Screening for glucosephosphate dehydrogenase deficiency prior to dapsone therapy.
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SpringerPlus volume 4 , Article number: 29 Cite this article. Metrics details. Dapsone is a commonly used second line drug for prophylaxis of pneumocystis jirovecii pneumonia PJP in immunocompromised patients. Her anemia improved after cessation of therapy with dapsone.
We review the literature of dapsone induced hemolysis in patients who have normal G6PD level and discuss potential pathways leading to hemolytic anemia and its implications for clinical practice.
Pneumocystis jirovecii pneumonia PJP is a common infectious complication in immunocompromised patients including HIV patients and organ transplant recipients. The ANCA associated vasculitides include granulomatosis with polyangiitis, microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis. Although there are no randomized controlled trials, data from case series and observational data from trials support the use of PJP prophylaxis due to high mortality associated with PJP.
Dapsone is a commonly used alternative for prophylaxis of pneumocystis jerovicci pneumonia PJP in immunocompromised patients who are intolerant to trimethoprim and sulfamethoxazole Hughes Oxidant hemolysis caused by its metabolite hydroxylamine is a reported side effect in patients with glucosephosphate dehydrogenase G6PD deficiency and therefore screening for G6PD deficiency is recommended before the drug is started.
Although dapsone induced hemolytic anemia is mostly reported in patients with G6PD deficiency, there are reports of dapsone induced hemolytic anemia in literature regarding transplant recipients who have normal G6PD levels Lee et al. Dapsone is also often used for PJP prophylaxis in patients with AAV who receive immunosuppressive drug therapy to induce remission. We report the first case of dapsone induced hemolytic anemia in a patient with AAV in the setting of a normal G6PD level. We provide a literature review of dapsone induced hemolysis in patients who have normal G6PD level and discuss potential pathways leading to hemolytic anemia in this setting and its implications for patient care.
A 60 year old Caucasian female was diagnosed with ANCA associated vasculitis in October, when she presented acute renal failure with a serum creatinine of 2. She was initially treated with oral cyclophosphamide and prednisone and after one month, her cyclophosphamide was stopped and she was given rituximab for remission induction. Due to her renal insufficiency, she was started on dapsone for pneumocystis jirovecii pneumonia prophylaxis after confirmation of normal glucosephosphate dehydrogenase G6PD activity level by quantitative testing twice.
Her serum creatinine peaked at 3. Her hemoglobin prior to initiation of dapsone was About a month later, her hemoglobin was noted on routine labs to be 7. She had normal iron stores, serum B12 and folate levels. Her haptoglobulin was less than 7. Her dapsone was stopped with improvement in her hemoglobin to 8. We report the first case of dapsone induced hemolysis in the setting of a normal G6PD level in a patient with ANCA associated vasculitis which improved after dapsone was discontinued.
We speculate that the severe renal dysfunction in our patient could have led to high dapsone blood level predisposing to hemolysis despite the presence of normal G6PD activity level. This case highlights the need for close clinical follow up in high risk patients. G6PD deficiency is one of the most common genetic disorders of red blood cells worldwide with an estimated million people carrying a mutation of the gene that causes G6PD deficiency.
The red blood cells depend upon an adequate supply of reduced glutathione which helps to detoxify hydrogen peroxide and other reactive oxygen species. When there is a deficiency of G6PD and red blood cells are exposed to oxidative challenge such as exposure to medications like dapsone, the glutathione stores are rapidly exhausted and as a result reactive oxygen species are not detoxified Beutler et al. This results in attack of sulfhydryl groups in hemoglobin which causes damage to the cell membrane, formation of Heinz bodies, and eventually the destruction of red cells Fischer et al.
Anemia caused by dapsone induced hemolysis can be mild and asymptomatic or severe requiring blood transfusion. We summarize the data from these case series in Table 1. Lee et al. There were 6 male patients and 9 were Caucasian. Hemolysis was defined as a decrease in hemoglobin with presence of at least one laboratory marker of hemolysis and an improvement to baseline hemoglobin after discontinuation of dapsone.
