case study of food poisoning

Case Study: Clostridium botulinum Poisoning Caused by Canned Pate

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Clostridium botulinum  is a  bacterium  that produces a  powerful neurotoxin tha t penetrates nerve cells, blocking  the release of the neurotransmitter acetylcholine from nerve endings  and  causing muscles to become paralyzed.   However, t he  bacterium  is vulnerable to high heat.   At   two minutes at  100   ° C  (212  ° F) , the  bacterium  begins to  lose its  virulence,  and it  can be destroyed  by cooking at this high temperature for ten minutes .  This means that cooking fresh food at the boiling temperature of water for ten minutes should kill  Clostridium botulinum . The addition of nitrite to preserve foods, especially meat products,   is  also  effective in inhibiting  Clostridium botulinum .  

Where is   Clostridium b otulinum  F ound?  

Clostridium b otulinum   is fo u nd  in   high-protein  foods .  A ll animal products are  considered to be  high-risk  for this toxin ,  including  sausage , ham, canned  meat, canned fish, smoked meat , and processed mea t .   Milk and dairy  products are also at risk for  Clostridium botulinum   contamination  if the processing  or distribution  environment is not hygienic .   Plant-based foods  can be contaminated with  Clostri di um b otulinum , as well.  A variety of  processed  products are susceptible to  Clostri di um b otulinum  contamination such as soy sauce, soy products, tofu, bean curd, and raw vegetables.  

Symptoms  of   Clostridium botulinum   poisoning appear  from  12 to 36 hours after a meal, but  they can also manifest up to several days later. A shorter incubation period  generally means a greater amount of  bacteria  has been ingested, resulting in a  higher risk of death.   Initial symptoms  of poisoning  incl ude fatigue, dizziness,   loss of   appetite, diarrhea, abdominal pain, vomiting, and ot her symptoms of gastroenteritis.  A t  low  levels   of  toxin  ingestion, these symptoms  will  abate  within a few  hour s or a day .

The toxin  then  further penetrates the peripheral cranial nerves. The most obvious manif estation is damage to the eyes  ( blurred vision, double vision, drooping eyelids, dila ted pupils, no light reflection ) . Mandibular manifestations  include   facial paralysis, salivation disorders, dry mouth, difficulty swallowing,  hoarseness , and   difficulty speaking .   More severe symptoms involve weakness and paralysis of the muscles  in  the upper   or  lower body, such as not being able to lift one's head, stand, or  sit up. Aggravation presents with generalized paralysis, decreased systemic muscle tone,  or  functional bowel obstructi on. The final stage is dyspnea ,  which is associated with a  mortality  rate of 30–60 percent  due to respiratory failure.  

Case S tudy of  Canned, Plant-Based P ate  Poisoning  

Ten cases of  Clostridium botulinum   poisoning occurred from  mid-July to mid-August  of  2020 , according to the Food Safety Department of Vietnam .  All ten victims were treated in the hospital, with two exhibiting  sev ere symptoms. The two elderly victims with severe symptoms of  Clostridium botulinum   poisoning reported having eaten  canned ,  plant-based pate . Samples of the leftover pate were analyzed by two separate institutions and found to contain  Clostridium botulinum   toxin, which  can be fatal   when  ingested in a quantity of less than 0.1 mg.  

The Food Safety department convened an  urgent meeting  with the manufacturer of the pate . The pate was  confirmed to have become contaminated   with  Clostridium botulinum   during production.  P roduct  recall notices, consumer recommendations ,  and written requests for handling the case  were issued in quick  succession.  

Preventing  Clostridium botulinum  Poisoning  

Clostridium botulinu m  is  an obligate anaerobic bacterium  that  live s  and  grow s  in the absence of oxygen.  It  form s  spores  that   survive well  in unfavorable conditions .  Spores of  Clostridium botulinu m  bacteria exist widely in soil, river water,  and sea water; however, in  hypoxic conditions ,  they will germinate, grow ,  and secrete  toxin .   Clostridium botulinum   poisoning  typically  occur s  when people eat canned foods that  do not undergo hygienic  processing.  

To prevent  Clostridium botulinum  poisoning,   hygienic  processing, especially during  the heating and  sterilization  steps, must be maintained .   A  high - temperature treatment  of at least  121   °C  (250  ° F)  is recommended   to kill  bacterial spores of  Clostridium botulinum .   Although the spores are difficult to destroy,  the toxins produced  are sensitive to temperature.   H eating food to  a  normal cooking temperature  of  around   80   °C   ( 176  ° F ) for 30 minutes or boiling at  100  °C   ( 212  ° F ) for ten  minutes before eating can significantly reduce the risk o f  Clostridium botulinum   poisoning.  

In addition, the preservation of food at cold temperatures (below 4   °C / 39  ° F )  in an acidic environment (pH   <   4.6) ,  and the use of preservatives such as nitrite, sorbic acid, phenolic antioxida nts, polyphosphates,  and ascorbates have  been shown to reduce microbial growth and reduce the risk of  Clostridium botulinum   poisoning.   Clostridium botulinum   contamination  usually occurs with foods that are sealed in an  airtight  environment ( cans,  bottles, jars,  or  bags ) during  commercial or home kitchen  processing .    

C onsumers  are  advised not to  repack  airtight   foods into different jars, bottles, or  bags  to extend shelf life  without freezing , as t his may result in bacterial growth. Also,  if the packaging of  a canned food,  bottle , or jar  is damaged   in any way (dents, dings, or  any  other damage/ deformity   of  the  container  or seal) ,  it should be discarded and the food should not be consumed.  Damaged packaging may indicate  unhygienic  production conditions ,  or damage during transport and distribution that  may  encourage bacterial growth  in the food .  

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Dr. Bảo Thy Vương is Head of the Health Sciences Faculty at Mekong University in Vietnam. Her research interests include food safety, public health, and nutrition.

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Case Study: e Coli Food Poisoning – Taken Out by a Toxic Taco

This case study focuses on the outbreaks of e coli food poisoning similar to those at the Chipotle Mexican Grill which have been in the news recently.  With medical algorithms, healthcare providers can quickly distinguish which foodborne illness the patient has and help identify its cause.

Mary is a grandmother with three grandchildren. On Saturday she took them shopping and afterwards they went to their favorite taco restaurant.

On Tuesday Mary felt a little sick when she woke up with some abdominal cramping. Her grandchildren also felt too sick to go to school. Their parents felt fine and the father stayed home to watch the children. Later that day, everyone who had eaten at the taco restaurant developed diarrhea. That evening Mary noticed that her stool was bloody. She developed fever, fatigue, bruising and decreased urine output.

Her daughter took Mary to the Emergency Room early Wednesday morning. Her serum creatinine concentration was high and her platelet count was low. A peripheral blood smear showed numerous schistocytes without platelet clumping. She was admitted to the hospital and started on hemodialysis that afternoon.

The stool culture was positive for Escherichia coli. The isolate was positive for Shiga toxin. A diagnosis of Shiga-toxin producing E. coli (STEC) was made.

Mary was in the hospital for 2 weeks and was discharged home. Recuperation was slow but she gradually recovered without residua.

