ORIGINAL ARTICLE
Elements Associated With Early Mortality in Children
With B Cell Acute Lymphoblastic Leukemia in Chiapas,
Mexico: A Case-control Study
Jose L. Lepe-Zuniga, MD, DSci and Virginia Ramirez-Nova, MD
Summary: Childhood Lymphoblastic leukemia’s (ALL) early
mortality (EM) is an undesirable treatment outcome for a disease
for which > 90% long term success is achievable. In the Western
world EM constitutes no > 3%; yet, in Chiapas, Mexico, remains
Downloaded from http://journals.lww.com/jpho-online by BhDMf5ePHKbH4TTImqenVHHw8h8Dt9keS0MTQ1SwF7VSm8M26Xmiyc3CDAkKIVOO on 01/06/2019
around 15%. With the objective of improving on EM, we deter-
mined associated elements in 28 ALL who died within 60 days
of arriving at Hospital de Especialidades Pediátricas in Chiapas
(HEP), by comparing them to those in 84 controls who lived
beyond the first 90 days. χ2, t test, and binary logistic regression
(BLR) were used to determine significant individual and multiple
variables associated to outcome. On arrival, fever, liver and spleen
enlargement, active bleeding, lower albumin, less platelets, higher
creatinine, and uric acid, more diploid and less hyperdiploid cases
were associated with EM cases. Time to diagnosis, nutritional
status, risk group and leukocyte count were not related. Antileukemic
treatment approach was similar in both groups. The BLR model
including fever, active bleeding, liver enlargement, <10,000 platelets/
µL, and > 2X upper normal lactic dehydrogenase, determined out-
come in 66.7% EM and 90.2% controls. To improve on EM in ALL,
patients with characteristics defined here ought to be treated differ-
ently at HEP.
Key Words: childhood lymphoblastic leukemia, early mortality,
tumor lysis syndrome, sepsis in leukemia, leukemia and steroids,
platelet support, leukemia treatment in the South of Mexico
(J Pediatr Hematol Oncol 2019;41:1–6)
T reatment outcome of childhood B cell acute lympho-
blastic leukemia (ALL) has been improving over time
worldwide. Today, most specialized medical centers in the
developed world achieve long lasting remissions in > 80%
to 90% of their patients.1–3 In Mexico, treatment outcome
has also been improving in the last 30 to 40 years, reaching
between 55% to > 80% complete long-lasting remissions
depending on location, structure and level of specialization
of the treatment centers.4–6 One of the reasons preventing
higher rates of success in Mexico as well as in other devel-
oping countries is the fraction of patients dying early during
Received for publication November 6, 2017; accepted September 18,
2018.
From the Hospital de Especialidades Pediátricas, Chiapas, México.
Supported by internal funds from the Hospital de Especialidades Pediá-
tricas de Tuxtla Gutiérrez, Chiapas, Mexico.
The authors declare no conflict of interest.
Reprints: Jose L. Lepe-Zuniga, MD, DSci, Research Department,
Hospital de Especialidades Pediátricas, Chiapas, SS Juan Pablo II
S/N, Tuxtla Gutiérrez, Chiapas, CP 29070, México (e-mail:
joselepe36@Hotmail.com).
Supplemental Digital Content is available for this article. Direct URL
citations appear in the printed text and are provided in the HTML
and PDF versions of this article on the journal’s website, www.jpho-
online.com.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
J Pediatr Hematol Oncol  Volume 41, Number 1, January 2019
Copyright r 2018 Wolters Kluwer Health, Inc. All rights reserved.
treatment (Early Mortality, EM); meaning those who die
during or as a direct consequence of the initial phase
of treatment known as induction of remission (First
2 months). During this phase a profound transient aplastic
pancytopenia develops in patients as a direct effect of
treatment, impairing their competence for maintaining
normal hemostasis and the ability to cope with infections.
In spite of this precarious transient initial condition, in
the developed world, ALL EM represents only 1% to
3%.7,8 Compared with this prevalence, in Mexico it has
been reported from 5% to 12% in hospitals of the central
part of the country4,9,10 and in our hospital (“Hospital de
Especialidades Pediátricas”; HEP), located in the South,
EM reached 14.6% from 2013 to 2015 (Statistics Depart-
ment, HEP).
Because of the higher rate of ALL EM in our hospital
compared with others, we sought to determine which vari-
ables from before arrival, at arrival at HEP and during
hospitalization until death or first release from the hospital
were significantly associated to EM and if found, propose
modifications for the clinical approach such that we might
improve on EM and on the overall results of ALL treatment
in our patients. We approach the investigation using a case
control design in which all EM cases from 2013 to 2015 were
compared with 84 randomly selected cases who outlived
initial treatment beyond the first 90 days during the same
years.
MATERIALS AND METHODS
We conducted a nonpaired case control study in which
the case group (EM group) consisted of 28 B cell ALL cases
treated at the HEP, between the years 2013 and 2015, who
died within the first 60 days of being admitted for diagnosis
and treatment. Patients that rejected treatment and cases
previously treated for leukemia at any other facility were
excluded. For the control group (CTRL), a list of 84 unique
random numbers was generated out of 162 using Microsoft
Excel 2010, random() function (Microsoft Corp.) and
applied to the consecutive chronological list of the 162 B cell
leukemia patients who had lived beyond the first 90 days
of treatment during the same years (EM:CTRL = 1:3).
For each case in both groups, a number of clinical and
laboratory variables were analyzed. Primary source of
information were the institutional electronic medical
records and the laboratory registry system. Data set
included clinical data at diagnosis in which, fever was
defined as having a temperature of 38°C (100.4°F) or more
within the first 24 hours of admission; hepatomegaly and
splenomegaly were noted when mentioned in the admis-
sion note regardless of size and bleeding diathesis was
considered when WHO grade 2 or more. Data set also
included initial and subsequent laboratory parameters,
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Lepe-Zuniga and Ramirez-Nova J Pediatr Hematol Oncol  Volume 41, Number 1, January 2019

