Health care utilization
Although payer source and median household income were not significantly
different between the transplant and the non-transplant arms, the total
charge for each admission was higher in the transplant arm.(Table 2) . ED visits were similar in both arms (p = 0.56).
Elective admissions were more in the transplant arm compared to the
non-transplant arm (p = 0.0244). Length of stay was prolonged in
transplant arm (18 days) compared to non-transplant arm (6.8 days) and
was statistically significant (p<0.001). When comparing the
morbidities, lymphomas, ulcerative colitis and autoimmune complications
of WAS were seen only in the non-transplant arm (Figure 2) . Of
85 centers, only 10% centers had 42% (2.8-9.1% each) of the
hospitalizations and 90% of the centers had less than 2.5% of
hospitalizations each (Table 3) .
DISCUSSION :
This study is one of the largest database reviews for patients with WAS,
with data from all over the United States over a 6-year period. We found
very interesting results with the review of the KIDS inpatient database
made available through HCUP.
The study showed 7 female patients with WAS seeking medical care, and
all of them were in the non-transplant arm. Females with WASP gene
mutations are usually asymptomatic as their mature blood cells have
nonrandom X chromosome inactivation, with the chromosome having normal
WASP gene active in most cells. Prchal et al12 looked
at X-chromosome expression in the mother of two siblings with WAS and
suggested that there is selection against cells expressing the defective
WASP gene in the hematopoietic system in carriers.
Fearon13 et al studied eight carriers of WAS defect
and identified skewed patterns of X chromosome inactivation in T-cells,
granulocytes and B cells. Multiple other studies have been done to look
at the carrier state in WAS14,15,16. A case report for
a female presenting with mild WAS symptoms was found to have 60% of
normal WASP levels in peripheral blood mononuclear cells, compared to
actual cases of WAS where WASP levels were 0-20%.17She was noted to have heterozygosity with 2 distinct populations in her
lymphocytes and monocytes. Many other case reports have been described
with females with WAS symptoms.18-22 Hypothesis for
disease expression in a female with heterozygosity to the WASP mutation
are either : abnormality in transcriptional X chromosome silencing in
the hematopoietic stem cells, or abnormality in the process that leads
to preferential survival and expansion of cells that bear the active
wild-type X chromosome.23
Post-transplant hospitalization is the largest contributor to health
care utilization for transplant patients. We noted that the length of
stay (LOS) was longer in transplant patients compared to the
non-transplant patients, especially in admissions associated with
transplant as a procedure code, with mean LOS of 8 days for
non-transplant arm and 18 days in the transplant arm. In a study using
national claims database of commercially insured population in the
United States, Majhail et al24 showed that the median
duration of hospitalization was 19 days for autologous HCT recipients
and 31 days in allogenic HCT recipients. The median days of hospital
stay after the transplant was 21 days in <20-year age group
for autologous HCT and 42 days for allogenic HCT. In another multicenter
cohort study25, LOS compared between different graft
sources in the first 100 days after transplant for acute leukemias
showed umbilical cord blood (UCB) and mismatched unrelated donor
transplants (MMUD) to have a longer hospital stay compared to matched
unrelated donors (MUD). The median value of LOS in the pediatric group
were 50 days for single UCB, 54 days for double UCB and 60 days for MUD
HCT. Our study suggests a much lesser LOS in WAS patients, but the graft
source for our patients was not available in the database.
Due to restricted availability of HCT, concerns have been raised
regarding disparities based on race, socioeconomic status, education and
insurance status. Our study revealed more African Americans (18.3%) in
the non-transplant arm compared to transplant arm (6.8%). This
disparity could be explained by lack of donor sources, access to HCT and
outcomes of HCT. Cancer facts and figures summarized by the American
Cancer Society in 2019 show highest incidence of cancer and deaths in
African Americans when compared to other races26. HCT
is an expensive procedure, hence socioeconomic factors create a barrier
to its easy access. Also, allogenic HCT needs appropriate HLA-matched
donors, and the likelihood of matching between two random individuals
increases if they are of the same race. The National Marrow Donor
Program’s Registry27 has about 16 million potential
donors, 7% of them are African Americans, 6% Asians and 1% American
Indian/Alaskan Native, and they have ongoing initiatives to increase the
diversity of the pool. Barker et al28 in a prospective
study conducted between 2005–2017 found that increasing registry size
has not resolved the racial disparity and suggested use of alternative
graft sources such as cord blood transplant. However, unavailable
matched donors continue to be a barrier to HCT in these populations.
