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1. Hot Topics in Pediatric Infectious Diseases 2011 Hayley A. Gans, MD Assistant Professor of Pediatrics, Stanford University School of Medicine Stanford University School of Medicine
2. Hot Topics in Pediatric Infectious Diseases 2011 Globalization: “their disease is our disease” Pertussis: the epidemic continues…. Tuberculosis: Old disease; new diagnostics?
3. Clinical Case 5yo previously healthy male 2 days prior: rhinorrhea, congestion, croupy cough 1 day prior: attended daycare, but sent home for temp 99oF Developed rash on face/trunk Seen in urgent care; 103oF, ill appearing Conjunctiva injection; OP petechiae on posterior buccal mucosa Maculopapular rash pronounced on face/trunk; sparse on LE, included palms PMH: UTD on immunizations: 5 year vaccines 6 days prior SH: Returned 12 days prior from 7 day trip to London and Spain Stanford University School of Medicine
4. Clinical Case-Laboratory RubeolaIgG of 0.56 (negative is <0.91) RubeolaIgM of 1.15 (positive > 1.10) Urine and nasal swabs for measles PCR were positive for wild type measles, type D4. Clinic shut down and public health measures practiced for 3 weeks No secondary cases MRSA
5. Measles Is Fighting Back Against Eradication Air travelers possibly exposed to measles U.S. sees largest outbreak of measles in 15 years Measles is a global problem, meaning it's everyone's problem
6. Measles Resurgence US declared measles free 2000 Prior to vaccine 3–4 million infected each year, 400–500 died 48,000 hospitalized, 1,000 developed chronic disability from measles encephalitis Outbreak : 1989-1991 55,000 cases 100 deaths
7. Measles 2011 To date in 2011 -118 cases reported -highest case incidence since 1996 -89% associated with importation from other countries: 87% from the WHO European and South-East Asia regions 15% <12 mo: 20% 1-4 yrs 87% unvaccinated 40% hospitalized; all but 1 was unvaccinated 52% were < 12 mo
8. > 95% coverage required to stop transmission
9. International Travelers 50-80 million travelers annually from industrialized countries to developing countries Only ½ seek medical advice prior to travel 22-64% report health problems 8-19% seek medical care
10. Travel Advice Infants 6 -11 moshould have at least one dose of measles-containing vaccine Does not replace routine 2 dose regimen Children 12 mo or older should have two doses separated by at least 28 days. Fulfills school entry requirement Adults proof of protection or vaccinate
11. Clinical Case 2-year-old previously healthy female 12 days PTA: developed fevers 10 days PTA: seen by PMD Temp 102-103oF at home No rhinnorhea, cough, vomiting, diarrhea, or rash Physical exam: well-appearing and normal Rec: close observation; possible roseola; RTC for fevers 7 days PTA: had been afebrile x 2 days, then fever returned
12. Clinical Case 6 days PTA: seen by PMD Temp 103.3oF in clinic Otherwise asymptomatic as before Physical exam: well appearing UA & Ucx sent CXR with no infiltrate UA was (+) and Ucx later (+) for 50-75,000 GNRs Treated with PO cephalexin Continued having fevers at home
13. Clinical Case 4 days PTA: seen by PMD for WCC Temp 104.8oF at home Noted to have decreased appetite “Recently returned from India. Since then she has not been eating well.” Her mother estimates she lost 2 lbs in India Impression: Healthy 2-year-old female growing & developing normally except a UTI with persistent fevers despite cephalexin. Given fever, IM ceftriaxone was given. Will not order a BCx today as she has already been on antibiotics and the culture will likely be sterile. Later that day UCx identified as ESBL E.coli Cephalexin changed to nitrofurantoin
14. Clinical Case 1 day PTA: seen in Urgent Care Clinic Persistent fevers; 103.6oF in clinic Now with vomiting, diarrhea, and lethargy for the past 2 days “Weak, cranky, and limp when standing” Impression: acute UTI with vomiting and dehydration as well as concern for bacteremia Referred to El Camino ED -> Admitted to LPCH BCx later grew Salmonella typhi
15. Clinical Case Summary 2-year-old female with fever onset 7 days after coming back to the U.S. from a 5 week family visit to Mumbai, India. No typhoid vaccine was given. She took malaria prophylaxis. BCx grew Salmonella typhi. Diagnosis made after 13 days of fever and 3 days vomiting, diarrhea (and potential red-herring UTI) 3 PMD visits, 1 urgent care visit First documentation of travel to India in 3rd PMD visit.
