From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
12 MARCH 2015
I VOLUME 125, NUMBER 11
l l l CLINICAL TRIALS & OBSERVATIONS
Comment on Waghmare et al, page 1724
Enterovirus D68: a new threat to hematology patients? ----------------------------------------------------------------------------------------------------Per Ljungman
KAROLINSKA UNIVERSITY HOSPITAL; KAROLINSKA INSTITUTET
In this issue of Blood, Waghmare et al report 8 patients with hematologic malignancies retrospectively diagnosed with enterovirus D68 (EV-D68) infections.1
E
nterovirus D68 is not a new virus, as it was identified in 1962, and small numbers of cases have been regularly reported to the US Centers for Disease Control and Prevention (CDC). However, during the summer of 2014, outbreaks of severe respiratory disease, especially in children and teenagers with a history of asthma, occurred in Missouri and Illinois.2,3 EV-D68 was identified in a majority of these cases, and during the rest of 2014, more than 1100 cases with documented EV-D68 infections were diagnosed all over the United States and reported to the CDC, including a small number of fatal infections. It has been suggested that the diagnosed cases are only “the tip of the iceberg,” with a large number of undiagnosed mild infections occurring as well. Therefore, the proportion of severe infections is difficult to assess. Outbreaks with EV-D68 have also been documented in other countries, including Norway4 and the Netherlands.5 The latter report also included 3 cases occurring in solid organ transplant recipients. For decades, viral infections have been recognized as threats to hematology patients, especially to hematopoietic stem cell transplant recipients. In the study by Waghmare et al, 6 patients were stem cell transplant recipients. Similarly to what is commonly seen with other respiratory viruses, the clinical manifestations
varied greatly from mild upper respiratory symptoms to respiratory failure, with 2 of 8 patients requiring mechanical ventilation. All 8 diagnosed infections occurred in adults, and most patients had lymphopenia, a well-known risk factor for more severe disease in infections caused by other respiratory viruses such as respiratory syncytial virus and influenza virus.6-8 Obviously, these observations are too limited to allow assessment of the pathogenic potential of EV-D68 in hematology and stem cell transplant patients, but if EV-D68 infections become more prevalent in the community, as recent epidemiology suggests, we will most likely get more information regarding the clinical importance of infections with this virus during the next couple of years. With the development of molecular virology techniques, the number of “new” viruses is steadily increasing, and investigators need to address the impact of these new viruses in immunocompromised patients. The authors employed an interesting strategy by analyzing samples from patients with respiratory symptoms who had either tested negative for respiratory viruses by multiplex polymerase chain reaction (PCR) or tested positive for rhinoviruses. The latter group is interesting, because 10% of patients who tested positive for rhinovirus were in fact, after sequencing, proven to have EV-D68, showing that the rhinovirus primers
BLOOD, 12 MARCH 2015 x VOLUME 125, NUMBER 11
used in the original multiplex PCR had limited specificity. This report illustrates a couple of important points. First, it shows the importance of having repositories of saved specimens allowing reanalysis when new technology becomes available. Second, this might explain some of the uncertainties about whether and how frequently rhinovirus causes severe lower respiratory tract disease, including respiratory failure.9,10 Third, as discussed by the authors, there is no way to guarantee, even with negative diagnostic test results in patients with respiratory symptoms, that such patients are not contagious and cannot contribute to nosocomial spread of viral infections in hematology and stem cell transplant units. It is therefore important to include EV-D68 in the diagnostic strategy used in highly immunocompromised patients with upper or lower respiratory symptoms despite the fact that there is no available antiviral therapy for infections caused by EV-D68. Conflict-of-interest disclosure: The author declares no competing financial interests. n REFERENCES 1. Waghmare A, Pergam SA, Jerome KR, Englund JA, Boeckh M, Kuypers J. Clinical disease due to enterovirus D68 in adult hematologic malignancy patients and hematopoietic cell transplant recipients. Blood. 2015; 125(11):1724-1729. 2. Stephenson J. CDC tracking enterovirus D-68 outbreak causing severe respiratory illness in children in the Midwest. JAMA. 2014;312(13):1290. 3. Midgley CM, Jackson MA, Selvarangan R, et al. Severe respiratory illness associated with enterovirus D68—Missouri and Illinois, 2014. MMWR Morb Mortal Wkly Rep. 2014;63(36):798-799. 4. Bragstad K, Jakobsen K, Rojahn AE, et al. High frequency of enterovirus D68 in children hospitalised with respiratory illness in Norway, autumn 2014 [published online ahead of print December 23, 2014]. Influenza Other Respir Viruses. doi:10.1111/irv.12300. 5. Poelman R, Sch¨olvinck EH, Borger R, Niesters HGM, van Leer-Buter C. The emergence of enterovirus D68 in a Dutch University Medical Center and the necessity for routinely screening for respiratory viruses. J Clin Virol. 2015;62(1):1-5. 6. Kim YJ, Guthrie KA, Waghmare A, et al. Respiratory syncytial virus in hematopoietic cell transplant recipients:
1683
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
factors determining progression to lower respiratory tract disease. J Infect Dis. 2014;209(8):1195-1204.
transplant recipients. Haematologica. 2011;96(8): 1231-1235.
