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Prospective study of sickle cell anemia in infancy
August 1976
TheJournalofPEDIATRICS
205
Prospective study of sickle cell anemia in infancy Twelve infants with sickle cell anemia identified in the course of a cord blood screening program have been followed Wospectively for up to three years o f age. The development of hemolytic anemia paralleled the postnatal decline in fetal hemoglobin and was evident in all infants by 12 weeks of age. Vasoocclusive episodes occurred in more than half the infants and seven aplastic crises were documented in four patients. Febrile illnesses were common and one o f the twelve infants developed pneumococcal sepsis. This study also demonstrated that functional asplenia is an acquired defect in sickle cell disease. The onset of functional asplenia was documented with splenic scans in six of the nine infants followed for more than one year after birth. There have been no deaths in this series.
Richard T. O'Brien, M.D.,* Sue MeIntosh, M.D., Gregg T. Aspnes, M.D., and Howard A. P e a r s o n , M . D . , N e w H a v e n , C o n n .
F o L L O W I N G the initial description of sickle cell anemia by Herfick 1 in 1910, a massive collection of clinical and scientific data concerning the disease has accumulated in the literature. Despite this voluminous record, there is a paucity of prospective studies of the disease, particularly during infancy and early childhood.-' We have identified 12 newborn infants with sickle cell anemia in the course of an umbilical cord blood screening program for major sickle hemoglobinopathies, and we have followed these infants serially for up to three years. The purpose of this paper is to report on the hematologic, clinical, and splenic changes in sickle cell disease during the first years of life. The screening program has also provided unexplained data on an ungxpectedly high occurrence of the disease at birth. PATIENTS
A N D METHODS
For the past three years (June, 1972-June, 1975) we have conducted a screening program of,umbilical cord blood of all black infants born at the two hospitals in New Haven, Connecticut, Yale-New Haven Hospital and the Hospital of St. Raphael? The purpose of this study was to From the Department of Pediatrics, Yale University School of Medicine. Supported by Contract NO1-HB-2-2950, NHLL NIH, and Grant RR-00125, GCRC Branch, DRR, NIH. *ReDrint address: Department of Pediatrics, 333 Cedar St., New Haven, Conn. 06510.
detect major sickle hemoglobinopathies as early as possible in an effort to prevent high morbidity and mortality rates in the first few years of life. Blood from infants born of mothers identified as "black" on their hospital admission card was screened. The cord blood specimen obtained routinely at both hospitals for serology and Coombs testing was utilized. Only in cases when the delivery was precipitous were cord blood specimens not obtained; in these instances a specimen of capillary blood was obtained during hospitalization. Blood was subjected to agar gel hemoglobin electrophoresis at pH 6.2. 4 With this technique hemoglobin F migrates rapidly permitting clea r recognition of hemoglobins A, S, and C. In addition, hemoglobin electrophoresis at alkaline pH on cellulose acetate was also performed? In over 2,700 specimens of cord blood, 18 infants have been identified who have majo r hemoglobinopathies: 12 sickle cell anemia, two sickle fl-thalassemia, three hemoglobin SC disease, and one hemoglobin C disease. The results of the screening program are shown on Table I. Family studies were used to differentiate the infants with sickle/?-thalassemia from those wih sickle cell anemia. Laboratory results of those infants identified as having sickle cell trait or hemoglobin C trait were sent to the patients' physician and the medical record. The infants with major hemoglo~inopathies have been followed at approximately six-week intervals with serial hematologic determinations including complete blood counts, peripheral smears for red blood cell morphology
Vol. 89, No. 2, pp. 205-210
206
O'Brien et aL
The Journal of Pediatrics August 1976
tO0 I
[]NORMAL [ ] SICKLE CELL DISEASE
80 [iii~iiiii:i:.
2o iiiiii~.
18
LI-
iii
[ ] NORMAL [ ] SICKLE CELL DISEASE
60
Z
m o .J
E
c9
40
o Z m 0 .J (.9 0 :E
i..d ,.1-
bJ 14
20
12
0
10
20
30
40
50
60
AGE (weeks)
Fig. 2. Change in percentage of hemoglobin F with age in sickle cell anemia.
0
I0
20
30
40
50
60
Table I. Cord blood screening program: Yale-New Haven Hospital and Hospital of St. Raphael (June, 1972-June, 1975)
AGE (weeks)
1. Change in hemoglobin concentration with age in sickle cell anemia. Fig.
and presence of Howell-Jolly bodies, reticulocyte counts, quantitation of the percentage of hemoglobin F by the alkali denaturation method)' and quantitative sickle cell preparations. Nine of the 12 infants with sickle cell anemia and one infant with sickle /3-thalassemia have been followed for more than one year. Liver-spleen scans were performed using 10/~Ci/kg of "~mTC-sulfur colloid and a gamma camera.