16. Typhoid Fever In-Depth Report In-Depth From A.D.A.M. General Health Precautions Typhoid Fever News and Research Typhoid Fever at Simsbury School Warning After N.Y. Restaurant Worker Tests Positive for Typhoid Fever
17. Enteric Fever
18. Enteric Fever Risk
19. 150 million people live outside their country of birth Comprise 25-40% of travelers= Travelers visiting friends and relatives (VFR)
20. Enteric Fever Risk Highest risk for travelers to South Asia Other areas of risk are SE and east Asia, Caribbean, and South & Central America. Travelers to South Asia also at risk for drug resistant typhoid Highest risk are VFRs Specific Risk Factors Travel to rural areas Not following food and water precautions Longer duration of stay
21. VFRs VFRs = Travelers returning to their country of origin to “visit friends and relatives” Risk is increased several-fold compared to tourists, expatriates, & other travelers Higher risk of exposure & insufficient protection measures Less likely to seek pre-travel health care Less likely to be adequately vaccinated More likely to stay in remote rural areas More likely to consume high-risk foods/beverages Have close contact with local populations Immigrant VFRs are more likely to seek care only for more life-threatening illnesses requiring hospitalization
22. Fever in Returned Travelers Children are a particularly difficult age group for evaluation of fever because they have frequent febrile illnesses at baseline Many times their fever will be due to common childhood illnesses In the more rare occasion that it is enteric fever or malaria, delay in diagnosis leads to increased morbidity and mortality
23. Travel history Sometimes difficult to elicit travel history The family may view travel as “vacation” They often do not view it as a risk factor It sometimes comes up in passing (ex. of becoming sick on the plane) Important to not only ask about recent travel, but in some cases past travel Also, ask about visiting friends/relatives Important for transmissible diseases (i.e. typhoid, TB, etc)
24. Febrile Returning Travelers The “Big 3” Malaria Enteric fever (typhoid, paratyphoid) Dengue Others Chikungunya Leptosporosis Hepatitis A Tuberculosis Acute schistosomiasis Brucella Histoplasmosis Acute HIV Rickettsiae: African tick bite fever, scrub typhus Viral hemorrhagic fevers Vaccine Preventable Illness Meningococcal disease, Measles, Hepatitis A & B, Yellow fever, Japanese encephalitis, Rabies
25. Diagnosis by Travel History N Engl J Med 2006; 354:119-130
26. Diagnosis by Incubation Period Determining the incubation period can be helpful in ruling out possible causes of fever Malaria can occur during the short, intermediate, or long incubation period & enteric fever during the short & intermediate incubation periods If the fever begins >21 days after a traveler’s return, then dengue, rickettsial infections, yellow fever, & Lassa fever are unlikely
27. Short Incubation Period N Engl J Med 2002; 347: 505-516
28. Intermediate Incubation Period
29. Long Incubation Period
30. Typhoid Vaccine Oral: live-attenuated Ty21a > 6 years old; Revaccinate every 5 years Should not be given to immunocompromised hosts/those on antibiotics IM: Vi capsular polysaccharide > 2 years old; Revaccinate every 2 years Protective efficacy (both) 70-80%
31. Case Presentation 3wk-old term BB with 10d history cough and poor feeding followed by breath-holding spells and cyanosis requiring vigorous stimulation. Afebrile, not fussy, no GI symptoms, no rash, normal amount of wet diapers ER in Modesto: sats 92%  85%  2.5L NC Wbc 57 (44% polys, 36% lymphs, 20% monos)
32. Case Presentation Rapidly worsening respiratory over 1st 24hrs  intubated  HFOV  iNO Hypotensive  DA Wbc increased to 101 (18% polys, 21% bands, 9% metas, 26% lymphs, 24% monos), CRP 6.8mg/dL Anemic, coagulopathic Lyteswnl; AST 72, ALT 31, alb 1.8 CXR: patchy perihilar consolidations, small R pleural effusion Ampicillin, cefotaxime started Transferred to LPCH PICU for higher level of care