Only six patients had G6PD level checked prior to treatment and all six patients had normal levels. The mean decrease in hemoglobin was 2. Four patients required transfusion of packed red blood cells. The majority of these patients were on tacrolimus based immunosuppression. It was postulated that elevated dapsone blood levels caused by concurrent therapy with tacrolimus due to sharing of the cytochrome P isoenzyme for metabolism by these drugs may have predisposed to hemolysis.
A retrospective review of 43 lung transplant recipients by Naik et al. Nine patients were Caucasian and 7 were females. Mean drop in hemoglobin was 2. Peak serum creatinine ranged from 0. Patients with increased serum creatinine and lower body weight were at higher risk of hemolysis suggesting that dose adjustment for dapsone may be needed in patients with renal insufficiency and lower body weight.
Another retrospective study of 30 recipients with stem cell transplants and normal G6PD level treated with dapsone for PJP prophylaxis identified 26 cases of dapsone induced hemolysis Olteanu et al. In this series, the hemolysis, defined by a peripheral blood smear evidence of bite cells and eccentrocytes, was mild and patients were continued on dapsone with no adverse consequences. The occurrence of hemolysis in patients with normal G6PD level suggest that the hemolysis may be a dose related event as may be seen with elevated dapsone levels in patients with renal dysfunction or due to concurrent use of medications that use the cytochrome P isoenzyme system.
Alternatively, there may be mutations in hexose monophosphate shunt or glutathione metabolism that lead to glutathione depletion and subsequent hemolysis. In patients with renal dysfunction, lower body weight or use of concurrent medications that interact with dapsone, we propose that regular monitoring of hemoglobin should be done after initiation of dapsone even if G6PD level is normal. Beutler E, Robson M, Buttenwieser E The mechanism of glutathione destruction and protection in drug-sensitive and non-sensitive erythrocytes; in vitro studies.
J Clin Invest 36 4 — Article Google Scholar. Br J Haematol 59 1 — Arthritis Rheum 40 12 — Hughes WT Use of dapsone in the prevention and treatment of Pneumocystis carinii pneumonia: a review. Clin Infect Dis 27 1 — Am J Transplant 5 11 — Br J Haematol 4 — Blood Rev 21 5 — Ann Rheum Dis 68 3 — J Heart Lung Transplant 27 11 — Google Scholar.
Bone Marrow Transplant 47 3 — Arthritis Rheum 43 5 — Download references. You can also search for this author in PubMed Google Scholar. Correspondence to Duvuru Geetha. SML: participated in collection of clinical information from the case patient, review of literature and writing of manuscript.
DG: participated in providing clinical care for the case patient, review of literature and writing of manuscript. Both authors read and approved the final manuscript. Reprints and Permissions. Lee, S. Dapsone induced hemolysis in a patient with ANCA associated glomerulonephritis and normal G6PD level and implications for clinical practice: case report and review of the literature.
SpringerPlus 4 , 29 Download citation. Received : 25 December Accepted : 14 January Published : 23 January Anyone you share the following link with will be able to read this content:.
Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search all SpringerOpen articles Search. Download PDF. Abstract Dapsone is a commonly used second line drug for prophylaxis of pneumocystis jirovecii pneumonia PJP in immunocompromised patients. Introduction Pneumocystis jirovecii pneumonia PJP is a common infectious complication in immunocompromised patients including HIV patients and organ transplant recipients.
Case report A 60 year old Caucasian female was diagnosed with ANCA associated vasculitis in October, when she presented acute renal failure with a serum creatinine of 2. Discussion We report the first case of dapsone induced hemolysis in the setting of a normal G6PD level in a patient with ANCA associated vasculitis which improved after dapsone was discontinued. Table 1 Summary of studies of dapsone induced hemolytic anemia with normal G6PD activity Full size table.
