advantage in rectal carcinoid.
Introduction
Rectal carcinoid tumors are rare but the second most common carcinoid in the gastrointestinal tract. They are usually found incidentally during endoscopic or rectal examination. They do not often produce carcinoid syndrome like manifestations although they may manifest as rectal bleeding. Rectal carcinoid patients also have a higher morbidity for other cancers such as stomach, small intestine, or secondary lung cancer.
Methods
We retrospectively explored factors associated with survival in Veterans with rectal carcinoid tumors over a ten-year period from 2007-2017 using the National Veterans Affairs Cancer Cube Registry using specific histological ICD-03 coding. We identified 1110 cases of rectal carcinoid. Chi-squared tests were used for statistical analysis.
Results
Regarding age distribution in our cohort, there were 2.61% of patients ages 40-50 group, 14.0% in the 50-60 age group, 41.5% in the 60-70 age group, and 40.7% above ages 70. There was a higher proportion of rectal cancer in stage 1 compared to other stages (86.3%). The majority of diagnoses occur after age 50 (89.8%). A higher proportion of rectal carcinoid was identified in the 60-70 years category compared to <60 and >70 years old. In the general VA population, there are 80.2% White and 12.8% Black patients. We found a higher proportion of rectal carcinoid in Black patients (47.8%) over White patients (42.8%, p=0.02), which differs significantly from the racial makeup of the VA population (12.8% Black vs 80.3% White). Looking at survival time based on diagnosis, it is notable that 82.7% of individuals survive longer than 5 years when the diagnosis is made in ages 50-60 when compared to 68.7% when the diagnosis is made between ages 60-70 (p<0.001).
Conclusions
Our data is consistent with the SEER data in that the incidence and prevalence of rectal carcinoid are higher in Black patients compared to White patients. Further analysis into reasons for this racial disparity may prove beneficial to our understanding of this malignancy in the Veteran population. Further research is needed to determine whether diagnosis at a younger age offers a survival advantage in rectal carcinoid.
Introduction
Rectal carcinoid tumors are rare but the second most common carcinoid in the gastrointestinal tract. They are usually found incidentally during endoscopic or rectal examination. They do not often produce carcinoid syndrome like manifestations although they may manifest as rectal bleeding. Rectal carcinoid patients also have a higher morbidity for other cancers such as stomach, small intestine, or secondary lung cancer.
Methods
We retrospectively explored factors associated with survival in Veterans with rectal carcinoid tumors over a ten-year period from 2007-2017 using the National Veterans Affairs Cancer Cube Registry using specific histological ICD-03 coding. We identified 1110 cases of rectal carcinoid. Chi-squared tests were used for statistical analysis.
Results
Regarding age distribution in our cohort, there were 2.61% of patients ages 40-50 group, 14.0% in the 50-60 age group, 41.5% in the 60-70 age group, and 40.7% above ages 70. There was a higher proportion of rectal cancer in stage 1 compared to other stages (86.3%). The majority of diagnoses occur after age 50 (89.8%). A higher proportion of rectal carcinoid was identified in the 60-70 years category compared to <60 and >70 years old. In the general VA population, there are 80.2% White and 12.8% Black patients. We found a higher proportion of rectal carcinoid in Black patients (47.8%) over White patients (42.8%, p=0.02), which differs significantly from the racial makeup of the VA population (12.8% Black vs 80.3% White). Looking at survival time based on diagnosis, it is notable that 82.7% of individuals survive longer than 5 years when the diagnosis is made in ages 50-60 when compared to 68.7% when the diagnosis is made between ages 60-70 (p<0.001).
Conclusions
Our data is consistent with the SEER data in that the incidence and prevalence of rectal carcinoid are higher in Black patients compared to White patients. Further analysis into reasons for this racial disparity may prove beneficial to our understanding of this malignancy in the Veteran population. Further research is needed to determine whether diagnosis at a younger age offers a survival advantage in rectal carcinoid.
Development of Debilitating Neuropathy After Two Cycles of Pembrolizumab
Case Report
73-year-old white male presented with large right shoulder soft tissue mass (17x5 cm) near the scapula, and was subsequently sent for surgical resection by his primary care. Pathology showed nodular melanoma with positive margin, lymphovascular invasion and neurotropism present with high mitosis. PET-CT scan showed positive uptake in axillary and supraclavicular lymph nodes as well as uptake in the left proximal tibia. Biopsy of the bone was also positive for melanoma. Molecular study showed BRAF mutation at L597, high tumor mutation burden (24 mutations/Mb), and PD-L1 positive in 60% of tumor cells and PD-1 was positive in immune cells, but not in tumor cells. One other distinct feature of this clinical presentation was the abundance of macrophages (CD68+) in the tumor microenvironment. Patient was initiated therapy with pembrolizumab. However, three weeks after his second cycle, he was admitted to hospital due to severe weakness in both upper extremities and pain at night. He also experienced a new onset of polyarthralgia in both hands, unable to play musical instruments. He was started on steroid treatment and showed significant improvement. Once steroid was tapered off, the sensation of pain substantially decreased but persisted. EMG showed right median motor neuropathy and left median sensory neuropathy. Blood test detected ANA positive, and as TSH was high, levothyroxine was initiated.
Outcome
His PET-CT scan showed improvement after only two cycles of treatment and has remained stable for over ten months without any treatment (patient elected to stop pembrolizumab treatment due to frequent traveling). We have performed a more detailed study of the macrophages in his tumor sample and interestingly, the majority of macrophages were type-1 (CD 80+), with some, type-2 macrophages (CD163+). It is known that type-1 macrophages are pro-inflammatory and have antitumor effect, while type-2 macrophages have opposite effect and often promote tumor growth and metastasis. This could explain the side effect and long duration of response despite only two cycles of pembrolizumab treatment. Characteristics of macrophages in melanoma tumor samples may be an important parameter to predict side effect and tumor response beyond PD1 or PD-L1 expression.
Case Report
73-year-old white male presented with large right shoulder soft tissue mass (17x5 cm) near the scapula, and was subsequently sent for surgical resection by his primary care. Pathology showed nodular melanoma with positive margin, lymphovascular invasion and neurotropism present with high mitosis. PET-CT scan showed positive uptake in axillary and supraclavicular lymph nodes as well as uptake in the left proximal tibia. Biopsy of the bone was also positive for melanoma. Molecular study showed BRAF mutation at L597, high tumor mutation burden (24 mutations/Mb), and PD-L1 positive in 60% of tumor cells and PD-1 was positive in immune cells, but not in tumor cells. One other distinct feature of this clinical presentation was the abundance of macrophages (CD68+) in the tumor microenvironment. Patient was initiated therapy with pembrolizumab. However, three weeks after his second cycle, he was admitted to hospital due to severe weakness in both upper extremities and pain at night. He also experienced a new onset of polyarthralgia in both hands, unable to play musical instruments. He was started on steroid treatment and showed significant improvement. Once steroid was tapered off, the sensation of pain substantially decreased but persisted. EMG showed right median motor neuropathy and left median sensory neuropathy. Blood test detected ANA positive, and as TSH was high, levothyroxine was initiated.
Outcome
His PET-CT scan showed improvement after only two cycles of treatment and has remained stable for over ten months without any treatment (patient elected to stop pembrolizumab treatment due to frequent traveling). We have performed a more detailed study of the macrophages in his tumor sample and interestingly, the majority of macrophages were type-1 (CD 80+), with some, type-2 macrophages (CD163+). It is known that type-1 macrophages are pro-inflammatory and have antitumor effect, while type-2 macrophages have opposite effect and often promote tumor growth and metastasis. This could explain the side effect and long duration of response despite only two cycles of pembrolizumab treatment. Characteristics of macrophages in melanoma tumor samples may be an important parameter to predict side effect and tumor response beyond PD1 or PD-L1 expression.
Case Report
73-year-old white male presented with large right shoulder soft tissue mass (17x5 cm) near the scapula, and was subsequently sent for surgical resection by his primary care. Pathology showed nodular melanoma with positive margin, lymphovascular invasion and neurotropism present with high mitosis. PET-CT scan showed positive uptake in axillary and supraclavicular lymph nodes as well as uptake in the left proximal tibia. Biopsy of the bone was also positive for melanoma. Molecular study showed BRAF mutation at L597, high tumor mutation burden (24 mutations/Mb), and PD-L1 positive in 60% of tumor cells and PD-1 was positive in immune cells, but not in tumor cells. One other distinct feature of this clinical presentation was the abundance of macrophages (CD68+) in the tumor microenvironment. Patient was initiated therapy with pembrolizumab. However, three weeks after his second cycle, he was admitted to hospital due to severe weakness in both upper extremities and pain at night. He also experienced a new onset of polyarthralgia in both hands, unable to play musical instruments. He was started on steroid treatment and showed significant improvement. Once steroid was tapered off, the sensation of pain substantially decreased but persisted. EMG showed right median motor neuropathy and left median sensory neuropathy. Blood test detected ANA positive, and as TSH was high, levothyroxine was initiated.
Outcome
His PET-CT scan showed improvement after only two cycles of treatment and has remained stable for over ten months without any treatment (patient elected to stop pembrolizumab treatment due to frequent traveling). We have performed a more detailed study of the macrophages in his tumor sample and interestingly, the majority of macrophages were type-1 (CD 80+), with some, type-2 macrophages (CD163+). It is known that type-1 macrophages are pro-inflammatory and have antitumor effect, while type-2 macrophages have opposite effect and often promote tumor growth and metastasis. This could explain the side effect and long duration of response despite only two cycles of pembrolizumab treatment. Characteristics of macrophages in melanoma tumor samples may be an important parameter to predict side effect and tumor response beyond PD1 or PD-L1 expression.
Double Hit: Epstein-Barr Virus Causing Infectious Mononucleosis Followed by Hemolytic Uremic Syndrome
Introduction
Epstein-Barr virus (EBV) is a herpes virus that commonly causes infectious mononucleosis (IM) and linked to different hematological conditions. Here we present a case of EBV-triggered Hemolytic Uremic Syndrome (HUS) with pulmonary involvement.