HGB pattern
FA FAS FAC FS FS FC FSC FA-fast
No.
%
New%Haven in children TM
2,361 227 78 12 2
85.4 8.2 2.8 0.4 <0.1
89.3 6.8 2.6 --
Diagnosis
Normal Sickle cell trait Hgb C trait Sickle cell anemia Sickle betathalassemia Hgb C disease Hgb SC disease Alpha-thalassemia Total
--
1
<0.1
--
3
<0.1 2.9
---
81 2,765
RESULTS Hematologic. Evidence for a hemolytic process as indicated by reticulocytosis was not present in any of the infants at 6 weeks of age, and none of the infants was significantly anemic at that time. Definite evidence of hemolysis, however, was seen in all infants by 12 weeks of -age. Fig. 1 shows the changes in hemoglobin concentration with age of the infants with sickle cell anemia who have been followed for more than one year. The hemoglobin concentration fell rapidly during the first three months of life and then declined more slowly, stabilizing at 7 to 10 gm/dl by 10months of age. There was marked individual variation both in the rate of fall as well as in the final hemoglobin concentration achieved. The infants with sickle/?-thalassemia developed hemolytic anemia in distinguishable from those infants with sickle cell disease.
The postnatal decline in fetal hemoglobin, as depicted in Fig. 2, was slower than normal, but there was considerable variability. There was h correlation between the rate rate of fall of fetal hemoglobin and the development and severity of hemolysis. Those infants who developed the more severe degrees of anemia had the most rapid fall in fetal hemoglobin. The two infants with sickle /?-thalassemia had a slower decline in fetal hemoglobin than any of the infants with sickle cell anemia; at 15 months of age, one of these infants had 27% hemoglobin F and no hemoglobin A. The other infant with sickle/?-thalassemia had no detectable hemoglobin )k at birth and at one month of age, but by five months had developed 10% hemoglobin A. Clinical. Symptomatology compatible with vasoocclu-
Volume 89 Number 2
Sickle cell anemia in infancy
20 7
KC BR KC CB Or)
DS
I- AK Z
LU TJ I.-
,,~ GR 0_
MB DP LS FM KF I
0
I
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AGE (months)
Fig. 3. Time of onset of functional asplenia. Asterisk (*) indicates documentation of functional asplenia with splenic scan. Length of line indicates duration of observation for each patient. Patient D. S. had functional asplenia at 5 months of age when she was first seen. All other patients had normal spleen scans prior to 6 months of age. sive crises ~ has occurred in at least 17 occasions in 7 of the 12 infants with sickle cell disease. Four of these patients had vasoocclusive crises prior to one year o f age. Classic hand-foot syndrome was observed as early as five months of age. There seemed to be no correlation between the severity of the hemolytic anemia and the occurrence of vasoocclusive episodes. Vasoocclnsive crises were not recognized among the infants with other major sickle hemoglobinopathies. Aplastic crises (reticulocytopenia and falling hemoglobin concentration) were detected on seven occasions among 4 of the 12 patients with sickle cell anemia. Most, however, were mild with decreases in hemoglobin o f only 2 to 3 g m / d l and resolved spontaneously. One infant required a transfusion of packed red blood cells. All of the aplastic episodes were associated w i t h a febrile illness. Aplastic crises were not recognized among infants with other major sickle hemoglobinopathies. Splenic sequestration crises were no t observed a m o n g any of the 12 infants with sickle cell anemia. Sequestration episodes were noted in an infant with sickle /?-thalassemia at 23 months of age and at 6 months of age in an infant born elsewhere but identified as having sickle cell anemia at 5 months of age at this institution. Each of these infants required blood transfusion. Splenomegaly was noted in all infants with sickle cell anemia sometime after 6 months of age. The degree of splenomegaly (measured as centimeters below the left costal margin) varied greatly from patient to patient and also with time in the individual patient. Unusual hepatomegaly was not noted.
