Pediatric Case Management

By

Dr. Rachel Gast MD

&

Dr. Apryle Funderburk MD

March 2 nd 2010

 BR  TD  KT

January Cases

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 Teenager with Wrist laceration, tendon exposure-transferred to Union Memorial for Hand surgery 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 Fam Hx Social: UTD, received H1N1 (I.M.) one month prior Mother-COPD, arthritis, Father Hepatitis B & cysts in brain, “misalignment” in spine, healthy siblings Attends 10 th grade, lives with mom & step-dad and cats, mom smokes

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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. – Labs – 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       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

Vaccine 27 (2009) 2114-2120  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

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

GBS and H1N1 vaccination

  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…”

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

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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 9 th , 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 2 nd 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: HEENT: Neck: CV: No lesion or rashes No oropharyngeal erythema, PERRL, anicteric, no nystagmus Normal ROM with some tenderness 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: MS: CN II-XII intact with motor/sensation intact throughout. Alert/oriented X3 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

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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 1 st trimester/safe in 2 nd and 3rd Chloroquine resistent areas Atovaquone/proguanil  Insufficient data Primaquine  Never use in pregnancy

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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 1 st /2 nd 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

Uncomplicated P.falciparum

Region of Infection

Chloroquine resistant or unknown resistance

Adult drug

Atovaquone proguanil

Pediatric Drug

Atovaquone proguanil Artemether lumefantrine Quinine sulfate+ Clindamycine, Doxycycline or Tetracylcine Mefloquine Artemether lumefantrine Quinine sulfate +Clindamycin, Doxycycline or Tetracycline Mefloquine

CDC Treatment Guidelines

Clinical 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

Uncomlicated malariae for pregnant women All regions Chloroquine-sensitve Choloroquine or Hydroxychloroquine + Primaquine Chloroquine or Hydroxychloroquine N/A Chloroquine – resistant Falciprum Quinine sulfate+Clindamycin Chloroquine-resistant P. Vivax Quinine sulfate primaquine s/p birth N/A N/A

CDC Treatment Guidelines

Clinical Diagnosis

P.vivax

Region of Infection

Chloroquine resistant

Adult drug Pediatric Drug

Quinine+Doxyclin e or Tetracycline +Primaquine Quinine+Doxyclin e or Tetracycline +Primaquine Atovaquine proguanil +Primaquine Mefloquine+ Primaquine Atovaquine proguanil +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/malaria.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.