Case Presentation
A 20-year-old male presented with fever, thrombocytopenia, and splenomegaly. Acute EBV serology was positive. Creatinine and hemoglobin were normal. He was diagnosed with IM. platelet count improved within 3 weeks. 4 weeks later, he returned with severe hemoptysis. Hgb 6.8g/dL, platelet 133,000/uL, lactate dehydrogenase 969u/L, creatinine 21mg/dL, and schistocytes on peripheral smear. Chest computed tomography showed bilateral opacities consistent with diffuse alveolar hemorrhage (DAH). Emergent hemodialysis and plasmapheresis were started. Infectious work up was negative. Autoimmune work up was also negative (anti-neutrophil cytoplasmic, anti-basement membrane antibodies, ANA). Aadamts13 activity was 62% (normal ~66%) ruling out thrombotic thrombocytopenic purpura (TTP). Kidney biopsy revealed thrombotic microangiopathic process. The patient was eventually diagnosed with HUS and treated with Eculizumab. 4 months later his renal function has partially recovered and no longer needs hemodialysis.
Discussion
HUS is a rare entity that is known to be triggered by different underlying pathologies. However, its link to EBV remains unclear. Literature review has revealed only two cases of EBV-triggered HUS, even though almost 90-95% of adults are EBV-seropositive. What unique about our case is the patient initially presented with documented IM, and HUS happened a month later. This raises the theory that HUS could be a sequela of the infection, rather than an effect of acute viral phase and this is the first case to report such correlation. The other unique thing is pulmonary involvement in HUS. With consultation with pulmonary service, we believe our patient had DAH based on clinical and radiographic findings. To our knowledge this is the first case to show this association.
Conclusion
EBV is a common virus with high seropositivity among world’s population. Its link to HUS remains unclear and needs more investigation. Providers should recognize HUS as a complication of EBV infection, either in the acute phase or as a sequela. Adolescents are at higher risk for such complication since IM is common in this population.
Introduction
Epstein-Barr virus (EBV) is a herpes virus that commonly causes infectious mononucleosis (IM) and linked to different hematological conditions. Here we present a case of EBV-triggered Hemolytic Uremic Syndrome (HUS) with pulmonary involvement.
Case Presentation
A 20-year-old male presented with fever, thrombocytopenia, and splenomegaly. Acute EBV serology was positive. Creatinine and hemoglobin were normal. He was diagnosed with IM. platelet count improved within 3 weeks. 4 weeks later, he returned with severe hemoptysis. Hgb 6.8g/dL, platelet 133,000/uL, lactate dehydrogenase 969u/L, creatinine 21mg/dL, and schistocytes on peripheral smear. Chest computed tomography showed bilateral opacities consistent with diffuse alveolar hemorrhage (DAH). Emergent hemodialysis and plasmapheresis were started. Infectious work up was negative. Autoimmune work up was also negative (anti-neutrophil cytoplasmic, anti-basement membrane antibodies, ANA). Aadamts13 activity was 62% (normal ~66%) ruling out thrombotic thrombocytopenic purpura (TTP). Kidney biopsy revealed thrombotic microangiopathic process. The patient was eventually diagnosed with HUS and treated with Eculizumab. 4 months later his renal function has partially recovered and no longer needs hemodialysis.
Discussion
HUS is a rare entity that is known to be triggered by different underlying pathologies. However, its link to EBV remains unclear. Literature review has revealed only two cases of EBV-triggered HUS, even though almost 90-95% of adults are EBV-seropositive. What unique about our case is the patient initially presented with documented IM, and HUS happened a month later. This raises the theory that HUS could be a sequela of the infection, rather than an effect of acute viral phase and this is the first case to report such correlation. The other unique thing is pulmonary involvement in HUS. With consultation with pulmonary service, we believe our patient had DAH based on clinical and radiographic findings. To our knowledge this is the first case to show this association.
Conclusion
EBV is a common virus with high seropositivity among world’s population. Its link to HUS remains unclear and needs more investigation. Providers should recognize HUS as a complication of EBV infection, either in the acute phase or as a sequela. Adolescents are at higher risk for such complication since IM is common in this population.
Introduction
Epstein-Barr virus (EBV) is a herpes virus that commonly causes infectious mononucleosis (IM) and linked to different hematological conditions. Here we present a case of EBV-triggered Hemolytic Uremic Syndrome (HUS) with pulmonary involvement.
Case Presentation
A 20-year-old male presented with fever, thrombocytopenia, and splenomegaly. Acute EBV serology was positive. Creatinine and hemoglobin were normal. He was diagnosed with IM. platelet count improved within 3 weeks. 4 weeks later, he returned with severe hemoptysis. Hgb 6.8g/dL, platelet 133,000/uL, lactate dehydrogenase 969u/L, creatinine 21mg/dL, and schistocytes on peripheral smear. Chest computed tomography showed bilateral opacities consistent with diffuse alveolar hemorrhage (DAH). Emergent hemodialysis and plasmapheresis were started. Infectious work up was negative. Autoimmune work up was also negative (anti-neutrophil cytoplasmic, anti-basement membrane antibodies, ANA). Aadamts13 activity was 62% (normal ~66%) ruling out thrombotic thrombocytopenic purpura (TTP). Kidney biopsy revealed thrombotic microangiopathic process. The patient was eventually diagnosed with HUS and treated with Eculizumab. 4 months later his renal function has partially recovered and no longer needs hemodialysis.
Discussion
HUS is a rare entity that is known to be triggered by different underlying pathologies. However, its link to EBV remains unclear. Literature review has revealed only two cases of EBV-triggered HUS, even though almost 90-95% of adults are EBV-seropositive. What unique about our case is the patient initially presented with documented IM, and HUS happened a month later. This raises the theory that HUS could be a sequela of the infection, rather than an effect of acute viral phase and this is the first case to report such correlation. The other unique thing is pulmonary involvement in HUS. With consultation with pulmonary service, we believe our patient had DAH based on clinical and radiographic findings. To our knowledge this is the first case to show this association.
Conclusion
EBV is a common virus with high seropositivity among world’s population. Its link to HUS remains unclear and needs more investigation. Providers should recognize HUS as a complication of EBV infection, either in the acute phase or as a sequela. Adolescents are at higher risk for such complication since IM is common in this population.
Methods of Identifying Real World mCRPC Patients from the Veterans Health Administration System
Purpose
Prostate cancer is the fifth leading cause of death in the United States. Genomic testing is essential to guide treatment decisions in patients with metastatic castration resistant prostate cancer (mCRPC), the most advanced stage of prostate cancer. However, identifying mCRPC patients from administrative data is challenging and hinders researchers’ ability to assess testing among these patients. This study aims to develop algorithms using structured data and unstructured data with Natural language processing (NLP) methods to identify veterans by disease stage and hormone sensitivity, and to assess patient characteristics as well as receipt of tumor NGS testing.
Methods
We used biopsy, pathology, and diagnosis codes, to identify veterans with newly diagnosed PC within the Veterans Health Administration (VA) from January 1, 2017 to December 31, 2020. We developed and deployed: 1. A structured algorithm that used medication and Prostate-Specific Antigen (PSA) data to assess hormone sensitivity. 2. NLP tools to extract disease stage and hormone sensitivity from clinical notes. We report descriptive statistics on patient demographics, clinical characteristics, disease status, androgen deprivation therapy (ADT), and receipt of tumor NGS testing.
Results
There were 42,485 veterans with newly diagnosed prostate cancer between 2017-2020. This represented ~0.18% of veterans served in the VA and consisted of Whites (57%), Blacks (33%), and others (10%). During the study period, 3,113 (7.3%) patients had documentation of assessment for intraductal carcinoma, 5,160 (12.1%) had ADT treatment, 1,481 (3.5%) had CRPC, and 3,246 (7.6%) had metastatic disease. Among the 42,485 veterans, 422 received tumor NGS testing within VA, and 300 of them had metastatic disease. NLP tool and structured data algorithm collectively showed that 38% of the 422 tumor NGS testing recipients had mCRPC. Among all newly diagnosed PC patients, White patients had highest rates of tumor-based testing (2.3%), then Native Hawaiians (1.7%), Asians and Blacks (1.2% each), compared to Native Americans (0.4%).
Implications
NLP tools alongside structured data algorithms successfully identified variables required to measure access to tumor NGS testing. Efforts to validate and apply this method is ongoing to assess receipt of precision prostate cancer care in VA.
Purpose
Prostate cancer is the fifth leading cause of death in the United States. Genomic testing is essential to guide treatment decisions in patients with metastatic castration resistant prostate cancer (mCRPC), the most advanced stage of prostate cancer. However, identifying mCRPC patients from administrative data is challenging and hinders researchers’ ability to assess testing among these patients. This study aims to develop algorithms using structured data and unstructured data with Natural language processing (NLP) methods to identify veterans by disease stage and hormone sensitivity, and to assess patient characteristics as well as receipt of tumor NGS testing.
Methods
We used biopsy, pathology, and diagnosis codes, to identify veterans with newly diagnosed PC within the Veterans Health Administration (VA) from January 1, 2017 to December 31, 2020. We developed and deployed: 1. A structured algorithm that used medication and Prostate-Specific Antigen (PSA) data to assess hormone sensitivity. 2. NLP tools to extract disease stage and hormone sensitivity from clinical notes. We report descriptive statistics on patient demographics, clinical characteristics, disease status, androgen deprivation therapy (ADT), and receipt of tumor NGS testing.
Results
There were 42,485 veterans with newly diagnosed prostate cancer between 2017-2020. This represented ~0.18% of veterans served in the VA and consisted of Whites (57%), Blacks (33%), and others (10%). During the study period, 3,113 (7.3%) patients had documentation of assessment for intraductal carcinoma, 5,160 (12.1%) had ADT treatment, 1,481 (3.5%) had CRPC, and 3,246 (7.6%) had metastatic disease. Among the 42,485 veterans, 422 received tumor NGS testing within VA, and 300 of them had metastatic disease. NLP tool and structured data algorithm collectively showed that 38% of the 422 tumor NGS testing recipients had mCRPC. Among all newly diagnosed PC patients, White patients had highest rates of tumor-based testing (2.3%), then Native Hawaiians (1.7%), Asians and Blacks (1.2% each), compared to Native Americans (0.4%).
