correspondence
Daniel L. Kastner, M.D., Ph.D. Qing Zhou, Ph.D. Ivona Aksentijevich, M.D. National Human Genome Research Institute Bethesda, MD Since publication of their article, the authors report no further potential conflict of interest. DOI: 10.1056/NEJMc1405506
sequence) is carried by 1 in 700 controls of European ancestry1 and may be even more common in specific geographic areas, leading to homozygosity. Treatment of the affected siblings reported by Van Eyck, Liston, and Meyts and by van Montfrans et al. is intriguing in that in each family one sibling had a response to medical therapy while the other required, and was cured by, HSCT. The effectiveness of HSCT is consistent with the observation that monocytes and macrophages are the main source of serum ADA2 and provides further support for the feasibility of ADA2 replacement therapy. In sum, genetic analysis of CECR1 mutations may be warranted in vascular and immune disorders related to polyarteritis nodosa and the other phenotypes observed, and the diagnosis of ADA2 deficiency presents the immediate opportunity for effective treatments. Reeval Segel, M.D.
Dr. Segel and Colleagues Reply: It is very informative to learn of additional clinical presentations caused by mutations altering ADA2 and to consider treatments addressing the underlying loss of ADA2 protein. Sneddon’s syndrome in adults (reported by Bras et al.), and overt immunodeficiency and Castleman-like disease in pediatric patients with ADA2 deficiency (reported by Van Eyck, Liston, and Meyts; van Montfrans et al.; and Van Eyck, Liston, and Wouters) illustrate emerging phenotypes. These reports suggest that ADA2 deficiency may unify syndromes previously thought to be distinct and may also underlie a Shaare Zedek Medical Center Jerusalem, Israel wider range of phenotypes. ADA2 deficiency may be more common than Mary-Claire King, Ph.D. anticipated. Compound heterozygosity for the University of Washington p.Arg169Gln mutation was found in the German Seattle, WA family we reported and by Zhou et al. in two Ephrat Levy-Lahad, M.D. patients, in whom the mutation occurred on the Shaare Zedek Medical Center Jerusalem, Israel same ancestral haplotype. Both Van Eyck, Liston, [email protected] and Meyts and van Montfrans et al. report paSince publication of their article, the authors report no furtients homozygous for this mutation in two ap- ther potential conflict of interest. parently unrelated families from Belgium and 1. NHLBI GO Exome Sequencing Project (ESP) home page the Netherlands. The p.Arg169Gln mutation (http://evs.gs.washington.edu/EVS). (designated as rs77563738 in the human genome DOI: 10.1056/NEJMc1405506
Parasite Burden and Severity of Malaria in Tanzanian Children To the Editor: In their 4-year study of malaria in Tanzanian children, Gonçalves et al. (May 9 issue)1 observed diverging rates of severe disease and markers of parasite biomass after infancy. However, the results contrast with the findings of a study by Hendriksen et al.2 of 3826 African children with parasitemia and severe febrile illness in whom high plasma levels of PfHRP-2, reflecting total parasite biomass, strongly predicted a fatal outcome. Plasma PfHRP-2 level has also been shown to discriminate severe malaria from other severe illnesses accompanied by co
incidental peripheral-blood parasitemia, with accuracy confirmed on autopsy3 or retinal findings.4 These new observations by Gonçalves et al., which were based on a purely clinical case definition of severe malaria, may reflect a higher rate of false positive diagnoses; the authors’ supplementary data indicate many cases of “severe malaria” in which PfHRP-2 levels were well below established thresholds.2,3 The apparent clustering of false positive diagnoses in infants may be caused by confounding biases, such as age-dependent rates of diseases that clinically
n engl j med 371;5 nejm.org july 31, 2014
The New England Journal of Medicine Downloaded from nejm.org at EMORY UNIVERSITY on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
481
The
n e w e ng l a n d j o u r na l
overlap with severe malaria and changing transmission intensity, and this confounding affects the calculation of risk that can be attributed to malaria.5 In our view, these fundamental issues undermine the study’s conclusions; parasite biomass should continue to be considered as the dominant factor mediating severe malaria. Charles J. Woodrow, M.D., Ph.D. Arjen M. Dondorp, M.D., Ph.D. Mahidol–Oxford Tropical Medicine Research Unit Bangkok, Thailand
[email protected] No potential conflict of interest relevant to this letter was reported. 1. Gonçalves BP, Huang CY, Morrison R, et al. Parasite burden