Infections and fever. Febrile episodes (temperature > 102~ were recorded on 35 occasions in 10 of the 12 patients with sickle cell anemia. A likely cause for the fever (otitis media, viral exanthem, gastroententis, pneumonia) was usually found. All infants with febrile episodes were treated with antibiotics regardless of associated findings; blood cultures were obtained prior to beginning antibiotic therapy. One episode of pneumococcal sepsis occurred in an l l - m o n t h - o l d infant two weeks after functional asplenia had been documented. She was treated with antibiotics and recovered. The infant with hemoglobin C disease developed salmonella septicemia and was successfully treated with antibiotics. There have been no deaths among these infants~ Splenic function. ~"'~Tc-sulfur colloid scans showed normal splenic uptake in all infants prior to 6 months of age. The onset of functional asplenia, defined as loss of splenic reticuloendothelial activity of the palpably enlarged organ, '~ was documented with serial scans in six of the nine infants followed for more than one year since birth (Fig. 3). Functional asplenia was not present at birth but rather is an acquired defect in sickle cell disease (Fig. 4). In one infant, serial scans demonstrated a progressive decrease in splenic uptake of the radiocolloid (Fig. 5). The onset of functional asplenia was correlated with a decrease in fetal hemoglobin levels below 20%. Three of the nine infants with sickle cell anemia who have been followed for more than one yea} retain normal splenic reticuloendothelial function at 1~, 20, and 29 months of age, respectively. Howell-Jolly bodies, or red blood cell inculsions, were not noted before functional asplenia was
2 08
O'Brien et al.
The Journal of Pediatrics August 1976
Fig. 4. The development of functional asplenia documented by serial spleen scans. Top scan at -5 months of age shows normal splenic uptake. Bottom scan at 7 months of age shows no splenic uptake.
documented by scanning techniques. None of the infants with other major sickle hemoglobinopathies has shown evidence of splenic dysfunction. DISCUSSION Since sickle cell hemoglobin is inherited in an autosomal recessive manner, the relative frequencies of the three possible genotypes (AA, AS, and SS) in a population are expressed by the Hardy-Weinberg equation. Based on a prevalence rate of 8% for heterozygous persons (sickle cell trait) among black Americans, the disease has been estimated to occur in o n e i n 500 black newborn infants in the United StatesY In our screening program of all black infants born in New Haven, we have detected 12 newborn infants with sickle cell anemia among 2,765 individuals tested, or a frequency of approximately 1 in 250 (Table I). The difference between the observed and predicted frequencies is statistically significant (P = <0.001). The reason for this apparent increase in incidence is unclear. We have no evidence to suggest a selection for sickle
Fig. 5. Serial spleen scans demonstrating progressive decline in splenic uptake of the radiocolioid. hemoglobin among women delivering at our hospital. All births in New Haven occur at the Yale-New Haven Hospital or Hospital of St. Raphael, the only hospitals in the city. The obstetrical services have not received consultations for hemoglobinopathies from outside the area during the period of the study. In addition, sickle cell trait was observed in 8.2% of black newborn infants, a prevalence similar to that observed amoflg older children from the same communityY' We have attempted to examine any possible biases in our population or program which would lead to.increases in the prevalence of the disease
Volume 89 Number 2
and find none. The explanation for this difference eludes us at this time. Clearly more studies are necessary. Family studies documenting sickle cell trait in both parents of the infants with sickle cell disease could not be performed in all cases, and the possibility that some of these infants have sickle /?-thalassemia could not be unequivocally excluded. All of the mothers had sickle cell trait. This prospective study does illustrate the variability in the development of the hematologic and clinical manifestations of sickle cell disease during the first years of life. T h e development of hemolytic anemia paralleled the postnatal decline in fetal hemoglobin and was evident in all infants by 12 weeks of age, although there was marked individual variation in the final degree of compensation for the hemolysis. Vasoocclusive crises occurred as early as 5 months of age and were observed in more than half the infants followed for over a year. These episodes were generally brief and required minimal symptomatic treatment. Aplastic crises were detected more frequently than anticipated and were invariably associated with febrile illness. Febrile episodes were relatively common and usually associated with a probable cause. One of the 12 infants with sickle cell anemia developed pneumococcal sepsis. Prompt institution of antibiotic therapy early in the course of febrile episodes may have prevented other episodes of septicemia. There have been no deaths in this series. We have previously described a state of functional asplenia-a deficit in splenic reticuloendothelial function of anatomically enlarged spleens of young children with sickle cell anemiaY This prospective study demonstrates that functional asplenia is an acquired defect in sickle cell disease with an onset as early as five months of age. The mean age of death in sickle cell disease is during childhood with approximately 30% of the deaths occurring before