Journal of the Pediatric Infectious Diseases Society

ORIGINAL ARTICLE

Epidemiology of Diarrheal Illness in Pediatric Oncology

Patients
Mohammad N. Mhaissen,1 Alicia Rodriguez,2 Zhengming Gu,2 Haiqing Zhu,2 Li Tang,3 Yilun Sun,3 Stacey T. Schultz-Cherry,1,4 Randall T. Hayden,2
Elisabeth E. Adderson1,5 
1
Department of Infectious Diseases; 2Department of Pathology; 3Biostatistics, St. Jude Children's Research Hospital; 4Department of Microbiology, Immunology and Biochemistry,
and 5Department of Pediatrics, University of Tennessee Health Sciences Center, Memphis

Background.  Diarrhea is common in children with cancer, but this has not been systematically studied to date.
Methods.  Remnant stool samples collected between January 2010 and June 2011 from pediatric oncology patients with diar-
rhea were tested for bacterial, viral, and parasitic enteropathogens using a combination of standard-of-care (SOC) diagnostic tests,

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including broad-range, real-time polymerase chain reaction (PCR) assays for adenoviruses, astroviruses, and sapoviruses and 2
commercially available multiplexed PCR assays. Corresponding demographic and clinical data were abstracted from patients' med-
ical records.
Results.  One hundred fourteen episodes of diarrhea in 93 patients (median age, 3.7 years; range, 0.2–18.8) were included in the
study. No patients died, but morbidity was significant. A total of 158 potential pathogens were detected in 114 diarrhea episodes,
with >1 organism in one third of these; the most common were Clostridium difficile, noroviruses, adenoviruses, and astroviruses.
Clostridium difficile, in combination with norovirus or adenovirus, was most common when >1 pathogen was detected. When both
studies were obtained, SOC and broadly multiplexed PCR tests were concordant in 64 episodes (56%). Forty-five pathogens (28%)
were identified retrospectively by broadly multiplexed PCR assays only. A total of 19 (13%) were detected by SOC real-time PCR
assays but not by either commercially available multiplexed PCR assay.
Conclusions.  Most pediatric oncology patients in this study had 1 or more potential infectious causes for their diarrhea.
Additional studies are warranted to understand the natural history of gastroenteritis in this patient population. Although broadly
multiplexed PCR assays offer some advantages over conventional testing, there may be disadvantages to their use for the diagnosis
of infectious gastroenteritis that are unique to pediatric oncology patients.
Keywords.  diarrhea; gastroenteritis; oncology; pediatric; american Lebanese Syrian Associated Charities.

Diarrheal illnesses are a common cause of morbidity and cause unusually severe or disseminated infections in immuno-
occasional mortality in children undergoing cancer therapy compromised patients, protracted illness, or prolonged asymp-
[1, 2]. The etiological spectrum of these illnesses is broad and tomatic shedding [5–10]. However, many such reports include
includes disorders that are unique to this population (such as small numbers of cases, and the contribution of individual
diarrhea related to malignancies and chemotherapeutic medi- pathogens to the overall burden of gastrointestinal disease in
cations) and some that are common to all children [3]. Despite pediatric oncology patients is not well understood.
its clinical importance, the epidemiology of gastroenteritis in Obstacles to characterizing infectious diarrhea in children
children with cancer has not been systematically characterized. with cancer include the large number of potential pathogens, the
Studies suggest that the clinical manifestations of infectious gas- limited availability of diagnostic tests for some of these organ-
troenteritis in pediatric cancer patients may differ from those isms (especially recently recognized causes of gastroenteritis),
of otherwise healthy children or children with other comor- and the limited sensitivity of conventional diagnostic methods
bid conditions. Cancer, for example, has been identified as an (such as stool culture and antigen testing). Multiplexed molec-
important predisposing factor for Clostridium difficile-associ- ular amplification assays that are able to identify a broad range
ated colitis in hospitalized children [4]. Some reports suggest of gastrointestinal pathogens have a number of potential advan-
that other conventional and emerging enteropathogens may tages over traditional tests, including timely results, an overall
greater analytic sensitivity and specificity than conventional
Received 1 March 2016; accepted 25 July 2016; published online August 30, 2016. techniques, the ability to rapidly detect a wide range of entero-
Correspondence: E. E. Adderson, MD, Mailstop 320, 262 Danny Thomas Place, Memphis, TN
38105. ([email protected]).
pathogens simultaneously, and the capability of differentiating
Journal of the Pediatric Infectious Diseases Society   2017;6(3):275–80 pathogen subtypes [11]. These new diagnostic tests offer the
© The Author 2016. Published by Oxford University Press on behalf of the Pediatric Infectious opportunity to gain a more comprehensive picture of the epi-
Diseases Society. All rights reserved. For Permissions, please e-mail: journals.permissions@
oup.com.
demiology of infectious diarrhea in pediatric oncology patients.
DOI: 10.1093/jpids/piw050 To inform future studies of the epidemiology of infectious

