Fever in infants and children


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  • True fever is not harmful to a child if the fever is not due to a serious infection and the temperature elevation is not due to excess heat load, defective heat loss mechanism, CNS damage or disease, or excess heat production.
  • These children may have had early meninigitis that was missed or occult bacteremia that progressed to meningitis.
  • Toxicity assessment: loss of alertness, decreased activity, irritability, higher fever, sustained fever, anorexia, vomiting, pallor, grunting, and maternal worry.
  • Fever in infants and children

    1. 1. 1 Fever in Infants and Children: Mohamed Abunada, MD Department of pediatric Neurology Al Rantisi Specialized pediatric Hospital
    2. 2. 2 Fever • Fever is the most common pediatric complaint, second only to routine care for clinic visits, and the most common reason kids are brought to the ER. • 5-20% have no localizing signs on PE with no history to explain the fever. • The majority of kids with fever do not have a serious illness, although a small percentage harbor or may develop a serious bacterial infection.
    3. 3. 3 ‘True’ Fever • Occurs when IL-1, IL-6 or other cytokines are released from monocytes and macrophages in response to infection, tissue injury, drugs, and other inflammatory processes, increasing the body’s set point. The anterior hypothalamus maintains an inherent set point near 36ºC(98.6ºF). • Normal circadian rhythm, which is highest(up to 2ºC) ~6pm and lowest at 6am. This accounts for increased volume of ER visits that peaks in the evening. Most true fevers follow this diurnal pattern.
    4. 4. 4 ‘False’ fever • Does not directly increase the body’s set point. • CNS disease that directly affects the hypothalamus--ICH, infection. • Diseases that increase the body’s production of heat-- hyperthyroidism, malignant hyperthermia, salicylate overdose. • Excess heat load--child left in a car or left next to a heater for too long. • Defective heat loss mechanisms--burns, heat stroke, drugs that compromise blood flow and sweating mechanisms. • Normal causes of temperature elevation include physical activity, ovulation, and environmental temperature.
    5. 5. 5 Malignant hyperthermia • can follow intense muscle contraction (cocaine overdose) or muscle metabolism altered by drugs (neuroleptic agents) or anesthetics.
    6. 6. 6 Heatstroke, • Heatstroke, a potentially fatal febrile illness, is caused by excessively high environmental temperatures and failure of physiologic body heat-losing mechanisms
    7. 7. 7 Fever • does not always represent infection. • Rheumatologic disease, inflammatory bowel disease, Kawasaki disease, poisoning, and malignancy also may present with fever. • The varied manifestations of infectious diseases frequently mimic rheumatoid arthritis, lupus erythematosus, inflammatory bowel disease, leukemia, and lymphoma
    8. 8. 8 Reliable Temperature Measurement • All measurements are estimates of the body’s true core temp—central • RECTAL—gold standard • Esophageal—accurate but impractical • Tactile and axillary—inaccurate, varies considerably with environmental temperature • Tympanic—inaccurate in age <3 years
    9. 9. 9 Categories • Fever of short Duration accompanied by localizing signs and symptoms, in which a diagnosis can be established by clinical history and physical examination • Fever without localizing signs (without a Source or Focus) frequently in a child younger than 3 years old, in which a history and PE fail to establish a cause, although a diagnosis of occult bacteremia may be suggested by laboratory studies • Fever with unknown origin (FUO) which defines fever for more than 14 days without an identified etiology despite history, physical examination, and routine laboratory tests or after 1 week of hospitalization and evaluation
    10. 10. 10 Fever of short Duration • Initial complaints of infection may be nonspecific, especially in infants who present with fever, lethargy, irritability, excessive sleeping, or poor feeding. Certain individual physical findings, such as unique rashes, may be diagnostic . • Because of the varied presentations of infectious diseases, it is important to investigate thoroughly every objective finding from the history and physical examination