During her hospitalization, the State Health Department completed an investigation of the restaurant and was unable to find an identifiable source. The restaurant (and its sister locations in the same city) were closed for terminal cleaning and re-opened after no source was found and additional preventive measures were taken.

Shiga-toxin e Coli Poisoning Symptoms & Causes

Shiga-toxin producing Escherichia coli (STEC) can be acquired in several ways, but usually it is acquired from contaminated food. Possible sources include ground beef, poultry, sprouts, cucumbers, lettuce, and other produce. Produce from a single contaminated site may be transported large distances, resulting in multi-state outbreaks.

An infection often presents as a diarrheal disease which must to be distinguished from other food-borne diseases (Salmonella, Shigella, Listeria, Campylobacter, etc). This usually involves stool testing for both bacteria and Shiga toxin.

What makes STEC of concern is that some patients develop hemolytic-uremic syndrome (HUS). This is a much more serious condition which can result in renal and multiple organ failure. HUS overlaps with Thrombotic Thrombocytopenic Purpura (TTP).

HUS or TTP are syndromes that can have multiple causes. Management involves identifying the cause so that specific therapy can be initiated in addition to management of organ failures.

With modern therapy most patients can be successfully treated. Some patients may have prolonged admissions to the intensive care unit. Fatalities can occur in vulnerable patients, patients with delayed care, or fulminant disease. Medical algorithms can help to identify high risk patients who may benefit from more aggressive management.

e coli Prevention

Prevention of STEC infection can be challenging, especially for restaurants. Produce should be carefully cleaned and workers trained in proper food preparation. Meat products should be thoroughly cooked based on internal temperature.

If a case is identified then it is important for food suppliers, restaurants and local health departments to work together to find the source so that further cases can be avoided.

Take-Home Points

• While STEC may be rare, foodborne illness and gastroenteritis is quite common. A powerful algorithm assists physicians in the identification of both common and uncommon pathogens.
• Combining medical training with powerful, evidence-based algorithms can help physicians diagnose, assess, and manage diseases.

The medical algorithms highlighted in this case study are available at  The Medical Algorithms Company  and also on the a pervita   health analytics platform.

About the Authors

Umang Jain is the Health Innovations Fellow at Apervita. He is passionate about medicine, research, and business. He is a fourth year medical student at Northwestern University’s Feinberg School of Medicine and will pursue Emergency Medicine residency. Umang’s scholarly interests include surgical outcomes research, in which he is published in the fields of ENT, orthopedic, plastic, cardiac, and urologic surgery. He has also participated in research in neurodegenerative disease at MIT and Boston University. Umang’s business experience stems from his work at the Institute of Healthcare Improvement (IHI) in Boston, MA. He worked closely with Dr. Donald Berwick, Administrator of Medicare and Medicaid Services (CMS) and Sir Nigel Crisp, the former Chief Executive of UK’s National Health Service, on engaging in evidence-based healthcare improvement interventions on a global scale. Umang was also an intern at Senticare Inc. and Personica, where he evaluated EHRs and in-home health monitoring equipment.

Dr. Chad Rudnick, MD, FAAP is a board-certified pediatrician in Boca Raton, FL. He is the Medical Director of The Medical Algorithms Company. A proponent of incorporating medical technology into his practice, Dr. Rudnick uses telemedicine and medical algorithms from The Medical Algorithms Company in his daily practice to better serve his patients and their families. An accomplished medical writer, he maintains a popular pediatric blog, All Things Pediatric, and has written for numerous online and print publications including KevinMD.com.

John Svirbely, MD is a founder and Chief Medical Officer of The Medical Algorithms Company and the primary author of its medical algorithms. John is a co-founder of the Medical Algorithms Project and has developed its medical content for nearly 20 years. He has a BA degree from the Johns Hopkins University and his MD from the University of Maryland. He is a board-certified pathologist with a fellowship in medical microbiology and biomedical computing at Ohio State University. Currently he is in private practice in Cincinnati, Ohio. He has authored multiple books and articles on medical algorithms.

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Food poisoning due to Salmonella Enteritidis--a case report

Affiliation.

• 1 Department of Legal Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan. [email protected]
• PMID: 19269228
• DOI: 10.1016/j.legalmed.2009.01.089

A male in his early seventies complained of abdominal pain and diarrhea at 7h after ingesting a small piece of gratin from a box lunch prepared by a caterer. He was admitted to a hospital, but died 37 h later. Dozens of people who had eaten the same box lunch also complained of diarrhea. All of them recovered after medical treatment. A later investigation demonstrated Salmonella Enteritidis (SE) in the gratin from the box lunch. An autopsy revealed very severe typhloenteritis with edema and submucosal hemorrhage. The digestive tract contained fluid contents without foodstuffs. Bacteriological examination revealed SE in the contents of the lower ileum and large intestine. Based on these findings, we concluded that the cause of death was food poisoning due to SE. In this case, ingesting only a small piece of contaminated food caused fatal food poisoning due to SE. These results emphasize the importance of prevention against food poisoning due to Salmonella, particularly SE.

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• [Accumulated occurrence of illnesses with Salmonella enteritidis in hospitals and nursing homes in the district Oberallgaeu, Bavaria, in July 2004]. Heissenhuber A, Hautmann W, Arenz S, Kugler R, Kleih W, Ludwig S, Wildner M. Heissenhuber A, et al. Gesundheitswesen. 2005 Dec;67(12):845-52. doi: 10.1055/s-2005-858898. Gesundheitswesen. 2005. PMID: 16379046 German.
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Environmental Medicine: Integrating a Missing Element into Medical Education (1995)

Chapter: case study 34: poisoning of an urban family due to misapplication of household organophosphate and carbamate pesticides, poisoning of an urban family due to misapplication of household organophosphate and carbamate pesticides.

Steven B.Markowitz, M.D.

Department of Community Medicine, Mt. Sinai

School of Medicine, New York, New York

A case report of an urban family who experienced excessive exposure to organophosphate and carbamate pesticides is presented. All three family members developed symptoms that were compatible with cholinesterase inhibition: headache, lightheadedness, wheezing, shortness of breath, nausea, and fatigue. Serial measurement of red blood cell and serum cholinesterases soon after exposure and during subsequent months confirmed the diagnosis of pesticide poisoning. This report demonstrates that the misapplication of pesticides commonly used in residences in urban areas can cause acute pesticide poisoning and demonstrates the usefulness of repeated measurements of cholinesterase during the post-exposure period in establishing the correct diagnosis. (Key Words: pesticides; organophosphorus compounds; residential facilities; pest control; poisoning, human.)

Copyright © 1992 by Marcel Dekker, Inc.

Reprinted with permission from Clinical Toxicology 30(2):295–303, Copyright 1992, Marcel Dekkar, Inc.

INTRODUCTION

Organophosphate and carbamate pesticides have been well documented to cause acute poisoning in humans in a variety of settings (1,2). These settings include occupational exposures among pesticide applicators, manufacturing workers and farm workers; accidental inhalation, skin absorption and ingestion, especially by children; and intentional attempts at suicide ( 1 – 6 ).

Organophosphates and carbamates are two of the dominant classes of pesticides used for residential pest control in urban areas in the United States. Despite widespread use of these agents and considerable concern about their possible deleterious effects, especially given the large population potentially exposed, there have been few reports of urban residents made acutely or chronically ill by pesticides ( 5 – 7 ).