Diarrhea in Pediatric Cancer Patients  • JPIDS 2017:6 (September) • 275

diarrhea in pediatric oncology patients, we retrospectively iden- as previously described [11]. We previously reported that the
tified gastrointestinal pathogens in pediatric oncology patients performance of the BioFire and Luminex systems was compa-
with diarrhea, using both conventional and broadly multiplexed rable when evaluated using a collection of stool samples that
amplification techniques. partially overlapped with those included in this study [11].
Detection of a gastrointestinal pathogen by any method was
MATERIALS AND METHODS regarded as a positive test, although these may not have been
causally related to an episode of diarrhea, because confirmatory
Study Design
tests were not obtained in real-time or as part of this retrospec-
St. Jude Children's Research Hospital (St. Jude) provides com-
tive analysis.
prehensive care for approximately 6000 children with cancer
and other immunocompromising conditions annually. Stool
Statistical Analysis
specimens obtained from pediatric oncology patients that were
Statistical analysis was performed using the SAS 9.3 (SAS
submitted to the St. Jude Diagnostic Microbiology laboratory
Institute, Inc., Cary, North Carolina). Descriptive statistics
over an 18-month period from January 2010 to June 2011 were
are presented as frequencies and percentages for categori-

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selected for inclusion based on the availability of remnant stool
cal variables or median and range for continuous variables.
specimens for comprehensive molecular diagnostic testing.
Demographic and clinical characteristics were compared using
Patients with recent hematopoietic stem cell transplant (within
Fisher's exact or Wilcoxon–Mann–Whitney tests, as appropri-
12 months) were excluded. An episode of diarrhea was defined
ate. P values <.05 (2-tailed test) were considered statistically
as the onset of loose stools of sufficient severity that healthcare
significant.
providers were prompted to initiate a diagnostic evaluation, and
that began at least 14  days after the resolution of any preced-
RESULTS
ing diarrheal illness. If multiple stool specimens were received
during an episode of diarrhea, only the results of the first spec- A total of 185 distinct diarrheal episodes affecting 146 patients
imen were included in the analysis. Demographic and clinical were identified during the study period. Patient demographic
characteristics, including age, sex, underlying malignancy and characteristics and the signs and symptoms observed during
therapy, recent antimicrobial therapy (within the preceding their illnesses are summarized in Table  1. Molecular testing
30 days), symptoms at presentation, results of laboratory inves- using the BioFire and Luminex systems was performed on
tigations, and outcomes were abstracted from the health infor- specimens from 114 episodes affecting 93 patients. The char-
mation records. Standard-of-care (SOC) diagnostic tests were acteristics of these episodes and patients were similar to the
ordered at the discretion of treating physicians; not all patients overall group. Most (89%) of the patients had received anti-
had had the full range of SOC tests obtained during a given epi- microbials in the 30 days preceding their illness, and 81% had
sode of diarrhea. Fever was defined as an oral temperature >38o received cancer chemotherapy. Two patients had undergone
C. The St. Jude Institutional Review Board approved this study hematopoietic stem cell infection >1  year before their illness;
