Pediatric Case ManagementBy

Dr. Rachel Gast MD&

Dr. Apryle Funderburk MD

March 2nd 2010

January Cases BR 3 mo FT baby found face down, not

breathing in crib, after 1.5 weeks of nasal congestion, presented to ER, RSV +,CXR

wnl died TD Teenager with Wrist laceration, tendon

exposure-transferred to Union Memorial for Hand surgery

KT 4yo presented to ER with facial, LE swelling & abd distension x 1 week, Hpt, Blood and pr in urine –transferred to JHU for acute Hpt in face of AGN.

HPI

15 year old male Headache x 2 days Pain in middle of back on morning of

admission radiating to chest Progressive weakness in L.E. bilaterally Patient First → St. Joseph’s E.D.

Past History

PMH ADHD, exercised-induced asthma, depression, migraines

Meds Atomoxetine, Trazadone Allergy Shellfish, wheat, soybeans, peanuts Vacc UTD, received H1N1 (I.M.) one

month prior Fam Hx Mother-COPD, arthritis, Father -

Hepatitis B & cysts in brain, “misalignment” in spine, healthysiblings

Social: Attends 10th grade, lives with mom & step-dad and cats, mom smokes

Physical Exam – St. Joseph E.D. Pulse = 58, B.P. = 160/100 General: unable to walk, nausea with emesis x 1

Moving legs per ED physician; absent reflex in right LE and diminished in RE

Weak grasp ↑ tone in upper extremities with intact reflexes

WBC = 8.6 Hgb = 14.8/Hematocrit = 43.8 Platelets = 275 Electrolytes and coags normal Toxicology screen = normal CXR/Head CT/ECG = normal

Solu-medrol 125 mg, IV Labetolol Zofran Transferred to Sinai PICU

Case #2

7 yr. old male with juvenile-onset D.M. type 2, in usual state of health

Flu-like symptoms week prior to presentation “Bronchitis” – prednisone, clarithromycin, albuterol

Day prior to presentation – at school – left leg weakness, limping, gradual loss of motor function

No tingling, numbness nor loss of sensation No incontinence

ED – progression of weakness, loss of function, areflexia; symptoms starting in opposite leg

Admitted to PICU for further work-up

P.E./Labs

P.E. – Flaccid left LE, strength 0/5, intact sensation and vibratory sense, ↓ tone in right LE, motor 0-1/5,

able to dorsi-/plantar flex right foot, absent DTRs, negative Babinski

Labs – CBC WBC 13.7 ( N 51 L 36, M 9.2, E 2.2, B 0.2) CSF WBC 168 (N 38, L50,M12 RBC = 59, Glu 95, Pr59 CSF (-)GS/Cx Stool Cx (+) for heavy Candida albicans EBV IgM 2.3 , VCA Ab IgG positive, EBNA Ab IgG positive Anticardiolipin Ab IgM positive

Objectives

To discuss updates on current influenza activity

To discuss neuronal injury from influenza / influenza vaccine

To discuss adverse events from H1N1 2009 influenza strain vs. those from H1N1 vaccine

To discuss current CDC statement concerning H1N1 vaccine

www.cdc.gov

Pediatric Deaths from Influenza 2009-10

www.cdc.gov

Influenza Vaccine

Seasonal Flu – trivalent inactivated, live attenuated – 3 virus strains A

H1N1 H3N2

B For the 2009--10 influenza season, the influenza B vaccine

virus strain was changed to B/Brisbane/60/2008, a representative of the B/Victoria lineage, compared with the 2008--09 season. The influenza A, H1N1 and H3N2 vaccine virus strains were not changed

“Swine” Flu – A/California/07/2009

Mechanism of neuronal Injury

• Vaccinations may induce autoimmune process Influenza vaccines made in chicken eggs which are

endemically infected with Campylobactor Antibodies cross-react against peripheral-nerve

antigen

• However, the immunologic process that leads to GBS or other neuronal injury is largely unknown

Vaccine Adverse Event Reporting System

National reporting system jointly administered by CDC Immunization Safety Office and FDA reports submitted voluntarily by people who believe

an adverse event occurred after vaccination May be submitted healthcare providers, patients, or

family members VAERS staff follow-up on all serious and other selected

adverse event reports

Data does not infer causality

Addressing parents’ concerns: do vaccines contain harmful preservatives, adjuvants, additives or residuals? Offit, Paul A., Jew, Rita K. Pediatrics, 2003

Preservatives Adjuvants Additives Residuals Antibiotics Cellular residuals

www.cdc.gov

Pediatric hospitalizations associated with 2009 pandemic influenza a (H1N1) in Argentina. Libster, R., et al. N. Engl J Med 2010