Implications
NLP tools alongside structured data algorithms successfully identified variables required to measure access to tumor NGS testing. Efforts to validate and apply this method is ongoing to assess receipt of precision prostate cancer care in VA.
Purpose
Prostate cancer is the fifth leading cause of death in the United States. Genomic testing is essential to guide treatment decisions in patients with metastatic castration resistant prostate cancer (mCRPC), the most advanced stage of prostate cancer. However, identifying mCRPC patients from administrative data is challenging and hinders researchers’ ability to assess testing among these patients. This study aims to develop algorithms using structured data and unstructured data with Natural language processing (NLP) methods to identify veterans by disease stage and hormone sensitivity, and to assess patient characteristics as well as receipt of tumor NGS testing.
Methods
We used biopsy, pathology, and diagnosis codes, to identify veterans with newly diagnosed PC within the Veterans Health Administration (VA) from January 1, 2017 to December 31, 2020. We developed and deployed: 1. A structured algorithm that used medication and Prostate-Specific Antigen (PSA) data to assess hormone sensitivity. 2. NLP tools to extract disease stage and hormone sensitivity from clinical notes. We report descriptive statistics on patient demographics, clinical characteristics, disease status, androgen deprivation therapy (ADT), and receipt of tumor NGS testing.
Results
There were 42,485 veterans with newly diagnosed prostate cancer between 2017-2020. This represented ~0.18% of veterans served in the VA and consisted of Whites (57%), Blacks (33%), and others (10%). During the study period, 3,113 (7.3%) patients had documentation of assessment for intraductal carcinoma, 5,160 (12.1%) had ADT treatment, 1,481 (3.5%) had CRPC, and 3,246 (7.6%) had metastatic disease. Among the 42,485 veterans, 422 received tumor NGS testing within VA, and 300 of them had metastatic disease. NLP tool and structured data algorithm collectively showed that 38% of the 422 tumor NGS testing recipients had mCRPC. Among all newly diagnosed PC patients, White patients had highest rates of tumor-based testing (2.3%), then Native Hawaiians (1.7%), Asians and Blacks (1.2% each), compared to Native Americans (0.4%).
Implications
NLP tools alongside structured data algorithms successfully identified variables required to measure access to tumor NGS testing. Efforts to validate and apply this method is ongoing to assess receipt of precision prostate cancer care in VA.
Diagnosis of Prostate Cancer and Prostate-specific Antigen Level on Initial Prostate Biopsy: Does Race Matter?
Objective
To determine whether Black Veterans are at higher risk for prostate cancer diagnosis on their first prostate biopsy compared to non-Hispanic White (White) Veterans.
Background
Prostate-specific antigen (PSA) testing is widely used to screen for prostate cancer. Although men of African ancestry display an increased incidence of prostate cancer and more aggressive disease, specific PSA thresholds for biopsy referral have yet to be proposed for this population.
Methods
We used the VHA’s electronic medical record data to collect Veterans’ demographic and clinical characteristics including self-identified race/ethnicity, age, date of first prostate biopsy, PSA results, and prostate cancer diagnosis. Veterans’ ZIP code of residence was used to determine urban/rural status, income, and education. We estimated multivariable logistic regression models to predict the likelihood of prostate cancer diagnosis on the first biopsy using race, baseline PSA, age at first PSA test, age at initial biopsy, smoking status, use of statins, and socioeconomic factors as predictors. We calculated adjusted predicted probabilities of cancer detection on the first prostate biopsy from the logistic models at different PSA levels.
Results
We identified 246,056 White and 71,653 Black Veterans who underwent their first prostate biopsy through February 28, 2020 and who had no previous prostate cancer diagnosis or treatment prior to that biopsy. Black Veterans appeared to receive their first PSA test four years earlier and undergo their first prostate biopsy two years earlier than their White counterparts (median age of 57 vs. 61 and 63 vs. 65, respectively). After controlling for selected covariates, we found that Black Veterans were 52% more likely to be diagnosed with prostate cancer on their first prostate biopsy compared to White Veterans (OR 1.52, 95% CI 1.49-1.55). Our model indicated that a Black Veteran with a PSA of 4.0 ng/ml has an equivalent risk of prostate cancer detection as a White Veteran with a PSA of 9.7 ng/ml.
Implications
Our findings suggested that developing a risk-based PSA threshold for referral to prostate biopsy may lead to earlier diagnosis of clinically significant prostate cancer in a population of Veterans known to have an increased incidence and risk of aggressive disease.
Objective
To determine whether Black Veterans are at higher risk for prostate cancer diagnosis on their first prostate biopsy compared to non-Hispanic White (White) Veterans.
Background
Prostate-specific antigen (PSA) testing is widely used to screen for prostate cancer. Although men of African ancestry display an increased incidence of prostate cancer and more aggressive disease, specific PSA thresholds for biopsy referral have yet to be proposed for this population.
Methods
We used the VHA’s electronic medical record data to collect Veterans’ demographic and clinical characteristics including self-identified race/ethnicity, age, date of first prostate biopsy, PSA results, and prostate cancer diagnosis. Veterans’ ZIP code of residence was used to determine urban/rural status, income, and education. We estimated multivariable logistic regression models to predict the likelihood of prostate cancer diagnosis on the first biopsy using race, baseline PSA, age at first PSA test, age at initial biopsy, smoking status, use of statins, and socioeconomic factors as predictors. We calculated adjusted predicted probabilities of cancer detection on the first prostate biopsy from the logistic models at different PSA levels.
Results
We identified 246,056 White and 71,653 Black Veterans who underwent their first prostate biopsy through February 28, 2020 and who had no previous prostate cancer diagnosis or treatment prior to that biopsy. Black Veterans appeared to receive their first PSA test four years earlier and undergo their first prostate biopsy two years earlier than their White counterparts (median age of 57 vs. 61 and 63 vs. 65, respectively). After controlling for selected covariates, we found that Black Veterans were 52% more likely to be diagnosed with prostate cancer on their first prostate biopsy compared to White Veterans (OR 1.52, 95% CI 1.49-1.55). Our model indicated that a Black Veteran with a PSA of 4.0 ng/ml has an equivalent risk of prostate cancer detection as a White Veteran with a PSA of 9.7 ng/ml.
Implications
Our findings suggested that developing a risk-based PSA threshold for referral to prostate biopsy may lead to earlier diagnosis of clinically significant prostate cancer in a population of Veterans known to have an increased incidence and risk of aggressive disease.
Objective
To determine whether Black Veterans are at higher risk for prostate cancer diagnosis on their first prostate biopsy compared to non-Hispanic White (White) Veterans.
Background
Prostate-specific antigen (PSA) testing is widely used to screen for prostate cancer. Although men of African ancestry display an increased incidence of prostate cancer and more aggressive disease, specific PSA thresholds for biopsy referral have yet to be proposed for this population.
Methods
We used the VHA’s electronic medical record data to collect Veterans’ demographic and clinical characteristics including self-identified race/ethnicity, age, date of first prostate biopsy, PSA results, and prostate cancer diagnosis. Veterans’ ZIP code of residence was used to determine urban/rural status, income, and education. We estimated multivariable logistic regression models to predict the likelihood of prostate cancer diagnosis on the first biopsy using race, baseline PSA, age at first PSA test, age at initial biopsy, smoking status, use of statins, and socioeconomic factors as predictors. We calculated adjusted predicted probabilities of cancer detection on the first prostate biopsy from the logistic models at different PSA levels.
Results
We identified 246,056 White and 71,653 Black Veterans who underwent their first prostate biopsy through February 28, 2020 and who had no previous prostate cancer diagnosis or treatment prior to that biopsy. Black Veterans appeared to receive their first PSA test four years earlier and undergo their first prostate biopsy two years earlier than their White counterparts (median age of 57 vs. 61 and 63 vs. 65, respectively). After controlling for selected covariates, we found that Black Veterans were 52% more likely to be diagnosed with prostate cancer on their first prostate biopsy compared to White Veterans (OR 1.52, 95% CI 1.49-1.55). Our model indicated that a Black Veteran with a PSA of 4.0 ng/ml has an equivalent risk of prostate cancer detection as a White Veteran with a PSA of 9.7 ng/ml.
Implications
Our findings suggested that developing a risk-based PSA threshold for referral to prostate biopsy may lead to earlier diagnosis of clinically significant prostate cancer in a population of Veterans known to have an increased incidence and risk of aggressive disease.
Racial Disparities in Treatment and Survival for Early-Stage Non-Small Cell Lung Cancer: Is Equal Access Health Care System the Answer?
Background
Survival for early-stage non-small cell lung cancer (NSCLC) has dramatically improved with advancement in surgical and radiation techniques over last two decades but there exists a disparity for African Americans (AA) having worse overall survival (OS) in recent studies on the general US population. We studied this racial disparity in Veteran population.
Methods
Data for 2589 AA and 14184 Caucasian Veterans diagnosed with early-stage (I, II) NSCLC between 2011-2017 was obtained from the Cancer Cube Registry (VACCR). IRB approval was obtained.
Results
The distribution of newly diagnosed cases of Stage I (73.92% AA vs 74.71% Caucasians) and Stage II (26.07% vs 25.29%) between the two races was comparable (p = .41). More Caucasians were diagnosed above the age of 60 compared to AA (92.22% vs 84.51%, p < .05). More AA were diagnosed with adenocarcinoma at diagnosis (56.01% vs 45.88% Caucasians, p < .05) for both Stage I and II disease. For the limited number of Veterans with reported performance status (PS), similar proportion of patients had a good PS defined as ECOG 0-2 among the two races (93.70% AA vs 93.97% Caucasians, p = .73). There was no statistically significant difference between 5-year OS for AA and Caucasians (69.81% vs 70.78%, p = .33) for both Stage I and II NSCLC. Both groups had similar rate of receipt of surgery as first line treatment or in combination with other treatments (58.90% AA vs 59.07% Caucasians, p = .90). Similarly, the rate of receiving radiation therapy was comparable between AA and Caucasians (42.4% vs 42.3%, p = .96). Although both races showed improved 5-year OS after surgery, there was no statistical difference in survival benefit between AA and Caucasians (69.8% vs 70.8%, p = .33).
