immune-mediated polyradiculoneuropathy among abattoir workers ...

1. Immune-mediated Polyradiculoneuropathy among Abattoir Workers exposed to Aerosolized Porcine Brains, Indiana, United States LT Jennifer Adjemian, PhD Epidemic Intelligence Service Officer National Center for Zoonotic, Vectorborne, and Enteric Diseases Centers for Disease Control and Prevention

3. The first Pin cases associated with Plant A had onset in November 2006 with additional cases presenting periodically over the next year. The median age was 31 years. Sixty percent were female. The first Pin cases associated with Plant A had onset in November 2006 with additional cases presenting periodically over the next year. The median age was 31 years. Sixty percent were female.

4. Clinical Diagnosis Illness most consistent with immune-mediated inflammatory neuropathies Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) & Guillain-Barr� syndrome (GBS) Immune system attacks myelin of peripheral nerves Infectious antecedent in 1/3 to 2/3 cases Characterized by progressive weakness & impaired sensory function in legs/arms Tingling & numbness (starting in the toes/fingers) Weakness of arms & legs Loss of deep tendon reflexes (areflexia) The patients presented with illness that was most consistent with two immune-mediated inflammatory polyneuropathies of the peripheral nervous system, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), or Acute Inflammatory Demyelinating Polyneuropathy (AIDP). The patients presented with illness that was most consistent with two immune-mediated inflammatory polyneuropathies of the peripheral nervous system, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), or Acute Inflammatory Demyelinating Polyneuropathy (AIDP).

5. Distinct Neuropathy

6. Clustering of Cases All cases worked at same swine slaughter facility in MN (Plant A) Plant A employs ~1200 workers, for incidence rate of 834 cases per 100,000 people 400 Xs greater than rate of other neuropathies CIDP: 0.5 � 2 cases per 100,000 GBS: 1.2 � 1.9 cases per 100,000

7. Novel Neurological Illness Nov. 2007: MDH contacted CDC regarding cluster of cases at Plant A Determined to be a new neuropathy, termed �Immune-mediated Polyradiculoneuropathy� (IP) Case definition developed & joint investigation initiated by CDC & MDH

8. IP Case Definition Epidemiologic Criteria: Participation in or close exposure to butchering of pigs Clinical Criteria: New onset of bilateral, symmetric flaccid weakness/paralysis of limbs New onset of decreased or absent deep tendon reflexes Diagnostic Criteria: Electrodiagnostics with axonal/demyelinating peripheral neuropathy Neuroimaging consistent with radiculitis, myelitis, or encephalitis Cerebrospinal fluid protein >45 mg/dL Confirmed case: Meets epidemiologic criteria, both clinical criteria, & EMG consistent with axonal and / or demyelinating neuropathy Probable case: Meets epidemiologic criteria, at least 1 clinical criterion, & at least one diagnostic criterion Possible case: Meets epidemiologic criteria & at least 1 clinical criterion Exclusion Criteria: Alternative recognized etiology may explain the clinical and diagnostic findings Exclusion Criteria: Alternative recognized etiology may explain the clinical and diagnostic findings

9. MDH Preliminary Investigation MDH conducted case-control study of Plant A 10 reported cases (8 confirmed, 2 probable) 50 random plant controls Preliminary results suggested strong epidemiologic link to �Brain Blowing� Unique procedure used to remove pig brains with a high-pressure air extraction technique

10. Preliminary Odds Ratio implicating �Brain Blowing�

12. CDC Investigation Findings prompted concern that workers in other slaughter plants removing porcine brains may be at similar risk Dec. 2007: CDC partnered with state health depts & USDA to survey swine abattoirs Establish frequency of brain extraction Establish frequency of the high-pressure air technique Inquire about potential IP cases USDA�food safety inspection service (fsis)USDA�food safety inspection service (fsis)

13. How common is porcine brain removal? 26 large federally-inspected swine abattoirs identified by USDA & contacted by CDC > 500 workers Of these, 9 (35%) remove pig brains 6 take out whole brains (scoop) 3 �blow brains� using compressed air MN plant (Plant A) NE plant IN plant

14. Preliminary Investigations for IP at IN & NE Swine Abattoirs CDC & State Health Depts visited both plants in Dec. 2007 to observe practices & any IP cases Sent health alerts to area physicians Contacted neurologists in the area

15. Possible IP in Indiana & Nebraska Health alerts & news reports prompted reporting of 3 suspect cases in IN & 1 in NE All reported by local treating neurologists All hospitalized for neurological symptoms All worked at abattoirs identified by CDC as �blowing brains� Plant X in Indiana Plant Y in Nebraska

16. Epi-Aid to Investigate Plants X & Y Jan. 2008: CDC, IN State Health Dept, & NE State Health Dept initiated Epi-Aid CDC teams sent to investigate Plants X & Y Preliminary site visits confirmed 1 IP case only in NE Large-scale study conducted at Plant X Objectives: Evaluate identified suspect cases Investigate Plants for additional suspect cases Identify risk factors associated with any IP cases

17. Plant X Investigation

18. Case-finding Activities Evaluated 3 known suspect cases for IP Questionnaire Neuroepidemiologist Obtained list of employees terminated from Plant X within past year Contacted those with illness or medical reason listed as cause for termination

19. Plant X Investigation Interviews & blood samples for employees from �kill floor� (where hogs are processed) All workers in �head-boning workers� Room where heads & brains were processed Sample of �non-head-boning workers� Other parts of kill floor where rest of pig is processed Sample of �mixed-job workers� Spent time in head-boning & non-head-boning areas

