Hot Topics in Pediatric Infectious Diseases 2011

Hayley A. Gans, MDAssistant Professor of Pediatrics, Stanford University School of Medicine

Stanford UniversitySchool of Medicine

Hot Topics in Pediatric Infectious Diseases 2011

Globalization: “their disease is our disease”

Pertussis: the epidemic continues….

Tuberculosis: Old disease; new diagnostics?

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

SpainStanford UniversitySchool of Medicine

Clinical Case-LaboratoryRubeola IgG of 0.56 (negative is <0.91) Rubeola

IgM 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

MRSAMRSA

Measles Is Fighting Back Against Eradication

Air travelers possibly exposed to measles 

Measles is a global problem, meaning it's everyone's problem

U.S. sees largest outbreak of measles in 15 years

Measles Resurgence

US declared measles free 2000Prior to vaccine

• 3–4 million infected each year, • 400–500 died• 48,000 hospitalized, • 1,000 developed chronic disability from measles

encephalitisOutbreak : 1989-1991

• 55,000 cases• 100 deaths

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

> 95% coverage required to stop transmission

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

Travel Advice

Infants 6 -11 mo should 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

Clinical Case

2-year-old previously healthy female12 days PTA: developed fevers10 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

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 GNRsTreated with PO cephalexinContinued having fevers at home

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

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

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.

Typhoid Fever In-Depth ReportIn-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

Enteric Fever

Enteric Fever Risk

150 million people live outside their country of birthComprise 25-40% of travelers=

Travelers visiting friends and relatives (VFR)

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

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

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

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 travelAlso, ask about visiting friends/relatives

• Important for transmissible diseases (i.e. typhoid, TB, etc)

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

Diagnosis by Travel History

N Engl J Med 2006; 354:119-130

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

Short Incubation Period

N Engl J Med 2002; 347: 505-516

Intermediate Incubation Period

Long Incubation Period

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%

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)

Case Presentation

Rapidly worsening respiratory over 1st 24hrs intubated HFOV iNO

Hypotensive DAWbc increased to 101 (18% polys, 21% bands, 9% metas,

26% lymphs, 24% monos), CRP 6.8mg/dLAnemic, coagulopathicLytes wnl; AST 72, ALT 31, alb 1.8CXR: patchy perihilar consolidations, small R pleural effusionAmpicillin, cefotaxime startedTransferred to LPCH PICU for higher level of care

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

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

Case Presentation

Positive for Bordetella pertussis by PCRDespite use of selective media, cultures were

negativeAzithromycin changed to 10mg/kg q24hDeveloped pulmonary hypertension, worsening

hemodynamic instabilityExchange transfusion performedRequired ECMO, CVVHSupport was withdrawn on hospital day 7

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

Pertussis: Incidence

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.

Pertussis: Incidence

Pertussis: Incidence

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

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

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

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

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 deathsHighest rate in 65 years

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.

Hypothetical Ex 2

5yo routine TST for school (SCC)TST 13mm; IGRA negativeHistory denotes domestic (NYC) and

international (W&E. Europe) travel; PE normal; Chest x-ray with no abnormalities.

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.

Dr. Julie Higashi – Deputy Health Officer SCCPHD

Hospital Employee Exposes Nearly 800 Patients and Staff to Tuberculosis

Four People Exposed To Tuberculosis Test Positive

Tests for TB Infection

Tuberculin skin test (TST)Interferon-gamma release assays (IGRA)

Andersen P. Lancet 2000, 356:1099

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)

Red Book – IGRA Excerpt Children with a positive result from an IGRA should be considered infected

with M. tuberculosis complex. A negative IGRA result cannot universally be interpreted as absence of infection.

Because of their higher specificity and lack of cross-reaction with BCG, IGRAs may be useful in children who have received BCG vaccine. IGRAs may be useful to determine whether a BCG-immunized child with a reactive TST more likely has LTBI or has a false-positive TST reaction caused by the BCG.

IGRAs cannot be recommended routinely for use in children younger than 5 years of age or for immune-compromised children of any age because of a lack of published data about their utility with these groups.

Indeterminate IGRA results do not exclude tuberculosis infection and should not be used to make clinical decisions.

Quantiferon® TB Gold In-Tube

Quantiferon® TB Gold In-Tube

T-SPOT®. TB

T-SPOT®. TB

M. tuberculosis Testing

TST-tuberculin skin testing; BCG-Bacille Calmette-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.

Test Measures T-cell Response

Distinguishes Infection vs. Disease *

Antigens (quantity)

Incubation Cross-reactivity

TST Yes No PPD-SRT-23(multiple)

48-72h BCGM. bovisMultiple NTM

QIT Yes No ESAT-6CFP-10TB 7.7 (3)

16-24h M. bovisM. kansasiiM. marinumM. szulgai

T-SPOT yes No ESAT-6CFP-10(2)

16-24h M. bovisM. kansasiiM. marinumM. szulgai

IGRA Does not Identify TB Disease

Kampmann B. Eur Respir J 2009, 33:1374

0-5 years old: Lifetime Risk of TB Disease = 10-20%

Horsburgh. NEJM 2004, 350:2060

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.

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).

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

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

BCG does not prevent primary TB Infection

Young Children and IFN-γ Response (mitogen stimulation)

Pediatrics 2009, 123:e419

Indeterminate Quantiferon®

Cut-Off Points

Pai M. JAMA 2005, 293:2746

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

T-Spot TST

Mean age 7.5 y (1m – 16y)Mean F/u duration 1.3 y

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.

Hypothetical Ex 2

5yo routine TST for school (SCC)TST 13mm; IGRA negativeHistory denotes domestic (NYC) and

international (W&E. Europe) travel; PE normal; Chest x-ray with no abnormalities.

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.