How Well Does Palivizumab Work?

Patient Presentation
A 28-week-old male infant came to clinic for follow-up of a respiratory syncytial virus (RSV) inpatient admission.
He had been given Synagis®(palivizumab) prior to discharge from the neonatal intensive care unit at 68 days of age. His 3 year old sister had common cold symptoms.
At 81 days of age he came to clinic for cough, runny nose and mild respiratory distress without cyanosis or apnea.
Nasal secretions were positive for RSV and he was admitted for 12 days because of wheezing and an oxygen requirement.
His mother was worried that he would get RSV again and wanted to know if he needed to continue getting the Synagis®.
The pertinent physical exam showed a male infant in no distress. Growth parameters were at the < 3 % but he was gaining 7-15 grams/day.
His examination was consistent with a 2 week old male.
The diagnosis of a former premie with adequate growth, status-post RSV infection was made.
The pediatrician described the natural history of RSV particularly that it is highly contagious, ubiquitous and produces little long-term immunity.
The pediatrician emphasized the need for good hand hygiene, keeping the infant away from persons who were infectious if possible, and continuing the palivizumab throughout the rest of the RSV season.
At the next follow-up appointment, the patient would receive his next dose of palivizumab.

Discussion
RSV is a paramyxovirus and is one of the most common causes of lower respiratory tract disease in children.
It is seasonal with predictable outbreaks during the winter in temperate climates and the rainy season in tropical climates.
Its only host is humans. It is spread by droplets that remain on environmental items for minutes to hours, and has an incubation period of 2-8 days.
The infection rate is high: 65% in the first year of life, 35% in the second year of life, with a peak infectivity at 2 months of age.
It causes a poor immune response with frequent reoccurrence: 74-83% reinfection in the subsequent year and 46-55% in the third year.
Serum antibodies help protect against pulmonary involvement but healthy adults often are symptomatic and reinfections occur throughout life.
Hospitalization rate varies between 2-5% of the general population. Premature infants and the elderly are at higher risk.

Learning Point
In 1998, the IMpact RSV study was published. It was the first randomized controlled trial of premature infants (those < 35 weeks gestation) with the monoclonal antibody palivizumab.
The premature infants had an overall 55% reduction in RSV-associated hospitalizations when compared to placebo (4.8% vs 10.6%).
The infants who still got RSV had few hospital days, fewer days with supplemental oxygen and fewer admissions to the intensive care unit.
Patients without chronic lung disease had fewer hospital admissions than those with chronic lung disease.

Studies of palivizumab in other patient populations such as those with congenital heart disease and various pulmonary diseases have shown benefit in certain circumstances.
Specific indications for palivizumab use have been developed based upon chronological age, gestational age, and underlying disease.

Questions for Further Discussion
1. What are the indications for administration of prophylactic palivizumab?
2. What treatments are available for RSV and how efficacious are they?
3. What is the cost of palivizumab locally?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Information prescriptions for patients can be found at MedlinePlus for this topic: Respiratory Syncytial Virus

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

The IMpact-RSV Study Group.
Palivizumab, a Humanized Respiratory Syncytial Virus Monoclonal Antibody, Reduces Hospitalization From Respiratory Syncytial Virus Infection in High-risk Infants.
Pediatrics 1998; 102: 531-537. Available from the Internet at http://pediatrics.aappublications.org/content/vol102/issue3/index.shtml (cited 2/4/2008).

Durbin JE, Durbin RK. Respiratory syncytial virus-induced immunoprotection and immunopathology.
Viral Immunol. 2004;17(3):370-80.

Harkensee C, Brodlie M, Embleton ND, Mckean M. Passive immunisation of preterm infants with palivizumab against RSV infection.
J Infect. 2006 Jan;52(1):2-8.

DeVincenzo J. Passive antibody prophylaxis for RSV.
Pediatr Infect Dis J. 2008 Jan;27(1):69-70.

ACGME Competencies Highlighted by Case

  • Patient Care
    1. When interacting with patients and their families, the health care professional communicates effectively and demonstrates caring and respectful behaviors.
    2. Essential and accurate information about the patients’ is gathered.
    3. Informed decisions about diagnostic and therapeutic interventions based on patient information and preferences, up-to-date scientific evidence, and clinical judgment is made.
    4. Patient management plans are developed and carried out.
    5. Patients and their families are counseled and educated.
    7. All medical and invasive procedures considered essential for the area of practice are competently performed.
    8. Health care services aimed at preventing health problems or maintaining health are provided.
    9. Patient-focused care is provided by working with health care professionals, including those from other disciplines.