1990-2005 Adults > 18 years of age 747.1 million doses of TIV Event reporting rate to VAERS of 24.4 per

million TIV 18,245 (14%) were classified as serious

events

Vaccine 27 (2009) 2114-2120

VAERS

Vellozzi, C., et al. Safety of trivalent inactivated influenza vaccines in adults: Vaccine 27 (2009) 2114-2120

Lancet 2010; 375: 49-55

• Pandemic vaccine – Fluval P – monovalent vaccine with 6 υg haemagglutinin per 0.5 ml content and aluminum phosphate gel adjuvent (n = 178)

•Seasonal vaccine – Fluval AB - trivalent inactivated whole-virion (n = 177)

Vajo, Z., et al. Safety and immunogenicity of a 2009 pandemic influenza A,H1N1 vaccine , Lancet 2010; 375: 49-55

VAERS

October 1997 – the Advisory Committee on Immunization Practices of the U.S. Public Health Service recommendations noted:

“ Among persons who received the swine influenza vaccine in 1976, the rate of Gullain-Barre syndrome that exceeded the background rate was slightly less than 10 cases per million vaccinated. Even if Guillain-Barre syndrome were a true side effect in subsequent years, the estimated risk for Guillain-Barre syndrome of 1-2 cases per million persons vaccinated is substantially less than that for severe influenza…”

GBS and H1N1 vaccination

CDC Statement

As of November 24, VAERS had received 10 reports of Guillain-Barré syndrome, and two additional reports of possible Guillain-Barré syndrome were identified by medical officers reviewing other reports to VAERS describing neurologic events

After chart review, four of these 12 reports met Brighton Collaboration criteria for Guillain-Barré syndrome, four did not meet the criteria, and four are under review

References Libster, R., et al. Pediatric hospitalizations associated with 2009 pandemic

influenza a (h1n1) in argentina. N Engl J Med 2010; 362: 45-55 Vellozzi, C., et al. Safety of trivalent inactivated influenza vaccines in adults:

background for pandemic influenza vaccine safety monitoring. Vaccine 27 (2009) 2114-2120

Kerr, Douglas A., Ayetey, Harold. Immunopathogenesis of acute transverse myelitis. Current Opinion in Neurology 2002, 15: 330-347

Mossad, Sherif B. The resurgence of swine-origin influenza a (h1n1). Cleveland Clinic Journal of Medicine Volume 76 Number 6 June 2009

Haber, P., et al. Guillain-barre syndrome following influenza vaccination. JAMA, November 24, 2004—Vol 292, No. 20

Scheibner, Viera. Adverse effects of adjuvents in vaccines. Nexus Dec 2000 (Vol 8, No1) & Feb 2001 (Vol 8, Number 2)

Vajo, Z., et al. Safety and immunogenicity of a 2009 pandemic influenza a h1n1 vaccine when administered alone or simultaneously with the seasonal influenza vaccine for the 2009-10 influenza season: a multicentre, randomised controlled trial. Lancet 2010; 375: 49-55.

MMWR. “Update on Influenza A (H1N1) 2009 Monovalent Vaccines.” October 9th, 2009. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5839a3.htm

HPI

C.A Day 1

Severe HA, b/L hip pain, low grade fever, generalized malaise/ mylagias, H/o visit to Nigeria 3 weeks prior.

Day 2 -Taken to PMD Congestion /T-103 with HA dx as acute sinusitis Sent home on Bactrim

Day 3 - Taken to first OHS Symptoms worsen with persistent fevers Chest-xray –negative/Rapid strep positive Sent home with Pen VK (no h/o sore throat)

HPI

Day 3 Symptoms persisted plus onset of abdominal

pain/vomiting Taken to 2nd OHS ER

CT-negative for acute abdominal process/patchy infiltrate of LLL- on chest x-ray

Thrombocytopenia/elevated LFT’s/hyponatremia/ febrile

Patient admitted for w/u of poor clinical status and abnormal labs

HPI

Day 4-5 HD 2-3

Worsening thrombocytopenia, onset of anemia and hyponatremia with elevated creatinine

Persistent fevers CMV neg, EBV positive, Hepatitis panel neg, Mono spot

neg, Urine cx / Blood cx neg HD 2-Malaria Smear obtained HD 3- Worsening labs/ Smear positive for

P.falciparum Obtained first dose of atovaquine-proguanil Hypotensive to 80/50’s with heart rate 100’s/dizzy/

decreased UOP transferred to Sinai PICU

Physical Examination, Day 5 Day 5, Transfer to Sinai PICU

VS: Wt-74.6kg, B.P-100/50, H.R-90’s,R.R-18 100% on 1LNC General: Tired appearing but interactive Skin: No lesion or rashes HEENT: No oropharyngeal erythema, PERRL, anicteric, no

nystagmus Neck: Normal ROM with some tenderness CV: RRR,S1S2 normal. No murmurs, rubs, gallops.

cap refill < 2sec Lungs: Occasional course BS with adequate/equal air entry Abdomen: Tender diffusely, RUQ most tender, No guarding or

rebound, No HSM with normal BS Neuro: CN II-XII intact with motor/sensation intact throughout.