This report describes a family with clinical and laboratory evidence of acute pesticide poisoning caused by the excessive application of pesticide products used for urban residential pest control.

Environmental History

The affected family consisted of three members, a 32 year-old mother, a 35 year-old father, and their 14 year-old daughter, who were well prior to late November, 1984, when their apartment underwent commercial pesticide application for extermination of fleas. The apartment had been sprayed with unknown pesticides two times several weeks previously without the desired result and without causing illness in the family. The father reported that on November 24, 1984, a professional pesticide applicator sprayed an unknown pesticide using a tank and hose apparatus; he subsequently used eight pressurized canisters (bombs) of a specific pesticide formulation. These canisters were filled with a commercial product containing two active pesticidal ingredients: an organophosphate pesticide, dichlorvos (2,2 dichlorovinyl dimethyl phosphate), and a carbamate pesticide, propoxur (2-(1-methylethoxy) phenol methylcarbamate). Additional “inert” ingredients of the preparation were not identified. Each container was recommended to be used for 6000 cubic feet; the apartment was estimated to have a volume of 7000 cubic feet.

Three hours after application of these pesticides, the father entered the apartment and saw “clouds of vapor still lingering in the air”. He covered his face with a cloth, opened the windows of the apartment, and promptly left. He returned with the mother and daughter 3–4 hours later and noted that the previously observed fog of pesticides had cleared; the apartment, however, retained a residual odor of pesticides. The family slept in the apartment that night.

Clinical History

All three family members reported experiencing the following symptoms on the following morning: burning of the throat, chest heaviness, wheezing, shortness of breath, headache, fatigue and nausea. The mother and the daughter also experienced lightheadedness. The mother additionally noted abdominal cramping and loose stools. The father went to work for 8 h, while the others stayed in the apartment. On the following day, the family moved to a local motel for 2 w, during which the apartment was reportedly cleaned twice. Details concerning the extent of cleaning are not available. The family then returned to occupy the apartment, where they noted persistence of the odor of the sprayed material.

All family members visited their personal physician four days after the pesticide application, complaining of the symptoms noted above, which had diminished somewhat during the intervening days. The results of serum and erythrocyte cholinesterase are shown in Table 1 . Serum and erythrocyte cholinesterase analyses were performed by Metpath Laboratory (Teterboro, NJ) using kits supplied by Boehringer-Mannheim Diagnostics (erythrocyte cholinesterase) and Gilford (serum cholinesterase) employing a modification of the Ellman method ( 8 ).

Upon examination six weeks after initial exposure, the father reported persistence of selected symptoms including headache, fatigue and throat irritation, though these had diminished in intensity. The mother continued to complain of slight shortness of breath, chest tightness, wheezing and minimal abdominal cramping. She reported having used albuterol during the several weeks prior to her visit. The daughter’s symptoms had also decreased but she still experienced nausea, headache, sore throat, and some wheezing when in the apartment.

TABLE 1 Recovery of Red Blood Cell Serum and Cholinesterase Levels

The father had a history of allergic rhinitis, which occurred only during the spring. He worked as a carpenter. The mother had a past history of childhood asthma, which had abated by the age of 7. She experienced occasional wheezing as an adult, which she treated with a non-prescription bronchodilator. The child also had a history of asthma, which had not been recently active and had received albuterol from her personal physician during the current illness.

Physical examinations of all three family members were normal with the exception of minimal wheezing on forced expiration heard in the lower left lung of the mother. Pulmonary function tests performed on the two adults were also normal, except for a minimal decrease in the mother’s forced vital capacity (78% predicted).

Sequential measurements of serum and red blood cholinesterase over the three month period following the incident until mid-February 1985 are provided in Table 1 . The father’s initial values of serum and erythrocyte cholinesterase were within normal limits (2.60 µ /mL and 3.81 IU/mL,

respectively). The mother’s serum cholinesterase level was initially low, 2.20 U/mL, and her erythrocyte cholinesterase was normal at 3.20 IU/mL. The daughter had low initial values of both serum and erythrocyte cholinesterase levels (0.90 U/mL and 2.71 IU/mL, respectively). All measurements were performed by Metpath.

Repeat testing of red blood cell and serum cholinesterase on all three patients in January and February, 1985, showed significant increases in values for these tests during the intervening 6 and 11 weeks. All members of the family demonstrated a 24 to 29% increase in the erythrocyte cholinesterase from the immediate post-exposure measurement to the measurement obtained 11 weeks later. The mean increase was 26.1 % (paired t=−19.92, two tail p=.003) ( 9 ). For the serum cholinesterase, there was a 48 to 76% increase for all members in the family during the same time interval. The mean increase was 59.4% (paired t=−6.75, two tail p= .021) ( 9 ).

Diagnosis of mild to moderate organophosphate or carbamate poisoning is frequently difficult ( 1 , 10 ). The symptoms are non-specific and mimic other common disorders, such as viral infections. Laboratory confirmation of the diagnosis of such poisoning is, therefore, essential in all but the most severe clinical cases or in circumstances of obvious over-exposure to relevant pesticides. The clinical significance of any specific level of erythrocyte or plasma cholinesterase is measured by its percent decrease from a baseline pre-exposure level or by the degree to which the values are frankly below the established reference range ( 11 ).

Laboratory assessment of organophosphate or carbamate poisoning is complicated, however, by the relatively high inter-individual and intra-individual variability in levels of erythrocyte and serum cholinesterase. The coefficient of variation in cholinesterase between individuals is relatively high, ranging from 13% to 16% or higher for erythrocyte cholinesterase ( 1 , 12 , 13 ) and 15% to 27% for plasma cholinesterase ( 1 , 12 , 14 ).

Intra-individual variation over time is somewhat lower. The average coefficient of intra-individual variation for plasma and erythrocyte cholinesterases in the published literature ranges from 7.6% to 11.3% ( 1 , 15 – 17 ), though individual samples may fluctuate as much as 25% ( 1 , 17 , 18 ).

According to Gallo and Lawryk ( 1 ), if one pre-exposure cholinesterase measurement is available, then the subsequent depression of cholinesterase must be at least 20% for the plasma enzyme and 15% for the erythrocyte enzyme to reflect a significant statistical change. The percentage alterations in erythrocyte cholinesterase of 24–29% and of serum cholinesterase of 48% to 75% are higher than that expected due to normal variation.

While having pre-exposure measurements of cholinesterase levels in individuals is preferred due to the narrower intra-individual variation, they are usually not available in cases with non-occupational exposure to pesticides ( 11 , 19 ). In the absence of such pre-exposure measurements, sequential post-exposure measurements can be used to estimate the pre-exposure cholinesterase levels in the patients. Midtling and others described an outbreak of acute mevinphos poisoning among a group of 16 lettuce growers in California who developed symptoms compatible with organophosphate poisoning. Cholinesterase levels rose in the weeks following the outbreak of illness ( 4 ). In this report, the father had normal values initially for both erythrocyte and serum cholinesterases. Sequential measurements taken 6 and 11 weeks later, however, clearly demonstrated that the father experienced the recovery of cholinesterase levels of the same magnitude as the other two family members.