with waiver of consent. neither had graft-versus-host disease. Patients were relatively
young (median age, 3.7 years). Most had solid tumors and were
Diagnostic Testing neutropenic and lymphopenic at the onset of diarrhea. These
Standard-of-care microbiological diagnostic tests used during illnesses were associated with significant morbidity—45% of
the study period included the detection of C difficile tcdB outpatients were hospitalized, over half of these with fever and
and cdt genes by real-time polymerase chain reaction (PCR) neutropenia. Hemodynamic instability was reported in 10% of
(GeneXpert C difficile System; Cepheid, Sunnyvale, CA), patients and dehydration was reported in 6%.
Shiga-like toxins A  and B by immunochromatographic rapid A total of 158 potential pathogens were identified in 114
assay (ImmunoCard STAT! EHEC; Meridian Bioscience, Inc., diarrhea episodes (95%) (Table  2). Overall, results of broadly
Cincinnati, OH), and rotavirus, Cryptosporidium parvum and multiplexed PCR and SOC testing were concordant in 64 epi-
Giardia intestinalis antigens by enzyme-linked immunoassay sodes (56%). A total of 45 enteropathogens in 39 episodes were
(Premier Rotaclone and ImmunoCard STAT! Crypto/Giardia; identified retrospectively by broadly multiplexed PCR assays
Meridian Bioscience, Inc.) as well as by in-house designed real- only, either because clinicians did not order SOC tests for these
time PCR assays for detection of human adenovirus, astrovi- pathogens (n = 19), no SOC test was available (n = 5, all patho-
rus, norovirus, and sapovirus. (Supplementary Table S1). Stool genic Escherichia coli), or because organisms were not detected
samples were also tested in parallel using 2 broadly multiplexed by SOC tests (ie, a potential false-negative result; n = 21). The
PCR assays (FilmArray Gastrointestinal [GI] Panel [BioFire latter included Entamoeba histolytica (n = 7, all detected by
Diagnostics, Salt Lake City, Utah] and xTAG Gastrointestinal Luminex only), Salmonella spp (n = 6; all detected by Luminex
Pathogen Panel [GPP] [Luminex Corporation, Austin, Texas]), only), norovirus GI/GII (n = 5; all detected by Luminex only), C

276  • JPIDS 2017:6 (September) •  Mhaissen et al

Table 1.  Demographic and Clinical Characteristics of Patients and States (Florida [n = 2], Virginia, Michigan, and Missouri [n =
Diarrheal Episodes
1 each]). Vibrio cholerae was detected in the stool of 1 patient
by BioFire. Positive results for most E histolytica and V chol-
Patients
erae were considered unlikely to be true positives, based on the
Included in Analysis
patients' demographic and clinical characteristics.
Total (n = 146) (n = 93)
A total of 19 enteropathogens were detected in 19 episodes
Hematological malignancy (%) 60 (41) 41 (44)
Nonbrain tumor solid tumor (%) 32 (22) 11 (12) of diarrhea by SOC real-time PCR assays but not by either
Brain tumor (%) 54 (37) 41 (44) broadly multiplexed PCR assay. These included adenovirus (n =
Episodes 11), astrovirus (n = 6), norovirus (n = 1), and sapovirus (n = 1).
Included in Analysis More than 1 potential pathogen was identified in 36 of 108
Total (n = 185) (n = 114) diarrheal episodes (33%) in which tests were positive. The most
Median age (yr, IQR) 3.8 (2.1–8.7) 3.7 (2.0–7.2) common codetected pathogens included C difficile and noro-
Median ANC (mm3, IQR) 900 (100–3100) 900 (0–2800)
virus (n = 15) and C difficile and adenovirus (n = 8). Patients
Median ALC (mm3, IQR) 700 (366–1222) 756 (429–1330)
with more than 1 organism detected were more likely to present