initial risk group assignment (see File, Supplemental RESULTS

Digital Content 1, http://links.lww.com/JPHO/A271 which
demonstrates Risk Groups criteria), leukemia treatment,
blood components support, complications and cause of
death (EM group).
For each group the following variables were also cal-
culated from primary data: Days from initial symptoms to
diagnosis, development of tumor lysis syndrome (TLS)
during the first week according to Cairo and Bishop11 and
nutritional status at diagnosis by two methods: using the
Centers for Disease Control (CDC) growth charts12 and
using the World Health Organization (WHO) Anthro or
Anthro Plus software.13,14 For both methods the reference
values used were weight for length for less than two years
old and body mass index (BMI) for children 2 to 20 years
old. When using the CDC charts, cases were classified in
four categories according to an internal procedure based on
Barlow SE:15 Underweight (Below 5th percentile, Normal
(Percentile 5th to <85th), Overweight (Percentile 85th to
<95th) and Obese (Percentile > 95th). WHO software
classifies cases according to z-score in 6 categories: Severely
wasted (< 3), wasted (< 2), Normal (< 1 to 1), Possible risk
of overweight ( > 1 to 2), Overweight ( > 2 to 3) and Obese
(above 3).16
Statistical Analysis
Each individual variable was compared between
groups. Continuous variables were compared using non-
paired t test. Categorical and ordinal variables were com-
pared using the χ2 square or Fisher exact test when deemed
proper using Epi Info, Version 7.2.0.1, Atlanta, GA. Cen-
ters for Disease Control and Prevention, or the statistical
options of Microsoft Excel 2010, Microsoft Corp. A binary
logistic regression (BLR) model for variables on admission
and outcome was developed using SPSS software (IBM
SPSS Statistics v.21; IBM Corp.). Odds Ratios (OR) and
95% confidence intervals were determined for individual
nominal variables and for those contributing significantly
to the BLR model. A P-value of <0.05 was considered
significant.
Average age was 6.2 years in the EM group (95% CI,
4.5 to 7.9) and 6.6 years in the CTRL group (95% CI, 5.7-
7.4; P = 0.668). Male to female ratio was 1:1 for EM cases
and 1.4:1 for CTRLs (P = 0.44). There was no difference
between groups in time to diagnosis from the start of
symptoms, either in absolute terms (mean = 49 Vs. 41 d;
P = 0.379) or when time was stratified in 15-day periods
(P = 0.941). Clinically, patients in both groups initiated with
fever and weakness with or without pallor and/or bleeding.
In general, patients had received antibiotics for initial
symptoms during the first medical contact and were referred
to our hospital after treatment failure or other findings that
prompted suspicion of malignancy.
In Table 1 results of initial clinical and laboratory
examination are shown. Clinically, there were significantly
more cases in the EM group with fever, hepatomegaly,
splenomegaly and bleeding signs or active bleeding than in
the CTRL group. Fever was related to a specific infection in
6 of 11 febrile EM patients (2 skin abscesses, 2 urinary, 1
ear, 1 digestive) and in 1 of 5 CTRL febrile cases (Diges-
tive). Additional mild to moderate afebrile infections (dental
cavities, skin, oropharyngeal) were identified in 3 EM and in
12 CTRL patients on admission. EM patients had sig-
nificantly lower values for platelets and albumin, higher
values for creatinine and uric acid, and more cases with > 2
times the upper laboratory reference value for lactic dehy-
drogenase [lactate dehydrogenase (LDH); risk factor for
tumor lysis syndrome].17 There were no differences between
groups in hemoglobin, total leukocyte count, stratified leu-
kocyte count, and LDH absolute values.
Morphologic and immunophenotypical classification
of leukemia was comparable between groups with predom-
inance of L1, Pre-B CD10+ cases in both groups (79% and
82%). There were no differences in the proportion of
abnormal karyotypes (EM 16%; CTRL 22%) and the
presence of translocations between groups [EM 3/25 (12%);
CTRL 14/77 (18%)]. Translocations were [t(1;19) EM 1,
CTRL 6; t(12;21) EM 1, CTRL 5; t(4:11) EM 1, CTRL 1,
Other EM 0, CTRL 2]. There were significantly more

