A Case of Adult Intestinal Toxemia Botulism During Prolonged Hospitalization in an Allogeneic Hematopoietic Cell Transplant Recipient

Clinical Infectious Diseases, Jan 2018

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.

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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. CASE REPORT 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. abu sca e g itv l(o0.010 a l e R 0.001 0.000 Cyclosporine Micafungin Vanco Cefep Pentam Ganciclovir Hydrocortisone Metro Linezolid Levofloxacin Foscarnet zo zo Imipenem zo Cyclosporine Vanco Vanco 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 S100 • CID 2018:66 (Suppl 1) • Parameswaran et al Downloaded from https://academic.oup.com/cid/article-abstract/66/suppl_1/S99/4780432 by guest 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. DISCUSSION 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 [ 1 ]. 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 [ 3–6 ]. In allo-HCT patients, gastrointestinal symptoms and significant disturbances of the intestinal microbiota are common [7]. 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 [ 8 ]. 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 [ 9 ]. 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. Botulism in a BMT During Hospitalization • CID 2018:66 (Suppl 1) • S101 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 [ 10 ]. Most 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. Notes 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 Prevention. 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. 1. Sobel J. Botulism . Clin Infect Dis 2005 ; 41 : 1167 - 73 . 2. CDC. CSTE Botulism Surveillance Summary , 2014 . 2014 . Available at: http:// www.cdc.gov/nationalsurveillance/botulism-surveillance. html. Accessed 8 March 2017 . 3. Chia JK , Clark JB , Ryan CA , Pollack M. Botulism in an adult associated with food-borne intestinal infection with Clostridium botulinum . N Engl J Med 1986 ; 315 : 239 - 41 . 4. Fenicia L , Franciosa G , Pourshaban M , Aureli P . Intestinal toxemia botulism in two young people, caused by Clostridium butyricum type E. Clin Infect Dis 1999 ; 29 : 1381 - 7 . 5. Sheppard YD , Middleton D , Whitfield Y , et al. Intestinal toxemia botulism in 3 adults , Ontario, Canada, 2006 - 2008 . Emerg Infect Dis 2012 ; 18 : 1 . 6. McCroskey LM , Hatheway CL . Laboratory findings in four cases of adult botulism suggest colonization of the intestinal tract . J Clin Microbiol 1988 ; 26 : 1052 - 4 . 7. Taur Y , Jenq RR , Perales MA , et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation . Blood 2014 ; 124 : 1174 - 82 . 8. Shen WP , Felsing N , Lang D , Goodman G , Cairo MS . Development of infant botulism in a 3-year-old female with neuroblastoma following autologous bone marrow transplantation: potential use of human botulism immune globulin . Bone Marrow Transplant 1994 ; 13 : 345 - 7 . 9. Burr DH , Sugiyama H . Susceptibility to enteric botulinum colonization of antibiotic-treated adult mice . Infect Immun 1982 ; 36 : 103 - 6 . 10. Taur Y , Xavier JB , Lipuma L , et al. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation . Clin Infect Dis 2012 ; 55 : 905 - 14 .


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Parameswaran, Lalitha, Rao, Agam, Chastain, Katherine, Ackelsburg, Joel, Adams, Eleanor, Jackson, Brendan, Voigt, Louis P, Chen, Xi, Boulad, Farid, Taur, Ying. A Case of Adult Intestinal Toxemia Botulism During Prolonged Hospitalization in an Allogeneic Hematopoietic Cell Transplant Recipient, Clinical Infectious Diseases, 2018, S99-S102, DOI: 10.1093/cid/cix847