Alert/oriented X3 MS: Pain on passive extension/flexion of hip. Negative hip

roll. No effusions or tenderness of joints. 3/5 strength of b/l lower extremities ,5/5 strength of upper extremities

Labs

Remarkable for Creatinine of 1.13 T/D.bilirubin of 7.4/5.8, AST of 164, ALT of 140

and CBC with Hgb / Hct of 9.8/29.6 and Platelets of 28

Slightly abnormal coagulapathy with INR of 1.2, D-dimer of 35.2, PT of 12.3,PTT of 38.7

Low haptoglobulin Negative urine dip and normal VBG Normal: Hgb electrophoresis, G-6PD study

PICU Course Day 5-8

Continue on atovaquine-proguanil with improvement in fever curve after 24 hours

Anemia persisted but all other labs improved Blood smears collected every 12 hours,parasite density fell

from 13% to 4% in 24 hours and less than 1% prior to floor transfer

Day 8-12 On the floor improving symptoms except on Day of illness 11

Double vision and headache reoccurred with dizziness CT of head negative Transfused with PRBCS for Hgb of 5.8 with resolution of

symptoms D/C home after 3 negative smears, Course of 3 days of oral

anti-malarial and improved fever

Labs

Remarkable for Creatinine of 1.13 T/D.bilirubin of 7.4/5.8, AST of 164, ALT of 140

and CBC with Hgb / Hct of 9.8/29.6 and Platelets of 28

Slightly abnormal coagulapathy with INR of 1.2, D-dimer of 35.2, PT of 12.3,PTT of 38.7

Low haptoglobulin Negative urine dip and normal VBG Normal: Hgb electrophoresis, G-6PD study

Blood Smear : Pre-treatment

Pre-treatment

Pre-treatment

Post treatment

Post Treatment

Objectives

Discuss Malaria and its Presentation Review Differential Diagnosis of Febrile

Traveler Study CDC Guidelines for

chemoprophylaxis of malaria Present CDC Treatment Guidelines Investigate recent studies on Treatment

of Severe Anemia caused by malaria

Definition

Parasitic infection with Plasmodium protozoa

Transmitted by vector female Anopheles mosquito

4 species to cause infection in humans P. falciparum P.vivax P.ovale P.malariae

Plasmodium knowlesis recently identified to cause human infection

Epidemiology

350-500 million cases worldwide Predominates in tropical areas Over 1 million people die

Most young children in Sub-Saharan Africa Account 20% of childhood deaths in Africa Every 30 seconds a child dies from malaria

1200 malaria cases reported annually

Epidemiology

http://wonder.cdc.gov/wonder

Sources of Infection in U.S

Imported Majority of cases

Airport Malaria Mosquitoes fly from endemic to non-endemic area

and infect local residents Locally transmitted

h/o of outbreaks in Southeast Congenital Blood Transfusions

One case every 2 years 1 case per 4 million units of blood

Sources of Infection in U.S

1997 to 2006-10, 745 cases of malaria reported in the U.S 59.3% -sub-Saharan Africa 13.9% -Asia 13.3%-Caribbean and Central/South America 0.03% -Oceania 54 fatal cases reported in the U.S

85.2% caused by P.falciparum 71.1% from sub-Saharan Africa

Life Cycle

Clinical Presentation

Symptoms present as early as 7-14 days or as late as several months or longer after exposure

Uncomplicated Fever, Anemia, influenza-like symptoms, jaundice,

transient HA, myalgias Severe

>5% parasite load Mental confusion, seizures, kidney failure, acute

respiratory distress syndrome, coma, death

Differential To Consider

Typhoid Fever Dengue Filarians Leishmanians Onchoncerciasis African trypanosomiasis

Diagnosis

Smear Microscopy gold standard Thick: Identify presence of parasite Thin: Determine speciation/Parasite level

Rapid Diagnostic Test (RDT) FDA approved for hospital use Results in 2-15 minutes