Of note is that the serum cholinesterase was more severely inhibited in these cases than the erythrocyte cholinesterase, an effect that has been previously observed with dichlorvos ( 20 ). It is possible that the recovery of the erythrocyte cholinesterase may be underestimated in this report since the interval between the first and last cholinesterase measurements was less than 12 weeks, which is the average life span of erythrocytes and the period over which a diminished level of erythrocyte cholinesterase can be expected to normalize. Serum cholinesterase, on the other hand, recovers in one to three weeks.

Many of the symptoms experienced by the exposed persons in the present report—chest tightness, shortness of breath, headaches, lightheadedness, fatigue, nausea, and diarrhea—are compatible with the diagnosis of mild to moderate organophosphate and carbamate poisoning. Many of these same symptoms may be caused by excessive exposure to the solvent carriers that are often contained in commercial pesticide formulations. In the absence of exposure measurements or the identity of the solvents that were likely present, solvents may have contributed to the symptoms experienced. However, the level of cholinesterase inhibition strongly supports the contention that anti-cholinesterase activity was a significant factor in the complex of symptoms suffered by this family.

The persistence of symptoms, albeit attenuated, after six weeks following initial exposure is not fully explained. Since the levels of the cholinesterases had reverted to the normal range by six weeks, the symptoms that were still present at six weeks were not due to the short-term anti-cholinesterase effect of dichlorvos and propoxur. One possible explanation is that exposure to other toxins such as the solvent carriers continued, which is unlikely in view of the repeated cleaning of the apartment and the expectedly rapid volatilization of the solvents typically used as carriers. Another possible explanation is the lingering of the symptoms associated with cholinesterase inhibition, even in the absence of active inhibition. There is limited evidence of the persistence of symptoms beyond the immediate period of organophosphate poisoning ( 4 , 21 ), though most of the studies of persistent effects have focused on central nervous system effects rather the multi-organ symptoms that characterize acute organophosphate poisoning ( 22 – 24 ).

Use of pesticides in buildings and on lawns is widespread throughout the United States and represents an important means by which a large proportion of the population of the United States is potentially exposed to pesticides. Instances of organophosphate or carbamate poisoning such as described in this case report are unusual in the medical literature ( 5 – 7 ). This may be due to the widespread safe use of pesticides, the difficulty in diagnosing mild acute and chronic pesticide poisoning, or the general lack of

knowledge on the part of health care providers about eliciting environmental and occupational information from patients ( 25 ). With the progressive interest in environmental health, it is likely that additional cases of environmental pesticide poisoning will be recognized, especially if a carefully elicited environmental and occupational history results in the appropriate clinical and laboratory assessment of potential cases of such poisoning.

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2. Moses M. Pesticides. In: Environmental and Occupational Medicine . Rom W, ed., Boston: Little, Brown and Company, 1983:547–572.

3. Jackson RJ, Stratum JW, Goldman LR, et al. Aldicarb food poisoning from contaminated melons—California. MMWR 1986; 35 : 254–258.

4. Midtling JE, Barnett PG, Coye MJ, et al. Clinical management of field worker organophosphate poisoning. West J Med 1985; 142 : 514–518.

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6. Woody RC. The clinical spectrum of pediatric organophosphate intoxications. Neurotoxicology 1984; 5 : 75.

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9. Zar JH. Biostatistical Analysis . 2nd Ed., Englewood Cliffs, NJ: Prentice-Hall, 1984.

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11. State of California Department of Health. Epidemiological Studies Laboratory. Medical Supervision of Pesticide Workers: Guidelines for Physicians . Berkeley, California, 1988.

12. Augustinsson K. The normal variation of human blood cholinesterase activity. Acta Physiol Scand 1955; 35 : 40–52.

13. George PM, Abernethy MH. Improved procedure for erythrocyte cholinesterase. Clin Chem 1983; 29 : 365–368.

14. Lewis PJ, Lowing RK, Gompertz D. Automated discrete kinetic method for erythrocyte acetylcholinesterase and plasma cholinesterase. Clin Chem 1981; 27 : 926–929.

15. Wetstone HJ, LaMotta RV. The clinical stability of serum cholinesterase activity. Clin Chem 1965; 1 : 370.

16. Gage JC. Blood cholinesterase values in early diagnosis of excessive exposure to phosphorous insecticides. Br Med J 1955; 1 : 370.

17. Callaway S, Davies DR, Rutland PJ. Blood cholinesterase levels and range of personal variation in a healthy adult population. Br Med J 1951; 2 : 812–816.

18. Fryer JH, Steel RGD, Williams HH. Cholinesterase activity levels in normal human subjects. AMA Arch Ind Health 1955; 12 : 406–411.

19. Coye MJ, Lowe JA, Madday KT. Biological monitoring of agricultural workers exposed to pesticides: Cholinesterase activity determinations. J Occup Med 1988; 28 : 619–627.

20. Rasmussin WA, Jensen JA, Stein WJ, Hayes WJ. Jr. Toxicological studies of DDVP for disinfection of aircraft. Aerospace Med 1963; 34 : 594–600.

21. Tabershaw IR, Cooper WC. Sequelae of acute organic phosphate poisoning. J Occup Med 1966; 8 : 5–20.

22. Savage EP, Keefe TH, Mounce LM, et al. Chronic neurological sequelae of acute organophosphate pesticide poisoning. Arch Environ Health 1988; 43 : 38–45.

23. Korsak RJ, Sato MM. Effects of chronic organophosphate pesticide exposure on the central nervous system. Clin Toxicol 1977; 11 : 83–95.

24. Rosenstock L, Keifer M, Daniell WE, et al. Chronic central nervous system effects of acute organophosphate pesticide intoxication. Lancet 1991; 338 : 223–227.

25. Demers RY, Wall SJ. Occupational history taking in a family practice setting. J Med Educ 1983; 58 : 151–153.

People are increasingly concerned about potential environmental health hazards and often ask their physicians questions such as: "Is the tap water safe to drink?" "Is it safe to live near power lines?" Unfortunately, physicians often lack the information and training related to environmental health risks needed to answer such questions. This book discusses six competency based learning objectives for all medical school students, discusses the relevance of environmental health to specific courses and clerkships, and demonstrates how to integrate environmental health into the curriculum through published case studies, some of which are included in one of the book's three appendices. Also included is a guide on where to obtain additional information for treatment, referral, and follow-up for diseases with possible environmental and/or occupational origins.

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• J Clin Microbiol
• v.49(12); 2011 Dec

Sudden Death of a Young Adult Associated with Bacillus cereus Food Poisoning ▿

María naranjo.

1 Scientific Service Food-borne Pathogens

Sarah Denayer

Nadine botteldoorn, laurence delbrassinne.

2 Food, Medicines and Consumer Safety Section

3 Scientific Institute of Public Health, B-1050 Brussels, Belgium; Saint-Pierre Hospital and Etterbeek-Ixelles Hospital, Brussels, Belgium

Jacques Waegenaere

4 Health Inspection, B-1050 Brussels, Belgium

Nicolas Sirtaine

5 Pathology Department, Hôpital Bordet, Université Libre de Bruxelles, B-1000 Brussels, Belgium

Ronald B. Driesen

6 Division of Experimental Cardiology, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium

Karin R. Sipido

Jacques mahillon.