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Outpatient (%) 113 (61) 78 (68)
If outpatient, hospitalized due to illness (%) 56 (50) 35 (45) with dehydration and had a longer duration of diarrhea than
Fever (%) 108 (58) 63 (55) those with a single organism (Table  3), but, otherwise, these
Fever and neutropenia (%) 63 (58) 35 (57) episodes did not seem more severe than those during which a
Hemodynamic instability (%) 16 (9) 11 (10) single pathogen was detected. The characteristics of episodes in
Dehydration (%) 10 (5) 7 (6)
which C difficile, norovirus, or astrovirus were detected as sole
Bloody diarrhea (%) 8 (4) 5 (4)
Abdominal pain (%) 42 (23) 26 (23)
pathogens are summarized in Table 4. Patients with astrovirus
Abdominal tenderness (%) 23 (12) 15 (13) as a single pathogen were more likely to have fever than those
Nausea/vomiting (%) 59 (32) 35 (31) with only C difficle or only norovirus, and patients with norovi-
Median duration of diarrhea (days, IQR) 5 (3–11) 5 (3–11) rus had a longer median duration of diarrhea (6 days vs 4 days),
Abbreviations: ALC, absolute neutrophil count; ANC, absolute neutrophil count; IQR, interquartile range. but the small numbers of episodes and clinical heterogeneity of
patients precludes detailed analysis.
difficile (n = 2; detected by both BioFire and Luminex), Giardia
(n = 1; detected by both BioFire and Luminex), and adenovirus DISCUSSION
F 40/41 (n = 1; detected by both BioFire and Luminex). Two
The aim of this study was to describe infectious diarrhea in
patients with stools positive for E histolytica resided outside the
pediatric oncology patients and the potential utility of includ-
United States before their cancer diagnosis (1 each in Mexico
ing broad-based multiplexed PCR assays in the management
and China), whereas the others had lived only in the United
of these diseases. Our results confirm that considerable mor-
bidity is associated with diarrheal illness in this population.
Table 2.  Potential Pathogens Identified in 114 Episodes of Diarrhea
by Either Standard of Care or Broadly Multiplexed Polymerase Chain Patients required fluid resuscitation or inotropic support in
Reaction Assays almost 10% of episodes, and diarrhea persisted for a median
of 5 days. Almost half of the patients who were outpatients at
Pathogen Number (%) the time of onset of their diarrhea were hospitalized for obser-
Clostridium difficile 58 (51) vation or treatment. Fever and neutropenia were common, and
Norovirus GI/GII 36 (32)
this, rather than the severity of gastroenteritis per se, may have
Adenovirus F40/F41 17 (15)
Astrovirus 10 (9)
prompted hospitaliations.
Entamoeba histolytica 9 (8) Most (95%) of the patients in this study had 1 or more
Salmonella spp 7 (6) enteropathogens detected during episodes of diarrhea, a higher
Sapovirus 6 (5) rate than has been reported in otherwise healthy children with
Escherichia coli† 5 (4) community-acquired gastroenteritis using similar molecular
Cryptosporidium spp 3 (3)
diagnostic tests [12–14]. However, it is not clear what propor-
Giardia lamblia 2 (2)
Rotavirus A 2 (2)
tion of these organisms are causally associated with diarrhea
Aeromonas spp 1 (1) in this population. Recent studies suggest that symptomatic
Shigella spp 1 (1) shedding of enteropathogens is common in young children.
Vibrio spp 1 (1) For example, almost 80% of Dutch childcare center attendees
No pathogen detected 6 (5)
who were systematically evaluated using molecular techniques
*Test performed but not detected: Campylobacter spp, Cyclospora cayetanensis, enteroaggregative had 1 or more of 16 enteropathogenics identified in randomly
E coli, enterotoxogenic E coli, Pleisiomonas shigalloides, Yersinia enterocolitica.
†
Includes enteropathogenic E coli (n = 3) and enteroinvasive E coli (n = 1). selected stool samples [15]. Only rotavirus and norovirus were