7. Ljungman P, Ward KN, Crooks BN, et al. Respiratory virus infections after stem cell transplantation: a prospective study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 2001;28(5):479-484.
9. Abandeh FI, Lustberg M, Devine S, Elder P, Andritsos L, Martin SI. Outcomes of hematopoietic SCT recipients with rhinovirus infection: a matched, casecontrol study. Bone Marrow Transplant. 2013;48(12): 1554-1557.
8. Ljungman P, de la Camara R, Perez-Bercoff L, et al; Infectious Diseases Working Party, European Group for Blood and Marrow Transplantation; Infectious Complications Subcommittee, Spanish Group of Haematopoietic Stem-cell Transplantation. Outcome of pandemic H1N1 infections in hematopoietic stem cell
10. Milano F, Campbell AP, Guthrie KA, et al. Human rhinovirus and coronavirus detection among allogeneic hematopoietic stem cell transplantation recipients. Blood. 2010;115(10):2088-2094. © 2015 by The American Society of Hematology
l l l IMMUNOBIOLOGY
Comment on Mei et al, page 1739
Thucydides and longer-lived plasma cells ----------------------------------------------------------------------------------------------------Stuart G. Tangye
GARVAN INSTITUTE OF MEDICAL RESEARCH; UNIVERSITY OF NEW SOUTH WALES
In this issue of Blood, Mei and colleagues characterize the population of CD192 plasma cells in human bone marrow and provide evidence that this plasma-cell subset substantially contributes to long-lived protection against infections and vaccination.1
D
uring the Peloponnesian War, the plague killed nearly one-third of the Athenian population. In his writings, The History of the Peloponnesian War (late fifth century BC), the Greek philosopher and historian Thucydides observed that “the same man was never attacked twice—never at least fatally.” This was an astute observation, and probably the first to recognize that after an individual was exposed to a pathogen, he or she could be protected from disease on subsequent exposures without suffering the effects of infection. Although he did not realize it at the time, Thucydides was describing the process by which the mammalian immune system elicits long-lived serological memory that can often persist for a lifetime.2 In the ;2400 years since, we have learned a lot about the cellular and molecular processes underlying this phenomenon. For instance, we know that plasma cells (PCs) are largely responsible for serological memory.2-5 PCs are generated in germinal centers (GCs) from naive precursors that are activated after exposure to T-cell–dependent antigens. GC B cells undergo affinity-based selection and, depending on which and when signals are received, differentiate into plasmablasts, exit the physical structure of the GC, and start heading to the bone marrow (BM). In the
1684
BM, plasmablasts begin a new life as long-lived PCs, lodged in a survival niche, comfortably surrounded by supportive cell types that enable them to do their job: secrete copious quantities of high-affinity, antibody (Ab)-specific immunoglobulin that rapidly disarms invading pathogens before the host is aware it has been infected.3-5 Remarkably, it has been estimated that the half-life of neutralizing Abs ranges from 10 to .10 000 years, depending on the pathogen.2 So, if those survivors from the fifth century BC were alive today, they might still be immune to the plague! Although this summary gives the impression that all is known about PC biology, this is far from reality. Indeed, many caveats exist in this simplified version of events. For instance, not all PCs home to the BM; they can remain in their tissue of origin, such as spleen, lymph nodes, tonsils, or gut.4-7 Numerous PC subsets have been identified on the basis of their expression of different immunoglobulin isotypes and homing receptors that allow trafficking to distinct sites and endow these subsets with specific functions.4-8 Not all PCs are long-lived: both short-lived and long-lived PCs have been identified.3,4,8 And despite the terminology, PCs are not intrinsically long-lived: they rely on a microenvironment provided by
