To the editor:

Survival of patients with sickle cell disease (SCD) has increased progressively since the 1980s.1-5  Patients with SCD in their sixth or seventh decade have been described previously.6  This report describes 4 patients with SCD who survived beyond the age of 80 years. Three of these were US citizens enrolled in the Sickle Cell Center of Thomas Jefferson University. The center and all its projects were approved by the institutional review board (IRB). The report of the fourth Brazilian patient was approved by the IRB of the Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti. Table 1 lists the demographic and clinical characteristics of these patients, and Table 2 shows their most recent (within 3-5 years) key laboratory data at a time when they were in a stable steady state.

Table 1

Demographic and clinical data of octogenarians with sickle cell disease

 Patient A Patient B Patient C Patient D 
Age/sex 82/F 86/F 82/F 82/F 
Ancestry African American Italian American African American African Brazilian 
Obstetrical history* G3P1A2 G2P1A1 G5P5 G2P2 
Diagnosis SS SS Hb SC disease Hb SC disease 
VOCs/y 1-2 0-1 0-3 0-1 
Cerebrovascular accident No No No No 
Retinopathy Yes Yes No No 
Cataracts Yes Yes, OU No Yes, OS 
Deafness No No No Yes, left ear 
ACS No No No Yes 
Congestive heart failure Yes Yes No No 
Hypertension Yes No Yes Yes 
Avascular necrosis Yes + right hip replacement Yes + replacement of both hips and right knee No No 
Leg ulcer Yes Yes No No 
Splenomegaly No No Yes Yes 
Cholecystectomy Yes No Yes No 
Infection Tuberculosis, pneumonia Urinary tract infection Clostridium difficile colitis Tuberculosis 
Transfusion Frequent Occasional Occasional Frequent 
Iron overload Yes No No Yes 
Comorbidity Complete heart block, glaucoma OU, mild Parkinson disease Paroxysmal AFIB, IBS, MVP, osteoporosis Osteoma of mandible, depression Diabetes mellitus type 2 
Smoking No No No No 
Alcohol No Occasional No Occasional 
Body mass index 21.6 20.4 24.8 23.1 
Compliance Excellent Excellent Excellent Excellent 
Family support Excellent Excellent Excellent Excellent 
Status Alive Deceased Deceased Deceased 
Cause of death N/A Cardiac complications Unknown ACS + septicemia 
 Patient A Patient B Patient C Patient D 
Age/sex 82/F 86/F 82/F 82/F 
Ancestry African American Italian American African American African Brazilian 
Obstetrical history* G3P1A2 G2P1A1 G5P5 G2P2 
Diagnosis SS SS Hb SC disease Hb SC disease 
VOCs/y 1-2 0-1 0-3 0-1 
Cerebrovascular accident No No No No 
Retinopathy Yes Yes No No 
Cataracts Yes Yes, OU No Yes, OS 
Deafness No No No Yes, left ear 
ACS No No No Yes 
Congestive heart failure Yes Yes No No 
Hypertension Yes No Yes Yes 
Avascular necrosis Yes + right hip replacement Yes + replacement of both hips and right knee No No 
Leg ulcer Yes Yes No No 
Splenomegaly No No Yes Yes 
Cholecystectomy Yes No Yes No 
Infection Tuberculosis, pneumonia Urinary tract infection Clostridium difficile colitis Tuberculosis 
Transfusion Frequent Occasional Occasional Frequent 
Iron overload Yes No No Yes 
Comorbidity Complete heart block, glaucoma OU, mild Parkinson disease Paroxysmal AFIB, IBS, MVP, osteoporosis Osteoma of mandible, depression Diabetes mellitus type 2 
Smoking No No No No 
Alcohol No Occasional No Occasional 
Body mass index 21.6 20.4 24.8 23.1 
Compliance Excellent Excellent Excellent Excellent 
Family support Excellent Excellent Excellent Excellent 
Status Alive Deceased Deceased Deceased 
Cause of death N/A Cardiac complications Unknown ACS + septicemia 

A, abortus; ACS, acute chest syndrome; AFIB, Atrial fibrillation; F, female; G, gravidity; Hb SC, sickle cell–hemoglobin C; IBS, irritable bowel syndrome; MVP, mitral valve prolapse; N/A, not applicable; OS, oculus sinister; OU, oculus uterque; P, parity; SS, sickle cell anemia; VOCs, vaso-occlusive crises.