and severity of malaria in Tanzanian children. N Engl J Med 2014;370:1799-808. 2. Hendriksen IC, Mwanga-Amumpaire J, von Seidlein L, et al. Diagnosing severe falciparum malaria in parasitaemic African children: a prospective evaluation of plasma PfHRP2 measurement. PLoS Med 2012;9(8):e1001297. 3. Taylor TE, Fu WJ, Carr RA, et al. Differentiating the pathologies of cerebral malaria by postmortem parasite counts. Nat Med 2004;10:143-5. 4. Seydel KB, Fox LL, Glover SJ, et al. Plasma concentrations of parasite histidine-rich protein 2 distinguish between retinopathypositive and retinopathy-negative cerebral malaria in Malawian children. J Infect Dis 2012;206:309-18. 5. Bejon P, Berkley JA, Mwangi T, et al. Defining childhood severe falciparum malaria for intervention studies. PLoS Med 2007;4(8):e251. DOI: 10.1056/NEJMc1407114
The Authors Reply: Like the study by Hendriksen et al.,1 in which 3826 African children were enrolled during hospitalization for severe malaria, our birth cohort study revealed high PfHRP-2 levels during fatal severe malaria (4619 to 30,169 ng per milliliter), a similar mean level during nonfatal severe malaria (1245 ng per milliliter in our study vs. 1046 ng per milliliter in Hendriksen et al.), and occasionally low or undetectable levels of PfHRP-2 during severe malaria. We also reported higher mean PfHRP-2 levels in children with high-density infections and only mild symptoms than in the same children during severe
of
m e dic i n e
malaria episodes, which suggests that PfHRP-2 level is an indicator of parasite biomass and the duration of infection rather than disease. Mean parasite density and PfHRP-2 level are generally higher during severe malaria, but there is considerable overlap of PfHRP-2 values in severe and uncomplicated cases of malaria,2-4 an observation that has been reported in studies that incorporate retinal findings.5 Severe malaria with very low or undetectable levels of PfHRP-2 has often been reported.2-4 Our findings and earlier observations2,3 suggest that factors in addition to total parasite biomass may contribute to malaria severity, including organ-specific parasite burden, local or systemic immunopathology, and parasite virulence. Our study also shows that immunity to severe malaria develops long before immunity that controls parasite burden. Bronner P. Gonçalves, M.D. Michal Fried, Ph.D. Patrick E. Duffy, M.D. National Institute of Allergy and Infectious Diseases Rockville, MD
[email protected] Since publication of their article, the authors report no further potential conflict of interest. 1. Hendriksen IC, Mwanga-Amumpaire J, von Seidlein L, et al.
Diagnosing severe falciparum malaria in parasitaemic African children: a prospective evaluation of plasma PfHRP2 measurement. PLoS Med 2012;9(8):e1001297. 2. Manning L, Laman M, Stanisic D, et al. Plasma Plasmodium falciparum histidine-rich protein-2 concentrations do not reflect severity of malaria in Papua New Guinean children. Clin Infect Dis 2011;52:440-6. 3. Rubach MP, Mukemba J, Florence S, et al. Plasma Plasmodium falciparum histidine-rich protein-2 concentrations are associated with malaria severity and mortality in Tanzanian children. PLoS One 2012;7(5):e35985. 4. Hendriksen IC, White LJ, Veenemans J, et al. Defining falciparum-malaria-attributable severe febrile illness in moderate-tohigh transmission settings on the basis of plasma PfHRP2 concentration. J Infect Dis 2013;207:351-61. 5. Seydel KB, Fox LL, Glover SJ, et al. Plasma concentrations of parasite histidine-rich protein 2 distinguish between retinopathy-positive and retinopathy-negative cerebral malaria in Malawian children. J Infect Dis 2012;206:309-18. DOI: 10.1056/NEJMc1407114
More on Hepatitis B Virus rtI233V Mutation and Resistance to Adefovir To the Editor: The letter by Geipel et al. (April 24 issue)1 contradicts previous data regarding resistance to adefovir in three patients with hepatitis B virus (HBV) infection with an rtI233V muta482
tion.2,3 Although new assays may be more accurate, in our study, we used an autologous and thus authentic HBV-promoter-based replication system that closely emulates the natural
n engl j med 371;5 nejm.org july 31, 2014
The New England Journal of Medicine Downloaded from nejm.org at EMORY UNIVERSITY on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
Daniel L. Kastner, M.D., Ph.D. Qing Zhou, Ph.D. Ivona Aksentijevich, M.D. National Human Genome Research Institute Bethesda, MD Since publication of their article, the authors report no further potential conflict of interest. DOI: 10.1056/NEJMc1405506
sequence) is carried by 1 in 700 controls of European ancestry1 and may be even more common in specific geographic areas, leading to homozygosity. Treatment of the affected siblings reported by Van Eyck, Liston, and Meyts and by van Montfrans et al. is intriguing in that in each family one sibling had a response to medical therapy while the other required, and was cured by, HSCT. The effectiveness of HSCT is consistent with the observation that monocytes and macrophages are the main source of serum ADA2 and provides further support for the feasibility of ADA2 replacement therapy. In sum, genetic analysis of CECR1 mutations may be warranted in vascular and immune disorders related to polyarteritis nodosa and the other phenotypes observed, and the diagnosis of ADA2 deficiency presents the immediate opportunity for effective treatments. Reeval Segel, M.D.