hematopoietic and nonhematopoietic cells that produce survival factors (eg, BAFF [B cell–activating factor], APRIL [a proliferation-inducing ligand], interleukin-6) critical for their long-term persistence.3-5,8 Lastly, our immune tissues can only support the survival of a finite number of PCs; thus, continual exposure to new pathogens generates new PCs that have to compete for limited survival niches.8,9 In the classic setting of Darwin’s survival of the fittest, only those PCs capable of maintaining access to such niches will remain for protracted periods of time, whereas “weaker” PCs will be “bumped” from survival niches and undergo apoptosis.8,9 One inference from this scenario is that the half-lives of all immunoglobulins should be approximately similar; however, this is clearly not the case because half-lives can differ by orders of magnitude.2 Thus, many questions remain about the nature and dynamics of PC generation and survival. Importantly, PCs not only are the linchpin of long-lived protective immunity against pathogens and, by extension, underlie the success of vaccination but also contribute to human diseases such as autoimmunity (eg, systemic lupus erythematosus, rheumatoid arthritis), malignancies (eg, multiple myeloma, PC leukemia), and primary immunodeficiency in which they are not produced in sufficient quantities, rendering affected individuals susceptible to pathogen infection. For these reasons, it is necessary to elucidate the “unknowns” of PC biology. Human PCs are typically identified by a CD38highCD27highCD20low phenotype, with expression of other markers varying depending on the tissue harvested.6,7 Mei and colleagues have now investigated the subset of CD192 PCs.1 These cells were largely restricted to the BM and preferentially expressed intracellular immunoglobulin G (IgG). In contrast, CD191 PCs are detected in blood, tonsils, and spleen, as well as in BM, and most express IgA or IgG.1,6,7 CD192 BMPCs exhibited a unique transcriptome, with elevated expression of prosurvival genes, as well as features associated with a state of advanced maturation and terminal differentiation. Consistent with these findings, CD192 BMPCs were nonproliferating cells with greater survival capacity than CD191 BMPCs, at least during in vitro culture. However, CD192 PCs did not appear to be simply derived from CD191 PCs
BLOOD, 12 MARCH 2015 x VOLUME 125, NUMBER 11
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2015 125: 1683-1684 doi:10.1182/blood-2015-01-623785
Enterovirus D68: a new threat to hematology patients? Per Ljungman
Updated information and services can be found at: http://www.bloodjournal.org/content/125/11/1683.full.html Articles on similar topics can be found in the following Blood collections Free Research Articles (4041 articles) Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.
12 MARCH 2015
I VOLUME 125, NUMBER 11
l l l CLINICAL TRIALS & OBSERVATIONS
Comment on Waghmare et al, page 1724
Enterovirus D68: a new threat to hematology patients? ----------------------------------------------------------------------------------------------------Per Ljungman
KAROLINSKA UNIVERSITY HOSPITAL; KAROLINSKA INSTITUTET
In this issue of Blood, Waghmare et al report 8 patients with hematologic malignancies retrospectively diagnosed with enterovirus D68 (EV-D68) infections.1
E
nterovirus D68 is not a new virus, as it was identified in 1962, and small numbers of cases have been regularly reported to the US Centers for Disease Control and Prevention (CDC). However, during the summer of 2014, outbreaks of severe respiratory disease, especially in children and teenagers with a history of asthma, occurred in Missouri and Illinois.2,3 EV-D68 was identified in a majority of these cases, and during the rest of 2014, more than 1100 cases with documented EV-D68 infections were diagnosed all over the United States and reported to the CDC, including a small number of fatal infections. It has been suggested that the diagnosed cases are only “the tip of the iceberg,” with a large number of undiagnosed mild infections occurring as well. Therefore, the proportion of severe infections is difficult to assess. Outbreaks with EV-D68 have also been documented in other countries, including Norway4 and the Netherlands.5 The latter report also included 3 cases occurring in solid organ transplant recipients. For decades, viral infections have been recognized as threats to hematology patients, especially to hematopoietic stem cell transplant recipients. In the study by Waghmare et al, 6 patients were stem cell transplant recipients. Similarly to what is commonly seen with other respiratory viruses, the clinical manifestations