five years of age1:; the majority are due to infection.1: Overwhelming infection with ~the pneumococcus, meningococcus, or H. influenzae, the kinds of infection seen in association with the surgical or congenital asplenic state, presents one of the greatest threats to the infant or young child with sickle cell anemia2 :~It is likely that the onset of functional asplenia in s]~kle cell disease dates the beginning of the period of increased risk from these organisms. The documentation of the onset of functional asplenia by splenic scan in this study correlated with the appearance of red blood cell inclusions or Howell-Jolly bodies. Thus the presence of Howell-Jolly bodies on peripheral blood smears seems to be a reliable and practical indicator of the presence of functional asplenia, obviating the need for serial isotopic scans. Differential interference-contrast microscopy may be another poten-
Sickle cell anem& in infancy
209
tially useful, noninvasive method to detect splenic dysfunction,1~ but it is not a widely available technique. The rationale for screening for major sickle hemoglobinopathy must be clearly differentiated from screening for sickle cell trait. The latter has generally been used for the purposes of genetic counselling1~ and is of questionable benefit. Screening for major disease, on the other hand, is aimed at early detection for the purpose of preventing significantly high morbidity and mortality rates from disease which may occur in the first year of life. We have seen infants in whom death from overwhelming infection was the initial manifestation of sickle cell anemia. The optimal time for screening for disease is early infancy before there is any significant morbidity or mortality. Since virtually all infants in the country are born in a hospital, screening of cord blood could assure 100% compliance. We have found the acid agar gel hemoglobin electrophoresis method reliable, simple, and inexpensive for cord blood screening. It can also be adapted for use of dried hemoglobin specimens obtained from capillary blood collected on filter paper. 1'~ Others have found microcolumn chromatography useful for sickle screening of cord blood? 7 Regardless of the method used, the neonatal detection of sickle cell anemia should be regarded as merely the initial step in the effort to prevent serious illness as well as death from the disease. To achieve this goal, we have established a clinic for infants with sickle cell disease; management includes extensive education of the family about the disease, social assistance, and continuous comprehensive medical care. We are hopeful that effective education of the family about the disease and the provision of accessible and expert care will permit early medical intervention. The prompt treatment of many of the complications of sickle cell anemia may prevent some of the excessive illness and deaths associated with the disease in early life. Without such a comprehensive approach, the value of neonatal screening for sickle cell disease is dubious. REFERENCES
1. Herrick JB: Peculiar elongated and sickle,shaped red corpuscles in a case of severe anemia, Arch int Med 6:517, 1910. 2. Van Baelen H, Vandepitte J, and Eeckels R: Observations on sickle-cellanaemia and haemoglobin Bart's in Congolese neonates, Ann Soc Belge Med Trop 49:157~ 1969. 3. Pearson HA, O'Brien RT, Mcln~:osh S, et al: Routine screening of umbilical cord blood ~for sickle cell diseases, JAMA 227:420, 1974. 4. Robinson AR, Robson M, Harrison AP, et al: A new technique for differentiation of hemoglobin, J Lab Clin Med 50:745, 1957.
2 10
5.
6.
7.
8.
9.
10.
11.
O'Brien et aL
Barnes MG, Komarmy L, Wardlow SC, et al: A simple electrophoretic apparatus for rapid hemoglobin screening, Am J Clin Pathol 58:275, 1972. Singer L, Chernoff AI, and Singer L: Studies of abnormal hemoglobins. I. Their demonstration in sickle cell anemia and other hematologic disorders by means of alkali denaturation, Blood 6:413, 1951. Pearson HA, and Diamond LK: The critically ill child: sickle cell disease crises and their management, Pediatrics 48:629, 1971. Pearson HA, Spencer RP, and Cornelius EP: Functional asplenia in sickle cell anemia, N. Engl J Med 281: 923, 1969. Neel JV: In Abramson H, Bertles JF, and Wethers DL, editors: Sickle cell disease, St Louis, 1973, The C V Mosby Company, p 5. Barnes MG, Komarmy L, and Novack AH: A comprehensive screening program for hemoglobinopathies, JAMA 219:701, 1972. Diggs LW: In Abramson H, Bertles JF, and Wethers DL, editors: Sickle cell disease, St Louis, 1973, The C V Mosby Company, p 218.
The Journal of Pediatrics August 1976
12. Powars D, Haywood LJ, and Gilani D: Sickle cell disease: demographic factors influencing morbidity, American Society of Hematology, Chicago, 1973. Abst. 13. Seeler RA, Metzger W, and Mufson MA: Diplococcus pneumoniae infections in children with sickle cell anemia, Am J Dis Child 123:8, 1972. 14. Casper JT, Koethe SM, Rodey GE, et al: A rapid simple method for evaluation of functional asplenia in sickle cell disease, in Hercules et al, editors: Proceedings of First National Symposium on Sickle Cell Disease, Bethesda, Md, 1974, DHEW Publication No (NIH) 75-723, p 351. 15. Pearson HA, and O'Brien RT: Sickle cell testing programs, J PEDIATR 81:1201, 1972. 16. Gerrick MD, Dembure P, and Gutree R: Sickle cell anemia and other hemoglobinopathies: proceedures and strategy for screening employing spots of blood on filter paper specimens, N Engl J Med 288:1265, 1973. 17. Powars D, Schroeder WA, and White L: Rapid diagnosis of sickle cell disease at birth by microcolumn chromatography, Pediatrics 55:630, 1975.