Conclusion In patients with renal dysfunction, lower body weight or use of concurrent medications that interact with dapsone, we propose that regular monitoring of hemoglobin should be done after initiation of dapsone even if G6PD level is normal.
References Beutler E, Robson M, Buttenwieser E The mechanism of glutathione destruction and protection in drug-sensitive and non-sensitive erythrocytes; in vitro studies. View author publications. Additional information Competing interests Duvuru Geetha: served as consultant to Genentech. Scott M Lee: none. About this article. Cite this article Lee, S. Copy to clipboard.
❾-50%}G6pd test and dapsone. Screening for glucose-6-phosphate dehydrogenase deficiency prior to dapsone therapy
Almost all of the G6PD-deficient children who received dapsone showed evidence of hemolysis, with a marked decrease in hemoglobin Figure 1 , Figure 3. Whereas before treatment the erythrocyte morphology often was normal, except for the presence of P falciparum Figure 4 A , morphologic changes in the erythrocytes consistent with oxidative damage could be seen clearly in these G6PD-deficient children from day 1 approximately 24 hours after the first dapsone dose , at a time when malaria parasites were still visible Figure 4 B.
By day 3, the morphologic evidence of oxidative damage was prominent Figure 4 C. Variability in hemoglobin levels in individual patients. Blood smears from a 3-year-old boy with acute malaria and G6PD deficiency treated with chlorproguanil-dapsone. A Pretreatment: black arrows point to erythrocytes parasitized by P falciparum ring forms , the white arrow points to an erythrocyte containing 2 rings of P falciparum. B Approximately 24 hours after starting treatment day 1 : on the left abnormally shaped parasites are seen within spherocytes, on the right a parasite in a severely contracted erythrocyte.
Inset: another hemighost at a greater magnification; the part of the erythrocyte that appears to be missing is the negative image of a Heinz body.
An Orthoplan light microscope was used Leitz. In most G6PD-deficient children receiving dapsone, there was a gradual recovery of hemoglobin, which returned to the original level between days 28 and this was heralded by a highly significant increase in reticulocytes, peaking at day 7 Figure 2 B.
A substantial fraction of hemolysis in G6PD-deficient subjects exposed to an oxidative agent is extravascular 27 and therefore reflected in hyperbilirubinemia Figure 2 D. Statistical analysis of all of these findings is presented in Table 2. Unfortunately, we do not have complete records of hemoglobinuria, a reliable index of intravascular hemolysis.
The average lowest hemoglobin concentration across the observation period was 7. All of these parameters were significantly different from the AL group; statistical data are presented in Table 3.
Changes in clinically important hematologic and clinical chemistry parameters in G6PD-deficient malaria patients after receiving dapsone.
The control group received artemether-lumefantrine. Changes from pretreatment were defined as maximum decrease or minimum increase for hemoglobin and hematocrit and as maximum increase or minimum decrease for other parameters. Difference between treatment groups adjusted for sex, center, age, weight, pretreatment hemoglobin, and G6PD status. In 13 of One heterozygous female and 2 G6PD-normal male patients also required a blood transfusion.
In 2 of the 95 G6PD-deficient hemizygous boys who received dapsone, there was no decrease in hemoglobin. The other was a 3-year-old hemizygous boy who had a pretreatment hemoglobin level of 7. The maximum decrease in hemoglobin for heterozygotes was intermediate between that of G6PD-normal and G6PD-deficient patients Figure 5. However, in some of the heterozygotes, the hemolytic attack was as severe as in some of the homozygous females Figure 6.
The G6PD genotype was a major determinant of the severity of anemia in children given dapsone. The cumulative frequency of the maximum decrease in hemoglobin concentration versus pretreatment levels in G6PD-normal children given dapsone was similar to that of the control group; in G6PD-deficient children it is much greater, and in girls heterozygous for G6PD deficiency it is intermediate.