varied greatly from mild upper respiratory symptoms to respiratory failure, with 2 of 8 patients requiring mechanical ventilation. All 8 diagnosed infections occurred in adults, and most patients had lymphopenia, a well-known risk factor for more severe disease in infections caused by other respiratory viruses such as respiratory syncytial virus and influenza virus.6-8 Obviously, these observations are too limited to allow assessment of the pathogenic potential of EV-D68 in hematology and stem cell transplant patients, but if EV-D68 infections become more prevalent in the community, as recent epidemiology suggests, we will most likely get more information regarding the clinical importance of infections with this virus during the next couple of years. With the development of molecular virology techniques, the number of “new” viruses is steadily increasing, and investigators need to address the impact of these new viruses in immunocompromised patients. The authors employed an interesting strategy by analyzing samples from patients with respiratory symptoms who had either tested negative for respiratory viruses by multiplex polymerase chain reaction (PCR) or tested positive for rhinoviruses. The latter group is interesting, because 10% of patients who tested positive for rhinovirus were in fact, after sequencing, proven to have EV-D68, showing that the rhinovirus primers
BLOOD, 12 MARCH 2015 x VOLUME 125, NUMBER 11
used in the original multiplex PCR had limited specificity. This report illustrates a couple of important points. First, it shows the importance of having repositories of saved specimens allowing reanalysis when new technology becomes available. Second, this might explain some of the uncertainties about whether and how frequently rhinovirus causes severe lower respiratory tract disease, including respiratory failure.9,10 Third, as discussed by the authors, there is no way to guarantee, even with negative diagnostic test results in patients with respiratory symptoms, that such patients are not contagious and cannot contribute to nosocomial spread of viral infections in hematology and stem cell transplant units. It is therefore important to include EV-D68 in the diagnostic strategy used in highly immunocompromised patients with upper or lower respiratory symptoms despite the fact that there is no available antiviral therapy for infections caused by EV-D68. Conflict-of-interest disclosure: The author declares no competing financial interests. n REFERENCES 1. Waghmare A, Pergam SA, Jerome KR, Englund JA, Boeckh M, Kuypers J. Clinical disease due to enterovirus D68 in adult hematologic malignancy patients and hematopoietic cell transplant recipients. Blood. 2015; 125(11):1724-1729. 2. Stephenson J. CDC tracking enterovirus D-68 outbreak causing severe respiratory illness in children in the Midwest. JAMA. 2014;312(13):1290. 3. Midgley CM, Jackson MA, Selvarangan R, et al. Severe respiratory illness associated with enterovirus D68—Missouri and Illinois, 2014. MMWR Morb Mortal Wkly Rep. 2014;63(36):798-799. 4. Bragstad K, Jakobsen K, Rojahn AE, et al. High frequency of enterovirus D68 in children hospitalised with respiratory illness in Norway, autumn 2014 [published online ahead of print December 23, 2014]. Influenza Other Respir Viruses. doi:10.1111/irv.12300. 5. Poelman R, Sch¨olvinck EH, Borger R, Niesters HGM, van Leer-Buter C. The emergence of enterovirus D68 in a Dutch University Medical Center and the necessity for routinely screening for respiratory viruses. J Clin Virol. 2015;62(1):1-5. 6. Kim YJ, Guthrie KA, Waghmare A, et al. Respiratory syncytial virus in hematopoietic cell transplant recipients:
1683
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
factors determining progression to lower respiratory tract disease. J Infect Dis. 2014;209(8):1195-1204.
transplant recipients. Haematologica. 2011;96(8): 1231-1235.
7. Ljungman P, Ward KN, Crooks BN, et al. Respiratory virus infections after stem cell transplantation: a prospective study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 2001;28(5):479-484.
9. Abandeh FI, Lustberg M, Devine S, Elder P, Andritsos L, Martin SI. Outcomes of hematopoietic SCT recipients with rhinovirus infection: a matched, casecontrol study. Bone Marrow Transplant. 2013;48(12): 1554-1557.