TheJournalofPEDIATRICS
205
Prospective study of sickle cell anemia in infancy Twelve infants with sickle cell anemia identified in the course of a cord blood screening program have been followed Wospectively for up to three years o f age. The development of hemolytic anemia paralleled the postnatal decline in fetal hemoglobin and was evident in all infants by 12 weeks of age. Vasoocclusive episodes occurred in more than half the infants and seven aplastic crises were documented in four patients. Febrile illnesses were common and one o f the twelve infants developed pneumococcal sepsis. This study also demonstrated that functional asplenia is an acquired defect in sickle cell disease. The onset of functional asplenia was documented with splenic scans in six of the nine infants followed for more than one year after birth. There have been no deaths in this series.
Richard T. O'Brien, M.D.,* Sue MeIntosh, M.D., Gregg T. Aspnes, M.D., and Howard A. P e a r s o n , M . D . , N e w H a v e n , C o n n .
F o L L O W I N G the initial description of sickle cell anemia by Herfick 1 in 1910, a massive collection of clinical and scientific data concerning the disease has accumulated in the literature. Despite this voluminous record, there is a paucity of prospective studies of the disease, particularly during infancy and early childhood.-' We have identified 12 newborn infants with sickle cell anemia in the course of an umbilical cord blood screening program for major sickle hemoglobinopathies, and we have followed these infants serially for up to three years. The purpose of this paper is to report on the hematologic, clinical, and splenic changes in sickle cell disease during the first years of life. The screening program has also provided unexplained data on an ungxpectedly high occurrence of the disease at birth. PATIENTS
A N D METHODS
For the past three years (June, 1972-June, 1975) we have conducted a screening program of,umbilical cord blood of all black infants born at the two hospitals in New Haven, Connecticut, Yale-New Haven Hospital and the Hospital of St. Raphael? The purpose of this study was to From the Department of Pediatrics, Yale University School of Medicine. Supported by Contract NO1-HB-2-2950, NHLL NIH, and Grant RR-00125, GCRC Branch, DRR, NIH. *ReDrint address: Department of Pediatrics, 333 Cedar St., New Haven, Conn. 06510.
detect major sickle hemoglobinopathies as early as possible in an effort to prevent high morbidity and mortality rates in the first few years of life. Blood from infants born of mothers identified as "black" on their hospital admission card was screened. The cord blood specimen obtained routinely at both hospitals for serology and Coombs testing was utilized. Only in cases when the delivery was precipitous were cord blood specimens not obtained; in these instances a specimen of capillary blood was obtained during hospitalization. Blood was subjected to agar gel hemoglobin electrophoresis at pH 6.2. 4 With this technique hemoglobin F migrates rapidly permitting clea r recognition of hemoglobins A, S, and C. In addition, hemoglobin electrophoresis at alkaline pH on cellulose acetate was also performed? In over 2,700 specimens of cord blood, 18 infants have been identified who have majo r hemoglobinopathies: 12 sickle cell anemia, two sickle fl-thalassemia, three hemoglobin SC disease, and one hemoglobin C disease. The results of the screening program are shown on Table I. Family studies were used to differentiate the infants with sickle/?-thalassemia from those wih sickle cell anemia. Laboratory results of those infants identified as having sickle cell trait or hemoglobin C trait were sent to the patients' physician and the medical record. The infants with major hemoglo~inopathies have been followed at approximately six-week intervals with serial hematologic determinations including complete blood counts, peripheral smears for red blood cell morphology
Vol. 89, No. 2, pp. 205-210
206
O'Brien et aL
The Journal of Pediatrics August 1976
tO0 I
[]NORMAL [ ] SICKLE CELL DISEASE
80 [iii~iiiii:i:.
2o iiiiii~.
18
LI-
iii
[ ] NORMAL [ ] SICKLE CELL DISEASE
60
Z
m o .J
E
c9
40
o Z m 0 .J (.9 0 :E
i..d ,.1-
bJ 14
20
12
0
10
20
30
40
50
60
AGE (weeks)
Fig. 2. Change in percentage of hemoglobin F with age in sickle cell anemia.
0
I0
20
30
40
50
60
Table I. Cord blood screening program: Yale-New Haven Hospital and Hospital of St. Raphael (June, 1972-June, 1975)
AGE (weeks)
1. Change in hemoglobin concentration with age in sickle cell anemia. Fig.
and presence of Howell-Jolly bodies, reticulocyte counts, quantitation of the percentage of hemoglobin F by the alkali denaturation method)' and quantitative sickle cell preparations. Nine of the 12 infants with sickle cell anemia and one infant with sickle /3-thalassemia have been followed for more than one year. Liver-spleen scans were performed using 10/~Ci/kg of "~mTC-sulfur colloid and a gamma camera.