    11. 11. 11 URTI Rhinorrhea, sore throat, cough, drooling, stridor, sinus pain, tooth pain, hoarse voice Nasal congestion, pharyngeal erythema, enlarged tonsils with exudate, swollen red epiglottis, regional lymphadenopathy Ear Ear pain or drainage Red bulging tympanic membrane, drainage from ear canal LRTI Cough, chest pain, dyspnea, sputum production, cyanosis Tachypnea, crackles, wheezing, localized diminished breath sounds, intercostal retractions Localizing Manifestations of Infection
    12. 12. 12 GIT Nausea, vomiting, diarrhea, abdominal pain, anorexia Hypoactive or hyperactive bowel sounds, abdominal tenderness (generalized or focal). Liver Anorexia, vomiting, dark urine, light stools Jaundice, hepatomegaly, hepatic tenderness, bleeding diatheses, coma Genitourinary tract Dysuria, frequency, urgency, flank or suprapubic pain, vaginal discharge Costovertebral angle or suprapubic tenderness, cervical motion and adnexal tenderness CNS Lethargy, irritability, headache, neck stiffness, seizures Nuchal rigidity, Kernig sign, Brudzinski sign, bulging fontanel, altered mental status, focal neurologic deficits, coma Cardiovascular Dyspnea, palpitations, fatigue, exercise intolerance, chest pain Tachycardia, hypotension, cardiomegaly, hepatomegaly, splenomegaly, crackles, petechiae, Osler nodes, new or change in murmur, distended neck veins, pericardial friction rub, muffled heart sounds Skeletal Limp, bone pain, limited function (pseudoparalysis) Local swelling, erythema, warmth, limited range of motion, point bone tenderness, joint line tenderness
    13. 13. 13 The acute phase response • nonspecific inflammatory response to infection, trauma, autoimmune disease, and malignancies. • such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), are commonly elevated during an infection, but are not specific for infection and do not identify any specific infection. • These tests are often useful to show response to therapy (e.g., osteomyelitis).
    14. 14. 14 complete blood count CBC • obtained to identify evidence of bone marrow response to infection. • The initial response to infection, especially in children, is usually a leukocytosis, with a neutrophilic response to bacterial and viral infections. • With most viral infections, the initial neutrophilic response is transient and is followed quickly by the characteristic mononuclear response. • In general, bacterial infections are associated with greater neutrophilia than are viral infections.
    15. 15. 15 • A shift to the left is an increase in the numbers of circulating immature cells of the neutrophil series (band forms, myelocytes) . • A shift to the left indicates the rapid release of cells from the bone marrow and characteristically is seen in the early stages of infection and with bacterial infections. • Transient lymphopenia at the beginning of illness and lasting 24 to 48 hours has been described with many viral infections.
    16. 16. 16 • Atypical lymphocytes are mature T lymphocytes that classically are seen with infectious mononucleosis caused by Epstein- Barr virus (EBV). • Other infections associated with atypical lymphocytosis include cytomegalovirus (CMV) infection, toxoplasmosis, viral hepatitis, rubella, roseola, mumps, and some drug reactions.
    17. 17. 17 Other common screening tests include • Urinalysis for (UTIs), • Transaminases for liver function, and • Lumbar puncture for evaluation of the CSF if there is concern for meningitis or encephalitis . • A grouping of various tests may help distinguish viral versus bacterial infection, but definitive diagnosis requires culture or PCR.
    18. 18. 18 Differentiating Viral from Bacterial Infections Variable Viral Bacterial Leukocytosis Uncommon Common Shift to left (↑ bands) Uncommon Common Neutropenia Possible Suggests overwhelming infection ↑ ESR Unusual Common ↑ CRP Unusual Common IL-1 Uncommon Common Meningitis (pleocytosis) Lymphocytic Neutrophilic
    19. 19. 19 Cultures are the mainstay of diagnosis. • Blood cultures are sensitive and specific for bacteremia that may be primary or secondary to a focus (osteomyelitis, GE, UTI, endocarditis). • Urine cultures confirm UTI, which may be occult in young infants. • CSF cultures should be obtained with any lumbar puncture. • Other cultures are determined by the presence of fluid collections or masses that are suspected to be infectious. • Serologic tests, using enzyme-linked immunosorbent assay (ELISA) showing an IgM response, high IgG, or seroconversion between acute and convalescent sera can be used for diagnosis. • Molecular detection methods, such as PCR for DNA or RNA, offer the specificity of culture, high sensitivity, and rapid results.
