A Case of Adult Intestinal Toxemia Botulism During Prolonged Hospitalization in an Allogeneic Hematopoietic Cell Transplant Recipient
Botulism in a BMT During Hospitalization • CID
A Case of Adult Intestinal Toxemia Botulism During Prolonged Hospitalization in an Allogeneic Hematopoietic Cell Transplant Recipient
Lalitha Parameswaran 2
Agam Rao 1
Katherine Chastain 0
Joel Ackelsburg 6
Eleanor Adams 5
Brendan Jackson 1
Louis P. Voigt 4
Xi Chen 3 8
Farid Boulad 0 8
Ying Taur 2 7 8
0 Department of Pediatrics, Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center , New York , USA
1 Enteric Diseases Epidemiology Branch, Division of Foodborne , Waterborne, and Environmental Diseases , National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention , Atlanta , Georgia
2 Department of Medicine, Infectious Disease Service, Memorial Sloan Kettering Cancer Center , New York , New York
3 Department of Neurology, Memorial Sloan Kettering Cancer Center , New York , USA
4 Department of Medicine, Critical Care Medicine Service
5 New York State Department of Health , Albany , USA
6 Bureau of Communicable Disease, New York City Department of Health and Mental Hygiene , New York , USA
7 Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan-Kettering Cancer Center , New York , New York
8 Weill Cornell Medical College , New York , USA
We report a laboratory-confirmed case of adult intestinal toxemia botulism in an allogeneic hematopoietic stem cell transplantation (allo-HCT) recipient. Onset of symptoms occurred within the hospitalized setting, making this case particularly unique. Botulism may have arisen because of significant intestinal disruption and compromise, and not directly from immune compromise.
A 27-year-old male with Fanconi anemia and secondary
myelodysplastic syndrome underwent a T-cell–depleted allo-HCT
from his human leukocyte antigen (HLA)-haploidentical
mother 4 months before the case presentation. His
post-transplantation course was marked by CMV viremia for which he
was receiving ongoing treatment with oral valganciclovir. In the
weeks preceding this hospitalization, he experienced nausea,
vomiting, and abdominal pain. He was initially diagnosed with
Clostridium difficile–associated diarrhea based on laboratory
testing and was treated with metronidazole without
improvement. Endoscopic biopsy of the upper gastrointestinal tract
to evaluate for graft-versus-host disease (GVHD) was
inconclusive. He had mild improvement in symptoms while taking
empiric oral budesonide therapy.
Despite valganciclovir maintenance therapy, the patient’s CMV
viremia persisted, and he was hospitalized for treatment with
intravenous ganciclovir, followed by additional therapies for CMV,
including foscarnet, intravenous immune globulin (IVIG),
CMVspecific immune globulin (CMV-IG), and 3 doses of
donor-derived cytotoxic T lymphocytes (Figure 1A). His hematologic and
immunologic functions during this period were normal.
During the first 50 days of hospitalization, the patient
continued to experience nausea and diarrhea. Stool studies were
unrevealing for bacterial or viral causes. A colonoscopy with
biopsy showed chronic mucosal injury of unclear etiology.
On hospital day 56, after 3 days of constipation, the patient
developed unremitting abdominal pain. He also reported
blurry vision. Over the next 2 days, he sequentially
developed bilateral ptosis, slurred speech, difficulty swallowing,
and shortness of breath, which led to respiratory insufficiency
that required endotracheal intubation. A neurological exam
revealed cranial nerve deficits and normal sensation and
strength in the limbs. By hospital day 59, he had developed
complete ophthalmoplegia with asymmetric pupils that were
poorly reactive to light.
30 Hz. Needle EMG revealed fibrillations and positive waves,
food and nutrition records. Throughout this period, he was
with a myopathic recruitment pattern that consisted of small,
maintained on a low-microbial diet, which is standard for all
brief, polyphasic motor unit potentials. Testing of cerebrospinal
HCT recipients at our institution during the first months
folfluid showed normal protein and glucose and absence of white
lowing transplantation. Although he was placed on additional
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dietary restrictions at various times, including a BRAT (bananas,
rice, applesauce, and toast) diet and low-fat diet for management
of gastrointestinal symptoms, the low-microbial diet was strictly
adhered to. This diet included well-cooked meat, poultry, fish,
and eggs; pasteurized dairy products; and cooked or well-washed
and peeled thick-skinned fruits and vegetables. Raw honey was
never used. Additionally, all food was prepared and stored in a
highly controlled environment in which all staff had undergone
extensive food safety training. Routine temperature checks were
used to ensure that all food was cooked to safe temperatures and
all canned goods were inspected for dents and swelling prior to
use. All foods consumed by the patient were from the hospital’s
food and nutrition service. The one exception was a plain cheese
pizza bought from an outside local restaurant, which was
consumed hot and shared with family members.
Consultants at the Centers for Disease Control and
Prevention (CDC) believed foodborne or wound botulism was
unlikely. Botulism antitoxin was not administered, but
laboratory testing was performed. Initially, a lack of stool output due
to adynamic ileus precluded stool sample collection;
washings from a sterile water enema were sent instead, along with
serum. Stool output was later accomplished with repeated tap
water enemas and was also submitted for testing. Tests of the
sterile water enema and serum were negative. However, on
hospital day 78, stool testing demonstrated the presence of
botulinum neurotoxin A by mouse bioassay, growth of C. botulinum
organisms in culture, and detection of botulinum neurotoxin
genes types A and B by polymerase chain reaction assay. Based
on these results, the patient was promptly treated with
botulism antitoxin heptavalent (A, B, C, D, E, F, G)–(Equine) (BAT,
Emergent BioSolutions), obtained through the CDC.