7 Laboratory of Food and Environmental Microbiology, Université Catholique de Louvain, B-1348 Louvain-la-Neuve, Belgium

Katelijne Dierick

A lethal intoxication case, which occurred in Brussels, Belgium, is described. A 20-year-old man died following the ingestion of pasta contaminated with Bacillus cereus . Emetic strains of B. cereus were isolated, and high levels of cereulide (14.8 μg/g) were found in the spaghetti meal.

CASE REPORT

On 1 October 2008, a 20-year-old man became sick after eating a meal of leftovers of spaghetti with tomato sauce, which had been prepared 5 days before and left in the kitchen at room temperature. After school, he warmed the spaghetti in the microwave oven. Immediately after eating, he left home for his sports activities, but he returned 30 min later because of headache, abdominal pain, and nausea. At his arrival, he vomited profusely for several hours and at midnight had two episodes of watery diarrhea. He did not receive any medication and drank only water. After midnight, he fell asleep. The next morning at 11:00 AM, his parents were worried because he did not get up. When they went to his room, they found him dead.

Legal examination determined the time of death, presumably at 4:00 AM, approximately 10 h after ingestion of the suspected meal. An autopsy could not be performed until 5 days later. Macroscopically, brownish and moderately softened liver and ascites (550 ml of citrine liquid) were found. The heart was macroscopically normal. A total lysis of the pancreas was also found, but it could not be excluded that this finding was due to the autopsy delay.

Microscopic findings were as follows: moderate centrolobular liver necrosis without inflammatory signs and discrete biliary stasis, significant vascular congestion of the lungs, probably due to acute cardiac insufficiency, significant necrosis from all layers of colon mucosa and submucosa alternating with better-preserved zones, and mixed intestinal flora but no evidence of invasive bacterial lesions. Significant lysis of the adrenal glands was also reported. The exact cause of death could not be determined by the autopsy because the interpretation of findings was very difficult due to the autopsy delay.

Five fecal swabs and two feces samples were taken postmortem, and samples were tested for the presence of Bacillus cereus by growth on mannitol egg yolk polymyxin (MYP) agar. B. cereus was found in only two of the five fecal swabs, and the strains isolated were named ISP321 and ISP322. No B. cereus was cultured from the feces samples.

Pasta and tomato sauce samples, the leftovers of the dinner, were also sent for analysis to the National Reference Laboratory for Food-borne Outbreaks (NRLFBO). For enumeration of B. cereus in food samples, the ISO 7932 method ( 16 ) was used. Significant B. cereus counts (9.5 × 10 7 CFU/g) were found in the pasta, while B. cereus was absent in the tomato sauce. The strain isolated from the pasta meal was named ISP303.

PCR assays that detect the presence of toxin genes were applied to DNA from the pasta isolate (ISP303) and the two human isolates (ISP321 and ISP322), and the results are presented in Table 1 . The presence of genes encoding nonhemolytic enterotoxin (NHE) ( nheA ), phospholipase C ( plcA ), cytotoxin K ( cytK ), hemolysin II ( hlyII ), and hemolysin BL ( hblA ) was investigated ( 12 , 13 , 15 ). All three strains tested positive for the presence of the nheA and plcA genes. The strains were all negative for the other enterotoxin genes ( cytK , hlyII , and hblA ).

Characterization of the B. cereus isolates a

A specific cereulide-associated PCR test ( 7 ) was also used to target the ces genetic determinants, which are necessary for cereulide synthesis. The PCR test to detect ce s gave positive results for all three isolates. The actual production of cereulide was also confirmed by the boar sperm assay ( 4 ; data not shown). These results suggest that all three B. cereus isolates, ISP303, ISP321, and ISP322, are emetic strains. The concentration of the cereulide toxin in the spaghetti was determined by liquid chromatography-tandem mass spectrometry (LC-MS 2 ) ( 5 ; L. Delbrassinne, M. Andjelkovic, A. Rajkovic, P. Dubois, E. N'Guessan, J. Mahillon, and J. Van Loco, unpublished results) to be 14.8 μg/g of pasta. The amount of cereulide determined in the spaghetti by the present study was almost 10 times higher than the cereulide concentration of 1.6 μg/g previously found in a contaminated pasta dish ( 18 ) and seems consequently to be within the upper range of cereulide amounts reported in foods implicated in outbreaks.

Further characterization of the three isolates was performed using repetitive sequence-based PCR (rep-PCR) and pulsed-field gel electrophoresis (PFGE) ( 10 , 11 , 25 ) of genomic DNA. All three strains displayed the same rep-PCR and PFGE profiles (data not shown).

B. cereus is a well-known food-poisoning organism. It can cause two types of food poisoning, described as the emetic and diarrheal syndromes ( 12 ). The emetic type is caused by a heat-stable cereulide toxin that is preformed in food ( 2 ). The symptoms are usually mild but can be severe in some cases. Four fatal cases attributed to cereulide have been reported ( 6 , 22 , 24 , 26 ). The present results provided evidence for B. cereus food poisoning in a young, healthy man. Clinical data and the rapid onset of symptoms, together with microbiological and molecular study, point to B. cereus as the most likely cause for this fatal outcome.

Emetic strains of B. cereus are known to cause mitochondrial damage. Because the macroscopical methods used in autopsy could not reveal any specific cardiac symptoms, we performed further, specific microscopical staining. Immunostaining for activated caspase 3, a marker for apoptosis ( 1 , 27 ), was negative, indicating the absence of mitochondrial damage. The structure of cardiac myocytes was also intact, which suggested that the sudden cardiac arrest was caused indirectly, e.g., due to acidosis.

Fulminant hepatic failure is one of the most feared complications caused by emetic B. cereus strains. In this case, the liver damage was mild and could not be the only explanation for the sudden death of a healthy young man. Therefore, and because of the presence of diarrhea, together with the severe colonic necrosis, PCR assays that detect the presence of enterotoxin genes were applied to the samples.

As indicated above, PCR products were found for the nheA and plcA genes but not for cytK , hlyII , and hblA . These observations are rather difficult to interpret, since the actual implication of putative enterotoxins in diarrhea remains a matter of debate. The absence of HBL enterotoxin in B. cereus strains which produce cereulide is common, whereas the emetic strains usually produce NHE ( 8 ). The pattern of toxin production for the strains isolated in the present case is presumably classical for strains implicated in emetic poisoning. Nevertheless, some emetic strains producing NHE were found to be very cytotoxic for Caco-2 cells, as previously reported ( 14 ). Furthermore, the simultaneous presence of the genetic determinants for cereulide and the genes encoding potential enterotoxins was recently demonstrated for a B. cereus strain ( 19 , 20 ), which appeared to be particularly virulent. Could this fact have played a role in the necrosis of the colon, even though the cytK PCR was negative, since that this toxin is the one that has been implicated in necrotic enteritis ( 21 )? That is an important question for which no answer can be given at the moment.