Conclusion
In contrast to the studies assessing general US population trends, there was no racial disparity for 5-year OS in early-stage NSCLC for the Veteran population. This points to the inequities in access to treatment and preventive healthcare services as a possible contributing cause to the increased mortality in AA in general US population and a more equitable healthcare delivery within the VHA system.
Background
Survival for early-stage non-small cell lung cancer (NSCLC) has dramatically improved with advancement in surgical and radiation techniques over last two decades but there exists a disparity for African Americans (AA) having worse overall survival (OS) in recent studies on the general US population. We studied this racial disparity in Veteran population.
Methods
Data for 2589 AA and 14184 Caucasian Veterans diagnosed with early-stage (I, II) NSCLC between 2011-2017 was obtained from the Cancer Cube Registry (VACCR). IRB approval was obtained.
Results
The distribution of newly diagnosed cases of Stage I (73.92% AA vs 74.71% Caucasians) and Stage II (26.07% vs 25.29%) between the two races was comparable (p = .41). More Caucasians were diagnosed above the age of 60 compared to AA (92.22% vs 84.51%, p < .05). More AA were diagnosed with adenocarcinoma at diagnosis (56.01% vs 45.88% Caucasians, p < .05) for both Stage I and II disease. For the limited number of Veterans with reported performance status (PS), similar proportion of patients had a good PS defined as ECOG 0-2 among the two races (93.70% AA vs 93.97% Caucasians, p = .73). There was no statistically significant difference between 5-year OS for AA and Caucasians (69.81% vs 70.78%, p = .33) for both Stage I and II NSCLC. Both groups had similar rate of receipt of surgery as first line treatment or in combination with other treatments (58.90% AA vs 59.07% Caucasians, p = .90). Similarly, the rate of receiving radiation therapy was comparable between AA and Caucasians (42.4% vs 42.3%, p = .96). Although both races showed improved 5-year OS after surgery, there was no statistical difference in survival benefit between AA and Caucasians (69.8% vs 70.8%, p = .33).
Conclusion
In contrast to the studies assessing general US population trends, there was no racial disparity for 5-year OS in early-stage NSCLC for the Veteran population. This points to the inequities in access to treatment and preventive healthcare services as a possible contributing cause to the increased mortality in AA in general US population and a more equitable healthcare delivery within the VHA system.
Background
Survival for early-stage non-small cell lung cancer (NSCLC) has dramatically improved with advancement in surgical and radiation techniques over last two decades but there exists a disparity for African Americans (AA) having worse overall survival (OS) in recent studies on the general US population. We studied this racial disparity in Veteran population.
Methods
Data for 2589 AA and 14184 Caucasian Veterans diagnosed with early-stage (I, II) NSCLC between 2011-2017 was obtained from the Cancer Cube Registry (VACCR). IRB approval was obtained.
Results
The distribution of newly diagnosed cases of Stage I (73.92% AA vs 74.71% Caucasians) and Stage II (26.07% vs 25.29%) between the two races was comparable (p = .41). More Caucasians were diagnosed above the age of 60 compared to AA (92.22% vs 84.51%, p < .05). More AA were diagnosed with adenocarcinoma at diagnosis (56.01% vs 45.88% Caucasians, p < .05) for both Stage I and II disease. For the limited number of Veterans with reported performance status (PS), similar proportion of patients had a good PS defined as ECOG 0-2 among the two races (93.70% AA vs 93.97% Caucasians, p = .73). There was no statistically significant difference between 5-year OS for AA and Caucasians (69.81% vs 70.78%, p = .33) for both Stage I and II NSCLC. Both groups had similar rate of receipt of surgery as first line treatment or in combination with other treatments (58.90% AA vs 59.07% Caucasians, p = .90). Similarly, the rate of receiving radiation therapy was comparable between AA and Caucasians (42.4% vs 42.3%, p = .96). Although both races showed improved 5-year OS after surgery, there was no statistical difference in survival benefit between AA and Caucasians (69.8% vs 70.8%, p = .33).
Conclusion
In contrast to the studies assessing general US population trends, there was no racial disparity for 5-year OS in early-stage NSCLC for the Veteran population. This points to the inequities in access to treatment and preventive healthcare services as a possible contributing cause to the increased mortality in AA in general US population and a more equitable healthcare delivery within the VHA system.
Survival Analysis of Untreated Early-Stage Non-Small Cell Lung Cancer (NSCLC) in a Veteran Population
Introduction
Veterans with early-stage NSCLC who do not receive any form of treatment have been shown to have a worse overall survival compared to those who receive treatment. Factors that may influence the decision to administer treatment including age, performance status (PS), comorbidities, and racial disparity have not been assessed on a national level in recent years.
Methods
Data for 31,966 veterans diagnosed with early-stage (0, I) NSCLC between 2003-2017 was obtained from the Cancer cube registry (VACCR). IRB approval was obtained.
Results
Patients were divided into treatment (26,833/31,966, 83.16%) and no-treatment group (3096/31966, 9.68%). Of the no-treatment group, 3004 patients were stage I and 92 were stage 0 whereas in the treatment group, the distribution was 26,584 and 249 respectively. Gender, race, and histology distribution were comparable between the two. Patients with poor PS (defined as ECOG III and IV) received less treatment with any modality compared to those with good PS (ECOG I and II) (15.07% in no treatment group vs 4.03% in treatment group, p<0.05). The treatment group had a better 5-year overall survival (OS) as compared to no-treatment group (43.1% vs 14.7%, p<0.05). Regardless of treatment, patients above the age of 60 (41% vs 13.4%, p<0.05) and those with poor PS (19.6% vs 5.8%, p<0.05) had worse 5-year survival, with the effect being greater in the treatment group. Adenocarcinoma had a better 5-year survival compared to squamous cell carcinoma (SCC) in both groups (49.56% vs 39.1% p<0.05). There was no clinically significant OS difference in terms of race (Caucasian or African American) or tumor location (upper, middle, or lower lobe) in between the two groups. Our study was limited by lack of patient- level data including smoking status or reason why no treatment was given.
Conclusion
Patients with early-stage NSCLC who receive no treatment based on poor PS have a worse overall survival compared to the patients that receive treatment. Further investigation is required to assess what other criteria are used to decide treatment eligibility and whether these patients would be candidates for immunotherapy or targeted therapy in the future.
Introduction
Veterans with early-stage NSCLC who do not receive any form of treatment have been shown to have a worse overall survival compared to those who receive treatment. Factors that may influence the decision to administer treatment including age, performance status (PS), comorbidities, and racial disparity have not been assessed on a national level in recent years.
Methods
Data for 31,966 veterans diagnosed with early-stage (0, I) NSCLC between 2003-2017 was obtained from the Cancer cube registry (VACCR). IRB approval was obtained.
Results
Patients were divided into treatment (26,833/31,966, 83.16%) and no-treatment group (3096/31966, 9.68%). Of the no-treatment group, 3004 patients were stage I and 92 were stage 0 whereas in the treatment group, the distribution was 26,584 and 249 respectively. Gender, race, and histology distribution were comparable between the two. Patients with poor PS (defined as ECOG III and IV) received less treatment with any modality compared to those with good PS (ECOG I and II) (15.07% in no treatment group vs 4.03% in treatment group, p<0.05). The treatment group had a better 5-year overall survival (OS) as compared to no-treatment group (43.1% vs 14.7%, p<0.05). Regardless of treatment, patients above the age of 60 (41% vs 13.4%, p<0.05) and those with poor PS (19.6% vs 5.8%, p<0.05) had worse 5-year survival, with the effect being greater in the treatment group. Adenocarcinoma had a better 5-year survival compared to squamous cell carcinoma (SCC) in both groups (49.56% vs 39.1% p<0.05). There was no clinically significant OS difference in terms of race (Caucasian or African American) or tumor location (upper, middle, or lower lobe) in between the two groups. Our study was limited by lack of patient- level data including smoking status or reason why no treatment was given.
Conclusion
Patients with early-stage NSCLC who receive no treatment based on poor PS have a worse overall survival compared to the patients that receive treatment. Further investigation is required to assess what other criteria are used to decide treatment eligibility and whether these patients would be candidates for immunotherapy or targeted therapy in the future.
Introduction
Veterans with early-stage NSCLC who do not receive any form of treatment have been shown to have a worse overall survival compared to those who receive treatment. Factors that may influence the decision to administer treatment including age, performance status (PS), comorbidities, and racial disparity have not been assessed on a national level in recent years.
Methods
Data for 31,966 veterans diagnosed with early-stage (0, I) NSCLC between 2003-2017 was obtained from the Cancer cube registry (VACCR). IRB approval was obtained.
Results
Patients were divided into treatment (26,833/31,966, 83.16%) and no-treatment group (3096/31966, 9.68%). Of the no-treatment group, 3004 patients were stage I and 92 were stage 0 whereas in the treatment group, the distribution was 26,584 and 249 respectively. Gender, race, and histology distribution were comparable between the two. Patients with poor PS (defined as ECOG III and IV) received less treatment with any modality compared to those with good PS (ECOG I and II) (15.07% in no treatment group vs 4.03% in treatment group, p<0.05). The treatment group had a better 5-year overall survival (OS) as compared to no-treatment group (43.1% vs 14.7%, p<0.05). Regardless of treatment, patients above the age of 60 (41% vs 13.4%, p<0.05) and those with poor PS (19.6% vs 5.8%, p<0.05) had worse 5-year survival, with the effect being greater in the treatment group. Adenocarcinoma had a better 5-year survival compared to squamous cell carcinoma (SCC) in both groups (49.56% vs 39.1% p<0.05). There was no clinically significant OS difference in terms of race (Caucasian or African American) or tumor location (upper, middle, or lower lobe) in between the two groups. Our study was limited by lack of patient- level data including smoking status or reason why no treatment was given.