WAS is a disease identified at a young age due to multiple infections or
bleeding manifestations. Sullivan et al29 found that
36% patients with WAS experience non-HCT associated deaths at a mean
age of 8 years, mostly due to infections (44%), bleeding (23%) and
malignancy (26%). This study also found that the median survival was 20
years in patients with WAS with supportive care only. Our study showed
most admissions were in the 0-5 year age group for both arms, which
suggests early identification of the disease. Our hypothesis is due to
increased awareness and ease of diagnosis, cases are more easily
identified. Also, greater number of children > 5 years age
required admission in the non-transplant arm, suggesting increased
complications and medical needs with increased age. We were further able
to consolidate this hypothesis by looking at the complications in both
arms. We found that none of the patients in the transplant arm developed
lymphoma, whereas 5.6% patients in the non-transplant arm developed
lymphoma. Malignancies in untreated WAS has been reported as
13%29 and 22%30 in two different
case series, including lymphomas, leukemias and myelodysplasia.
Similarly, autoimmune manifestations are much more common in untreated
WAS, ranging from 22% to 72% in various case
series29,30,31,32. This was similarly reflected in our
study where ulcerative colitis was noted only in the non-transplant arm
compared to the transplant arm. Due to limitation of our database, we
were unable to compare the course of WAS in the two arms beyond 20 years
of age.
Our study did not show splenectomy done in either arm. There have been
controversies regarding splenectomy if a potential donor is present, but
this represents a shift in practice even in the non-transplant arm.
Mullen et al33 had shown median survival of 25 years
in splenectomized non HCT patients, compared to less than 5 years in
unsplenectomized patients. Infectious complications related to
splenectomy has been shown to be significant in WAS patients receiving
HCT.34 Moratto et al35 observed the
long term outcomes for WAS and HCT over a 30 year period and showed that
splenectomy may normalize platelet counts after HCT, however, there are
associated risks of potentially fatal infections that need to be
considered. Imai et al30 had similar results of
improvement in platelet counts after splenectomy, but with increased
risk of life-threatening meningitis/sepsis. Our study shows a
significant shift in practice away from splenectomy for management of
thrombocytopenia.
Our study did not show significant difference in mortality between the
two arms, but it is not reliable given that ours is an inpatient
database. However, our study agrees with other studies that HCTs done at
<5-year age group have better outcomes.34,35
STRENGTHS AND LIMITATIONS :
The KID inpatient database is one of the largest pediatric inpatient
databases, with each data set providing 3-years data, with roughly 2 to
3 million discharges (unweighted), which corresponds to a national
estimate of 6 to 7 million (weighted) discharges per data set. Our study
has incorporated 2 datasets, which amounts to about 12-14 million
(weighted) discharges and therefore, is a very powerful tool to study a
rare disease like WAS.
There are several limitations to this study that need to be discussed.
Since this is an administrative dataset, there are limitations to using
it for secondary analysis of clinical outcomes. The data is based on
each hospitalization and is patient specific, hence we are unable to
provide exact rates based on patient numbers. This is an inpatient
dataset, outpatient care and mortality in the outpatient setting cannot
be assessed. There might be errors secondary to incorrect ICD-9 coding,
which are not avoidable in a large dataset study like these. However,
there have been several studies that have looked at the sensitivity of
ICD-9 codes10,11. This dataset is a pediatric dataset
for <21 years of age, and hence we were not able to analyze
the course of the disease beyond that age.