人類狂犬病臨床診治及 暴露前疫苗使用實務

1. 人類狂犬病臨床診治及暴露前疫苗使用實務 三軍總醫院 內科部 感染科 王甯祺 醫師

2. Human Rabies with multiple organs failure

3. General Profile Chief Complaint • Right flank pain, dysphagia and easily choking for days. • Gender: Male • Age: 30-year-old • Admission date: 2012/07/23

4. Present illness • Got a Keeshond puppy from his employee April 5/18- 5/25 • Left Wuhan with his wife for a business trip • Found the puppy had a wound on its neck (bitten by a stray dog according to the apartment janitor) • His wife brought the puppy to the vet for rabies vaccination 6/18

5. Present illness 6/20 • Bitten at his second toe by the puppy, did not seek medical attention • The puppy bit two of his nephews. • The two boys received wound care and rabies vaccines immediately. 6/22 6/26 • The puppy was drown to river by patient’s family because its irritability and red eyes.

6. Present illness • Numbness and tingling over his left foot • Paresthesia over left leg and genitals 7/16 7/18- 7/19 • Left flank pain and low grade fever • Visited local clinic, got the diagnosis of common cold • Difficulty in swallowing water, throat discomfort, vomiting, aerophobia. • Visited another local clinic, got the diagnosis of nephritis 7/20

7. Present illness • Chills, vomiting, muscle spasm  • Transferred to the local hospital: • Hydrophobia, difficulty in swallowing, aerophobia, sweating • Panic appearance, injected throat • Clear consciousness 7/20 • Headache, twitching of limbs, decreased urine output, consciousness change. Endotrahceal intubation for respiratory failure 7/21 7/23 • Came back to Taiwan by an international SOS airplane

8. Past history ◎ Denied the history of hypertension, DM or other systemic diseases. ◎ History of intussusception in his childhood.

9. Personal history Smoking: 0.5-1 PPD for years. Drinking: socially. Occupation: 工廠老闆 Social relations: well Religious belief: Buddhism Animal contact history: Nil Traveling history: lives in 湖北(在大陸工作並定居2-3年) Married in Mainland China

10. Family history

11. Review of systems Positive findings: fever, consciousness change, dysphagia, easily chocking, hydrophobia, and focal seizure.

12. Physical exams-1 BT: 40 ℃; PR: 160 bpm; RR: 25 /min; BP: 74/40 mmHg Height: 180 cm; Weight: 80 Kgs Consciousness: semi-coma; Mentality: undetactable; Condition: critical; Nutrition status: moderate Skin: dry skin turgor, no skin rash or peripheral lymphadenopathy, no petechia or ecchymosis of the skin. Head & neck: s/p endotracheal intubation, s/p NG tube insertion, normal configuration of the head and its organs, congestion conjunctivae, Salivation, frequent swallowing movement

13. Physical exams-2 Chest & lungs: symmetrical expansion of the chest, no deformity of chest wall, bilateral crackles of breathing sounds. Heart: regular and rapid heart rate, no murmur or thrill, normal peripheral pulse. Abdomen: flat and soft abdomen, hypoactive bowel sounds, no hepatomegaly, no splenomegaly, no palpable mass, no rebounding tenderness, diffuse tympanic percussion. Extremities: No wound (left 2nd toe wound healed), frequent muscle spasms of upper limbs

14. Laboratory Findings

15. Diagnoses at admission Suspected human rabies complicated with semi-coma status. Pneumonia, suspected aspiration pneumonia with septic shock and multiple organ failure, including acute respiratory failure, acute kidney injury, myocardial injury and acute hepatitis Rhabdomyolysis with acute renal failure

16. Hospital Course • BT:41.3 C, Rhabdomyolysis and Acute kidney Injury • CVVHD(7/23-7/26) • Suspected pneumonia complicated with sepsis and MODS • B/C: Staphylococcus hominis • Tazocin as antibiotics treatment 7/23 7/24 • Brain CT • Lumbar puncture: pressure: 18.5 cm 7/25 • Lumbar puncture: pressure: 30.5 cm

17. Hospital Course • Shift antibiotics to Tagorcid and Mepem, for blood cultures Staphylococcus hominis x2 7/26 7/29 • Off neuromuscular blockade, Taper midazolam 8/5 • Sedation waned off • HCAP(XDR-A.baumannii, Enterobacter cloacae, SM), received piperacillin/tazobactum and Amikacin 8/6 • Double lumen infection->septic shock. Shift HD to CVVHD 8/14 • Intermittent VT • Suspected rabies virus with involvement of heart conductive system

18. Hospital Course 8/20 • Increased urine output • Urine Output:300-600 ml/ day • Shock improved. CVVHD->HD 8/28 • CMV viremia • Cymevene~9/19 9/3 • ESBL-K.pneumoniae / E.coli pneumonia • Shock and oligouria • HD->CVVHD

19. Hospital Course • Persistent hypercalcemia even under CVVHD • -> hypothyroidism/ adrenal insufficiency? • Endocrine survey 9/8 • Progressive increased urine output to over 3L/day • -> Central DI • DDAVP nasal spray 9/14 9/19 • LH releasing hormone stimulation test: neg. • -> Central failure • Panhypopituitarism