*

Reported using the gravida/para/abortus system.

Table 2

Laboratory data in the patients reported

Test Patient A Patient B Patient C Patient D 
Hb, g/dL 8.1 8.6 9.4 7.8 
Hematocrit, % 24.4 26.4 27.3 23.2 
MCV, fL 90 93 81 82 
Reticulocytes, % 11.2 9.1 5.8 2.4 
WBC, 109/L 8.6 7.8 6.8 6.5 
Platelets, 109/L 243 238 229 125 
Hb F, % 12 8.8 1.8 
Ferritin, ng/mL 2660 464 101 1250 
Creatinine, mg/dL 1.1 1.2 0.8 1.6 
ALT, IU/L 10 12 10 25 
AST, IU/L 27 25 14 26 
LDH, IU/L ND 322 243 154 
Total bilirubin, mg/dL 1.7 1.5 0.6 1.0 
ALK, IU/L 53 93 96 103 
UA, mg/dL ND 5.7 3.0 6.8 
α-Genes ND 
βs-Haplotype BEN/BEN BEN/BEN BEN/CTYPE 1 ND 
Test Patient A Patient B Patient C Patient D 
Hb, g/dL 8.1 8.6 9.4 7.8 
Hematocrit, % 24.4 26.4 27.3 23.2 
MCV, fL 90 93 81 82 
Reticulocytes, % 11.2 9.1 5.8 2.4 
WBC, 109/L 8.6 7.8 6.8 6.5 
Platelets, 109/L 243 238 229 125 
Hb F, % 12 8.8 1.8 
Ferritin, ng/mL 2660 464 101 1250 
Creatinine, mg/dL 1.1 1.2 0.8 1.6 
ALT, IU/L 10 12 10 25 
AST, IU/L 27 25 14 26 
LDH, IU/L ND 322 243 154 
Total bilirubin, mg/dL 1.7 1.5 0.6 1.0 
ALK, IU/L 53 93 96 103 
UA, mg/dL ND 5.7 3.0 6.8 
α-Genes ND 
βs-Haplotype BEN/BEN BEN/BEN BEN/CTYPE 1 ND 

ALK, alkaline phosphatase; ALT, alanine aminotransaminase; AST, aspartate aminotransferase; BEN, Benin; Hb, hemoglobin; LDH, lactate dehydrogenase; MCV, mean corpuscular volume; ND, not done; UA, uric acid; WBC, white blood cell count.

Old age in the general population usually refers to life expectancy of people beyond what is presumed to be the life expectancy of human beings. Specific numbers that define old age, however, vary greatly among countries, cultures, habitats, and social sciences. Thus, there are official definitions, popular definitions, subgroup definitions, and so forth. Gerontologists define subgroups in a number of ways7,8 ; however, the subgroup definitions that seem to be in common use are young-old (65-74 years), middle- or older-old (75-84 years), and oldest-old (≥85 years).8  Using these definitions, 3 of our patients are older-old and 1 is oldest-old. These definitions may replace those that are categorized by age measured in decades, such as quinquagenarian (50-59 years).

Analysis of the data in Tables 1 and 2 shows expected and unexpected features of SCD and identifies certain parameters that may contribute to longevity. Although our report of 4 patients over the age of 80 years is anecdotal in nature, certain demographic and clinical features are unusual. In comparison, a previous prospective study in patients enrolled in the Sickle Cell Center at Jefferson showed that the mean age of death of 17 women with SS who died during 5 years of observation was 39.1 ± 14.87 years.9  The cohort of patients with Hb SC disease at Jefferson included 172 men and women. Twenty-one (12%) of those patients were women who died at a mean age of 49.6 ± 13.22 years. In one Brazilian institution, the mean age of women with Hb SC disease at death was 28.15 ± 9.11 years (Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti, unpublished data).