  • Medical Knowledge
    10. An investigatory and analytic thinking approach to the clinical situation is demonstrated.
    11. Basic and clinically supportive sciences appropriate to their discipline are known and applied.

  • Practice Based Learning and Improvement
    12. Evidence from scientific studies related to the patients’ health problems is located, appraised and assimilated.
    13. Information about other populations of patients, especially the larger population from which this patient is drawn, is obtained and used.
    14. Knowledge of study designs and statistical methods to appraisal clinical studies and other information on diagnostic and therapeutic effectiveness is applied.

  • Interpersonal and Communication Skills
    19. The health professional works effectively with others as a member or leader of a health care team or other professional group.

  • Systems Based Practice
    23. Differing types of medical practice and delivery systems including methods of controlling health care costs and allocating resources are known.
    24. Cost-effective health care and resource allocation that does not compromise quality of care is practiced.
    25. Quality patient care and assisting patients in dealing with system complexities is advocated.
    26. Partnering with health care managers and health care providers to assess, coordinate, and improve health care and how these activities can affect system performance are known.

    Author
    Donna M. D’Alessandro, MD
    Professor of Pediatrics, University of Iowa Children’s Hospital

    March 31, 2008

  • What's the Difference Between Stridor and Stertor?

    Patient Presentation
    A 16-month-old female came to clinic with increased secretions and problems breathing.
    She had underlying severe mental retardation, cerebral palsy, gastroesophageal reflux with aspiration and increased oral secretions usually controlled by Robinul®.
    She has had copious rhinorrhea for 2 days and increased oral secretions.
    Her parents describe a barky-sound when breathing in since the previous night.
    She has had a fever to 100.6° F but no coughing, emesis, rashes or other symptoms.
    The pertinent physical exam shows an ill-appearing female with increased work of breathing. Her respiratory rate was 58 breaths/minute and temperature of 38° C. Her weight was 50% for a 12 month old.
    She had copious, clear rhinorrhea and increased oral secretions with drooling. She occasionally would choke on the secretions but easily cleared them.
    She had a mid-pitched inspiratory sound coming from the upper airway that sounded like stridor.
    During inspiration she had some tracheal tugging but no intercostal retractions.
    Her lung examination was normal with transmitted upper airway sounds.
    The rest of her examination was consistent with her baseline.
    The work-up included a nasal wash for respiratory pathogens that was negative and a chest radiograph that was negative.
    The patient was referred to otolaryngology for further evaluation. In the office, she was noted to have significant floppiness of the upper airways along with enlarged tonsils and adenoids.
    Her laryngeal apparatus appeared normal.
    The diagnosis of upper respiratory tract infection causing stertor and enlarged tonsils and adenoids was made.
    The primary care physician did not know the difference between stertor and stridor so the otolaryngologist explained how they were similar but distinctly different sounds with different causes.
    The patient’s clinical course over the next 2 days included having a direct laryngoscopy and bronchoscopy and tonsillectomy and adenoidectomy.
    Following surgery, she was placed on dexamethasone to decrease swelling and discharged on day 3.

    Discussion
    Upper respiratory tract infections are commonly caused by many different serotypes of rhinorviruses.
    Other viruses can present similarly. Rapid antigen detection of nasal secretions is generally available and reliable.
    The viruses specifically tested for varies by location but often includes viruses which may cause more severe disease especially Respiratory Syncytial Virus, Influenza A and B, and Parainfluenza and Adenovirus.
    Identifying the virus aids in cohorting similar patients in the hospital, institution of infection control measures and with community surveillance.

    Learning Point
    Stedman’s Medical Dictionary defines stertor as “[a] heavy snoring inspiratory sound occurring in coma or deep sleep, sometimes due to obstruction of the larynx or upper airways.”
    Causes of stertor include choanal stenosis, enlarged tonsils and/or adenoids, and redundant upper airway tissues.

    Stedman’s Medical Dictionary defines stridor as “[a] high-pitched noisy sound occurring during inhalation or exhalation, a sign of respiratory obstruction.”Common causes are croup, foreign body, bacterial tracheitis, pharyngeal abscesses, allergic reactions and epiglottitis.

    Questions for Further Discussion
    1. What are some other common causes of stertor?
    2. What are some other common causes of stridor?
    3. What are indications for evaluation by an otolaryngologist?