33. Case Presentation I.D. workup (in Modesto): Rapid flu A/B negative Respiratory DFA panel negative BCx NGTD Ucx NGTD CSF cx NGTD, gram stain neg, cells/chemistry wnl
34. Case Presentation I.D. workup (in Modesto): Rapid fluA/B negative Respiratory DFA panel negative BCx NGTD Ucx NGTD CSF cx NGTD, gram stain neg, cells/chemistry wnl ETT aspirate: 4+ gram-negative coccobacilli Azithromycin 5mg/kg/day added
35. Case Presentation Positive for Bordetella pertussis by PCR Despite use of selective media, cultures were negative Azithromycin changed to 10mg/kg q24h Developed pulmonary hypertension, worsening hemodynamic instability Exchange transfusion performed Required ECMO, CVVH Support was withdrawn on hospital day 7
36. Pertussis Resurgence 10 BABIES DEAD as WHOOPING COUGH (pertussis) is DECLARED an EPIDEMIC IN CALIFORNIA Vaccination Is Steady, But Pertussis Is Surging Whooping cough cases 'remain high' 38-Day-Old Baby Dies After Persisting Cough
37. Pertussis: Incidence
38. Pertussis: Incidence Why the increase? Vaccine failures due to genetic change in organism? Increased vaccine failures due to change from DPT to DTaP? Greater awareness of pertussis? Better diagnostic tests? Less antibiotic use?1 Macrolide resistance? 1. Finkelstein JA et al. Reduction in antibiotic use among US children. Pediatrics. 2003 Sep;112(3 Pt 1):620-7.
39. Pertussis: Incidence
40. Pertussis: Incidence
41. Pertussis: Incidence Pertussis is the most poorly controlled vaccine-preventable disease Adults are susceptible to pertussis 27% of reported cases in 2004 were among adults Pertussis immunity is not lifelong and wanes 4-12 years after the DTaP series and 4-20 years after natural infection ~20% of cough illness lasting >2 weeks is pertussis
42. Why here, why now? Pertussis epidemics occur every 3-5 years enough susceptible people accumulate in the population to sustain widespread transmission of pertussis Unvaccinated infants Waning population immunity from vaccines/disease Parental choice not to vaccinate It’s unclear why California has been the state most affected so far in current epidemic one of 11 states that does not have a requirement that all middle school students receive Tdap
43. California Pertussis Deaths Most of the fatal cases in 2010 had several contacts with health care providers before pertussis was considered All CA pertussis deaths (~3/year) since 1996, except one, have been in infants <3 months of age 80% Hispanic (50% of birth cohort is Hispanic) The mean WBC of fatal cases in 1998-2009 was 75,000 (range 15,000-148,000); Of those with known status, all had pulmonary HTN A risk factor study is being conducted
44. Why are Hispanic infants over-represented among infant cases? Increased incidence in Hispanic infants <6 months has been noted in other states as well Higher mortality rates have been estimated nationwide for Hispanic than for non-Hispanic infants since the 1990s In 2000, 30.6 percent of family households in which a Hispanic person was the householder consisted of five or more people vs. 11.8 percent of non-Hispanic white family households Haberling D, et al. Pediatr Infect Dis J 2009;28:194–198
45. Pertussis: Morbidity and Mortality 1926-1930: 36,013 deaths, most under 1yr of age 1900-1944: 5-fold decrease in infant mortality 1945-1980: 85-fold decrease in mortality 2010: 9,477, 10 infant deaths Highest rate in 65 years
46. Hypothetical Ex. 1 Adopted 18 month old who received BCG at birth. TST 14mm; IGRA is negative. History unrevealing; PE normal; Chest x-ray with no abnormalities.
47. Hypothetical Ex 2 5yo routine TST for school (SCC) TST 13mm; IGRA negative History denotes domestic (NYC) and international (W&E. Europe) travel; PE normal; Chest x-ray with no abnormalities.
48. Hypothetical Ex 3 2 yo with cervical lymph node (2cm) PPD 10mm; IGRA negative. History unrevealing (lives in SCC); PE normal except LN; Chest x-ray with no abnormalities.