HGB pattern
FA FAS FAC FS FS FC FSC FA-fast
No.
%
New%Haven in children TM
2,361 227 78 12 2
85.4 8.2 2.8 0.4 <0.1
89.3 6.8 2.6 --
Diagnosis
Normal Sickle cell trait Hgb C trait Sickle cell anemia Sickle betathalassemia Hgb C disease Hgb SC disease Alpha-thalassemia Total
--
1
<0.1
--
3
<0.1 2.9
---
81 2,765
RESULTS Hematologic. Evidence for a hemolytic process as indicated by reticulocytosis was not present in any of the infants at 6 weeks of age, and none of the infants was significantly anemic at that time. Definite evidence of hemolysis, however, was seen in all infants by 12 weeks of -age. Fig. 1 shows the changes in hemoglobin concentration with age of the infants with sickle cell anemia who have been followed for more than one year. The hemoglobin concentration fell rapidly during the first three months of life and then declined more slowly, stabilizing at 7 to 10 gm/dl by 10months of age. There was marked individual variation both in the rate of fall as well as in the final hemoglobin concentration achieved. The infants with sickle/?-thalassemia developed hemolytic anemia in distinguishable from those infants with sickle cell disease.
The postnatal decline in fetal hemoglobin, as depicted in Fig. 2, was slower than normal, but there was considerable variability. There was h correlation between the rate rate of fall of fetal hemoglobin and the development and severity of hemolysis. Those infants who developed the more severe degrees of anemia had the most rapid fall in fetal hemoglobin. The two infants with sickle /?-thalassemia had a slower decline in fetal hemoglobin than any of the infants with sickle cell anemia; at 15 months of age, one of these infants had 27% hemoglobin F and no hemoglobin A. The other infant with sickle/?-thalassemia had no detectable hemoglobin )k at birth and at one month of age, but by five months had developed 10% hemoglobin A. Clinical. Symptomatology compatible with vasoocclu-
Volume 89 Number 2
Sickle cell anemia in infancy
20 7
KC BR KC CB Or)
DS
I- AK Z
LU TJ I.-
,,~ GR 0_
MB DP LS FM KF I
0
I
4
I
I
8
I
I
I
12
I
16
I
I
20
[
24
I
1
2B
1
I
32
I
[
36
AGE (months)
Fig. 3. Time of onset of functional asplenia. Asterisk (*) indicates documentation of functional asplenia with splenic scan. Length of line indicates duration of observation for each patient. Patient D. S. had functional asplenia at 5 months of age when she was first seen. All other patients had normal spleen scans prior to 6 months of age. sive crises ~ has occurred in at least 17 occasions in 7 of the 12 infants with sickle cell disease. Four of these patients had vasoocclusive crises prior to one year o f age. Classic hand-foot syndrome was observed as early as five months of age. There seemed to be no correlation between the severity of the hemolytic anemia and the occurrence of vasoocclusive episodes. Vasoocclnsive crises were not recognized among the infants with other major sickle hemoglobinopathies. Aplastic crises (reticulocytopenia and falling hemoglobin concentration) were detected on seven occasions among 4 of the 12 patients with sickle cell anemia. Most, however, were mild with decreases in hemoglobin o f only 2 to 3 g m / d l and resolved spontaneously. One infant required a transfusion of packed red blood cells. All of the aplastic episodes were associated w i t h a febrile illness. Aplastic crises were not recognized among infants with other major sickle hemoglobinopathies. Splenic sequestration crises were no t observed a m o n g any of the 12 infants with sickle cell anemia. Sequestration episodes were noted in an infant with sickle /?-thalassemia at 23 months of age and at 6 months of age in an infant born elsewhere but identified as having sickle cell anemia at 5 months of age at this institution. Each of these infants required blood transfusion. Splenomegaly was noted in all infants with sickle cell anemia sometime after 6 months of age. The degree of splenomegaly (measured as centimeters below the left costal margin) varied greatly from patient to patient and also with time in the individual patient. Unusual hepatomegaly was not noted.