20. Hospital Course • Brain MRI: • Swelling of bilateral basal ganglion; • thalamus; hypothalamus; • brainstem; inferior temporal lobe • with compression of pituitary gland 9/28

21. Hospital Course 10/2 • Suspected rabies virus induced renal tubule injury type I RTA • Bicarbonate supplement; ceased HD. • Under isolation ICU monitoring due to: • Positive saliva RT-PCR result • Ventilator dependent respiration • Unstable hemodynamics

22. Rabies Laboratory Results

23. Rabies Laboratory Results 2013-1-13 CSF sent to CDC USA for viral cell culture: negative

24. Pan-hypopituitaridism

25. Rabies Endocine Work

26. Final diagnosis Human rabies complicated with deep coma status and multiple organs failure (respiratory failure, central failure, pan-hypopituitarism) Staphylococcus hominis bacteremia with septic shock, including acute respiratory failure status post tracheostomy with ventilator support. Rhabdomyolysis with acute renal failure, complicated with end-stage renal disease status post hemodialysis, improving. CMV reactivation. Healthcare associated pneumonia, bilateral

27. Discussion

28. Rabies post-exposure prophylaxis, which is highly effective if given promptly, includes: • wound cleansing, • immunization with a modern cell culture vaccine, • and administration of human rabies immunoglobulin (HRIG) • Once rabies encephalitis develops, no therapy has proved effective. CID 2003:36 (1 January) • Jackson et al.

29. Aggressive or Palliative approach to Therapy • For previously unvaccinated patients with rabies, reports to date have indicated agonizing symptoms and a 100% mortality rate. • Aggressive approach to therapy with the aim of curing the disease: even if such an approach were successful, the patient likely would be left with permanent disabling neurological deficits. CID 2003:36 (1 January) • Jackson et al.

30. Aggressive or Palliative approach to Therapy Making the decision to embark on an aggressive course of therapy: 1. Administration of any rabies vaccine before the onset of clinical rabies. 2. Presentation with a very early stage of disease, including paresthesias or pain at the site of a previous bite exposure, with minimal other neurological symptoms or signs. 3. Good health and absence of chronic disease. 4. Relatives who accept both the high probability of an unsuccessful outcome and the possibility of disabling neurological deficits in a rabies survivor CID 2003:36 (1 January) • Jackson et al.

31. Specific Therapies • Rabies vaccine • Human rabies vaccines are inactivated and do not elicit a cytotoxic T cell response. • No human live attenuated or recombinant rabies vaccine has been licensed for use in humans to date. • Rabies immunoglobulin(20 IU/kg): in rabies post-exposure prophylaxis, HRIG neutralizes the virus before its invasion of the nervous system. • Corticosteroids: Corticosteroidtherapy generally is not considered for themanagement of brain edema in rabies • In mouse models, administration of corticosteroids increased the mortality rate and shortened the incubation period. Can J Microbiol 1970; 16:667–75. CID 2003:36 (1 January) • Jackson et al.

32. Milwaukee_rabies_protocol_V3_1

33. Milwaukee_rabies_protocol_V3_1 What to do first: • DO NOT administer rabies vaccine or immunoglobulin. • This has never worked in rabid patients. • It violates a key assumption of the Milwaukee protocol. • It may cause “early death” phenomena, based on case reports and animal models.

34. Differential diagnosis • Rabies is NOT likely in patients: • Without a fever • With an illness lasting more than 14 days (other than Guillain-Barre-like syndrome) • With an incubation period following an animal bite or transplantation of < 10 days or > 1 year • Who completed a full course of rabies post-exposure prophylaxis including immune globulin

35. Once rabies is considered • Isolate the patient • Minimize early demise in 20% of patients from catecholamine storm or bradyarrythmia/asystole • If patient is extremely agitated, hypertensive, with tachyarrhythmia, consider diagnosis of CNS- mediated catecholamine storm. This may cause cardiomyopathy if untreated. Bradyarrhythmias and asystole are also common.

36. Once rabies is considered • Minimize stimulation – similar to management of tetanus. • Use heavy sedation (preferably midazolam ± fentanyl) x 24 h. Avoid barbiturates – these inhibit the immune response. • Propofol has a relative contraindication

37. Rabies vaccine Pre-exposure • 3 doses administered on Day 0, 7, and 21 (or 28 day). • Injected site deltoid muscle, never gluteal muscle. MMWR 2010;59:RR-2 Post exposure prophylaxis • 5 doses administered on Day 0, 3,7, and 14 and 28 day.

38. Are we ready to careRabies ? • Hospitals or clinics • Standard precaution • Wound cleaning techniques (soap 10-15 min + 70-75% alcohol wound care reduce 90% risk of rabies) • What kind of patients need vaccination

39. Are we ready to careRabies ? • Healthcare workers • Contact isolation (body fluid isolation) • Face mask, eye glasses, gloves, gowns • Post-exposure prophylaxis procedures • Educate patient’s families

40. 感謝大家的付出、支持與協助 • 病人 • 疾病管制署: 吳岫與全體防疫醫師, 病毒實驗室 楊博士 • 三軍總醫院: • 負壓隔離加護中心 全體護理同仁 • 感染科 邱勝康醫師,林德宇醫師, 楊雅頌 醫師 • 麻醉部醫師, 神經內科部醫師 • 參與照顧病人的醫療團隊

41. Thanks for your attention!