TABLE 1. Clinical and Laboratory Parameters of ALL Patients on Admission

Group [n (%)]

Parameters EM (28) CTRL (84) P OR (95% CI)

Fever ( ≥ 38°C;100.4°F) 11 (39) 5 (6.0) 0.001* 10.22 (3.1-33.3)
Hepatomegaly 22 (78.5) 45 (53.6) 0.019* 3.2 (1.2-8.6)
Splenomegaly 20 (71.4) 32 (38) 0.002* 4.0 (1.6-10.3)
Bleeding diathesis 15 (54) 19 (21.4) 0.002* 3.9 (1.6-9.7)
Hemoglobin (g/dL); [X (95% CI)] 7.6 (6.2-9.0) 7.1 (6.4-7.7) 0.436†
Leukocytes (/µL); [X (95% CI)] 43,841 (15,154-72,528) 27,348 (15,458-39,236) 0.223†
< 50,000/µL 21 (75.0) 73 (86.9)
50,000-100,000/µL 4 (14.3) 4 (4.8) 0.216‡
> 100,000/µL 3 (10.7) 7 (8.3)
Platelets (/µL); [X (95% CI)] 44,893 (28,048-61,737) 97,583 (71,881-123,285) 0.026†
Creatinine (mg/dL) [X (95% CI)] 0.72 (0.57-0.87) 0.53 (0.49-0.57) < 0.001†
Albumin g/dL [X (95% CI)] 3.0 (2.75-3.25) 3.3 (3.22-3.47) 0.010†
Uric Acid mg/dL [X (95% CI)] 6.4 (4.3-8.5) 4.8 (4.3-5.4) 0.045†
LDH U/L [X (95% CI)] 825 (576-1075) 733 (500-966) 0.675†
LDH > 542 U/L (2x ULN) 18 (64) 29 (34.5) 0.006* 3.41 (1.4-8.3)
*χ2.
†t test.
‡Fisher exact (Freeman-Halton extension).
CI indicates confidence interval; CTRL, control; EM, early mortality; LDH, lactate dehydrogenase; OR, odds ratio; ULN, upper laboratory normal.