Dr. Segel and Colleagues Reply: It is very informative to learn of additional clinical presentations caused by mutations altering ADA2 and to consider treatments addressing the underlying loss of ADA2 protein. Sneddon’s syndrome in adults (reported by Bras et al.), and overt immunodeficiency and Castleman-like disease in pediatric patients with ADA2 deficiency (reported by Van Eyck, Liston, and Meyts; van Montfrans et al.; and Van Eyck, Liston, and Wouters) illustrate emerging phenotypes. These reports suggest that ADA2 deficiency may unify syndromes previously thought to be distinct and may also underlie a Shaare Zedek Medical Center Jerusalem, Israel wider range of phenotypes. ADA2 deficiency may be more common than Mary-Claire King, Ph.D. anticipated. Compound heterozygosity for the University of Washington p.Arg169Gln mutation was found in the German Seattle, WA family we reported and by Zhou et al. in two Ephrat Levy-Lahad, M.D. patients, in whom the mutation occurred on the Shaare Zedek Medical Center Jerusalem, Israel same ancestral haplotype. Both Van Eyck, Liston, [email protected] and Meyts and van Montfrans et al. report paSince publication of their article, the authors report no furtients homozygous for this mutation in two ap- ther potential conflict of interest. parently unrelated families from Belgium and 1. NHLBI GO Exome Sequencing Project (ESP) home page the Netherlands. The p.Arg169Gln mutation (http://evs.gs.washington.edu/EVS). (designated as rs77563738 in the human genome DOI: 10.1056/NEJMc1405506
Parasite Burden and Severity of Malaria in Tanzanian Children To the Editor: In their 4-year study of malaria in Tanzanian children, Gonçalves et al. (May 9 issue)1 observed diverging rates of severe disease and markers of parasite biomass after infancy. However, the results contrast with the findings of a study by Hendriksen et al.2 of 3826 African children with parasitemia and severe febrile illness in whom high plasma levels of PfHRP-2, reflecting total parasite biomass, strongly predicted a fatal outcome. Plasma PfHRP-2 level has also been shown to discriminate severe malaria from other severe illnesses accompanied by co
incidental peripheral-blood parasitemia, with accuracy confirmed on autopsy3 or retinal findings.4 These new observations by Gonçalves et al., which were based on a purely clinical case definition of severe malaria, may reflect a higher rate of false positive diagnoses; the authors’ supplementary data indicate many cases of “severe malaria” in which PfHRP-2 levels were well below established thresholds.2,3 The apparent clustering of false positive diagnoses in infants may be caused by confounding biases, such as age-dependent rates of diseases that clinically
n engl j med 371;5 nejm.org july 31, 2014
The New England Journal of Medicine Downloaded from nejm.org at EMORY UNIVERSITY on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
481
The
n e w e ng l a n d j o u r na l
overlap with severe malaria and changing transmission intensity, and this confounding affects the calculation of risk that can be attributed to malaria.5 In our view, these fundamental issues undermine the study’s conclusions; parasite biomass should continue to be considered as the dominant factor mediating severe malaria. Charles J. Woodrow, M.D., Ph.D. Arjen M. Dondorp, M.D., Ph.D. Mahidol–Oxford Tropical Medicine Research Unit Bangkok, Thailand
[email protected] No potential conflict of interest relevant to this letter was reported. 1. Gonçalves BP, Huang CY, Morrison R, et al. Parasite burden