Two days after receiving BAT, the patient developed asystolic
cardiac arrest following complete airway occlusion due to mucus
plugging. He was resuscitated but remained unresponsive. Brain
imaging showed multiple hemorrhages and cerebellar
herniation, raising suspicion for brain death. Following discussion with
his family, ventilator support was removed and he died.
Here, we describe a case of botulism due to adult intestinal
toxemia in a patient who had received an allo-HCT. This case
is notable because botulism was not easily recognized; illness
onset occurred almost 2 months into hospitalization for a
complex illness; risk factors for foodborne and wound botulism were
absent. Typically, antitoxin treatment is administered based on
clinical suspicion for botulism based on a patient’s clinical
presentation; confirmatory specialized laboratory testing for
botulism is performed after treatment is initiated. Atypically, in this
case, because of the rare and complicated clinical picture,
laboratory testing led to treatment. Adult intestinal toxemia
(intestinal colonization) was the most likely cause of this patient’s
botulism. Foodborne botulism was exceedingly unlikely as
the patient almost exclusively ate low-microbial hospital food
that was carefully prepared under strict standards for weeks
preceding symptom onset and no other cases of botulism were
identified at the hospital. Wound botulism was also unlikely as
the patient had no infected wound identified. The detection of
botulinum neurotoxin type A, viable C. botulinum type A, and
genes for toxin type A production in the gut 3 weeks after onset
of disease (Figure 1A) further support the diagnosis of adult
intestinal toxemia botulism.
Adult intestinal toxemia is incompletely understood. Like
infant botulism, toxin production occurs endogenously within
the gastrointestinal tract in a person harboring C. botulinum.
Although C. botulinum spores are routinely ingested and excreted
by humans, the adult intestinal tract does not support spore
germination and toxin production under normal circumstances [
In previously identified cases of adult intestinal toxemia, patients
had anatomic or functional abnormalities of the gut due to
surgery, inflammatory bowel disease, or antibiotic-induced
perturbation of gut flora [
]. In allo-HCT patients, gastrointestinal
symptoms and significant disturbances of the intestinal
microbiota are common . This patient had experienced vomiting and
diarrhea for many weeks that might have been caused by intestinal
GVHD, infections with opportunistic pathogens such as CMV, or
both; colonoscopic biopsy documented chronic mucosal injury.
These intestinal disturbances might in some way parallel those
seen in previously reported cases of adult intestinal toxemia, as
described above, yet to our knowledge only 1 previous case of
intestinal toxemia has been reported in an HCT recipient. This
was a 3-year-old girl who underwent gut sterilization with
antibiotics during an autologous transplantation [
]. Though total
or selective gut sterilization during allo-HCT is not practiced at
our institution, our patient nonetheless experienced severe gut
derangements in the months following transplantation.
Our patient had no significant antibiotic exposure in the
weeks before botulism onset (Figure 1A). However, he had
received extensive antibiotic treatment during his allo-HCT.
Allo-HCT patients are treated with broad-spectrum
antimicrobials because of the high risk for infection during the
post-transplant period. Broad-spectrum antimicrobials and
gut sterilization procedures lead to significant disturbances
of normal flora of the bowel. It has been found that mice that
have undergone gut sterilization are more susceptible to
colonization by C. botulinum [
]. During his hospitalization, the
patient received oral corticosteroids for GVHD as well as IVIG,
CMV-IG, and CMV-specific cytotoxic T lymphocytes for
persistent CMV viremia. It is unclear whether these treatments had
a role in creating conditions amenable to C. botulinum
proliferation. We cannot say whether immunodeficiency (as occurs
universally in HCT recipients) played a contributing role; the
patient’s post-transplant hematologic and immune function
testing was normal. To our knowledge, GVHD has not been
reported as a predisposing factor for botulism.
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In order to gain insight into the composition of this patient’s
intestinal microbiome, we collected and analyzed a fecal
specimen just prior to BAT administration. We extracted, sequenced,
and classified taxonomically 16S rRNA gene sequences. The
microbial composition was dominated by Enterococcus faecium
and Streptococcus salivarius (Figure 1B), a finding that indicates
substantial disruption of the gut microbiome [
notably, C. botulinum was identified in the patient’s sample. The
relative abundance of clostridial sequences was not high. However,
botulinum toxin is exceedingly potent, and the presence of
relatively few organisms could lead to disease.
It is unclear whether perturbation of the bowel environment
due to GVHD, transplant, CMV viremia, therapy for these
conditions, or a yet unidentified factor contributed to the occurrence of
botulism in this patient. Patients with protracted gastrointestinal
symptoms who undergo long hospitalizations, including allo-HCT,
might be at risk for adult colonization botulism. Early diagnosis
is essential to the effective management of botulism. Patients with
acute onset bilateral cranial nerve palsies, with or without
progression to respiratory compromise and skeletal muscle paralysis,
should be immediately evaluated for botulism. Clinicians who
suspect botulism should immediately contact the CDC through
the state health department for an emergency clinical consultation
and, when indicated, immediate provision of botulinum antitoxin.
Acknowledgments. We thank Marissa Buchan for her assistance in
preparation of this manuscript.
Disclaimer. The findings and conclusions in this report are those of the
authors and do not necessarily represent the official position of the Centers
for Disease Control and Prevention.
Supplement sponsorship. This article appears as part of the
supplement “Botulism,” sponsored by the Centers for Disease Control and
Potential conflicts of interest. All authors: No reported conflicts of
interest. All authors have submitted the ICMJE Form for Disclosure of
Potential Conflicts of Interest. Conflicts that the editors consider relevant to
the content of the manuscript have been disclosed.
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