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J Pediatr Hematol Oncol  Volume 41, Number 1, January 2019 Early Mortality Childhood Lymphoblastic Leukemia

TABLE 2. Nutritional Status*

Group Group

CDC† (n) Percentile EM CTRL WHO‡ (n) Z-score EM CTRL

Obese ≥ 95 1 6 Obese >3 0 1
Overweight 85- < 95 3 10 Overweight > 2-3 0 5
Possible risk of overweight > 1-2 5 12
Normal 5- < 85 18 57 Normal < 1-1 18 59
Underweight <5 6 11 Wasted <2 4 6
Severely wasted <3 2 1
Total 28 84 Total 28 84
p (χ2) 0.693 p (χ2) 0.359
* < 2 years Weight for length, 2-20 years BMI for age.
†CDC indicates According to Centers for Disease Control charts.12,15
‡WHO indicates According to World Health Organization Anthro & Anthro Plus software.13,14,16
CTRL indicates control; EM, early mortality.

diploid and less hyperdiploid cases in the EM group (Dip- Treatment and Hospitalization Course
loid: EM 92%, CTRL 72%; P = 0.04, Hyperdiploid: EM 4%,
Antimicrobial Treatment
CTRL 24%; P = 0.027).
Within 24 hours of admission, 19 (68%) EM and 37
Risk stratification on admission did not differ between
(44%) CTRL patients (P = 0.029) with clinical evidence of
groups with most cases assigned to the standard risk group
an infection and/or C-reactive protein above normal,
(Risk distribution was 1,20,4,3 cases for EM low, standard,
received antibiotics after being cultured. Antibiotics used in
high and very high risk and 6,50,19,9 for CTRLs (P = 0.656).
both groups were roughly the same; most prescribed was
Nutritional Status ceftazidime/amikacin (EM, 63%; CTRL, 69%) followed by
Cefotaxime alone or in combination with amikacin or
Results of nutritional assessment using CDC charts dicloxacillin (EM, 37%; CTRL, 35%). Dicloxacillin was
and WHO software are shown in Table 2. Most of patients only used in 1 case in each group where skin infections were
were within normal nutritional status and there were no involved. All initial blood and urine cultures were negative.
significant differences in each nutritional subgroup between After the first antibiotic course, usually within 15 to 30 days
EM and CTRLs. CDC mean percentiles were compared of admission, all remaining EM patients (18; 100%) and 49
between groups and there were no differences [EM 41 (95% (58%) CTRL patients (P < 0.001 Fisher) were started or
CI, 21-42) CTRL 51 (95% CI, 26-40); P = 0.194)]. WHO Z progressed on antibiotic therapy either because they had not
scores means were also compared and again there were no responded to the initial treatment or because they had
differences [EM, −0.23 (95% CI, −0.75-0.29) CTRL 0.05 developed neutropenia and fever (EM, 15/19; CTRL, 34/84;
(95% CI, −0.25-0.34); P = 0.367]. P = 0.004 Fisher), neutropenic colitis (EM, 10/19; CTRL,
A binary logistic regression model including variables 12/84; P < 0.001), an overlapping or a new infection, or
at admission for EM versus CTRL group (continuous var- sepsis (EM, 17/19; CTRL, 21/84; P < 0.001). Secondary and
iables were transformed into nominal at selected cutoff tertiary line antibiotics included the following, usually in
values) showed: fever ( ≥ 38°C), liver enlargement, bleeding combination: Cefepime, Meropenem, Vancomycin, Metro-
diathesis, platelets (< 10,000/µL) and LDH ( > 2X ULN) nidazole, Clindamycin, Trimethroprim/Sulfa, and anti-
contributed significantly to the relevance of the model fungals (Fluconazole and Amphotericin). All CTRL
whereas splenomegaly, creatinine ( ≥ 0.59 mg/dL), albumin patients responded favorably and were eventually off
(< 3.2 g/dL), and uric acid ( ≥ 6.0 mg/dL) did not (Table 3). antibiotics.
The model was significant with χ2 47.9 (P < 0.001), sensi-
tivity of 71.4% and specificity of 88.1% for EM. Positive
predictive value was 66.7% and negative predictive value Leukemia Treatment
was 90.2%. Regardless of initial risk stratification, all treatment
protocols included an initial steroid window for 1 week
followed by 4. In 2 EM patients the steroid window was not
TABLE 3. Binary Logistic Regression Model at Admission administered due to their general condition. The EM
Variables B ET Wald P OR (95% CI) remaining and all CTRL patients received the steroid win-
dow and beyond in comparable amounts. Prednisone was
Fever ≥ 38°C −3.762 0.886 18.035 < 0.0001 43.04 (7.6-244.3) used throughout in most patients [EM, 22/28 (79%); CTRL,
Hepatomegaly −1.417 0.667 4.517 0.034 4.1 (1.1-15.2)
Bleeding −1.466 0.678 4.681 0.03 4.3 (1.1-16.3)
69/84 (82%)]; dexamethasone was used in 2/28 EM and 9/84
diathesis CTRL and dexamethasone followed by prednisone or
Platelets −1.762 0.859 4.209 0.04 5.8 (1.1-31.3) vice versa were used in 2/28 EM and in 6/84 CTRLs
<10,000/µL (P = 0.858). Seven EM patients, including those two that did
LDH > 542 −1.752 0.705 6.165 0.013 5.8 (1.4-23.0) not receive steroids died before any chemotherapy. All others,
U/L EM and CTRL patients, received the amount and type of
Model 4.573 0.869 27.721 0.000 chemotherapy deem adequate and tolerable based on their
B indicates coefficient B; ET, B standard error; LDH, lactate dehydrogenase;
individual clinical and laboratory parameters status using the
Wald, wald statistic; OR odds ratio. national protocols for ALL as a reference (see File, Supple-
mental Digital Content 2, http://links.lww.com/JPHO/A272,