Illustrative examples of the hematologic impact of dapsone in individual patients with falciparum malaria. These 4 girls were all from the same site Ouagadougou, Burkina Faso.
It is seen that one of the heterozygotes behaved almost exactly like a G6PD-normal child, whereas the other behaved almost exactly like a homozygous G6PD-deficient child. Methemoglobinemia is known to occur with dapsone; indeed, we found that in the children who received dapsone, the mean highest posttreatment level was 5.
Dapsone regularly causes hemolysis in G6PD-deficient children with malaria. Morphologic changes in the erythrocytes of these children were visible as early as 24 hours after the start of therapy, and the consequent hemolysis resulted in a hemoglobin nadir recorded at day 7, with eventual recovery in most children by day Although from different parts of Africa, the G6PD-deficient boys and girls included in this analysis constitute a rather homogenous group because they all presented with acute P falciparum malaria and received the same dose of dapsone 2.
The hemolysis was associated with hyperbilirubinemia, and it was regularly followed by a significant reticulocyte response Figure 2. To the best of our knowledge, the time course of these hematologic changes has never been previously reported for such a large series of G6PD-deficient patients with drug-induced AHA. Leukocytosis—with a predominance of granulocytes—may occur in favism, 28 and here we confirm that it also occurs in drug-induced AHA. Although urinalysis was not performed routinely, dark urine was noted, particularly in the children who required blood transfusion.
Dapsone-induced hemolysis had previously been studied experimentally in G6PD-deficient healthy adult male volunteers. Several factors can influence the severity of a drug-induced hemolytic attack in a G6PD-deficient subject, including the pharmacology of the drug, the dose, the G6PD mutation, the age, and coexisting disease conditions. If we take into account the differences between the current report and the volunteer studies, particularly with respect to age, the findings are remarkably similar.
First, in the volunteer studies, drug sensitivity decreased with continued drug challenge because of a gradual increase in the proportion of young erythrocytes, which have greater G6PD activity than aging cells. The other, more important difference is that the serious hemolytic effect of dapsone was made more dangerous and sometimes life-threatening in these children because they had malaria, and particularly malarial anemia; at study start 93 of Of G6PD-deficient children, 26 At the other end of the scale, 24 of Such a great variation may appear at first surprising.
We did not measure G6PD enzyme activity in this study, but it is possible that in some patients, previous anemia associated with either malnutrition or malaria or both could generate a young erythrocyte population relatively resistant to the oxidative effect of dapsone. Rat studies have shown that the hemolytic activity of dapsone resides in its N-hydroxy metabolites; exposure of rat red cells to N-hydroxy-dapsone in vitro followed by readministration to isologous rats results in premature splenic sequestration of the damaged cells.
This study examines the ability of the steroid, epiandrosterone, to inhibit rat red cell G6PD and the effect of such inhibition on the susceptibility of rat red cells to N-hydroxydapsone hemolytic activity. Select Format Select format. Permissions Icon Permissions. Summary Dapsone is widely used in dermatological practice. Issue Section:. You do not currently have access to this article. Download all slides. Sign in Get help with access. Get help with access Institutional access Access to content on Oxford Academic is often provided through institutional subscriptions and purchases.
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When on the institution site, please use the credentials provided by your institution. Do not use an Oxford Academic personal account. Following successful sign in, you will be returned to Oxford Academic. Lee et al. There were 6 male patients and 9 were Caucasian. Hemolysis was defined as a decrease in hemoglobin with presence of at least one laboratory marker of hemolysis and an improvement to baseline hemoglobin after discontinuation of dapsone.
Only six patients had G6PD level checked prior to treatment and all six patients had normal levels. The mean decrease in hemoglobin was 2. Four patients required transfusion of packed red blood cells. The majority of these patients were on tacrolimus based immunosuppression. It was postulated that elevated dapsone blood levels caused by concurrent therapy with tacrolimus due to sharing of the cytochrome P isoenzyme for metabolism by these drugs may have predisposed to hemolysis.