    20. 20. 20 DIAGNOSTIC IMAGING • Plain x-rays are useful for the middle and lower respiratory tract. • Ultrasonography is a noninvasive, nonirradiating technique, useful to identify soft tissue abscesses with lymphadenitis and to diagnose suppurative arthritis of the hip. • A voiding cystourethrogram (VCUG) is used to evaluate for ureteral reflux, which is a predisposing factor for upper UTIs. • Radionuclide scans, such as technetium-99m for osteomyelitis and dimercaptosuccinic acid (DMSA) for acute pyelonephritis or chronic renal scarring, are often informative.
    21. 21. 21 • CT (with contrast enhancement) and MRI (with gadolinium enhancement) allow characterization of lesions and precise anatomic localization and are the modalities of choice for the brain. • CT shows greater bone detail • MRI shows greater tissue detail. MRI is especially useful for diagnosis of osteomyelitis, myositis, and necrotizing fasciitis. • High-resolution CT is useful for complicated chest infections. • Contrast studies (upper gastrointestinal series, barium enema) are used to identify mucosal lesions of the gastrointestinal tract.
    22. 22. 22 INITIAL DIAGNOSTIC EVALUATION • requires accurately recognizing the site of the infection , • recognizing all of the manifestations that are present, • knowing all of the risk factors, • recognizing exposure to potential infectious agents, and • knowing the most likely organisms causing each infection . • Obtaining a thorough history identifies most of these risk factors.
    23. 23. 23 • Season of year • Age , Weight , Place of residence • General health • Change Fever-presence, duration, and pattern • Previous similar symptoms • Previous infections and other illnesses • Previous surgeries Preceding trauma • Presence of outbreaks or epidemics in the community • Similar illness in close contacts • Exposures to infected individuals • Exposures to farm or feral animals ,Exposures to ticks and mosquitoes. • Travel history • Daycare or school attendance • Sources of water • Food and ingestion history, especially of undercooked meat or unpasteurized dairy products • Home sanitary facilities and hygiene • Presence of foreign bodies (e.g., indwelling catheters, shunt, grafts) • Immunization history • Current medications Risk factors
    24. 24. 24 Fever without a source (FWS) • 5 to 20% of febrile children have no localizing signs on PE and nothing in the history to explain the fever. By definition, less than 7 days. • FWS (like fever) is most common in children younger than age 5, with a peak prevalence between 6 and 24 months of age. • Those <6 months retain protective maternal antibodies against common organisms, while those 18-24 months old are more immune competent, and are at a lower risk of developing bacteremia
    25. 25. 25 Diagnostic Assessment in Children 1) Age is important as etiologic pathogens, 2) clinical exam 3) immune system capacity changes as the newborn ages. • Most break them into the 1. Neonatal 2. 1-3 months 3. 3 to 36 months.
    26. 26. 26 Neonatal • PE is felt to be unreliable in detecting many serious bacterial infections. • Meningitis should always be considered— up to 10% appear well, 15% have a bulging fontanelle, and 10-15% have nuchal rigidity. So, a high index of suspicion is important!!! ~20% will not have fever initially. • Hyperthermia or hypothermia • Lethargy or irritability or Seizures • Poor feeding or vomiting • Apnea, Dyspnea • Jaundice • Hypotension • Diarrhea or abdominal distension • Bulging fontanelle
    27. 27. 27 Neonates • The majority of febrile neonates presenting to the ED have a nonspecific viral illness • 12% have serious bacterial infections (SBI) • Infected by more virulent bacteria. • The most common bacterial infections are UTI and occult bacteremia
    28. 28. 28 Neonatal Early Onset<7 Days Group B Strep E. Coli Listeria Monocytogenes Enterococcus Strep viridans Strep Pneumoniae Hemophilus influenza nt Herpes simplex Later Onset>7 Days Group B Strep Listeria Monocytogenes Strep Pneumoniae Neisseria meningitidis Herpes simplex
    29. 29. 29 Neonatal • Risk Factors • Preterm • Membrane rupture: prolonged>12 hours • Chorioamnionitis or maternal peripartum fever • UTI • Multiple pregnancy • Hypoxia or Apgar score <6 • Poverty or age <20 • 1/3-1/2 neonatal sepsis will have no risk factors!