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Lepe-Zuniga and Ramirez-Nova J Pediatr Hematol Oncol  Volume 41, Number 1, January 2019

TABLE 4. Percentage of EM and CTRL Patients Who Received TABLE 5. Complications in 28 EM Patients
Planned Induction of Remission Treatment and Range of Doses
Hospitalization Time Patients
EM CTRL remaining (n)
Treatment (%) Doses (%) Doses
Complication 15 d (28) 30 d (19) 60 d (10)
Intratechal Chemoprophylaxis 42.9 1-2 89 3-4
(Methotrexate 15 mg m2/ Neutropenia and fever 3 9 6
Hydrocortisone 15 mg m2/ Neutropenic colitis 0 5 5
Cytarabine 30 mg m2) Severe sepsis 5 8 9
Steroids 2-33 12-30 Intracerebral hemorrhage 1 3 2
Prednisone 78.6 82.1 Pulmonary hemorrhage 5 2 3
(30-60 mg m2 p.o. q.d) Gastrointestinal bleeding 5 3 3
Dexamethasone 7.1 10.7 Total 19/28 30/19 28/9
(IM 3-6 mg/m2 q.d) Events per patient 0.68 1.6 3.1
Pred-Dexa-Pred 7.1 7.1
Chemotherapy
L-Asparagine 6000-10000 UI/m2 75.0 1-9 96.4 3-9 15 days of admission, 9 additional within a month, and the
IM q.a.d last 10 within 2 months. Overall, 19 (68%) EM patients died
Dauno or Doxorubicin 30 mg/m2 71.4 1-2 96.4 1-2
because of sepsis, 10 patients with sepsis also had severe
IV
Vincristine 1.5 mg/m2 75.0 1-4 100.0 2-5 bleeding, 7 additional patients had only major bleeding as
(max 2.0 mg) the immediate cause of death [total bleeding patients were
Cytarabine 300 mg/m2 IV 3.6 1 75.0 1-3 19/28 (68%)], one patient had an anaphylactic reaction fol-
Etoposide 300 mg/m2 IV 3.6 1 75.0 1-3 lowing intrathecal cytarabine and one died from primary
cardiogenic shock. The immediate cause of death was in
CTRL indicates control; EM, early mortality.
most cases a combination of hemorrhagic, metabolic, and
septic shock, picture that dominated the last days in most
EM patients (Table 6).
which demonstrates Acute Lymphoblastic Leukemia treat-
ment protocols for the first 60 days according to risk strat-
ification).18 Because of their worse clinical condition and DISCUSSION
premature death, compared with CTRLs, EM received about HEP is a 90 bed (5 to 12 intensive care) hospital from
two-thirds initial planned induction of remission therapy and the Federal Public Health System, created to care for mostly
<5% completed the induction protocol (Table 4). Four of the uninsured socio economically disadvantaged families from the
EM patients had achieved remission at the time of death but Mexican southernmost region of Mexico through a “Seguro
only one of them had started the Consolidation treatment Popular” system. The hospital provides full highly specialized
phase (Methotrexate+6-MP). All CTRL patients were in treatment in > 25 board certified pediatric subspecialties to
remission when included and 96% of them had initiated the > 2500 admissions per year—most of them malignancies. Med-
Consolidation Phase by the end of the study period. Only 5 ications and blood products used for treatments are guaranteed
EM and thirteen CTRL patients received in hospital gran- and free of charge. In this context, getting > 14% EM in ALL
ulocyte colony stimulating factor (G-CSF) during the neu- patients compared with around 10% in other similar medical
tropenic period (P > 0.05). centers in the country and to 1% to 3% overseas, was unac-
ceptable and demanded analysis of elements possibly associated
Blood Components Support to the EM as the initial approach for improvement.
During the period studied, with the exception of one EM In agreement with the main objective of the present
and 2 CTRL Jehovah’s Witness, patients received adequate red study, results show that ALL patients who died within the
cell support to keep hemoglobin above 10 g/dL. Pheresis platelet
transfusions (PPT) were given either prophylactically when
platelet count was <20,000/µL or therapeutically when bleeding. TABLE 6. Immediate Cause of Early Death in ALL
Doses were 5 to 10 mL/kg; ≈0.5 to 1.0 ×1010 platelets/kg. More
EM patients (26/28) than CTRLs (57/84) received PPT Hospitalization Period Patients
(P = 0.011). EM patients also received more PPT per case (EM Remaining (n)
mean, 7.1; range, 1 to 23/patient Vs. CTRL mean 3.2; range, ≤ 15 d 16-30 d 31-60 d
1-11/patient; P = 0.009) Cause of Death (28) (19) (10) Total