A retrospective review of 43 lung transplant recipients by Naik et al. Nine patients were Caucasian and 7 were females. Mean drop in hemoglobin was 2. Peak serum creatinine ranged from 0. Patients with increased serum creatinine and lower body weight were at higher risk of hemolysis suggesting that dose adjustment for dapsone may be needed in patients with renal insufficiency and lower body weight.
Another retrospective study of 30 recipients with stem cell transplants and normal G6PD level treated with dapsone for PJP prophylaxis identified 26 cases of dapsone induced hemolysis Olteanu et al. In this series, the hemolysis, defined by a peripheral blood smear evidence of bite cells and eccentrocytes, was mild and patients were continued on dapsone with no adverse consequences. The occurrence of hemolysis in patients with normal G6PD level suggest that the hemolysis may be a dose related event as may be seen with elevated dapsone levels in patients with renal dysfunction or due to concurrent use of medications that use the cytochrome P isoenzyme system.
Alternatively, there may be mutations in hexose monophosphate shunt or glutathione metabolism that lead to glutathione depletion and subsequent hemolysis.
In patients with renal dysfunction, lower body weight or use of concurrent medications that interact with dapsone, we propose that regular monitoring of hemoglobin should be done after initiation of dapsone even if G6PD level is normal. Beutler E, Robson M, Buttenwieser E The mechanism of glutathione destruction and protection in drug-sensitive and non-sensitive erythrocytes; in vitro studies.
Background: Administration of dapsone in glucosephosphate dehydrogenase G6PD deficient patients can lead to hemolysis which may be severe enough to warrant discontinuation of the drug. Screening for G6PD deficiency in leprosy patients before initiating treatment can prevent such adverse events. Methods: Medical records of all leprosy patients presenting between 1st January to 30th June were reviewed. G6PD levels, if done, were recorded for all patients needing dapsone therapy.
Results: Of the 62 patients requiring treatment with dapsone 43 outpatients and 19 inpatients , G6PD estimation was done in 43 cases, i.
Background: Administration of dapsone in glucosephosphate dehydrogenase G6PD deficient patients can lead to hemolysis which may be severe enough to warrant discontinuation of the drug. Screening for G6PD deficiency in leprosy patients before initiating treatment can prevent such adverse events.
Methods: Medical records of all leprosy patients presenting between 1st January to 30th June were reviewed. G6PD levels, if done, were recorded for all patients needing dapsone therapy. Results: Of the 62 patients requiring treatment with dapsone 43 outpatients and 19 inpatientsG6PD estimation was done in 43 cases, i. Conclusions: G6PD levels were not uniformly estimated in all patients requiring dapsone therapy. It was done more commonly estimated in inpatients Dapsone: unapproved uses or indications.
Clin Dermatol. Hemolytic anemia in patients receiving daily dapsone for the treatment of leprosy. Lepr Rev. Screening for glucosephosphate dehydrogenase deficiency prior to dapsone therapy. Clin Exp Dermatol. G6PD deficiency in females screened at tertiary care hospital. Indian J Pathol Microbiol. Tripathy V, Reddy BM. Present status of understanding on the G6PD deficiency and natural selection. J Postgrad Med.
Study of erythrocyte G6PD deficiency in leprosy. Glucosephosphate dehydrogenase deficiency at Nagpur and in surrounding areas: a survey. Indian Med Gaz. User Username Password Remember me. Font Size. Notifications View Subscribe.
Study on estimation of glucosephosphate dehydrogenase in patients prior to initiation of dapsone therapy in leprosy. Abstract Background: Administration of dapsone in glucosephosphate dehydrogenase G6PD deficient patients can lead to hemolysis which may be severe enough to warrant discontinuation of the drug.