The obvious feature is that all described patients are women. Sex is known to influence longevity both in the general population and in patients with SCD. Previous studies showed that the mortality rate in children with SCD is similar for boys and girls.10-13  The divergence in the mortality rate between the sexes in favor of females becomes apparent in adults.4,10  The reason why adult women with SCD live longer than men is not known. One possibility is relatively lower blood viscosity due to lower Hb and hematocrit levels in women.

Some of the features our patients had are known to be associated with good prognosis. These include the infrequent VOCs that required hospitalization; no history of strokes; no previous history of ACS, except in the Brazilian patient; low white blood cell count; low hemoglobin level; and normal biochemical parameters.

Another common feature in our patients is that none of them was on hydroxyurea (HU) because none met the inclusion criterion of at least 3 VOCs that required hospitalization in the immediate previous year and because HU is not approved for Hb SC disease. Nevertheless, the Hb F levels (12% in patient A and 8.8% in patient B) are relatively high. The beneficial cutoff level of Hb F has not been well determined and verified. The primary end point of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) was not the level of Hb F but the frequency of VOCs.14  Two years after starting HU in the MSH study, the mean Hb F level in the HU group was 8.6% ± 6.8 compared with 4.7% ± 3.3 (P = .0001) in the placebo group.15  It is generally believed, however, that the higher the level of Hb F, the milder the SCD. Platt et al2  analyzed the risk factors for death in patients with SS in the Cooperative Study of Sickle Cell Disease and found that SS patients with Hb F levels >8.6% had better survival than those with Hb F levels <8.6%. It should be noted that the Hb F levels in patients A and B (Table 2) are the average of previous recent determinations. Higher Hb F levels are often seen in younger years (eg, the Hb F level of patient B was 12.2% when she was 64 years old), and Hb F levels and leukocyte counts are known to decrease with age.1  Accordingly, the relatively high endogenous levels of Hb F in patients A and B may have contributed to their longevity.

The utilization of blood transfusion differed among the 4 patients. Patient A received blood transfusion to keep her Hb level >7 g/dL due to her cardiac complications. She developed iron overload treated with deferasirox that was later discontinued due to an increase in serum creatinine level. Patient B refused blood transfusion unless it was absolutely necessary. Patient C had a Hb level of >9 g/dL and rarely required blood transfusion. The diagnosis of Hb SC disease in patient D was made at the age of 76 years when she presented with severe symptomatic anemia with a Hb level of 6 g/dL. Workup of the anemia revealed Hb SC disease, and she was started on simple transfusion. Within a few months, she developed ACS and was placed on chronic blood transfusion. Later, she developed the second episode of ACS, which was fatal.

Another common feature among the 4 patients is the family support and adherence to medication intake, appointments, and referrals. This adherence was based on the observations of the many providers they had, including the authors.

In addition to the common features, each patient had specific favorable lifestyle factors in addition to those mentioned in Table 1. Patient A is married, and her husband is highly supportive. Although Patient B was a widow for several years before her death, her son was very supportive. Patient C was a widow with five children; her oldest daughter was very supportive. Patient D was married and had two daughters who lived with her and took excellent care of her.

Despite the longevity of these patients, they did suffer from complications of their disease and from serious comorbidities, shown in Table 1. Comorbidities encompass both sickle and nonsickle complications that may emerge in older age. Over 20 comorbidities affecting patients with SCD have been described.16  Cognizance of the complexity of SCD and its polymorbidities and the implementation of preventative, educational, counseling, and prompt intervention measures may ameliorate the associated complexities of the disease and improve the quality of life of its victims.

In summary, the patients described had similar desirable features of SCD, despite their different ancestries, cultures, and countries. Their lifestyle of no smoking, no or occasional alcohol, normal body mass index, compliance, and excellent family support were, most likely, important contributors to their longevity. All these factors taken together indicate that these 4 women may provide a blueprint of how to live a long life, despite having a serious medical condition like SCD.

Authorship

Acknowledgment: This study was supported, in part, by the Sickle Cell Program of the Commonwealth of Pennsylvania for the Philadelphia Region.