Tumor Lysis Syndrome Hemorrhagic shock 4 2 1 7

Septic shock 1 3 3 7
During the first week of treatment 10/28 EM cases Primary cardiogenic 1 0 0 1
developed TLS versus 6/84 in the CTRL group (P < 0.001). shock
In 14 of all 16 cases, TLS was defined by hyperuricemia Multiorganic 2 3 5 10
( ≥ 8 mg/dL) plus either hyperkalemia ( ≥ 6 mmol/L or Δ dysfunction*
+25%), hypocalcemia ( ≤ 7 mg/dL or Δ-25%), hyper- Brain death (sepsis/ 0 1 1 2
phosphatemia ( ≥ 6.5 mg/dL or Δ+25%) or a combination of hemorrhage)
these parameters. In the remaining 2, uric acid was within Anaphylactic shock 1 0 0 1
normal limits and TLS was solely defined by abnormalities Total 9 9 10 28
in 2 (1) or 3 (1) of the other defining parameters. *Associated to hemorrhagic, metabolic, and septic shock.
EM patients experienced progressively more compli- ALL indicates Acute lymphoblastic leukemia.
cations per patient (Table 5). Nine EM patients died within

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J Pediatr Hematol Oncol  Volume 41, Number 1, January 2019
first 60 days at our hospital between 2013 and 2015, share
several clinical and laboratory features on admission that
defined them as a High-Risk EM population (HREM). The
HREM general picture was that of any age and gender
pediatric patients arriving at HEP from other medical unit
with fever ( ≥ 38°C; 100.4°F)—caused by an infection not
properly treated before arrival—, with liver enlargement,
active bleeding diathesis associated with less than 10,000
platelets/µL, certain degree of renal impairment (suggested
by creatinine ≥ 0.59 mg/dL, and albumin <3.2 g/dL), and at
risk for tumor lysis syndrome (uric acid ≥ 6.0 mg/dL and
LDH > 542 U/L). It is also noticeable that there were
clearly less HREM patients with hyperdiploidy than in the
CTRL group, suggesting that hyperdiploidy might be a
favorable prognosis factor not only for long but for short
term outcome as well.19
In the HREM picture it is noteworthy the lack of ele-
ments traditionally related to prognosis (usually long term),
like age, time to diagnosis, initial number of leukocytes,
nutritional status, and risk group assignment. Nutritional
status effect on ALL treatment outcome has been con-
troversial, even within our own country, with some studies
relating malnutrition to poor outcome20,21 and others (more
recently) not showing any relationship with EM.9,22 One
possibility for the discrepancy is that studies refer to dif-
ferent populations (private vs. public; urban vs. rural, poor
vs. wealthy, etc.) or different time for outcome (short term
vs. long term) or to the same populations that have evolved
over time. Our results are in line with those of Martín-Trejo
et al9 in central Mexico, a thorough, well planned, recently
made collaborative study of the main public health care
institutions in our country where no relationship of nutrition
status (assessed in several ways) to death within a year of
diagnosis was found.
The binary logistic regression model including relevant
variables at arrival reasonably predicted the final outcome
of HREM patients suggesting that their hospitalization
course and fate was mostly determined from the beginning
by their clinical and laboratory situation at arrival. Indeed,
more HREM patients than CTRLs later developed TLS,
neutropenia and fever, neutropenic colitis, severe and
overlapping infections and sepsis. The septic picture was
associated with persistent thrombocytopenia throughout
leading to severe bleeding, more red cells, and platelet
transfusions than CTRLs and a progressive worsening of
their general condition over time ending up with a combi-
nation of septic, hypovolemic and metabolic shock, and
severe bleeding in major organs.
Noticeable, there were no major differences in the
medical approach to the HREM compared with CTRLs; all