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Dapsone is widely used in dermatological practice. commencing dapsone therapy, despite a normal glucosephosphate dehydrogenase (G6PD) screening test. Profound hemolytic anemia developed in three glucose 6-phosphate dehydrogenase (G6PD)-deficient males while they were receiving 25 mg of dapsone. Glucose 6-phosphate dehydrogenase (G6PD) deficiency is common in Extensive use of dapsone in leprosy was generally at low doses and. The safety risks of dapsone were outlined at a World Health Organization (WHO) Technical Consultation; G6PD testing was recommended before treatment and a. Dapsone is widely used in dermatological practice. commencing dapsone therapy, despite a normal glucosephosphate dehydrogenase (G6PD) screening test. This Site. The large dataset also allows statistical analyses that were not possible within the individual studies. Methemoglobinemia is known to occur with dapsone; indeed, we found that in the children who received dapsone, the mean highest posttreatment level was 5. We report the first case of dapsone induced hemolysis in the setting of a normal G6PD level in a patient with ANCA associated vasculitis which improved after dapsone was discontinued.Allan Pamba, Naomi D. Tiono, Lucio Luzzatto; Clinical spectrum and severity of hemolytic anemia in glucose 6-phosphate dehydrogenase—deficient children receiving dapsone. Blood ; 20 : — Drug-induced acute hemolytic anemia led to the discovery of G6PD deficiency. However, most clinical data are from isolated case reports.
All children eventually recovered. Glucose 6-phosphate dehydrogenase G6PD deficiency is common in populations that have been exposed to malaria, either in the present or in the past. Malaria has been a powerful selective force in endemic areas for several thousands of years.
Thus, it is perhaps not surprising that an estimated million people worldwide are G6PD deficient. G6PD catalyzes the first step in the pentose phosphate pathway, oxidizing glucose 6-phosphate to 6-phosphogluconolactone, coupled to the reduction of nicotinamide adenine dinucleotide phosphate NADP to NADPH. In the erythrocyte, a cell with limited metabolic resources, this is the rate-limiting step in the production of NADPH, a key redox metabolite.
However, G6PD-deficient erythrocytes are uniquely sensitive to any extra oxidative stress: this will cause cellular damage and premature destruction of erythrocytes through both intravascular and extravascular hemolysis. The best characterized exogenous triggers of hemolysis in G6PD-deficient subjects are, apart from infection, fava beans and drugs.
By the year , the spread of chloroquine-resistant Plasmodium falciparum had made the malaria situation even worse than before in many African countries. A greater number of hematologic adverse events occurred in the dapsone-containing arm versus the comparator. In consideration of these issues, the protocol for 2 large phase 3 trials of the triple combination chlorproguanil-dapsone-artesunate CDA required G6PD genotyping of all patients and frequent blood monitoring.
This picture was clearly not the whole one because some heterozygous female patients had severe hemolysis. This series is the largest ever reported of the hematologic impact of any drug on G6PD-deficient subjects.
Most studies of drug-induced AHA are retrospective in the sense that investigations were initiated only after the patient had become ill. In contrast, this report is compiled from data collected prospectively in which a standard protocol was used. This allows us to examine the onset and time course and the full spectrum of hematologic effects of dapsone-induced AHA.
The large dataset also allows statistical analyses that were not possible within the individual studies. The analysis of the G6PD heterozygous females who received dapsone is unique in terms of pharmacogenetics because these individuals cannot be reliably identified by routine G6PD deficiency testing, only by appropriate genotyping. Data were obtained from 2 multicenter, randomized, double-blind, clinical trials of CDA in acute P falciparum malaria.
Details of the conduct of the 2 studies are included in 2 previous articles. Investigators were blind to drug treatment and G6PD genotype and phenotype. Both clinical trials were conducted according to Good Clinical Practices, applicable regulatory requirements, and the Declaration of Helsinki.
Ethical approval was obtained from the participating center's ethics committee or institutional review board and the WHO Special Program for Research and Training in Tropical Diseases.