Conclusion
Patients with early-stage NSCLC who receive no treatment based on poor PS have a worse overall survival compared to the patients that receive treatment. Further investigation is required to assess what other criteria are used to decide treatment eligibility and whether these patients would be candidates for immunotherapy or targeted therapy in the future.
Hemophagocytic Lymphohistiocytosis: Early Treatment Leading to an Excellent Outcome
HLH is a rare and deadly disease increasingly more present in adults, but following treatment protocol may yield favorable results.
Hemophagocytic lymphohistiocytosis (HLH) is a rare and deadly disease in which unregulated proliferation of histiocytes and T-cell infiltration takes place. It is known as a pediatric disease in which gene defects result in impaired cytotoxic NK- and T-cell function. It has been associated with autosomal recessive inheritance pattern. Without therapy, survival for these patients with active familial HLH is approximately 2 months.
Recognition of the disease has increased over the years, and as a result the diagnosis of HLH in adults also has increased. An acquired form can be triggered by viruses like Epstein-Barr virus, influenza, HIV, lymphoid malignancies, rheumatologic disorders, or immunodeficiency disorders. Survival rates for untreated HLH have been reported at < 5%.1 Despite early recognition and adequate treatment, HLH carries an overall mortality of 50% in the initial presentation, 90% die in the first 8 weeks of treatment due to uncontrolled disease.2
Case Presentation
A 56-year-old man with no active medical issues except for a remote history of non-Hodgkin lymphoma treated with chemotherapy and splenectomy in 1990 presented to the Veterans Affairs Caribbean Healthcare System in San Juan, Puerto Rico. He was admitted to the medicine ward due to community acquired pneumonia. Three days into admission his clinical status deteriorated, and the patient was transferred to the intensive care unit (ICU) due to acute respiratory failure and sepsis secondary to worsening pneumonia. Chest imaging demonstrated rapidly progressing diffuse bilateral infiltrates. Due to the severity of the chest imaging, a diagnostic bronchoscopy was performed.
The patient’s antibiotics regimen was empirically escalated to vancomycin 1500 mg IV every 12 hours and meropenem 2 g IV every 8 hours. Despite optimization of therapy, the patient did not show clinical signs of improvement. Febrile episodes persisted, pulmonary infiltrates and hypoxemia worsened, and the patient required a neuromuscular blockade. Since the bronchoscopy was nondiagnostic and deterioration persistent, the differential diagnosis was broadened. This led to the ordering of inflammatory markers. Laboratory testing showed ferritin levels > 16,000 ng/mL, pointing to HLH as a possible diagnosis. Further workup was remarkable for triglycerides of 1234 mg/dL and a fibrinogen of 0.77 g/L. In the setting of bicytopenia and persistent fever, HLH-94 regimen was started with dexamethasone 40 mg daily and etoposide 100 mg/m2. CD25 levels of 154,701 pg/mL were demonstrated as well as a decreased immunoglobulin (Ig) G levels with absent IgM and IgA. Bone marrow biopsy was consistent with hemophagocytosis. The patient eventually was extubated and sent to the oncology ward to continue chemotherapy.
Discussion
A high clinical suspicion is warranted for rapid diagnosis and treatment as HLH evolves in most cases to multiorgan failure and death. The diagnostic criteria for HLH was developed by the Histiocyte Society in 1991 and then restructured in 2004.3,4 In the first diagnostic tool developed in 1991, diagnosis was based on 5 criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). Three additional laboratory findings were also described as part of HLH diagnosis since 2004: low or absent NK-cell-activity, hyperferritinemia of > 500 ng/dL, and high-soluble interleukin-2-receptor levels (CD25) > 2400 U/mL. Overall, 5 of 8 criteria are needed for the HLH diagnosis.
Despite the common use of these diagnostic criteria, they were developed for the pediatric population but have not been validated for adult patients.5 For adult patients, the HScore was developed in 2014. It has 9 variables: 3 are based on clinical findings (known underlying immunosuppression, high temperature, and organomegaly; 5 are based on laboratory values (ferritin, serum glutamic oxaloacetic transaminase, cytopenia, triglycerides, and fibrinogen levels); the last variable uses cytologic findings in the bone marrow. In the initial study, probability of having HLH ranged from < 1% with an HScore of ≤ 90% to > 99% with an HScore of ≥ 250 in noncritically ill adults.5 A recently published retrospective study demonstrated the diagnostic reliability of both the HLH-2004 criteria and HScore in critically ill adult patients. This study concluded that the best prediction accuracy of HLH diagnosis for a cutoff of 4 fulfilled HLH-2004 criteria had a 95.0% sensitivity and 93.6% specificity and HScore cutoff of 168 reached a 100% sensitivity and 94.1% specificity.6
The early negative bronchoscopy lowered the possibility of an infection as the etiology of the clinical presentation and narrowed the hyperferritinemia differential diagnosis. Hyperferritinemia has a sensitivity and specificity of > 90% for diagnosis when above 10,000 ng/dL in the pediatric population.7 This is not the case in adults. Hyperferritinemia is a marker of different inflammatory responses, such as histoplasmosis infection, malignancy, or iron overload rather than an isolated diagnostic tool for HLH.8 It has been reported that CD25 levels less than the diagnostic threshold of 2400 U/mL have a 100% sensitivity for the diagnosis and therefore can rule out the diagnosis. When this is taken into consideration, it can be concluded that CD25 level is a better diagnostic tool when compared with ferritin, but its main limitation is its lack of widespread availability.9 Still, there is a limited number of pathologies that are associated with marked hyperferritinemia, specifically using thresholds of more than 6000 ng/dL.10 Taking into consideration the high mortality of untreated HLH, isolated hyperferritinemia still warrants HLH workup to aggressively pursue the diagnosis and improve outcomes.
The goal of therapy in HLH is prompt inactivation of the dysregulated inflammation with aggressive immunosuppression. In our deteriorating patient, the treatment was started with only 4 of the 8 HLH-2004 diagnostic criteria being met. As per the 2018 Histiocyte Society consensus statement, the decision to start the HLH-94 treatment relies on not only the HLH-2004 diagnostic criteria, but also the patient’s clinical evolution.11 In 1994 the Histiocyte Society also published a treatment protocol termed HLH-94. A Korean retrospective study demonstrated that this protocol led to a 5-year survival rate of 60 to 80% depending on the HLH trigger and response to initial treatment.12 The protocol consists of etoposide at 150 mg/m2, 2 weekly doses in the first 2 weeks and then 1 dose weekly for the next 6 weeks. Dexamethasone is the steroid of choice as it readily crosses the blood-brain barrier. Its dosage consists of 10 mg/m2 for the first 2 weeks and then it is halved every 2 weeks until the eighth week of treatment. A slow taper follows to avoid adrenal insufficiency. Once 8 weeks of treatment have been completed, cyclosporine is added to a goal trough of 200 mcg/dL. If there is central nervous system (CNS) involvement, early aggressive treatment with intrathecal methotrexate is indicated if no improvement is noted during initial therapy.11
In 2004 the Histiocyte Society restructured the HLH-94 treatment protocol with the aim of presenting a more aggressive treatment strategy. The protocol added cyclosporine to the initial induction therapy, rather than later in the ninth week as HLH-94. Neither the use of cyclosporine nor the HLH-2004 have been demonstrated to be superior to the use of etoposide and dexamethasone alone or in the HLH-94 protocol, respectively.13 Cyclosporine is associated with adverse effects (AEs) and may have many contraindications in the acute phase of the disease. Therefore, the HLH-94 protocol is still the recommended regimen.11
To assess adequate clinical response, several clinical and laboratory parameters are followed. Clinically, resolution of fever, improvement in hepatosplenomegaly, lymphadenopathy, and mental status can be useful. Laboratories can be used to assess improvement from organ specific damage such as hepatic involvement or cytopenia. The limitation of these diagnostic studies is that they could falsely suggest an inadequate response to treatment due to concomitant infection or medication AEs. Other markers such as ferritin levels, CD25, and NK cell activity levels are more specific to HLH. Out of them, a decreasing ferritin level has the needed specificity and widespread availability for repeated assessment. On the other hand, both CD25 and NK cell activity are readily available only in specialized centers. An initial high ferritin level is a marker for a poor prognosis, and the rate of decline correlates with mortality. Studies have demonstrated that persistently elevated ferritin levels after treatment initiation are associated with worse outcomes.14,15
Several salvage treatments have been identified in recalcitrant or relapsing disease. In general, chemotherapy needs to be intensified, either by returning to the initial high dosage if recurrence occurs in the weaning phase of treatment or adding other agents if no response was initially achieved. Emapalumab, an interferon γ antibody, was approved by the US Food and Drug Administration for the treatment of intractable HLH after it demonstrated that when added to dexamethasone, it lead to treatment response in 17 out of 27 pediatric patients, with a relatively safe AE profile.16 The goal of intensifying chemotherapy is to have the patient tolerate allogenic stem cell transplant, which is clinically indicated in familial HLH, malignancy induced HLH, and recalcitrant cases. In patients who undergo hematopoietic cell transplantation (HCT) there is a tendency to increase survival to 66% at 5 years.12
Conclusions
HLH is a rare and deadly disease increasingly more present in adults. Our patient who initially presented with a sepsis diagnosis was suspected of having a hematologic etiology for his clinical findings due to markedly elevated ferritin levels. In our patient, the HLH-94 treatment protocol was used, yielding favorable results. Given the lack of specific scientific data backing updated protocols such as HLH-2004 and a comparatively favorable safety profile, current guidelines still recommend using the HLH-94 treatment protocol. Decreasing ferritin levels may be used in conjunction with clinical improvement to demonstrate therapeutic response. Persistence of disease despite standard treatment may warrant novel therapies, such as emapalumab or HCT. Physicians need to be wary of an HLH diagnosis as early identification and treatment may improve its otherwise grim prognosis.