    30. 30. 30 Neonatal • Screening tests: WBC<5000 or >20,000, PMN <4000, Plt<100,000, CRP>1, LFTs elevated(suggest HSV) • So, if <28 days of age and rectal temp> 38ºC • Admit • Blood Culture • Urine Culture —cath specimen • Lumbar Puncture • Cell count, protein, glucose, culture, PCR • Parenteral Antibiotics • Ampicillin + Gentamicin (Cefotaxime), consider Acyclovir (primary maternal infxn, esp if delivered vaginally, PROM, fetal scalp electrodes, skin eye or mouth lesions, seizures, CSF pleocytosis)
    31. 31. 31 Infants 1 to 3 months • Causes • HSV (17% are 15 days to 6 weeks of age) • Bacterial sepsis/meningitis • Group B Strep, S. Pneumoniae, H. influenza, N. meningitidis. • Bone and joint infections • UTI • Bacterial enteritis (esp Salmonella) • Pneumonia • Enterovirus sepsis/meningitis(July-October) • The risk of bacteremia/meningitis is 3.3%, pneumonia, bone/joint infections and bacterial enteritis is 13.7% • 30-50% of those who are ultimately diagnosed with bacterial meningitis have been seen by a physician within the prior week(usually 1-2 days before) and were diagnosed as having a trivial illness and discharged on oral antibiotics.
    32. 32. 32 Infants 1 to 3 months Infants who are toxic and febrile have a much higher risk of serious bacterial infection. They should be admitted, have a full sepsis workup, and given antibiotics/antiviralsAmpicillin and Cefotaxime. Infants who are nontoxic and febrile who meet all Rochester criteria can ‘safely’ be treated as an outpatient. Generally, 1-3% of children meeting these criteria will develop a serious bacterial infection, 0.7% bacteremia, 0.14% meningitis.
    33. 33. 33 Infants 1 to 3 months • Rochester Criteria/Low Risk Criteria • Nontoxic—most critical and difficult • Previously healthy, not low birth weight • No focal bacterial infection on PE except Otitis Media • WBC 5,000-15,000/mm3 (normal) • Bands<1500/mm3 (normal) • Normal urinalysis, including gram stain • If diarrhea, must be non-bloody and WBC<5/hpf. • If respiratory symptoms present, normal CXR
    34. 34. 34 Infants 1 to 3 months • If all of the criteria are met, then there are 2 options for outpatient management: • 1) Blood, Urine Cultures, LP, Ceftriaxone 50mg/kg IM (to 1g), and return for reevaluation within 24 hours. • 2) Blood, Urine Cultures and careful observation. • Parents should have mature judgment, can return within 30 minutes and have a thermometer and a phone. • IF NO LP IS DONE, DO NOT GIVE CEFTRIAXONE
    35. 35. 35 Infants 1 to 3 months • Follow-up of low risk infants • If all cultures negative: afebrile, well appearingCareful observation • Blood cultures negative: well appearing, febrileCareful observation, may consider second dose of Ceftriaxone • Blood culture positiveadmit for sepsis workup and parenteral antibiotics pending results • Urine culture positive: if persistent feveradmit for sepsis workup, parenteral antibiotics pending results. If afebrile and welloutpatient antibiotics
    36. 36. 36 Infants 3 to 36 months • Infant sepsis syndrome: • Age 3-36 months • Fever>39ºC • ANC>10,000 • If a child meets all 3 criteria, he has a 3% risk for pneumococcemia. If untreated, 3% will progress to meningitis. • Other causes: HHV6(15%), UTI(girls 3%, boys 0.6%), menigococcemia(0.1%), Salmonella(0.2%), H. influenza (0.05%), Enterovirus (JulyOctober).
    37. 37. 37 Infants 3 to 36 months • UA with micro, CBC with differential, Blood Cultures • LP if meningeal signs, petechiae, purpura or toxic. • Antimicrobials: • OM or pneumonia: cover for pneumococcus, non-typable H. flu and Moraxella: amoxicillin+augmentin, ceftriaxone • URI or no focus: cover for pneumococcus and menigococcus: amoxicillin(80-100mg/dg/day), ceftriaxone • Pneumococcemia: promptly reassess, if well, should at least treat with 1 dose ceftriaxone.
    38. 38. 38 Occult Bacteremia 5% of children with FWS have OCCULT BACTEREMIA • The presence of a positive blood culture in kids who look well enough to be treated as outpatients .