Although we cannot incriminate B. cereus as the direct and unique cause of death, the present case illustrates the severity of the emetic and diarrheal syndromes and the importance of adequate refrigeration of prepared food. Because the emetic toxin is preformed in food and is not inactivated by heat treatment ( 2 , 23 ), it is important to prevent B. cereus growth and its cereulide production during storage. This toxin production is closely linked to temperature ( 9 ) and is not strictly correlated with bacterial counts, as recently demonstrated by Delbrassinne et al. ( 5 ; unpublished). The cereulide amounts produced by a B. cereus emetic strain inoculated at 10 6 CFU/g in cooked rice were higher at 23°C than at 30°C, whereas the opposite situation was observed for the cereulide producer counts. These results suggest that cereulide may be more actively produced at ambient temperatures. In this case, the spaghetti had been kept at room temperature for several days: this allowed B. cereus to grow to the previously mentioned very high concentrations and produced the high toxin concentration (14.8 μg/g) found in the pasta and which is likely responsible for the fatal outcome. According to previously published reports, toxin concentrations that induce emesis in humans, as determined by the cytotoxicity test of HEp-2 cells on the basis of several contaminated foods, extended from 0.01 to 1.28 μg cereulide/g of food ( 3 ) and from 0.005 to 32 μg cereulide/g of food ( 17 ), determined by LC-MS. Although those concentrations did not implicate lethal cases, we do not know what amounts were actually ingested. In the fatal case described by Mahler et al. ( 22 ), strains isolated from the pan residue produced NHE (detected by the BCE-VIA assay) and the emetic toxin when grown on cooked rice. This highlighted the virulence of strains capable of this simultaneous production, as reported in this study.

In conclusion, although the autopsy results were not conclusive, probably due to the delay in analysis, the large number of B. cereus cells and the significant cereulide concentration found in the leftovers are the most likely cause of death of the young healthy man. Further investigation of these isolates and this case may provide insights into the virulence mechanisms of emetic B. cereus isolates.

▿ Published ahead of print on 19 October 2011.

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Something’s Poisoning America’s Land. Farmers Fear ‘Forever’ Chemicals.

Fertilizer made from city sewage has been spread on millions of acres of farmland for decades. Scientists say it can contain high levels of the toxic substance.

Jordan Vonderhaar for The New York Times

Hiroko Tabuchi traveled to Texas and Michigan and interviewed ranchers, scientists, investigators and wastewater-treatment experts for this article.

Aug. 31, 2024

Supported by

For decades, farmers across America have been encouraged by the federal government to spread municipal sewage on millions of acres of farmland as fertilizer. It was rich in nutrients, and it helped keep the sludge out of landfills.

But a growing body of research shows that this black sludge, made from the sewage that flows from homes and factories, can contain heavy concentrations of chemicals thought to increase the risk of certain types of cancer and to cause birth defects and developmental delays in children.

Known as “forever chemicals” because of their longevity, these toxic contaminants are now being detected, sometimes at high levels, on farmland across the country , including in Texas, Maine, Michigan, New York and Tennessee. In some cases the chemicals are suspected of sickening or killing livestock and are turning up in produce. Farmers are beginning to fear for their own health.

The national scale of farmland contamination by these chemicals — which are used in everything from microwave popcorn bags and firefighting gear to nonstick pans and stain-resistant carpets — is only now starting to become apparent. There are now lawsuits against providers of the fertilizer, as well as against the Environmental Protection Agency, alleging that the agency failed to regulate the chemicals, known as PFAS.

In Michigan, among the first states to investigate the chemicals in sludge fertilizer, officials shut down one farm where tests found particularly high concentrations in the soil and in cattle that grazed on the land. This year, the state prohibited the property from ever again being used for agriculture. Michigan hasn’t conducted widespread testing at other farms, partly out of concern for the economic effects on its agriculture industry.

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How sugary or fatty snacks change your brain activity to make you like them more

Food preferences aren’t always  something we’re born with . A  study  published Wednesday in the journal Cell Metabolism suggests that eating fatty or sugary snacks alters our brain activity and creates lasting preferences for these less healthy items.

For the study, researchers at Yale University and the Max Planck Institute for Metabolism Research in Germany gave one group of participants a high-fat, high-sugar yogurt twice daily for eight weeks, while another got a low-fat, low-sugar version. Aside from that, both groups continued their normal eating habits.

At the end, the groups rated puddings with varying fat concentrations and apple juices with a range of sugar levels. The group that ate the high-fat, high-sugar yogurt said they did not like low-fat pudding and did not want low-sugar apple juice as much as they had at the start.

Next, the participants underwent MRI scans while drinking milkshakes. The scans showed that the treat increased brain activity in the group that had eaten the high-fat, high-sugar yogurt, but not in the other.

The researchers concluded that fatty, sugary snacks activate the brain’s dopamine system, which gives people a feeling of motivation or reward.

“Let’s say a new bakery opens up next to your work and you start stopping in and having a scone every morning. That alone can rewire your basic fundamental dopamine learning circuits,” said Dana Small, the study’s senior author and director of Yale University School of Medicine’s Modern Diet and Physiology Research Center.

It’s an intuitive idea for anyone who’s ever gotten into the habit of eating dessert frequently — say, around the holidays — then found the pattern hard to break.

Small said diet has such a strong effect on brain activity that dopamine signals can fire even when someone anticipates eating fatty or sugary food, like when they pass by a bakery or smell a pastry.

“It just tells us how sensitive we are to the food environment, and how the food environment can actually change our behavior,” she said.

Sugary and fatty foods alter brain activity

The new study was small: It included just 49 people, all of whom were healthy, didn’t smoke or take medication, and were not overweight or obese. Overall, the participants did not gain a significant amount of weight over the eight weeks.

Small said the study is the first to demonstrate in humans that even small dietary changes can rewire brain circuits and increase the long-term risk of overeating or weight gain.

Previous research has shown that obesity can  alter people’s brain activity , and that  people have an innate aversion to bitter foods  and a proclivity for things that taste sweet.

Experiments in rodents, meanwhile, have showed that high-fat, high-sugar foods can  rewire dopamine neurons  and  lead to overeating . But scientists knew less about how human eating habits influence food preferences.

“There’s enough evidence now to be pretty confident that this happens, and happens in multiple species,” Small said.

Susan Swithers, a behavioral neuroscientist at Purdue University who was not involved in the research, said it’s possible that people might start to prefer foods that they eat regularly, then gravitate toward them.

“People think that we eat what we like, but we actually like what we eat,” Swithers said.

There may even be biological reasons why people prefer fatty, sugary foods, according to Garret Stuber, a neuroscience professor at the University of Washington who wasn’t involved in the study. Early humans likely sought energy-dense foods high in carbohydrates and fat, he said, so people today could instinctively share those preferences.

“Thousands of years ago, those things were very sparse and not so widely abundant, but the fact that they’re everywhere now in pretty much everything we eat is sort of working against biology,” Stuber said.

How much can food preferences change over time?

One question left to answer, Small said, is whether people can change their preferences after they’ve gotten accustomed to a high-fat, high-sugar diet.

“Perhaps it is the case that if you decrease gradually to more acceptable levels of fat, that eventually you can change your preferences in a more sustainable way. But I don’t think we know that,” she said.

A  2012 study  showed that after being routinely exposed to soup without added salt, people eventually liked those soups as much as saltier versions. Small said it’s possible that such a process could work for fat and sugar, too.