1. Chen TY, Hsu MH, Kuo HC, Sheen JM, Cheng MC, Lin YJ. Outcome analysis of pediatric hemophagocytic lymphohistiocytosis. J Formos Med Assoc. 2021;120(1, pt 1):172-179. doi:10.1016/j.jfma.2020.03.025
2. Henter JI, Samuelsson-Horne A, Aricò M, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. 2002;100(7):2367-2373. doi:10.1182/blood-2002-01-0172
3. Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol. 1991;18(1):29-33.
4. Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-131. doi:10.1002/pbc.21039
5. Knaak C, Nyvlt P, Schuster FS, et al. Hemophagocytic lymphohistiocytosis in critically ill patients: diagnostic reliability of HLH-2004 criteria and HScore. Crit Care. 2020;24(1):244. Published 2020 May 24. doi:10.1186/s13054-020-02941-3
6. Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol. 2014;66(9):2613-2620. doi:10.1002/art.38690
7. La Rosée P, Horne A, Hines M, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019;133(23):2465-2477. doi:10.1182/blood.2018894618
8. Schaffner M, Rosenstein L, Ballas Z, Suneja M. Significance of Hyperferritinemia in Hospitalized Adults. Am J Med Sci. 2017;354(2):152-158. doi:10.1016/j.amjms.2017.04.016
9. Hayden A, Lin M, Park S, et al. Soluble interleukin-2 receptor is a sensitive diagnostic test in adult HLH. Blood Adv. 2017;1(26):2529-2534. Published 2017 Dec 6. doi:10.1182/bloodadvances.2017012310
10. Belfeki N, Strazzulla A, Picque M, Diamantis S. Extreme hyperferritinemia: etiological spectrum and impact on prognosis. Reumatismo. 2020;71(4):199-202. Published 2020 Jan 28. doi:10.4081/reumatismo.2019.1221
11. Ehl S, Astigarraga I, von Bahr Greenwood T, et al. Recommendations for the use of etoposide-based therapy and bone marrow transplantation for the treatment of HLH: consensus statements by the HLH Steering Committee of the Histiocyte Society. J Allergy Clin Immunol Pract. 2018;6(5):1508-1517. doi:10.1016/j.jaip.2018.05.031
12. Yoon JH, Park SS, Jeon YW, et al. Treatment outcomes and prognostic factors in adult patients with secondary hemophagocytic lymphohistiocytosis not associated with malignancy. Haematologica. 2019;104(2):269-276. doi:10.3324/haematol.2018.198655
13. Bergsten E, Horne A, Aricó M, et al. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 2017;130(25):2728-2738. doi:10.1182/blood-2017-06-788349
14. Lin TF, Ferlic-Stark LL, Allen CE, Kozinetz CA, McClain KL. Rate of decline of ferritin in patients with hemophagocytic lymphohistiocytosis as a prognostic variable for mortality. Pediatr Blood Cancer. 2011;56(1):154-155. doi:10.1002/pbc.22774
15. Zhou J, Zhou J, Shen DT, Goyal H, Wu ZQ, Xu HG. Development and validation of the prognostic value of ferritin in adult patients with Hemophagocytic Lymphohistiocytosis. Orphanet J Rare Dis. 2020;15(1):71. Published 2020 Mar 12. doi:10.1186/s13023-020-1336-616. Locatelli F, Jordan MB, Allen CE, et al. Safety and efficacy of emapalumab in pediatric patients with primary hemophagocytic lymphohistiocytosis. Presented at: American Society of Hematology Annual Meeting, November 29, 2018. Blood. 2018;132(suppl 1):LBA-6. doi:10.1182/blood-2018-120810
HLH is a rare and deadly disease increasingly more present in adults, but following treatment protocol may yield favorable results.
HLH is a rare and deadly disease increasingly more present in adults, but following treatment protocol may yield favorable results.
Hemophagocytic lymphohistiocytosis (HLH) is a rare and deadly disease in which unregulated proliferation of histiocytes and T-cell infiltration takes place. It is known as a pediatric disease in which gene defects result in impaired cytotoxic NK- and T-cell function. It has been associated with autosomal recessive inheritance pattern. Without therapy, survival for these patients with active familial HLH is approximately 2 months.
Recognition of the disease has increased over the years, and as a result the diagnosis of HLH in adults also has increased. An acquired form can be triggered by viruses like Epstein-Barr virus, influenza, HIV, lymphoid malignancies, rheumatologic disorders, or immunodeficiency disorders. Survival rates for untreated HLH have been reported at < 5%.1 Despite early recognition and adequate treatment, HLH carries an overall mortality of 50% in the initial presentation, 90% die in the first 8 weeks of treatment due to uncontrolled disease.2
Case Presentation
A 56-year-old man with no active medical issues except for a remote history of non-Hodgkin lymphoma treated with chemotherapy and splenectomy in 1990 presented to the Veterans Affairs Caribbean Healthcare System in San Juan, Puerto Rico. He was admitted to the medicine ward due to community acquired pneumonia. Three days into admission his clinical status deteriorated, and the patient was transferred to the intensive care unit (ICU) due to acute respiratory failure and sepsis secondary to worsening pneumonia. Chest imaging demonstrated rapidly progressing diffuse bilateral infiltrates. Due to the severity of the chest imaging, a diagnostic bronchoscopy was performed.
The patient’s antibiotics regimen was empirically escalated to vancomycin 1500 mg IV every 12 hours and meropenem 2 g IV every 8 hours. Despite optimization of therapy, the patient did not show clinical signs of improvement. Febrile episodes persisted, pulmonary infiltrates and hypoxemia worsened, and the patient required a neuromuscular blockade. Since the bronchoscopy was nondiagnostic and deterioration persistent, the differential diagnosis was broadened. This led to the ordering of inflammatory markers. Laboratory testing showed ferritin levels > 16,000 ng/mL, pointing to HLH as a possible diagnosis. Further workup was remarkable for triglycerides of 1234 mg/dL and a fibrinogen of 0.77 g/L. In the setting of bicytopenia and persistent fever, HLH-94 regimen was started with dexamethasone 40 mg daily and etoposide 100 mg/m2. CD25 levels of 154,701 pg/mL were demonstrated as well as a decreased immunoglobulin (Ig) G levels with absent IgM and IgA. Bone marrow biopsy was consistent with hemophagocytosis. The patient eventually was extubated and sent to the oncology ward to continue chemotherapy.
Discussion
A high clinical suspicion is warranted for rapid diagnosis and treatment as HLH evolves in most cases to multiorgan failure and death. The diagnostic criteria for HLH was developed by the Histiocyte Society in 1991 and then restructured in 2004.3,4 In the first diagnostic tool developed in 1991, diagnosis was based on 5 criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). Three additional laboratory findings were also described as part of HLH diagnosis since 2004: low or absent NK-cell-activity, hyperferritinemia of > 500 ng/dL, and high-soluble interleukin-2-receptor levels (CD25) > 2400 U/mL. Overall, 5 of 8 criteria are needed for the HLH diagnosis.
Despite the common use of these diagnostic criteria, they were developed for the pediatric population but have not been validated for adult patients.5 For adult patients, the HScore was developed in 2014. It has 9 variables: 3 are based on clinical findings (known underlying immunosuppression, high temperature, and organomegaly; 5 are based on laboratory values (ferritin, serum glutamic oxaloacetic transaminase, cytopenia, triglycerides, and fibrinogen levels); the last variable uses cytologic findings in the bone marrow. In the initial study, probability of having HLH ranged from < 1% with an HScore of ≤ 90% to > 99% with an HScore of ≥ 250 in noncritically ill adults.5 A recently published retrospective study demonstrated the diagnostic reliability of both the HLH-2004 criteria and HScore in critically ill adult patients. This study concluded that the best prediction accuracy of HLH diagnosis for a cutoff of 4 fulfilled HLH-2004 criteria had a 95.0% sensitivity and 93.6% specificity and HScore cutoff of 168 reached a 100% sensitivity and 94.1% specificity.6
The early negative bronchoscopy lowered the possibility of an infection as the etiology of the clinical presentation and narrowed the hyperferritinemia differential diagnosis. Hyperferritinemia has a sensitivity and specificity of > 90% for diagnosis when above 10,000 ng/dL in the pediatric population.7 This is not the case in adults. Hyperferritinemia is a marker of different inflammatory responses, such as histoplasmosis infection, malignancy, or iron overload rather than an isolated diagnostic tool for HLH.8 It has been reported that CD25 levels less than the diagnostic threshold of 2400 U/mL have a 100% sensitivity for the diagnosis and therefore can rule out the diagnosis. When this is taken into consideration, it can be concluded that CD25 level is a better diagnostic tool when compared with ferritin, but its main limitation is its lack of widespread availability.9 Still, there is a limited number of pathologies that are associated with marked hyperferritinemia, specifically using thresholds of more than 6000 ng/dL.10 Taking into consideration the high mortality of untreated HLH, isolated hyperferritinemia still warrants HLH workup to aggressively pursue the diagnosis and improve outcomes.