49. Dr. Julie Higashi – Deputy Health Officer SCCPHD
50. Hospital Employee Exposes Nearly 800 Patients and Staff to Tuberculosis Four People Exposed To Tuberculosis Test Positive
51. Tests for TB Infection Tuberculin skin test (TST) Interferon-gamma release assays (IGRA) Andersen P. Lancet 2000, 356:1099
52. Interferon-γ Release Assays (IGRA) Quantiferon®-TB Gold In-Tube (Cellestis, Victoria, Australia) T-SPOT®.TB (Oxford Immunotec, Oxford, United Kingdom) AAP allows use of IGRA for > 5 years old (plus cautions)
53. Red Book – IGRA Excerpt Children with a positive result from an IGRAshould be consideredinfected with M. tuberculosis complex. Anegative IGRA resultcannot universally be interpreted as absenceof infection. Because of their higher specificity and lackof cross-reactionwith BCG, IGRAs may be useful in childrenwho have received BCG vaccine. IGRAs may be useful to determinewhether a BCG-immunizedchild with a reactive TST more likelyhas LTBI or has a false-positiveTST reaction caused by theBCG. IGRAs cannot be recommended routinely for use in childrenyoungerthan 5 years of age or for immune-compromised childrenof anyage because of a lack of published data about their utilitywith these groups. Indeterminate IGRA results do not excludetuberculosis infectionand should not be used to make clinicaldecisions.
54. Quantiferon® TB Gold In-Tube
55. Quantiferon® TB Gold In-Tube
56. T-SPOT®. TB
57. T-SPOT®. TB
58. M. tuberculosis Testing TST-tuberculin skin testing; BCG-BacilleCalmette-Guérin; NTM-non-TB mycobacteria; QIT-Quantiferon®-TB Gold In-Tube; T-Spot-T-SPOT®.TB; PPD-purified protein derivative; ESAT-6-early secretory antigen target 6; CFP-10-culture filtrate protein 10.
59. IGRA Does not Identify TB Disease Kampmann B. EurRespir J 2009, 33:1374
60. 0-5 years old: Lifetime Risk of TB Disease = 10-20% Horsburgh. NEJM 2004, 350:2060
61. TB Infection No gold standard for diagnosis of TB infection Thus, no formal sensitivity or specificity Usefulness of TST for diagnosis of TB infection is based on long-term follow-up.
62. Interpretation of Positive Quantiferon®? Detected TB infection and increased risk of TB disease Based on surrogate endpoint of TB disease. TST also positive (and few discordant results).
63. Interpretation of Negative Quantiferon®? Did not detect TB infection and no risk of TB disease. Based on what? No long-term follow-up for future TB disease Large number of discordant results with TST
64. Quantiferon®≠ TST – Why? TST + due to BCG vaccine? Problem with IGRA test? Interferon-γ production low in young children Types of antigens used Appropriate “cut-off” points

65. BCG does not prevent primary TB Infection

66. Young Children and IFN-γ Response (mitogenstimulation) Pediatrics 2009, 123:e419
67. Indeterminate Quantiferon®
68. Cut-Off Points Pai M. JAMA 2005, 293:2746
69. Quantiferon®≠ TST – Why? TST + due to BCG vaccine? Not entirely. Problem with IGRA test? Yes especially in children Interferon-γ production low in young children Types of antigens used Appropriate “cut-off” points
70. TST T-Spot Mean age 7.5 y (1m – 16y) Mean F/u duration 1.3 y
71. Hypothetical Ex. 1 Adopted 18 month old who received BCG at birth. TST 14mm; IGRA is negative. History unrevealing; PE normal; Chest x-ray with no abnormalities.
72. Hypothetical Ex 2 5yo routine TST for school (SCC) TST 13mm; IGRA negative History denotes domestic (NYC) and international (W&E. Europe) travel; PE normal; Chest x-ray with no abnormalities.
73. Hypothetical Ex 3 2 yo with cervical lymph node (2cm) PPD 10mm; IGRA negative. History unrevealing (lives in SCC); PE normal except LN; Chest x-ray with no abnormalities.