    39. 39. 39 Occult Bacteremia • Streptococcus pneumonia is responsible for 2/3 to ¾ of all cases. • Peak prevalence between 6 and 24 months • Association with high fever(39.4ºC) • High WBC count(>15,000) • Absence of evident focal soft tissue infection. • Neisseria meningitidis, Haemophilus influenzae type b, and salmonellae account for most of the remaining cases.
    40. 40. 40 Risk of Occult Bacteremia Blood culture is the gold standardstill has a high number of false positives, take 24-48hrs, and most cases of occult pneumococcal bacteremia clear without treatment. Low Risk Age >3yr Temp <39.4ºC WBC >5000 and <15,000 High Risk <2yr >40ºC <5000 or >15,000 Hx of contact with H. Flu or N. meningitidis
    41. 41. 41 Occult Bacteremia • Empiric antibiotics should be targeted against S. pneumoniae, N. meningitidis, and H. influenza • Amoxicillin • Augmentin, Bactrim, 2nd or 3rd gen Cephalosporins • Single dose Ceftriaxone 50-75mg/kg • Follow up is essential !
    42. 42. 42 Definition of FUO? •Optimal definition of FUO: Fever greater than 38.3C for two weeks or longer Fever of Unknown Origin FUO
    43. 43. 43 Etiology of FUO • “A fever of unknown origin is more likely to be the unusual presentation of a common disorder than the common presentation of a rare disorder”
    44. 44. 44 Etiology of FUO • Infections 30-40% • Autoimmune 7-10% • Malignancy 2-5% • Other (incl.. factitious fever, drug fever) 2% • Never determined: In up to 50%
    45. 45. 45 Infectious Causes of FUO in children • n= 454 children from several studies • Infectious mononucleosis: (EBV or CMV) • Infection of the upper or lower respiratory tract • Urinary tract infection • Osteomyelitis • Cat scratch disease • CNS viral or bacterial infection • Tuberculosis
    46. 46. 46 Infectious Causes of FUO in children: less common pathogens • HIV, • brucellosis • Q fever • dengue fever • malaria • leptospirosis • toxocara canis and toxocara cati • histoplasmosis • coccidioidomycosis • blastomycosis • psittacosis • Lyme disease • salmonellosis (typhoid fever)
    47. 47. 47 Other considerations for infectious causes of FUO • Intraabominal abscess • Liver abscess • Occult dental infection • Endocarditis
    48. 48. 48 Non-infectious etiologies of FUO • Collagen vascular and immune mediated disease: • JRA • SLE • ARF • AKD (atypical Kawasaki Disease)
    49. 49. 49 Noninfectious Etiologies of FUO • Inflammatory bowel disease • Malignancy • Drug Fever • Munchausen syndrome by proxy • Dysautonomia • Central thermoregulatory disorder • Immune disorder
    50. 50. 50 Periodic Fever Syndromes • Idiopathic • Cyclic neutropenia • Hyper IgD Syndrome • Familial Mediterranean Fever
    51. 51. 51 Approach to the evaluation of the child with an FUO • “The tempo of the evaluation should match the clinical appearance of the child!” • Document the existence of fever • Note the general well being of the child • School absenteeism • Changes in social behavior
    52. 52. 52 Diagnosis: History • Leave no stone unturned. • May need to repeat the history • Remember to include: PH, Allergies, Medics, FH, Social History, Immunizations, Travel and Animal exposure
    53. 53. 53 Animals and bugs • Rabbits, squirrels: tularemia • Cats: cat scratch disease (Bartonella henselae), tularemia, rabies, toxoplasmosis • Birds: Psitticosis • Sheep: Q fever • Goats: Brucellosis • Ticks: Lyme disease, relapsing fever, ehrlichiosis. • Mosquitoes: Malaria, dengue fever, yellow fever, arboviral encephalitis • Fleas: Cat scratch disease (also need the cat). • Dogs, skunks, raccoons, bats: Rabies
    54. 54. 54 Travel History • Foreign: Consider calling the CDC to check for illnesses endemic to area visited. Think about malaria, dengue, typhoid, hepatitis A and tuberculosis, parasites, HIV
    55. 55. 55 Family and social history • Drug abuse • ?HIV • Previous history of transfusions • Ill family members (TB) • Frequent childhood deaths (immune deficiency)