Diarrhea in Pediatric Cancer Patients  • JPIDS 2017:6 (September) • 277

Table 3.  Demographic and Clinical Characteristics of Patients According to the Presence of Potential Copathogens

Overall (n = 108) Single Pathogen (n = 72) Multiple Pathogens (n = 36) P Value*

Median age (yr, IQR) 3.5 (2.0–7.1) 3.8 (1.9–7.5) 2.9 (2.1–6.4) .73
Median ANC (mm3, IQR) 900 (100–2800) 900 (100–3300) 1200 (0–2500) .37
Median ALC (mm3, IQR) 770 (400–1330) 710 (325–1170) 934 (429–2108) .24
Fever (%) 59 (55) 41 (57) 18 (50) .54
Outpatient (%) 75 (69) 47 (65) 28 (78) .27
If outpatient, hospitalized due to 33 (44) 22 (47) 11 (39) .63
illness (%)
Hemodynamic instability (%) 11 (10) 8 (11) 3 (8) .75
Dehydration (%) 6 (6) 1 (1) 5 (14) .015
Bloody diarrhea (%) 5 (5) 4 (6) 1 (3) .66
Abdominal pain (%) 24 (22) 17 (24) 7 (19) .81
Abdominal tenderness (%) 13 (12) 10 (14) 3 (8) .54
Abdominal distension (%) 8 (7) 6 (8) 2 (6) .72

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Nausea/vomiting (%) 34 (31) 20 (28) 14 (39) .28
Median duration of diarrhea (day, IQR) 5 (3–11) 4 (3–9) 9 (3.5–18.5) .016

Abbreviations: ALC, absolute neutrophil count; ANC, absolute neutrophil count; IQR, interquartile range.
*P values from Fisher's exact tests or Wilcoxon–Mann–Whitney tests.

associated with diarrhea in this study, suggesting that a posi- the overall group. Norovirus has also been detected for several
tive test did not necessarily imply that pathogens that were weeks to months in the stools of immunocompromised persons
detected were causally associated with disease. The interpreta- with serial episodes of diarrhea [9, 17, 18].
tion of positive stool tests for enteropathogens in children and More than 1 potential enteropathogen was detected in one
children with cancer is more complicated, because prolonged third of the episodes of diarrhea in this study. Again, this is
excretion, persistent colonization, or relapsing and remitting somewhat higher than the rates of codetection that have been
clinical courses have been reported for many enteropathogens. reported in otherwise healthy children with community-ac-
For example, Dominguez et  al [16] that found almost 30% of quired gastroenteritis [19]. A  greater likelihood of prolonged
pediatric oncology patients without gastrointestinal symptoms colonization and shedding may contribute to the high rates of
had positive surveillance tests for C difficile at the time of hospi- codetection of pathogens in the children in this study. However,
tal admission, and over half remained persistently or intermit- pediatric oncology patients may also have greater susceptibility
tently colonized over the subsequent 20 weeks. Asymptomatic or increased exposure to infections caused by these organisms;
colonization with C difficile is particularly common in children larger prospective studies are needed to evaluate these possibil-
<1  year of age. This organism was detected in the stools of 3 ities. We found that patients with multiple pathogens identified
of the 10 infants included in this study, compared with 51% of in their stool had a greater duration of diarrhea and likelihood

Table 4.  Demographic and Clinical Characteristics of Patients With Selected Pathogens*

Single Pathogen: Clostridium difficile (n = 35) Single Pathogen: Norovirus (n = 15) Single Pathogen: Astrovirus (n = 6)
Age (year, IQR) 3.9 (1.6–9) 3.8 (1.1–7.4) 2.1 (1.7–11.5)
Median ANC (mm3, IQR) 900 (100–4500) 1050 (0–2200) 950 (100–1600)
Median ALC (mm3, IQR) 777 (480–1247) 700 (198–1219) 1005 (504–1034)
Outpatient (%) 22 (63) 9 (60) 4 (67)
If outpatient, hospitalized due to illness (%) 8 (36) 4 (44) 3 (75)
Fever (%) 19 (54) 8 (53) 6 (100)
Hemodynamic instability (%) 4 (11) 2 (13) 0 (0)
Dehydration (%) 0 (0) 0 (0) 1 (17)
Bloody diarrhea (%) 1 (3) 2 (13) 0 (0)
Abdominal pain (%) 9 (26) 4 (27) 1 (17)
Abdominal tenderness (%) 5 (14) 2 (13) 1 (17)
Abdominal distension (%) 2 (6) 1 (7) 1 (17)
Nausea/vomiting (%) 8 (23) 2 (13) 1 (17)
Median duration of diarrhea (day, IQR) 4 (2–11) 6 (3–10) 4 (2–4)