Infections and fever. Febrile episodes (temperature > 102~ were recorded on 35 occasions in 10 of the 12 patients with sickle cell anemia. A likely cause for the fever (otitis media, viral exanthem, gastroententis, pneumonia) was usually found. All infants with febrile episodes were treated with antibiotics regardless of associated findings; blood cultures were obtained prior to beginning antibiotic therapy. One episode of pneumococcal sepsis occurred in an l l - m o n t h - o l d infant two weeks after functional asplenia had been documented. She was treated with antibiotics and recovered. The infant with hemoglobin C disease developed salmonella septicemia and was successfully treated with antibiotics. There have been no deaths among these infants~ Splenic function. ~"'~Tc-sulfur colloid scans showed normal splenic uptake in all infants prior to 6 months of age. The onset of functional asplenia, defined as loss of splenic reticuloendothelial activity of the palpably enlarged organ, '~ was documented with serial scans in six of the nine infants followed for more than one year since birth (Fig. 3). Functional asplenia was not present at birth but rather is an acquired defect in sickle cell disease (Fig. 4). In one infant, serial scans demonstrated a progressive decrease in splenic uptake of the radiocolloid (Fig. 5). The onset of functional asplenia was correlated with a decrease in fetal hemoglobin levels below 20%. Three of the nine infants with sickle cell anemia who have been followed for more than one yea} retain normal splenic reticuloendothelial function at 1~, 20, and 29 months of age, respectively. Howell-Jolly bodies, or red blood cell inculsions, were not noted before functional asplenia was
2 08
O'Brien et al.
The Journal of Pediatrics August 1976
Fig. 4. The development of functional asplenia documented by serial spleen scans. Top scan at -5 months of age shows normal splenic uptake. Bottom scan at 7 months of age shows no splenic uptake.
documented by scanning techniques. None of the infants with other major sickle hemoglobinopathies has shown evidence of splenic dysfunction. DISCUSSION Since sickle cell hemoglobin is inherited in an autosomal recessive manner, the relative frequencies of the three possible genotypes (AA, AS, and SS) in a population are expressed by the Hardy-Weinberg equation. Based on a prevalence rate of 8% for heterozygous persons (sickle cell trait) among black Americans, the disease has been estimated to occur in o n e i n 500 black newborn infants in the United StatesY In our screening program of all black infants born in New Haven, we have detected 12 newborn infants with sickle cell anemia among 2,765 individuals tested, or a frequency of approximately 1 in 250 (Table I). The difference between the observed and predicted frequencies is statistically significant (P = <0.001). The reason for this apparent increase in incidence is unclear. We have no evidence to suggest a selection for sickle
Fig. 5. Serial spleen scans demonstrating progressive decline in splenic uptake of the radiocolioid. hemoglobin among women delivering at our hospital. All births in New Haven occur at the Yale-New Haven Hospital or Hospital of St. Raphael, the only hospitals in the city. The obstetrical services have not received consultations for hemoglobinopathies from outside the area during the period of the study. In addition, sickle cell trait was observed in 8.2% of black newborn infants, a prevalence similar to that observed amoflg older children from the same communityY' We have attempted to examine any possible biases in our population or program which would lead to.increases in the prevalence of the disease
Volume 89 Number 2
and find none. The explanation for this difference eludes us at this time. Clearly more studies are necessary. Family studies documenting sickle cell trait in both parents of the infants with sickle cell disease could not be performed in all cases, and the possibility that some of these infants have sickle /?-thalassemia could not be unequivocally excluded. All of the mothers had sickle cell trait. This prospective study does illustrate the variability in the development of the hematologic and clinical manifestations of sickle cell disease during the first years of life. T h e development of hemolytic anemia paralleled the postnatal decline in fetal hemoglobin and was evident in all infants by 12 weeks of age, although there was marked individual variation in the final degree of compensation for the hemolysis. Vasoocclusive crises occurred as early as 5 months of age and were observed in more than half the infants followed for over a year. These episodes were generally brief and required minimal symptomatic treatment. Aplastic crises were detected more frequently than anticipated and were invariably associated with febrile illness. Febrile episodes were relatively common and usually associated with a probable cause. One of the 12 infants with sickle cell anemia developed pneumococcal sepsis. Prompt institution of antibiotic therapy early in the course of febrile episodes may have prevented other episodes of septicemia. There have been no deaths in this series. We have previously described a state of functional asplenia-a deficit in splenic reticuloendothelial function of anatomically enlarged spleens of young children with sickle cell anemiaY This prospective study demonstrates that functional asplenia is an acquired defect in sickle cell disease with an onset as early as five months of age. The mean age of death in sickle cell disease is during childhood with approximately 30% of the deaths occurring before five