The goal of therapy in HLH is prompt inactivation of the dysregulated inflammation with aggressive immunosuppression. In our deteriorating patient, the treatment was started with only 4 of the 8 HLH-2004 diagnostic criteria being met. As per the 2018 Histiocyte Society consensus statement, the decision to start the HLH-94 treatment relies on not only the HLH-2004 diagnostic criteria, but also the patient’s clinical evolution.11 In 1994 the Histiocyte Society also published a treatment protocol termed HLH-94. A Korean retrospective study demonstrated that this protocol led to a 5-year survival rate of 60 to 80% depending on the HLH trigger and response to initial treatment.12 The protocol consists of etoposide at 150 mg/m2, 2 weekly doses in the first 2 weeks and then 1 dose weekly for the next 6 weeks. Dexamethasone is the steroid of choice as it readily crosses the blood-brain barrier. Its dosage consists of 10 mg/m2 for the first 2 weeks and then it is halved every 2 weeks until the eighth week of treatment. A slow taper follows to avoid adrenal insufficiency. Once 8 weeks of treatment have been completed, cyclosporine is added to a goal trough of 200 mcg/dL. If there is central nervous system (CNS) involvement, early aggressive treatment with intrathecal methotrexate is indicated if no improvement is noted during initial therapy.11
In 2004 the Histiocyte Society restructured the HLH-94 treatment protocol with the aim of presenting a more aggressive treatment strategy. The protocol added cyclosporine to the initial induction therapy, rather than later in the ninth week as HLH-94. Neither the use of cyclosporine nor the HLH-2004 have been demonstrated to be superior to the use of etoposide and dexamethasone alone or in the HLH-94 protocol, respectively.13 Cyclosporine is associated with adverse effects (AEs) and may have many contraindications in the acute phase of the disease. Therefore, the HLH-94 protocol is still the recommended regimen.11
To assess adequate clinical response, several clinical and laboratory parameters are followed. Clinically, resolution of fever, improvement in hepatosplenomegaly, lymphadenopathy, and mental status can be useful. Laboratories can be used to assess improvement from organ specific damage such as hepatic involvement or cytopenia. The limitation of these diagnostic studies is that they could falsely suggest an inadequate response to treatment due to concomitant infection or medication AEs. Other markers such as ferritin levels, CD25, and NK cell activity levels are more specific to HLH. Out of them, a decreasing ferritin level has the needed specificity and widespread availability for repeated assessment. On the other hand, both CD25 and NK cell activity are readily available only in specialized centers. An initial high ferritin level is a marker for a poor prognosis, and the rate of decline correlates with mortality. Studies have demonstrated that persistently elevated ferritin levels after treatment initiation are associated with worse outcomes.14,15
Several salvage treatments have been identified in recalcitrant or relapsing disease. In general, chemotherapy needs to be intensified, either by returning to the initial high dosage if recurrence occurs in the weaning phase of treatment or adding other agents if no response was initially achieved. Emapalumab, an interferon γ antibody, was approved by the US Food and Drug Administration for the treatment of intractable HLH after it demonstrated that when added to dexamethasone, it lead to treatment response in 17 out of 27 pediatric patients, with a relatively safe AE profile.16 The goal of intensifying chemotherapy is to have the patient tolerate allogenic stem cell transplant, which is clinically indicated in familial HLH, malignancy induced HLH, and recalcitrant cases. In patients who undergo hematopoietic cell transplantation (HCT) there is a tendency to increase survival to 66% at 5 years.12
Conclusions
HLH is a rare and deadly disease increasingly more present in adults. Our patient who initially presented with a sepsis diagnosis was suspected of having a hematologic etiology for his clinical findings due to markedly elevated ferritin levels. In our patient, the HLH-94 treatment protocol was used, yielding favorable results. Given the lack of specific scientific data backing updated protocols such as HLH-2004 and a comparatively favorable safety profile, current guidelines still recommend using the HLH-94 treatment protocol. Decreasing ferritin levels may be used in conjunction with clinical improvement to demonstrate therapeutic response. Persistence of disease despite standard treatment may warrant novel therapies, such as emapalumab or HCT. Physicians need to be wary of an HLH diagnosis as early identification and treatment may improve its otherwise grim prognosis.
Hemophagocytic lymphohistiocytosis (HLH) is a rare and deadly disease in which unregulated proliferation of histiocytes and T-cell infiltration takes place. It is known as a pediatric disease in which gene defects result in impaired cytotoxic NK- and T-cell function. It has been associated with autosomal recessive inheritance pattern. Without therapy, survival for these patients with active familial HLH is approximately 2 months.
Recognition of the disease has increased over the years, and as a result the diagnosis of HLH in adults also has increased. An acquired form can be triggered by viruses like Epstein-Barr virus, influenza, HIV, lymphoid malignancies, rheumatologic disorders, or immunodeficiency disorders. Survival rates for untreated HLH have been reported at < 5%.1 Despite early recognition and adequate treatment, HLH carries an overall mortality of 50% in the initial presentation, 90% die in the first 8 weeks of treatment due to uncontrolled disease.2
Case Presentation
A 56-year-old man with no active medical issues except for a remote history of non-Hodgkin lymphoma treated with chemotherapy and splenectomy in 1990 presented to the Veterans Affairs Caribbean Healthcare System in San Juan, Puerto Rico. He was admitted to the medicine ward due to community acquired pneumonia. Three days into admission his clinical status deteriorated, and the patient was transferred to the intensive care unit (ICU) due to acute respiratory failure and sepsis secondary to worsening pneumonia. Chest imaging demonstrated rapidly progressing diffuse bilateral infiltrates. Due to the severity of the chest imaging, a diagnostic bronchoscopy was performed.
The patient’s antibiotics regimen was empirically escalated to vancomycin 1500 mg IV every 12 hours and meropenem 2 g IV every 8 hours. Despite optimization of therapy, the patient did not show clinical signs of improvement. Febrile episodes persisted, pulmonary infiltrates and hypoxemia worsened, and the patient required a neuromuscular blockade. Since the bronchoscopy was nondiagnostic and deterioration persistent, the differential diagnosis was broadened. This led to the ordering of inflammatory markers. Laboratory testing showed ferritin levels > 16,000 ng/mL, pointing to HLH as a possible diagnosis. Further workup was remarkable for triglycerides of 1234 mg/dL and a fibrinogen of 0.77 g/L. In the setting of bicytopenia and persistent fever, HLH-94 regimen was started with dexamethasone 40 mg daily and etoposide 100 mg/m2. CD25 levels of 154,701 pg/mL were demonstrated as well as a decreased immunoglobulin (Ig) G levels with absent IgM and IgA. Bone marrow biopsy was consistent with hemophagocytosis. The patient eventually was extubated and sent to the oncology ward to continue chemotherapy.
Discussion
A high clinical suspicion is warranted for rapid diagnosis and treatment as HLH evolves in most cases to multiorgan failure and death. The diagnostic criteria for HLH was developed by the Histiocyte Society in 1991 and then restructured in 2004.3,4 In the first diagnostic tool developed in 1991, diagnosis was based on 5 criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). Three additional laboratory findings were also described as part of HLH diagnosis since 2004: low or absent NK-cell-activity, hyperferritinemia of > 500 ng/dL, and high-soluble interleukin-2-receptor levels (CD25) > 2400 U/mL. Overall, 5 of 8 criteria are needed for the HLH diagnosis.
Despite the common use of these diagnostic criteria, they were developed for the pediatric population but have not been validated for adult patients.5 For adult patients, the HScore was developed in 2014. It has 9 variables: 3 are based on clinical findings (known underlying immunosuppression, high temperature, and organomegaly; 5 are based on laboratory values (ferritin, serum glutamic oxaloacetic transaminase, cytopenia, triglycerides, and fibrinogen levels); the last variable uses cytologic findings in the bone marrow. In the initial study, probability of having HLH ranged from < 1% with an HScore of ≤ 90% to > 99% with an HScore of ≥ 250 in noncritically ill adults.5 A recently published retrospective study demonstrated the diagnostic reliability of both the HLH-2004 criteria and HScore in critically ill adult patients. This study concluded that the best prediction accuracy of HLH diagnosis for a cutoff of 4 fulfilled HLH-2004 criteria had a 95.0% sensitivity and 93.6% specificity and HScore cutoff of 168 reached a 100% sensitivity and 94.1% specificity.6
The early negative bronchoscopy lowered the possibility of an infection as the etiology of the clinical presentation and narrowed the hyperferritinemia differential diagnosis. Hyperferritinemia has a sensitivity and specificity of > 90% for diagnosis when above 10,000 ng/dL in the pediatric population.7 This is not the case in adults. Hyperferritinemia is a marker of different inflammatory responses, such as histoplasmosis infection, malignancy, or iron overload rather than an isolated diagnostic tool for HLH.8 It has been reported that CD25 levels less than the diagnostic threshold of 2400 U/mL have a 100% sensitivity for the diagnosis and therefore can rule out the diagnosis. When this is taken into consideration, it can be concluded that CD25 level is a better diagnostic tool when compared with ferritin, but its main limitation is its lack of widespread availability.9 Still, there is a limited number of pathologies that are associated with marked hyperferritinemia, specifically using thresholds of more than 6000 ng/dL.10 Taking into consideration the high mortality of untreated HLH, isolated hyperferritinemia still warrants HLH workup to aggressively pursue the diagnosis and improve outcomes.