    56. 56. 56 Clues on physical exam • Pattern of fever Intermittent fevers (hectic or spiking fever) suggest pyogenic infection Remittent fevers, fluctuating peaks and a baseline that does not return to normal. viral infections, bacterial infections, especially endocarditis. Persistent fevers with little or no fluctuation are sustained fevers; typhoid fever and typhus Relapsing fevers with periods during which patients are afebrile for one or more days between febrile episodes malaria, infection with the Borrelia and lymphomas. Recurrent episodes of fever over periods of more than one year's duration suggest metabolic defects, (CNS) dysregulation of temperature control, periodic disorders (such as cyclic neutropenia, hyper IgD syndrome, and immunodeficiency states. • Sweating: Hyperthyroidism • No sweating: ectodermal dysplasia • Weight loss, growth curves • ArthralgiaArthritis, myalgia: collagen disease, neoplasm,
    57. 57. 57 Clues on physical exam • Heart murmur or previous history of heart disease: sub-acute bacterial endocarditis • GI: IBD, celiac disease, ruptured appendix, liver abscess, perinephric abscess • Large spleen: malignancy, endocarditis, infectious mononucleosis • Do a good neurologic exam
    58. 58. 58 Clues on physical exam • Remember to do a rectal and GU exam • Skin: eczema/seborrhea (histiocytosis, immune deficiency) • Palpate bones and extremities
    59. 59. 59 Diagnostic evaluation • *Adapted from Steele et. al • Phase I (outpatient) • Based on findings from the history and physical consider the following tests: • CBC • ESR • Urinalysis and culture • Serum chemistries to include LFT’s
    60. 60. 60 Diagnostic evaluation • Phase 1 Outpatient: continued • CXR, abdominal ultrasound • PPD, thick and thin smear for malaria • Monospot/EBV serology • Cat scratch serology (B. henselae and quintana) • HIV test (ELISA ab unless pt. <12 mos, then HIV PCR) • Blood culture, Stool, occult and culture
    61. 61. 61 Diagnostic evaluation • Phase 2 • Hospitalize for observation/Consider referral to ID, Rheumatology or Heme Onc • LP • Sinus CT • Repeat blood culture • Bone scan • Bone marrow • Echocardiogram
    62. 62. 62 Diagnostic evaluation • Serologic tests (generally helpful only if acute and convalescent titers are obtained or IgM is positive) • Gallium/Indium scans: Several studies have shown these tests are only helpful if probable focus of infection has been identified!
    63. 63. 63 Therapy • Try NOT to start empiric oral or parenteral antibiotic therapy if you don’t know what you are treating. • Empiric antibiotics only if patient appears ill (and remember to get cultures first) • NSAID • Never ever ever treat empirically with steroids
    64. 64. 64 Outcome • Depends on underlying diagnosis • Most patients in whom the source of fever is never determined after a thorough and comprehensive evaluation have resolution of symptoms and do well
    65. 65. 65 Antipyretics • Acetaminophen, Ibuprofen • Efficacy and safety of alternating acetaminophen and ibuprofen not studied
    66. 66. 66 Conclusion • A careful and complete history, frequent re- examination of the child and patience will usually reveal the answer.
    67. 67. 67 • Oski’s Pediatrics, 3rd edition • Harriet Lane, 16th edition • FWS in Children 0-36 months of age. TCNA 53(2006)167-194 • The Febrile Child. Emergency Medicine Reports. September 1995. • Antibiotic Choices: The critical first hour. Pediatric Annals. June 1996. • Evidence based approach to the febrile infant/child. Handout from Dr. Michael Cooperstock, MD. May 2000. • Advisory Committee on Immunization Practices. Preventing pneumococcal disease among infants and young children: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2000;49(RR- 9):1-35 • AAP; Committee on Infectious Disease. Policy statement: recommendations for the prevention of pneumococcal infections, including the use of pneumococcal conjugate vaccine, pneumococcal polysaccharide vaccine, and antibiotic porphylaxis/ Pediatrics. 2000;106:362-366. • Whitney CG, FarleyMM, Hadler J, et al. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide vaccine. NEnglJMed. 2003;348:1737-1746. • Poehling KA etal. Invasive Pneumococcal Disease Among Infants before and after Introductions of Pneumococcal Conjugate Vaccine. JAMA Apr 12, 2006,295:1668-74.