patients were initially treated at HEP with a standard
antibiotic scheme and once diagnosed with ALL, given the
amount clinically possible of similar antileukemic treatment
protocols in both groups.
Because of our findings, it can be suggested that ALL
suspected patients, with the characteristics described herein
for the HREM group, require a special medical approach to
avoid EM. From the variables identified as relevant for EM
in the present study, the special approach might include,
among other elements, a policy for initial antibiotic pre-
scription that takes into account the generalized usage of
newly developed antibiotics in primary care centers,23 the
possibility of a previous hospital acquired antibiotic resist-
ant infection,24,25 the inclusion of recent molecular biology
techniques for prompt identification of causative infectious
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Early Mortality Childhood Lymphoblastic Leukemia
agents,26 an initial formal renal function assessment and
management by nephrologists according to recent
guidelines,27,28 a uniform policy agreed upon by nephrolo-
gists, oncologists and emergency service personnel for TLS
prevention and treatment and a special effort for prompt
and effective platelet replacement.29 But, perhaps the most
important element to include in this special approach would
be to reconsider the timing of steroids usage. Steroids are
cytotoxic for malignant but also for normal lymphocytes,
causing acute T and B lymphopenia/cytolysis and the con-
sequent immune deficiency and overload of the kidneys with
uric acid leading to or worsening TLS.30 Steroids have also
been long known to increase susceptibility to infections by
several means; T cell suppression, inhibition of phagocytosis
and dampening other immune system components.31–33
Because of these facts, their use as soon as the diagnosis of
ALL is made in HREM patients, when they are struggling
to fight an infection under uric acid overload and certain
degree of renal impairment, has to be carefully considered
and balanced against the need to decrease the leukemic
mass. In the HREM setting it might be wiser holding off
steroids for the time needed to control the initial infection
and the renal function fully recovers. Infectious disease
specialists and nephrologists could jointly approve the tim-
ing and modulation of their use according to patient
response. HREM patients can then go on to chemotherapy
in a better general condition and achieve remission.
These suggestions could be clinically tested to deter-
mine their impact on EM and if successful inserted within
the general standards for providing optimal care in pediatric
patients with acute lymphoblastic leukemia in our hospital.34
From a larger perspective, the in-house special
approach proposed could benefit by an effort for a more
suitable handling of potential ALL patients in primary care
centers within the State; including a policy for antibiotic use,
better communication with tertiary care centers like HEP
for prompt referral, access to specialized testing and edu-
cational activities to enhance awareness of the special needs
of potential ALL patients.
The present findings have the limitation of being
derived from a unique population and hospital in the State
of Chiapas and might not be extrapolated to other regions
of the country or to other countries. Yet, they can certainly
be the basis for any effort to modify the local high EM rate
avoiding unnecessary deaths and to help reaching the goal
of achieving > 90% long term remissions for this disease in
our hospital and in our country.
ACKNOWLEDGMENT
The authors acknowledge the participation of Dr Benito
Salvatierra-Izaba for the critical review of the statistical data
in the manuscript.
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