The goal of therapy in HLH is prompt inactivation of the dysregulated inflammation with aggressive immunosuppression. In our deteriorating patient, the treatment was started with only 4 of the 8 HLH-2004 diagnostic criteria being met. As per the 2018 Histiocyte Society consensus statement, the decision to start the HLH-94 treatment relies on not only the HLH-2004 diagnostic criteria, but also the patient’s clinical evolution.11 In 1994 the Histiocyte Society also published a treatment protocol termed HLH-94. A Korean retrospective study demonstrated that this protocol led to a 5-year survival rate of 60 to 80% depending on the HLH trigger and response to initial treatment.12 The protocol consists of etoposide at 150 mg/m2, 2 weekly doses in the first 2 weeks and then 1 dose weekly for the next 6 weeks. Dexamethasone is the steroid of choice as it readily crosses the blood-brain barrier. Its dosage consists of 10 mg/m2 for the first 2 weeks and then it is halved every 2 weeks until the eighth week of treatment. A slow taper follows to avoid adrenal insufficiency. Once 8 weeks of treatment have been completed, cyclosporine is added to a goal trough of 200 mcg/dL. If there is central nervous system (CNS) involvement, early aggressive treatment with intrathecal methotrexate is indicated if no improvement is noted during initial therapy.11
In 2004 the Histiocyte Society restructured the HLH-94 treatment protocol with the aim of presenting a more aggressive treatment strategy. The protocol added cyclosporine to the initial induction therapy, rather than later in the ninth week as HLH-94. Neither the use of cyclosporine nor the HLH-2004 have been demonstrated to be superior to the use of etoposide and dexamethasone alone or in the HLH-94 protocol, respectively.13 Cyclosporine is associated with adverse effects (AEs) and may have many contraindications in the acute phase of the disease. Therefore, the HLH-94 protocol is still the recommended regimen.11
To assess adequate clinical response, several clinical and laboratory parameters are followed. Clinically, resolution of fever, improvement in hepatosplenomegaly, lymphadenopathy, and mental status can be useful. Laboratories can be used to assess improvement from organ specific damage such as hepatic involvement or cytopenia. The limitation of these diagnostic studies is that they could falsely suggest an inadequate response to treatment due to concomitant infection or medication AEs. Other markers such as ferritin levels, CD25, and NK cell activity levels are more specific to HLH. Out of them, a decreasing ferritin level has the needed specificity and widespread availability for repeated assessment. On the other hand, both CD25 and NK cell activity are readily available only in specialized centers. An initial high ferritin level is a marker for a poor prognosis, and the rate of decline correlates with mortality. Studies have demonstrated that persistently elevated ferritin levels after treatment initiation are associated with worse outcomes.14,15
Several salvage treatments have been identified in recalcitrant or relapsing disease. In general, chemotherapy needs to be intensified, either by returning to the initial high dosage if recurrence occurs in the weaning phase of treatment or adding other agents if no response was initially achieved. Emapalumab, an interferon γ antibody, was approved by the US Food and Drug Administration for the treatment of intractable HLH after it demonstrated that when added to dexamethasone, it lead to treatment response in 17 out of 27 pediatric patients, with a relatively safe AE profile.16 The goal of intensifying chemotherapy is to have the patient tolerate allogenic stem cell transplant, which is clinically indicated in familial HLH, malignancy induced HLH, and recalcitrant cases. In patients who undergo hematopoietic cell transplantation (HCT) there is a tendency to increase survival to 66% at 5 years.12
Conclusions
HLH is a rare and deadly disease increasingly more present in adults. Our patient who initially presented with a sepsis diagnosis was suspected of having a hematologic etiology for his clinical findings due to markedly elevated ferritin levels. In our patient, the HLH-94 treatment protocol was used, yielding favorable results. Given the lack of specific scientific data backing updated protocols such as HLH-2004 and a comparatively favorable safety profile, current guidelines still recommend using the HLH-94 treatment protocol. Decreasing ferritin levels may be used in conjunction with clinical improvement to demonstrate therapeutic response. Persistence of disease despite standard treatment may warrant novel therapies, such as emapalumab or HCT. Physicians need to be wary of an HLH diagnosis as early identification and treatment may improve its otherwise grim prognosis.
1. Chen TY, Hsu MH, Kuo HC, Sheen JM, Cheng MC, Lin YJ. Outcome analysis of pediatric hemophagocytic lymphohistiocytosis. J Formos Med Assoc. 2021;120(1, pt 1):172-179. doi:10.1016/j.jfma.2020.03.025
2. Henter JI, Samuelsson-Horne A, Aricò M, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. 2002;100(7):2367-2373. doi:10.1182/blood-2002-01-0172
3. Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol. 1991;18(1):29-33.
4. Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-131. doi:10.1002/pbc.21039
5. Knaak C, Nyvlt P, Schuster FS, et al. Hemophagocytic lymphohistiocytosis in critically ill patients: diagnostic reliability of HLH-2004 criteria and HScore. Crit Care. 2020;24(1):244. Published 2020 May 24. doi:10.1186/s13054-020-02941-3
6. Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol. 2014;66(9):2613-2620. doi:10.1002/art.38690
7. La Rosée P, Horne A, Hines M, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019;133(23):2465-2477. doi:10.1182/blood.2018894618
8. Schaffner M, Rosenstein L, Ballas Z, Suneja M. Significance of Hyperferritinemia in Hospitalized Adults. Am J Med Sci. 2017;354(2):152-158. doi:10.1016/j.amjms.2017.04.016
9. Hayden A, Lin M, Park S, et al. Soluble interleukin-2 receptor is a sensitive diagnostic test in adult HLH. Blood Adv. 2017;1(26):2529-2534. Published 2017 Dec 6. doi:10.1182/bloodadvances.2017012310
10. Belfeki N, Strazzulla A, Picque M, Diamantis S. Extreme hyperferritinemia: etiological spectrum and impact on prognosis. Reumatismo. 2020;71(4):199-202. Published 2020 Jan 28. doi:10.4081/reumatismo.2019.1221
11. Ehl S, Astigarraga I, von Bahr Greenwood T, et al. Recommendations for the use of etoposide-based therapy and bone marrow transplantation for the treatment of HLH: consensus statements by the HLH Steering Committee of the Histiocyte Society. J Allergy Clin Immunol Pract. 2018;6(5):1508-1517. doi:10.1016/j.jaip.2018.05.031
12. Yoon JH, Park SS, Jeon YW, et al. Treatment outcomes and prognostic factors in adult patients with secondary hemophagocytic lymphohistiocytosis not associated with malignancy. Haematologica. 2019;104(2):269-276. doi:10.3324/haematol.2018.198655
13. Bergsten E, Horne A, Aricó M, et al. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 2017;130(25):2728-2738. doi:10.1182/blood-2017-06-788349
14. Lin TF, Ferlic-Stark LL, Allen CE, Kozinetz CA, McClain KL. Rate of decline of ferritin in patients with hemophagocytic lymphohistiocytosis as a prognostic variable for mortality. Pediatr Blood Cancer. 2011;56(1):154-155. doi:10.1002/pbc.22774
15. Zhou J, Zhou J, Shen DT, Goyal H, Wu ZQ, Xu HG. Development and validation of the prognostic value of ferritin in adult patients with Hemophagocytic Lymphohistiocytosis. Orphanet J Rare Dis. 2020;15(1):71. Published 2020 Mar 12. doi:10.1186/s13023-020-1336-616. Locatelli F, Jordan MB, Allen CE, et al. Safety and efficacy of emapalumab in pediatric patients with primary hemophagocytic lymphohistiocytosis. Presented at: American Society of Hematology Annual Meeting, November 29, 2018. Blood. 2018;132(suppl 1):LBA-6. doi:10.1182/blood-2018-120810
1. Chen TY, Hsu MH, Kuo HC, Sheen JM, Cheng MC, Lin YJ. Outcome analysis of pediatric hemophagocytic lymphohistiocytosis. J Formos Med Assoc. 2021;120(1, pt 1):172-179. doi:10.1016/j.jfma.2020.03.025
2. Henter JI, Samuelsson-Horne A, Aricò M, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. 2002;100(7):2367-2373. doi:10.1182/blood-2002-01-0172
3. Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol. 1991;18(1):29-33.
4. Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-131. doi:10.1002/pbc.21039
5. Knaak C, Nyvlt P, Schuster FS, et al. Hemophagocytic lymphohistiocytosis in critically ill patients: diagnostic reliability of HLH-2004 criteria and HScore. Crit Care. 2020;24(1):244. Published 2020 May 24. doi:10.1186/s13054-020-02941-3
6. Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol. 2014;66(9):2613-2620. doi:10.1002/art.38690
7. La Rosée P, Horne A, Hines M, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019;133(23):2465-2477. doi:10.1182/blood.2018894618
8. Schaffner M, Rosenstein L, Ballas Z, Suneja M. Significance of Hyperferritinemia in Hospitalized Adults. Am J Med Sci. 2017;354(2):152-158. doi:10.1016/j.amjms.2017.04.016
9. Hayden A, Lin M, Park S, et al. Soluble interleukin-2 receptor is a sensitive diagnostic test in adult HLH. Blood Adv. 2017;1(26):2529-2534. Published 2017 Dec 6. doi:10.1182/bloodadvances.2017012310
10. Belfeki N, Strazzulla A, Picque M, Diamantis S. Extreme hyperferritinemia: etiological spectrum and impact on prognosis. Reumatismo. 2020;71(4):199-202. Published 2020 Jan 28. doi:10.4081/reumatismo.2019.1221
11. Ehl S, Astigarraga I, von Bahr Greenwood T, et al. Recommendations for the use of etoposide-based therapy and bone marrow transplantation for the treatment of HLH: consensus statements by the HLH Steering Committee of the Histiocyte Society. J Allergy Clin Immunol Pract. 2018;6(5):1508-1517. doi:10.1016/j.jaip.2018.05.031
12. Yoon JH, Park SS, Jeon YW, et al. Treatment outcomes and prognostic factors in adult patients with secondary hemophagocytic lymphohistiocytosis not associated with malignancy. Haematologica. 2019;104(2):269-276. doi:10.3324/haematol.2018.198655
13. Bergsten E, Horne A, Aricó M, et al. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 2017;130(25):2728-2738. doi:10.1182/blood-2017-06-788349
14. Lin TF, Ferlic-Stark LL, Allen CE, Kozinetz CA, McClain KL. Rate of decline of ferritin in patients with hemophagocytic lymphohistiocytosis as a prognostic variable for mortality. Pediatr Blood Cancer. 2011;56(1):154-155. doi:10.1002/pbc.22774
15. Zhou J, Zhou J, Shen DT, Goyal H, Wu ZQ, Xu HG. Development and validation of the prognostic value of ferritin in adult patients with Hemophagocytic Lymphohistiocytosis. Orphanet J Rare Dis. 2020;15(1):71. Published 2020 Mar 12. doi:10.1186/s13023-020-1336-616. Locatelli F, Jordan MB, Allen CE, et al. Safety and efficacy of emapalumab in pediatric patients with primary hemophagocytic lymphohistiocytosis. Presented at: American Society of Hematology Annual Meeting, November 29, 2018. Blood. 2018;132(suppl 1):LBA-6. doi:10.1182/blood-2018-120810