21. Worker interviews conducted Jan & Feb 2008 using a questionnaire to collect data on: Demographics Current & past job activities at Plant X Job rotation patterns Use of personal protection equipment (PPE) Previous employment history Medical history Other exposures (chemical, animal, vector) Activities outside the plant Plant X Interviews

22. Evaluation of Potential IP Cases Workers reporting symptoms of peripheral neuropathy (i.e. numbness, tingling, and/or weakness in extremities) On-site neurological assessment by board-certified neurologist to look for objective signs Individuals with features of IP were referred for further medical care and testing

23. Analytic Methods Data summarized with descriptive statistics Nested case-control study Separate analyses for all cases & confirmed cases only Both univariate & multivariate logistic regression Multivariate models built with backward step-wise selection in R (http://www.r-project.org)

24. Laboratory Analyses Blood samples tested for evidence of infections from human & swine pathogens Serum levels of cytokines and chemokines in cases & controls analyzed Used multiplexed, bead-based cytokine immunoassay (Upstate Beadlyte? human multi-cytokine/chemokine kit, Millipore, St. Charles, MO) & Luminex100 detection system (Luminex Corporation, Austin, TX)

25. Plant X Interview Results 244 kill floor workers employed at Plant X Interviewed 114 (54%) 51 (74%) of 69 head-boning workers 63 (36%) of 175 non-head-boning & mixed-job workers 300 kill floor workers terminated in past year 3 were the initial suspect cases 4 others listed illness as cause for termination None were suspect cases upon questioning

26. Indiana IP Case Results 10 cases detected 6 confirmed, 1 probable, 3 possible 5 identified through physician referrals 5 identified at plant during investigation All cases had peripheral neuropathy features Limb weakness, decreased reflexes Confirmed cases had additional laboratory or electrophysiologic evidence

27. IP Case Onset & Severity Onset from April 2005 to Dec 2007 Symptoms varied from mild to severe 6 of 10 hospitalized (mean 8.8 days; range 5-14)

28. Plant X Study Of 244 kill floor & 300 terminated workers Crude attack rate of 1.8% (all cases, n=10) Crude attack rate of 1.1% (confirmed cases only, n=6) 1100 cases per hundred thousand people Of interviewed workers, 8 cases & 106 controls included in case-control study 2 cases did not consent to interview

29. Demographic Comparisons ________________________________________ Cases Controls P-value Mean Age (yr) 34.8 31.3 0.3 M:F ratio 0.4 1.3 0.3 Hispanic (%) 100.0 77.4 0.1 _______________________________________________

30. Work-related Comparisons _______________________________________________ Cases Controls P-value Mean Total 3.5 2.9 0.7 Work Time (yr) Head room (%) 100.0 67.0 <0.0001 Brain 87.5 32.0 0.002 harvesting (%) Brain tissue in 75.0 22.6 0.02 eyes, nose, mouth (%) ____________________________________________________________________________________________________________________________________________

31. Logistic Regression Results

32. Pathogen Analysis Viral Testing Encephlomyocarditis virus (EMC) Hepatitis E virus (HEV) TGE Porcine adenovirus Porcine rotavirus Porcine reovirus Swine Influenza (H1N1) Porcine teschovirus Porcine enterovirus A Pseudorabies virus Porcine parvovirus

33. Serum Analysis Elevated serum levels of interferon-gamma (IFN-?) discovered among cases (P < 0.001) Approximately 94% of cases had IFN-? values above the control median (P = 0.002)

34. Summary of Risk Factors for IP IP cases were significantly more likely than controls to have: Reported brain tissue in eyes, nose, or mouth Harvested brains Worked in the head room Spent more time harvesting brains

35. Findings & Hypothesis for IP Identified 10 workers in IN with neurologic symptoms & exposure risks consistent with IP Like Plant A in MN, Plant X used high-pressure compressed air to extract porcine brains Hypothesis: Likely mechanism of IP pathogenesis is autoimmunity induced by exposure to aerosolized porcine brain matter

36. Biological Plausibility? Animal model: Neurologic illness, experimental allergic encephalomyelitis (EAE) & neuritis (EAN), induced in lab animals through injection of neural tissue Humans: Immune-mediated neurologic illness from Semple rabies vaccine, which is derived from inoculation of rabies virus into sheep or goat brain Elevated IFN? observed among persons with acute or chronic inflammatory demyelinating polyneuropathies

37. Development of IP Proximity to brain removal was strongest predictor of disease However not all workers removing brains became ill Indicates likely role for genetic or other host factors Ex. In Semple rabies vaccine recipients, unique MHC class II alleles found among persons in whom neuropathy developed

38. Mild IP Cases? IP cases were more likely to report weakness & numbness of the limbs However, these symptoms also reported in milder forms by other head room workers Tended to attribute such symptoms to duration & nature of their work Technique no longer used at plants, so full clinical spectrum may never be described

39. Earlier Cases? Case finding activities focused on past year, but several identified with earlier onset Plant X began using compressed air device to remove brains in 1993 May be related to 2004 USDA ban on bovine brain material for human consumption over concerns of Bovine Spongiform Encephalopathy

40. Conclusions Novel neuropathy, IP, detected at all 3 federally inspected swine abattoirs identified in US using this brain extraction method Cases significantly associated with brain extraction exposure All Plants voluntarily stopped practice by January 2008 To date, no additional IP cases reported Currently unknown if non-federal swine abattoirs or those processing other animals also extract brains using compressed-air devices

41. Public Health Recommendation Until further understanding of IP is obtained, we recommend all swine abattoirs using similar brain extraction methods discontinue process altogether

43. Thank you!