Parents or guardians of all patients provided written or oral witnessed informed consent; when patients were 12 years or older, their own assent was required as well. Exclusion criteria are detailed in the previously published articles. During screening, a full medical history was obtained and a clinical examination performed. Asexual parasite counts were determined via the use of WHO methods. In study , treatment was ambulatory from days 0 to 3; patients were subsequently visited at home from days 4 to 6 for early detection of clinical abnormalities.
Follow-up was until day 42 in study and day 28 in study Venous blood samples 2 mL for hematology evaluations were taken at pretreatment day 0 ; days 1, 2, 3, 7, 14, and 28 in both studies; and at day 42 in study Clinical chemistry assessments were made in study at pretreatment day 0 ; days 3, 7, and 42 plus days 14 and 28 if previous results were abnormal; and in study at pretreatment, days 3, 7, and 28 plus day 14 if previous results were abnormal.
The analytical methods have been reported previously. Data for patients who received dapsone within the CDA or chlorproguanil-dapsone combination were pooled referred to henceforth as the dapsone group and compared with results from the AL treatment arm. Patient pretreatment data were reported by the use of descriptive statistics.
All statistical analyses were performed posthoc. Differences between populations were compared with ANOVA, where adjustments were made for sex, center, age, weight, pretreatment hemoglobin, and G6PD status and in the case of the dapsone group also for study or Of patients with acute uncomplicated malaria, were male and female Table 1.
Of the males, Among females, Dapsone was received by G6PD-deficient children 95 were hemizygotes and 24 homozygotes as well as by heterozygotes. At the time they entered the study, most subjects were moderately anemic, probably resulting, at least in part, from their acute malaria Table 1.
Other pretreatment parameters were within normal limits, except for an elevated serum bilirubin, which commonly is observed in patients with acute malaria. There were no important differences in the pretreatment parameters of the dapsone group compared with the AL group data not shown.
From day 2 onward, hemoglobin levels stabilized and then increased in the majority of patients Figure 1. In principle, we can think of 2 not mutually exclusive explanations for this transient decrease in hemoglobin: 1 continuing hemolysis from malaria before parasitemia was cleared; 2 hemodilution as a result of adequate hydration being restored during clinical support of the patient. In corroboration of 1 , we know it takes up to 48 hours to clear parasitemia 22 ; in support of 2 , other analytes, such as unconjugated bilirubin, also decreased from day 1 to day 2 Figure 2 D.
None of the children required blood transfusion. Thus, we confirm that there is no evidence of AHA with AL and in this respect, the children who received AL can be regarded as a control group.
Change in hemoglobin concentrations relative to values obtained at day 1 in children receiving a dapsone-containing combination or AL for the treatment of falciparum malaria. For changes from pretreatment day 0 values, see supplemental Figure 1. Adjusted mean difference between G6PD genotypes in the maximum change from pretreatment values for clinically important laboratory parameters in malaria patients receiving dapsone or AL.
In this analysis, each treatment group was compared separately. For hemoglobin and hematocrit, the adjusted mean change is for the maximum decrease or minimum increase vs pretreatment values. For all other parameters it is the maximum increase or minimum decrease vs pretreatment. Analysis of variance model included terms for sex, center, age, weight, pretreatment hemoglobin, and G6PD status. For dapsone subjects, a term was also fitted for study trial or Hemolytic anemia in G6PD-deficient children with malaria receiving therapy with a dapsone-containing combination.
The 4 panels report the following clinically important parameters: A hematocrit; B reticulocytes; C white blood cell count; and D unconjugated bilirubin. Similar panels for other laboratory parameters are in supplemental Figures 1 and 2. With respect to platelets, there was an unexplained greater increase in platelet counts in heterozygotes than in G6PD-normal or G6PD-deficient patients Table 2.