Contribution: S.K.B. designed the research, treated the 3 American patients, analyzed the data, and wrote the manuscript; E.D.P. treated and summarized the history of 1 of the patients with sickle cell anemia, analyzed the data, and reviewed the manuscript; C.L. reviewed and wrote the history of the Brazilian patient with Hb SC disease and reviewed the manuscript; and G.R.-B. obtained pertinent information about the 3 American women, including their lifestyle and psychosocial features, and reviewed the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Samir K. Ballas, Cardeza Foundation for Hematologic Research, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, 1020 Locust St, Suite 390, Philadelphia, PA 19107; e-mail: samir.ballas@jefferson.edu.

References

References
1
Embury
SH
Hebble
RP
Mohandas
N
Steinberg
MH
Sickle Cell Disease Basic Principles and Clinical Practice
1994
New York, NY
Raven Press
2
Platt
OS
Brambilla
DJ
Rosse
WF
, et al. 
Mortality in sickle cell disease: life expectancy and risk factors for early death.
N Engl J Med
1994
, vol. 
330
 
23
(pg. 
1639
-
1644
)
3
Steinberg
MH
McCarthy
WF
Castro
O
, et al. 
Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia and MSH Patients’ Follow-Up
The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: a 17.5 year follow-up.
Am J Hematol
2010
, vol. 
85
 
6
(pg. 
403
-
408
)
4
Wierenga
KJ
Hambleton
IR
Lewis
NA
Survival estimates for patients with homozygous sickle-cell disease in Jamaica: a clinic-based population study.
Lancet
2001
, vol. 
357
 
9257
(pg. 
680
-
683
)
5
PQ
Gulbis
B
Dedeken
L
, et al. 
Survival among children and adults with sickle cell disease in Belgium: benefit from hydroxyurea treatment.
Pediatr Blood Cancer
2015
, vol. 
62
 
11
(pg. 
1956
-
1961
)
6
Steinberg
MH
Ballas
SK
Brunson
CY
Bookchin
R
Sickle cell anemia in septuagenarians.
Blood
1995
, vol. 
86
 
10
(pg. 
3997
-
3998
)
7
Forman
DE
Berman
AD
McCabe
CH
Baim
DS
Wei
JY
PTCA in the elderly: the “young-old” versus the “old-old”.
J Am Geriatr Soc
1992
, vol. 
40
 
1
(pg. 
19
-
22
)
8
Zizza
CA
Ellison
KJ
Wernette
CM
Total water intakes of community-living middle-old and oldest-old adults.
J Gerontol A Biol Sci Med Sci
2009
, vol. 
64A
 
4
(pg. 
481
-
486
)
9
Ballas
SK
Lusardi
M
Hospital readmission for adult acute sickle cell painful episodes: frequency, etiology, and prognostic significance.
Am J Hematol
2005
, vol. 
79
 
1
(pg. 
17
-
25
)
10
Leikin
SL
Gallagher
D
Kinney
TR
Sloane
D
Klug
P
Rida
W
Cooperative Study of Sickle Cell Disease
Mortality in children and adolescents with sickle cell disease.
Pediatrics
1989
, vol. 
84
 
3
(pg. 
500
-
508
)
11
Hamideh
D
Alvarez
O
Sickle cell disease related mortality in the United States (1999-2009).
Pediatr Blood Cancer
2013
, vol. 
60
 
9
(pg. 
1482
-
1486
)
12
Quinn
CT
Rogers
ZR
Buchanan
GR
Survival of children with sickle cell disease.
Blood
2004
, vol. 
103
 
11
(pg. 
4023
-
4027
)
13
Rogers
DW
Clarke
JM
Cupidore
L
Ramlal
AM
Sparke
BR
Serjeant
GR
Early deaths in Jamaican children with sickle cell disease.
BMJ
1978
, vol. 
1
 
6126
(pg. 
1515
-
1516
)
14
Charache
S
Terrin
ML
Moore
RD
, et al. 
Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia
Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia.
N Engl J Med
1995
, vol. 
332
 
20
(pg. 
1317
-
1322
)
15
Charache
S
Barton
FB
Moore
RD
, et al. 
The Multicenter Study of Hydroxyurea in Sickle Cell Anemia
Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive “switching” agent.
Medicine (Baltimore)
1996
, vol. 
75
 
6
(pg. 
300
-
326
)
16
Ballas
SK
Other Pain Syndromes. Sickle Cell Pain
2014
2nd ed
Washington, DC
International Association for the Study of Pain