PCR Not FDA approved More sensitive than microscopy/delay in

results Confirm species of parasite

CDC Chemoprophylaxis Guidelines Areas with Limited Malaria Transmission

Mosquito avoidance/dusk to dawn DEET repellant Insecticide covered Bed Tents

Areas with Mainly P.vivax Malaria Primaquine

If Pts not G-6PD-deficient Areas with Chloroquine-Sensitive Malaria

Chloroquine Areas with Chloroquine-Resistant Malaria

Atovaquone/proguanil Doxycycline Mefloquine

CDC Chemoprophylaxis Guidelines Areas with Mefloquine-Resistant Malaria

Atovaquone/proguanil Doxycyline

Infants, Children and Adolescents Chloroquine/mefloquine

All weights/all ages Doxycycline

8 years or older Atovaquone/proguanil

Not in infants less than 5kg Off-label less than 11kg

CDC Chemoprophylaxis Guidelines Pregnancy and Breastfeeding

Chloroquine/Hydroxychloroquine Not been shown to have harmful effects

Mefloquine Limited data in 1st trimester/safe in 2nd and 3rd Chloroquine resistent areas

Atovaquone/proguanil Insufficient data

Primaquine Never use in pregnancy

CDC Chemoprophylaxis Guidelines Atovaquone/Proguanil

“Malarone” 1-2 days PTT, Same day daily in area, 7 days post

Chloroquine and Hydroxychloroquine “Aralen”/“Plaquenil” 1-2 wks PTT, Same day weekly, 4wks post

Doxycycline 1-2 days PTT, Same time daily in area, 4wks daily post

Mefloquine 1-2 wks PTT, Same day weekly, 4wks post

Primaquine Primary: 1-2 days PTT, Same time daily in area, 7 days post Anti-relapse : 14 days post

Tips for Primary Doctor

Don’t hesitate to refer patient to local travel clinics prior to travel

Preventative Measures depend on variety of factors Destination of country, Season of year, age of

patient/underlying health conditions, itinerary of traveler Travel to malaria-endemic areas should be a part of

patients chart Highest risk of infection are 1st/2nd generation of non-

endemic visiting friends/family in endemic country Highest risk of severe infection are non-exposed

individuals, infants/children, pregnant women

CDC Treatment Guidelines

Clinical Diagnosis Region of Infection

Adult drug Pediatric Drug

Uncomplicated P.falciparum

Chloroquine-resistant or unknown resistance

Atovaquone-proguanil

Atovaquone-proguanil

Artemether-lumefantrine

Artemether-lumefantrine

Quinine sulfate+ Clindamycine, Doxycycline or Tetracylcine

Quinine sulfate +Clindamycin,Doxycycline or Tetracycline

Mefloquine Mefloquine

CDC Treatment GuidelinesClinical Diagnosis Region of Infection Adult Drug Pediatric Drug

P.Falciparum or unidentified

Chloroquine-sensitive Choloroquine or Hydroxychloroquine

Choloroquine or Hydroxychloroquine

P.Malariae or P.knowlesi

All regions Choloroquine or Hydroxychloroquine

Choloroquine or Hydroxychloroquine

P.Vivax or P.ovale All regions Choloroquine or Hydroxychloroquine+ Primaquine

Uncomlicated malariae for pregnant women

Chloroquine-sensitve Chloroquine or Hydroxychloroquine

N/A

Chloroquine –resistant Falciprum

Quinine sulfate+Clindamycin

N/A

Chloroquine-resistant P. Vivax

Quinine sulfate primaquine s/p birth

N/A

CDC Treatment Guidelines

Clinical Diagnosis

Region of Infection

Adult drug Pediatric Drug

P.vivax Chloroquine-resistant

Quinine+Doxycline or Tetracycline +Primaquine

Quinine+Doxycline or Tetracycline +Primaquine

Atovaquine-proguanil +Primaquine

Atovaquine-proguanil +Primaquine

Mefloquine+ Primaquine

Mefloquine+ Primaquine

Severe Malaria Treatment

Quinine/Quinidine Artesunate/Artemisinins

EBM

Artesunate versus quinine for treating severe malaria Cochrane Database Syst Rev. 2007 Six trials enrolling 1938 participants

1664 adults and 274 children Compared IV artesnuate vs. IV quinine for

treatment of severe malaria Treatment with artesunate significantly

reduced risk of death, reduced parasite clearance and incidence of hypoglycemia

References

• www.cdc.gov/malaria/about/biology/index.html• http://wwwnc.cdc.gov/travel/yellowbook/2010/chapter-2/mal

aria.aspx• Rosenthal P.J. Artesunate for the Treatment of Severe

Falciprum Malaria. NEJM 2008:358:1829-36.• Clinical Review:Evidence behind the WHO Guidelines:

Hospital Care for Children:Efficacy and Safety of Artemisinin Derivatives in Children with Malaria. Journal of Tropical Pediatrics 2006.52:1-2.

• Malaria. The Red Book 2009. 1:438.• Griffith et al. Treatment of Malaria in the United States: A

systematic Review. JAMA 2007.297:20.