But Stuber said it’s hard for people to forget that fatty, sugary foods taste good.

“If you just stop presenting something to people, something that’s rewarding, that memory doesn’t go away,” he said.

When it comes to disliking certain foods, he added, those preferences can last a lifetime.

“Think about food poisoning, for example — you can eat one food and get sick from it, and you’ll have an enduring and long-lasting aversion to that food,” Stuber said.

This story originally appeared on NBCNews.com .

Aria Bendix is the breaking health reporter for NBC News Digital.

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A 7-day meal plan with homemade versions of takeout favorites

• Case report
• Open access
• Published: 30 August 2024

Epstein–Barr virus-positive mucocutaneous ulcer resulting in severe methotrexate intoxication: a case report

• Kazutoshi Ebisawa 1 ,
• Toshihide Iwashita 2 ,
• Kohdai Uchiyama 3 ,
• Yasuhiko Kitayama 4 &
• Takahiro Takeuchi 1  

Journal of Medical Case Reports volume  18 , Article number:  409 ( 2024 ) Cite this article

Metrics details

Epstein–Barr virus-positive mucocutaneous ulcer is one of the mature B-cell lymphoproliferative diseases occurring in patients with immune dysfunction including those with immunosuppressive treatment such as methotrexate.

Case presentation

A Japanese elderly man in his 80s with rheumatoid arthritis on methotrexate was admitted to our hospital complaining persistent pharyngeal pain. Laboratory tests revealed severe pancytopenia, elevated C-reactive protein, and increased creatinine levels. An otolaryngological examination showed ulceration of the right tonsil, from which diagnostic biopsy was performed. The diagnosis of Epstein–Barr virus-positive mucocutaneous ulcer was made and bone marrow aspiration revealed hypocellularity and megaloblastic changes. Pancytopenia was improved after discontinuing methotrexate, and repeated bone marrow aspiration test revealed recovery of normal cellularity and disappearance of dysplasia, confirming the diagnosis of methotrexate intoxication. Tonsil ulcer was improved only with discontinuation of methotrexate, which strongly supported the diagnosis of EBV-MCU.

Our case suggested that even this best prognosis form of lymphoproliferative disease could lead to fatal complications if not appropriately managed.

Peer Review reports

Methotrexate (MTX) is considered as a safe and effective agent for autoimmune diseases including rheumatoid arthritis [ 1 , 2 ]. MTX directly inhibits dihydrofolate reductase, which is an essential enzyme for thymidylate synthesis, resulting in megaloblastic anemia [ 3 ]. Although rare, severe pancytopenia and febrile neutropenia could also occur as a severe adverse event of MTX [ 4 , 5 , 6 ]. In addition, long-term exposure to MTX induced chronic immunosuppressive conditions and reactivation of Epstein–Barr virus (EBV), resulting in the development of lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation [ 7 , 8 , 9 ]. EBV-positive mucocutaneous ulcer (EBV-MCU) is one of such mature B-cell lymphoproliferative diseases characterized with localized ulcerative lesions in skin or mucosa and proliferation of EBV-positive atypical B lymphocytes [ 9 , 10 ]. Initial treatment for EBV-MCU is to discontinue of MTX just as other immunodeficiency-associated lymphoproliferative disorders, and complete spontaneous regression is attained in most cases without further therapy [ 8 ].

We describe a case of pharyngeal EBV-MCU complicated with acute kidney injury and severe febrile neutropenia, in contrast to extremely favorable clinical courses generally considered to follow [ 8 , 11 ],

A Japanese elderly man in his 80 s with rheumatoid arthritis treated with 8 mg MTX every week combined with folic acid supplementation in other clinic for 11 years was admitted to our hospital for further examination of pharyngeal pain lasting 2 months. On general examination, blood pressure was 98/42 mmHg, pulse rate was 61 beats per minute, oxygen saturation was 93%, and body temperature was 36.3 ℃. Superficial lymph nodes were not swelling, and spleen was not enlarged. Otolaryngological examination revealed ulceration of the right tonsil with adhesions of white massive moss (Fig.  1 A), from which diagnostic biopsy was performed. Laboratory tests detected severe neutropenia (0.24 × 10 9 /L), thrombocytopenia (13 × 10 9 /L) and anemia (6.1 g/dL), and elevated C-reactive protein (CRP; 19.76 mg/dL) and creatinine levels (2.08 mg/dL). Other results were summarized in Table  1 . Computed tomography test revealed the right tonsil swollen, but other lymph nodes were not enlarged.

Macroscopic and microscopic findings of EBV-MCU. Massive ulcerative lesions of the right tonsil at diagnosis ( A ) could not be observed after MTX discontinuation ( B ). In hematoxylin–eosin (HE) stain, ×200 magnification ( C ) and EBER in situ hybridization (ISH), ×200 magnification ( D ), EBER-positive atypical cells were observed

Biopsy from this lesion showed proliferating EBV-encoded RNA (EBER)-positive atypical cells, but no evidences of lymphoma were observed (Fig.  1 C, D). The level of EBV-DNA in whole blood was significantly high at 3.63 logIU/mL. Although clinical signs of infection associated with neutropenia existed on the basis of the atypical EBER-positive lymphocytes attained from the oral ulcer the diagnosis of EBV-MCU was made.

To investigate the etiology of pancytopenia, bone marrow aspiration was performed immediately to reveal hypocellular marrow with remarkable megaloblastic changes in erythroid precursors (Fig.  2 A, B), which was a typical finding observed in MTX poisoning. The serum concentration of MTX measured 48 hours after the last dose was 0.12 µmol/L. From these findings, pancytopenia by MTX intoxication was suspected.

Bone marrow findings of methotrexate-induced myelosuppression. Wright–Giemsa stain, ×100 magnification ( A , C ) and ×600 magnification ( B , D ). Hypocellular marrow ( A ) with dysplastic erythroid cells with megaloblastic changes ( B ) was observed at diagnosis. Recovery of normal cellularity ( C ) and disappearance of dysplastic erythroid cells ( D ) were observed after MTX discontinuation

Thereafter, MTX was discontinued, and 15 mg of calcium folinate every 6 hours according to the protocol of high dose MTX therapy for malignant lymphoma was initiated until the serum MTX level was decreased below 0.1 µmol/L [ 12 ]. Antibiotic therapy with piperacillin–tazobactam in combination with filgrastim was immediately initiated. Three days later, CRP level was still high (15.026 mg/dL), and thus teicoplanin and micafungin were added empirically. Blood culture tests attained repeatedly before initiating these antibiotics were positive for Enterococcus faecium, which was resistant to piperacillin–tazobactam but sensitive to glycopeptide antibiotics.

A total of days later, his neutrophil count was recovered to 17.4 × 10 9 /L. Bone marrow aspiration was repeatedly performed to demonstrate normal cellularity and disappearance of megaloblastic changes (Fig.  2 C, D ), confirming that MTX-induced myelosuppression was responsible for the pancytopenia and erythroid dysplasia. Although G-banding analysis in the first bone marrow aspiration could not be performed because no dividing cells were attained, it was successfully performed in the follow-up bone marrow test to show normal karyotype. In both tests, no abnormal lymphocytes suggesting the marrow infiltration of lymphoma or lymphoproliferative diseases were observed.