On the other hand, on treatment of malaria, there was no statistically significant difference in platelets between G6PD-deficient and G6PD-normal patients Almost all of the G6PD-deficient children who received dapsone showed evidence of hemolysis, with a marked decrease in hemoglobin Figure 1 , Figure 3.
Whereas before treatment the erythrocyte morphology often was normal, except for the presence of P falciparum Figure 4 A , morphologic changes in the erythrocytes consistent with oxidative damage could be seen clearly in these G6PD-deficient children from day 1 approximately 24 hours after the first dapsone dose , at a time when malaria parasites were still visible Figure 4 B.
By day 3, the morphologic evidence of oxidative damage was prominent Figure 4 C. Variability in hemoglobin levels in individual patients. Blood smears from a 3-year-old boy with acute malaria and G6PD deficiency treated with chlorproguanil-dapsone.
A Pretreatment: black arrows point to erythrocytes parasitized by P falciparum ring forms , the white arrow points to an erythrocyte containing 2 rings of P falciparum. B Approximately 24 hours after starting treatment day 1 : on the left abnormally shaped parasites are seen within spherocytes, on the right a parasite in a severely contracted erythrocyte. Inset: another hemighost at a greater magnification; the part of the erythrocyte that appears to be missing is the negative image of a Heinz body.
An Orthoplan light microscope was used Leitz. In most G6PD-deficient children receiving dapsone, there was a gradual recovery of hemoglobin, which returned to the original level between days 28 and this was heralded by a highly significant increase in reticulocytes, peaking at day 7 Figure 2 B. A substantial fraction of hemolysis in G6PD-deficient subjects exposed to an oxidative agent is extravascular 27 and therefore reflected in hyperbilirubinemia Figure 2 D.
Statistical analysis of all of these findings is presented in Table 2. Unfortunately, we do not have complete records of hemoglobinuria, a reliable index of intravascular hemolysis. The average lowest hemoglobin concentration across the observation period was 7. All of these parameters were significantly different from the AL group; statistical data are presented in Table 3.
Changes in clinically important hematologic and clinical chemistry parameters in G6PD-deficient malaria patients after receiving dapsone. The control group received artemether-lumefantrine. Changes from pretreatment were defined as maximum decrease or minimum increase for hemoglobin and hematocrit and as maximum increase or minimum decrease for other parameters. Difference between treatment groups adjusted for sex, center, age, weight, pretreatment hemoglobin, and G6PD status.
In 13 of One heterozygous female and 2 G6PD-normal male patients also required a blood transfusion. In 2 of the 95 G6PD-deficient hemizygous boys who received dapsone, there was no decrease in hemoglobin. The other was a 3-year-old hemizygous boy who had a pretreatment hemoglobin level of 7. The maximum decrease in hemoglobin for heterozygotes was intermediate between that of G6PD-normal and G6PD-deficient patients Figure 5.
However, in some of the heterozygotes, the hemolytic attack was as severe as in some of the homozygous females Figure 6. The G6PD genotype was a major determinant of the severity of anemia in children given dapsone. The cumulative frequency of the maximum decrease in hemoglobin concentration versus pretreatment levels in G6PD-normal children given dapsone was similar to that of the control group; in G6PD-deficient children it is much greater, and in girls heterozygous for G6PD deficiency it is intermediate.
Illustrative examples of the hematologic impact of dapsone in individual patients with falciparum malaria. These 4 girls were all from the same site Ouagadougou, Burkina Faso. It is seen that one of the heterozygotes behaved almost exactly like a G6PD-normal child, whereas the other behaved almost exactly like a homozygous G6PD-deficient child. Methemoglobinemia is known to occur with dapsone; indeed, we found that in the children who received dapsone, the mean highest posttreatment level was 5.
Dapsone regularly causes hemolysis in G6PD-deficient children with malaria. Morphologic changes in the erythrocytes of these children were visible as early as 24 hours after the start of therapy, and the consequent hemolysis resulted in a hemoglobin nadir recorded at day 7, with eventual recovery in most children by day
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