8. Ljungman P, de la Camara R, Perez-Bercoff L, et al; Infectious Diseases Working Party, European Group for Blood and Marrow Transplantation; Infectious Complications Subcommittee, Spanish Group of Haematopoietic Stem-cell Transplantation. Outcome of pandemic H1N1 infections in hematopoietic stem cell
10. Milano F, Campbell AP, Guthrie KA, et al. Human rhinovirus and coronavirus detection among allogeneic hematopoietic stem cell transplantation recipients. Blood. 2010;115(10):2088-2094. © 2015 by The American Society of Hematology
l l l IMMUNOBIOLOGY
Comment on Mei et al, page 1739
Thucydides and longer-lived plasma cells ----------------------------------------------------------------------------------------------------Stuart G. Tangye
GARVAN INSTITUTE OF MEDICAL RESEARCH; UNIVERSITY OF NEW SOUTH WALES
In this issue of Blood, Mei and colleagues characterize the population of CD192 plasma cells in human bone marrow and provide evidence that this plasma-cell subset substantially contributes to long-lived protection against infections and vaccination.1
D
uring the Peloponnesian War, the plague killed nearly one-third of the Athenian population. In his writings, The History of the Peloponnesian War (late fifth century BC), the Greek philosopher and historian Thucydides observed that “the same man was never attacked twice—never at least fatally.” This was an astute observation, and probably the first to recognize that after an individual was exposed to a pathogen, he or she could be protected from disease on subsequent exposures without suffering the effects of infection. Although he did not realize it at the time, Thucydides was describing the process by which the mammalian immune system elicits long-lived serological memory that can often persist for a lifetime.2 In the ;2400 years since, we have learned a lot about the cellular and molecular processes underlying this phenomenon. For instance, we know that plasma cells (PCs) are largely responsible for serological memory.2-5 PCs are generated in germinal centers (GCs) from naive precursors that are activated after exposure to T-cell–dependent antigens. GC B cells undergo affinity-based selection and, depending on which and when signals are received, differentiate into plasmablasts, exit the physical structure of the GC, and start heading to the bone marrow (BM). In the
1684
BM, plasmablasts begin a new life as long-lived PCs, lodged in a survival niche, comfortably surrounded by supportive cell types that enable them to do their job: secrete copious quantities of high-affinity, antibody (Ab)-specific immunoglobulin that rapidly disarms invading pathogens before the host is aware it has been infected.3-5 Remarkably, it has been estimated that the half-life of neutralizing Abs ranges from 10 to .10 000 years, depending on the pathogen.2 So, if those survivors from the fifth century BC were alive today, they might still be immune to the plague! Although this summary gives the impression that all is known about PC biology, this is far from reality. Indeed, many caveats exist in this simplified version of events. For instance, not all PCs home to the BM; they can remain in their tissue of origin, such as spleen, lymph nodes, tonsils, or gut.4-7 Numerous PC subsets have been identified on the basis of their expression of different immunoglobulin isotypes and homing receptors that allow trafficking to distinct sites and endow these subsets with specific functions.4-8 Not all PCs are long-lived: both short-lived and long-lived PCs have been identified.3,4,8 And despite the terminology, PCs are not intrinsically long-lived: they rely on a microenvironment provided by
hematopoietic and nonhematopoietic cells that produce survival factors (eg, BAFF [B cell–activating factor], APRIL [a proliferation-inducing ligand], interleukin-6) critical for their long-term persistence.3-5,8 Lastly, our immune tissues can only support the survival of a finite number of PCs; thus, continual exposure to new pathogens generates new PCs that have to compete for limited survival niches.8,9 In the classic setting of Darwin’s survival of the fittest, only those PCs capable of maintaining access to such niches will remain for protracted periods of time, whereas “weaker” PCs will be “bumped” from survival niches and undergo apoptosis.8,9 One inference from this scenario is that the half-lives of all immunoglobulins should be approximately similar; however, this is clearly not the case because half-lives can differ by orders of magnitude.2 Thus, many questions remain about the nature and dynamics of PC generation and survival. Importantly, PCs not only are the linchpin of long-lived protective immunity against pathogens and, by extension, underlie the success of vaccination but also contribute to human diseases such as autoimmunity (eg, systemic lupus erythematosus, rheumatoid arthritis), malignancies (eg, multiple myeloma, PC leukemia), and primary immunodeficiency in which they are not produced in sufficient quantities, rendering affected individuals susceptible to pathogen infection. For these reasons, it is necessary to elucidate the “unknowns” of PC biology. Human PCs are typically identified by a CD38highCD27highCD20low phenotype, with expression of other markers varying depending on the tissue harvested.6,7 Mei and colleagues have now investigated the subset of CD192 PCs.1 These cells were largely restricted to the BM and preferentially expressed intracellular immunoglobulin G (IgG). In contrast, CD191 PCs are detected in blood, tonsils, and spleen, as well as in BM, and most express IgA or IgG.1,6,7 CD192 BMPCs exhibited a unique transcriptome, with elevated expression of prosurvival genes, as well as features associated with a state of advanced maturation and terminal differentiation. Consistent with these findings, CD192 BMPCs were nonproliferating cells with greater survival capacity than CD191 BMPCs, at least during in vitro culture. However, CD192 PCs did not appear to be simply derived from CD191 PCs
BLOOD, 12 MARCH 2015 x VOLUME 125, NUMBER 11
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2015 125: 1683-1684 doi:10.1182/blood-2015-01-623785
Enterovirus D68: a new threat to hematology patients? Per Ljungman
Updated information and services can be found at: http://www.bloodjournal.org/content/125/11/1683.full.html Articles on similar topics can be found in the following Blood collections Free Research Articles (4041 articles) Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.