Abbreviations: ALC, absolute neutrophil count; ANC, absolute neutrophil count; IQR, interquartile range.
*Other pathogens were identified in less than 5 episodes.

278  • JPIDS 2017:6 (September) •  Mhaissen et al

of dehydration than did those with single pathogens, suggesting some of the causes of infectious diarrhea that may undergo
that true coinfections may occur and might be associated with year-to-year variability. Episodes of diarrhea were not selected
more severe disease. randomly for inclusion in this study, although inclusion was
A pathogen was not identified in 5% of diarrheal episodes based on the availability of archived specimens for analysis and,
in this study. Although these illnesses may have had a nonin- thus, unlikely to introduce significant bias.
fectious etiology, the diagnostic tests used in this study did not
target all causes of gastroenteritis in children (including some CONCLUSIONS
that may not be currently recognized) or all strains of some
pathogens [20–22]. Therefore, it is possible that emerging or Our data suggest that most pediatric cancer patients with diarrhea
unrecognized microorganisms may be responsible, alone or in have enteropathogens present in their stool and that codetection
combination, for some of the illnesses of children in this study. of organisms is common. Although broadly multiplexed PCR
Although the broadly multiplexed PCR assays tested in this assays are rapid and convenient, our data suggest that these diag-
study have the potential to provide both (1) an opportunity to nostic tests may have widely varying sensitivity and specificity in
simultaneously detect more pathogens (particularly E coli in this patient population, due to limitations in the range of targeted

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this study) and (2) greater sensitivity and specificity than con- pathogens and in internal validity. Additional studies are needed
ventional techniques, this study suggests that further evalua- to better understand the natural history of diarrheal diseases in
tion is required to understand the role of these new methods this population (the role of these agents in symptomatic gastro-
in the management of pediatric oncology patients. As previ- enteritis, in particular) and the utility of conventional and new
ously reported, poor concordance between these assays and diagnostic tests for infectious diarrhea in pediatric cancer patients.
between these assays and SOC testing was particularly notable
for adenovirus, norovirus, E histolytica, and Salmonella spp Supplementary Data
[11]. Whereas the multiplexed PCR tests detect only adenovi- Supplementary materials are available at Journal of the Pediatric Infectious
Diseases Society online.
rus types 40 and 41, the SOC adenovirus PCR used in this study
was designed to amplify both enteric and nonenteric serotypes
Notes
of virus [11, 23]. Likewise, the laboratory-developed assay for
Financial support.  This work was supported by the American Lebanese
astrovirus incorporated primers and probes for the detection Syrian Associated Charities. BioFire provided reagents and instrumenta-
of astrovirus types 1 to 8 and noncanonical strains MLB1 and tion. Luminex provided reagents.
VA2. This broader range of targets probably explains the larger Potential conflicts of interest.  R.  T. H.  previously served on the
Scientific Advisory Board for BioFire.
number of these viruses identified by SOC in large part. All authors have submitted the ICMJE Form for Disclosure of Potential
Overall rates of detection were higher for Luminex than Conflicts of Interest. Conflicts that the editors consider relevant to the con-
BioFire for pathogens that were targeted by both multiplexed tent of the manuscript have been disclosed.
systems. In 7 instances, E histolytica was detected by Luminex
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280  • JPIDS 2017:6 (September) •  Mhaissen et al