Tonsil ulcer was gradually improved after discontinuation of MTX (Fig.  1 B). EBV-DNA level was decreased by approximately one-tenth (2.73 logIU/mL) in 1 month. After approximately 3 months of hospitalization for intensive rehabilitation, he was discharged home. Three months later since then, multiple occurrences of joint pain by rheumatoid arthritis recurred, which was ameliorated by iguratimod 25 mg/day. EBV-MCU was still in remission and EBV-DNA was decreased to below the lower limit of quantification.

Discussion and conclusions

Although MTX is accepted as a safe and effective treatment for rheumatoid arthritis, severe pancytopenia is reported to occur in 0.3% to 2.1% patients, especially in patients with low renal function [ 2 , 4 , 13 ]. Bone marrow morphology in such cases is characterized with decreased cellularity and significant dysplasia including megaloblastic changes [ 5 , 6 , 14 , 15 ], as observed in our case. In this case, megaloblastic anemia owing to cobalamin or folate deficiency was less likely because it was characterized with hypercellular bone marrow [ 16 ]. Other major diseases that could cause bone marrow failure were myelodysplastic neoplasms (MDS) or aplastic anemia (AA). In our case, these diseases were ruled out by repetitive bone marrow aspiration showing recovery of normal hematopoiesis and disappearance of significant megaloblastic change. As a principle, these hematologic disorders could be diagnosed only when other conditions like MTX intoxication were excluded. Thus, further evaluation for these disorders should have been performed if cytopenia did not improved even after discontinuing MTX.

EBV-MCU is a newly recognized disease characterized by circumscribed ulcerative lesions occurring in skin or mucosa with infiltration of atypical EBV-positive B cells [ 8 ]. It has similarities to MTX-associated lymphoproliferative disorders (MTX-LPD), which are lymphoma-like diseases that develop after long-term exposure to MTX [ 7 ], in that both diseases occur in patients with immune dysfunction including those with immunosuppressive treatment such as MTX [ 8 , 11 ]. However, approximately 50% cases of MTX-LPD are negative for EBV [ 17 ], and spontaneous regression is observed in only a half of MTX-LPD cases after MTX discontinuation [ 18 ], while it is attained in most cases in EBV-MCU [ 7 , 8 , 11 ]. Considering that the diagnosis of EBV-MCU was based on the histological findings attained from punched biopsy, it might not be completely ruled out that more aggressive diseases such as MTX-LPD were detected if more extensive excisional biopsy had been performed. However, due to pancytopenia and sepsis, this procedure might carry an unacceptable risk. Further, considering the ulcerative lesions confined to the oral mucosa with EBV-positive cells and spontaneous regression, additional invasive procedure to suspect the presence of lymphoma might not be necessary.

In our case, in accordance with these previous reports, the large ulcerative lesion of EBV-MCU disappeared without therapy such as rituximab. However, in our patient, the clinical course of EBV-MCU, which should normally follow favorable course, was complicated with febrile neutropenia and sepsis by Enterococcus faecium subsequent to MTX intoxication and acute kidney injury. All of these complications were triggered by EBV-MCU. Namely, undiagnosed for a few months, the lesion of EBV-MCU gradually progressed with pain while MTX was continued. This worsening pain led to insufficient food and fluid intake, which in turn led to deteriorated renal function and chronically increased serum methotrexate concentration. Under the background of severe neutropenia, Enterococcus faecium , one of the commonly detected resident microbiota in the oral cavity [ 19 ], presumably entered into the bloodstream through the ulcerative lesion of EBV-MCU resulting in bacteremia, as was often the case with neutropenic patients with stomatitis who received stem cell transplantation or intensive chemotherapy for leukemia.

There were several reports in which clinical courses of EBV-MCU were complicated with various conditions such as bone necrosis [ 20 , 21 ] or erosion [ 22 ] and bowel perforation [ 23 , 24 ] or intestinal obstruction [ 25 ]. Theodoros et al. reported a case with postoperative would infection by Streptococcus anginosus possibly related to immunosuppressive state [ 23 ], and Nakauyaca et al. reported a case with postoperative complications of transient mild neutropenia (0.7 × 10 9 /L) without signs of infection and fatal hemorrhage from the ulcerative lesion in the absence of thrombocytopenia [ 26 ]. However, there were no reports like our case in which clinical course of EBV-MCU was complicated with profound neutropenia by MTX and subsequent opportunistic infection owing to direct entry of resident bacteria from the lesion of EBV-MCU. Our case underscores the importance of immediate biopsy and MTX discontinuation when patients on low-dose MTX therapy complain of stomatitis, especially in case with decreased oral intake. Further, our case strongly suggests that even this best prognosis form of lymphoproliferative disease could lead to fatal complications if not appropriately managed.

From a cost-effective standpoint, considering that oral ulcers or stomatitis were relatively common side effect of MTX, which were reported to appear approximately 10% of MTX treated patients [ 27 , 28 ], it seemed not realistic to perform biopsy on all cases. In clinical practice, simple stomatitis by MTX were sometimes managed with folate supplementation or topical steroids with MTX continued [ 27 ], but there would be no improvement if the lesion was EBV-MCU, for which discontinuation of MTX was mandatory. Therefore, it would be reasonable to limit immediate biopsy to severe or massive ulcerations like our case, or cases in which MTX was advisable to be continued unless withdrawal was truly necessary.

In conclusion, we experienced a case of EBV-MCU resulting in severe MTX-induced myelosuppression and fatal febrile neutropenia. As the serum concentration of MTX increases in presence of renal failure, when patients treated with MTX complain of oral ulcerative lesion, clinicians should perform biopsy and discontinue MTX to gain the accurate diagnosis and to prevent the development of MTX intoxication.

Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Abbreviations

• Methotrexate

Epstein–Barr virus

• EBV-positive mucocutaneous ulcer

C-reactive protein

EBV-encoded RNA

Myelodysplastic neoplasms

Aplastic anemia

MTX-associated lymphoproliferative disorders

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Department of Hematology, Shizuoka Saiseikai General Hospital, 1-1 Oshika, Suruga-ku, Shizuoka, 422-8021, Japan

Kazutoshi Ebisawa & Takahiro Takeuchi

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Toshihide Iwashita

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Kohdai Uchiyama

Department of Pathology, Shizuoka Saiseikai General Hospital, 1-1 Oshika, Suruga-ku, Shizuoka, 422-8021, Japan

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KE and TT treated the patient and provided clinical information. KU performed biopsy and TI, YK and KE reviewed the pathological specimen. KE wrote the manuscript. TI, KU, YK and TT advised and helped writing the manuscript.

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Correspondence to Kazutoshi Ebisawa .

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Ebisawa, K., Iwashita, T., Uchiyama, K. et al. Epstein–Barr virus-positive mucocutaneous ulcer resulting in severe methotrexate intoxication: a case report. J Med Case Reports 18 , 409 (2024). https://doi.org/10.1186/s13256-024-04730-w

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Received : 31 May 2024

Accepted : 30 July 2024

Published : 30 August 2024

DOI : https://doi.org/10.1186/s13256-024-04730-w

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