and severity of malaria in Tanzanian children. N Engl J Med 2014;370:1799-808. 2. Hendriksen IC, Mwanga-Amumpaire J, von Seidlein L, et al. Diagnosing severe falciparum malaria in parasitaemic African children: a prospective evaluation of plasma PfHRP2 measurement. PLoS Med 2012;9(8):e1001297. 3. Taylor TE, Fu WJ, Carr RA, et al. Differentiating the pathologies of cerebral malaria by postmortem parasite counts. Nat Med 2004;10:143-5. 4. Seydel KB, Fox LL, Glover SJ, et al. Plasma concentrations of parasite histidine-rich protein 2 distinguish between retinopathypositive and retinopathy-negative cerebral malaria in Malawian children. J Infect Dis 2012;206:309-18. 5. Bejon P, Berkley JA, Mwangi T, et al. Defining childhood severe falciparum malaria for intervention studies. PLoS Med 2007;4(8):e251. DOI: 10.1056/NEJMc1407114
The Authors Reply: Like the study by Hendriksen et al.,1 in which 3826 African children were enrolled during hospitalization for severe malaria, our birth cohort study revealed high PfHRP-2 levels during fatal severe malaria (4619 to 30,169 ng per milliliter), a similar mean level during nonfatal severe malaria (1245 ng per milliliter in our study vs. 1046 ng per milliliter in Hendriksen et al.), and occasionally low or undetectable levels of PfHRP-2 during severe malaria. We also reported higher mean PfHRP-2 levels in children with high-density infections and only mild symptoms than in the same children during severe
of
m e dic i n e
malaria episodes, which suggests that PfHRP-2 level is an indicator of parasite biomass and the duration of infection rather than disease. Mean parasite density and PfHRP-2 level are generally higher during severe malaria, but there is considerable overlap of PfHRP-2 values in severe and uncomplicated cases of malaria,2-4 an observation that has been reported in studies that incorporate retinal findings.5 Severe malaria with very low or undetectable levels of PfHRP-2 has often been reported.2-4 Our findings and earlier observations2,3 suggest that factors in addition to total parasite biomass may contribute to malaria severity, including organ-specific parasite burden, local or systemic immunopathology, and parasite virulence. Our study also shows that immunity to severe malaria develops long before immunity that controls parasite burden. Bronner P. Gonçalves, M.D. Michal Fried, Ph.D. Patrick E. Duffy, M.D. National Institute of Allergy and Infectious Diseases Rockville, MD
[email protected] Since publication of their article, the authors report no further potential conflict of interest. 1. Hendriksen IC, Mwanga-Amumpaire J, von Seidlein L, et al.
Diagnosing severe falciparum malaria in parasitaemic African children: a prospective evaluation of plasma PfHRP2 measurement. PLoS Med 2012;9(8):e1001297. 2. Manning L, Laman M, Stanisic D, et al. Plasma Plasmodium falciparum histidine-rich protein-2 concentrations do not reflect severity of malaria in Papua New Guinean children. Clin Infect Dis 2011;52:440-6. 3. Rubach MP, Mukemba J, Florence S, et al. Plasma Plasmodium falciparum histidine-rich protein-2 concentrations are associated with malaria severity and mortality in Tanzanian children. PLoS One 2012;7(5):e35985. 4. Hendriksen IC, White LJ, Veenemans J, et al. Defining falciparum-malaria-attributable severe febrile illness in moderate-tohigh transmission settings on the basis of plasma PfHRP2 concentration. J Infect Dis 2013;207:351-61. 5. Seydel KB, Fox LL, Glover SJ, et al. Plasma concentrations of parasite histidine-rich protein 2 distinguish between retinopathy-positive and retinopathy-negative cerebral malaria in Malawian children. J Infect Dis 2012;206:309-18. DOI: 10.1056/NEJMc1407114
More on Hepatitis B Virus rtI233V Mutation and Resistance to Adefovir To the Editor: The letter by Geipel et al. (April 24 issue)1 contradicts previous data regarding resistance to adefovir in three patients with hepatitis B virus (HBV) infection with an rtI233V muta482
tion.2,3 Although new assays may be more accurate, in our study, we used an autologous and thus authentic HBV-promoter-based replication system that closely emulates the natural
n engl j med 371;5 nejm.org july 31, 2014
The New England Journal of Medicine Downloaded from nejm.org at EMORY UNIVERSITY on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