years of age1:; the majority are due to infection.1: Overwhelming infection with ~the pneumococcus, meningococcus, or H. influenzae, the kinds of infection seen in association with the surgical or congenital asplenic state, presents one of the greatest threats to the infant or young child with sickle cell anemia2 :~It is likely that the onset of functional asplenia in s]~kle cell disease dates the beginning of the period of increased risk from these organisms. The documentation of the onset of functional asplenia by splenic scan in this study correlated with the appearance of red blood cell inclusions or Howell-Jolly bodies. Thus the presence of Howell-Jolly bodies on peripheral blood smears seems to be a reliable and practical indicator of the presence of functional asplenia, obviating the need for serial isotopic scans. Differential interference-contrast microscopy may be another poten-
Sickle cell anem& in infancy
209
tially useful, noninvasive method to detect splenic dysfunction,1~ but it is not a widely available technique. The rationale for screening for major sickle hemoglobinopathy must be clearly differentiated from screening for sickle cell trait. The latter has generally been used for the purposes of genetic counselling1~ and is of questionable benefit. Screening for major disease, on the other hand, is aimed at early detection for the purpose of preventing significantly high morbidity and mortality rates from disease which may occur in the first year of life. We have seen infants in whom death from overwhelming infection was the initial manifestation of sickle cell anemia. The optimal time for screening for disease is early infancy before there is any significant morbidity or mortality. Since virtually all infants in the country are born in a hospital, screening of cord blood could assure 100% compliance. We have found the acid agar gel hemoglobin electrophoresis method reliable, simple, and inexpensive for cord blood screening. It can also be adapted for use of dried hemoglobin specimens obtained from capillary blood collected on filter paper. 1'~ Others have found microcolumn chromatography useful for sickle screening of cord blood? 7 Regardless of the method used, the neonatal detection of sickle cell anemia should be regarded as merely the initial step in the effort to prevent serious illness as well as death from the disease. To achieve this goal, we have established a clinic for infants with sickle cell disease; management includes extensive education of the family about the disease, social assistance, and continuous comprehensive medical care. We are hopeful that effective education of the family about the disease and the provision of accessible and expert care will permit early medical intervention. The prompt treatment of many of the complications of sickle cell anemia may prevent some of the excessive illness and deaths associated with the disease in early life. Without such a comprehensive approach, the value of neonatal screening for sickle cell disease is dubious. REFERENCES
1. Herrick JB: Peculiar elongated and sickle,shaped red corpuscles in a case of severe anemia, Arch int Med 6:517, 1910. 2. Van Baelen H, Vandepitte J, and Eeckels R: Observations on sickle-cellanaemia and haemoglobin Bart's in Congolese neonates, Ann Soc Belge Med Trop 49:157~ 1969. 3. Pearson HA, O'Brien RT, Mcln~:osh S, et al: Routine screening of umbilical cord blood ~for sickle cell diseases, JAMA 227:420, 1974. 4. Robinson AR, Robson M, Harrison AP, et al: A new technique for differentiation of hemoglobin, J Lab Clin Med 50:745, 1957.
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Barnes MG, Komarmy L, Wardlow SC, et al: A simple electrophoretic apparatus for rapid hemoglobin screening, Am J Clin Pathol 58:275, 1972. Singer L, Chernoff AI, and Singer L: Studies of abnormal hemoglobins. I. Their demonstration in sickle cell anemia and other hematologic disorders by means of alkali denaturation, Blood 6:413, 1951. Pearson HA, and Diamond LK: The critically ill child: sickle cell disease crises and their management, Pediatrics 48:629, 1971. Pearson HA, Spencer RP, and Cornelius EP: Functional asplenia in sickle cell anemia, N. Engl J Med 281: 923, 1969. Neel JV: In Abramson H, Bertles JF, and Wethers DL, editors: Sickle cell disease, St Louis, 1973, The C V Mosby Company, p 5. Barnes MG, Komarmy L, and Novack AH: A comprehensive screening program for hemoglobinopathies, JAMA 219:701, 1972. Diggs LW: In Abramson H, Bertles JF, and Wethers DL, editors: Sickle cell disease, St Louis, 1973, The C V Mosby Company, p 218.
The Journal of Pediatrics August 1976
12. Powars D, Haywood LJ, and Gilani D: Sickle cell disease: demographic factors influencing morbidity, American Society of Hematology, Chicago, 1973. Abst. 13. Seeler RA, Metzger W, and Mufson MA: Diplococcus pneumoniae infections in children with sickle cell anemia, Am J Dis Child 123:8, 1972. 14. Casper JT, Koethe SM, Rodey GE, et al: A rapid simple method for evaluation of functional asplenia in sickle cell disease, in Hercules et al, editors: Proceedings of First National Symposium on Sickle Cell Disease, Bethesda, Md, 1974, DHEW Publication No (NIH) 75-723, p 351. 15. Pearson HA, and O'Brien RT: Sickle cell testing programs, J PEDIATR 81:1201, 1972. 16. Gerrick MD, Dembure P, and Gutree R: Sickle cell anemia and other hemoglobinopathies: proceedures and strategy for screening employing spots of blood on filter paper specimens, N Engl J Med 288:1265, 1973. 17. Powars D, Schroeder WA, and White L: Rapid diagnosis of sickle cell disease at birth by microcolumn chromatography, Pediatrics 55:630, 1975.