    Related Cases

    To Learn More
    To view pediatric review articles on this topic from the past year check PubMed.

    Information prescriptions for patients can be found at MedlinePlus for these topics: Snoring.

    To view current news articles on this topic check Google News.

    To view images related to this topic check Google Images.

    Stertor. The American Heritage® Stedman’s Medical Dictionary.
    Available from the Internet at http://dictionary.reference.com/browse/stertor (cited 2/4/08).

    Stridor. The American Heritage® Stedman’s Medical Dictionary. Available from the Internet at http://dictionary.reference.com/browse/stridor (cited 2/4/08).

    Benson BE, Baredes, S. Stridor. eMedicine.
    Available from the Internet at http://www.emedicine.com/ped/TOPIC2159.HTM (rev. 8/29/2006, cited 2/4/08).

    ACGME Competencies Highlighted by Case

  • Patient Care
    1. When interacting with patients and their families, the health care professional communicates effectively and demonstrates caring and respectful behaviors.
    2. Essential and accurate information about the patients’ is gathered.
    3. Informed decisions about diagnostic and therapeutic interventions based on patient information and preferences, up-to-date scientific evidence, and clinical judgment is made.
    4. Patient management plans are developed and carried out.
    6. Information technology to support patient care decisions and patient education is used.
    7. All medical and invasive procedures considered essential for the area of practice are competently performed.
    8. Health care services aimed at preventing health problems or maintaining health are provided.
    9. Patient-focused care is provided by working with health care professionals, including those from other disciplines.

  • Medical Knowledge
    10. An investigatory and analytic thinking approach to the clinical situation is demonstrated.
    11. Basic and clinically supportive sciences appropriate to their discipline are known and applied.

  • Practice Based Learning and Improvement
    16. Learning of students and other health care professionals is facilitated.

  • Interpersonal and Communication Skills
    19. The health professional works effectively with others as a member or leader of a health care team or other professional group.

    Author
    Donna M. D’Alessandro, MD
    Professor of Pediatrics, University of Iowa Children’s Hospital

    Date
    March 24, 2008

  • What Information Should Be in a Health Care Plan for a Child with Special Health Care Needs?

    Patient Presentation
    A pediatric resident was called to see an 6-year-old male in the emergency room, in a general community hospital where the residents worked on a small pediatric inpatient ward.
    The emergency medicine staff physician said the child was known to have familial dysautonomia and was vomiting with labile blood pressures.
    The surprised and worried resident told the staff physician that she didn’t know anything about this problem but would be there as soon as possible.
    The staff physician replied, “Oh, don’t worry, he comes in every so often and we just follow the laminated protocol his parents bring.”In the emergency room, the resident obtained the history that the child was in his normal state of health when his parents told him that they were would be flying the following day. He did not like to fly and became extremely upset and began vomiting.
    His parents were not able to calm him down and had given him some diazepam to try to abort the episode. This did not work and they came to the emergency room.
    There was no history of any symptoms of an infectious nature, possible ingestion or other similar provoking cause.
    The pertinent physical exam showed a child who was crying as an IV was being placed. Monitors showed his blood pressure to be swinging between normal and hypertensive.
    His heart rate was in the 140-190s and was labile. His temperature was 38.4° C. Height and weight were 3-10% for age.
    He had retching and had copious salivation and sweating. His skin had diffuse 0.5-1.0 areas of flaring without wheals.
    Neurological examination revealed an agitated child who had some rocking motions of his head, and repetition of words, with some generalized hypotonia.
    There was no evidence of localized infection.
    The diagnosis of familial dysautonomia in dysautonomic crisis was made. Blood work was drawn with the IV placement and he was given IV diazepam and fluids.
    He was taken to a private room within the emergency room where it was quieter and the lights could be dimmed.
    Slowly over the next 2-3 hours he had fewer retching spells and became less agitated. His blood pressure became less volatile but mean pressures were still elevated.
    His local physician was contacted and agreed that he could be admitted locally as his crisis seemed to be improving with the sedation and he didn’t want to upset the child by transporting him to another institution.
    His specialist in another city was also contacted who also agreed that overall the best option was to admit him locally and try to keep him calm, but to transport if he became worse.
    The child was moved to the pediatric floor and as it was late evening he fell asleep. Over the night his IVF and output were monitored.
    He had some spitting up and brief awakenings over the night, but in the morning most of his symptoms had resolved.
    He complained of some mild stomach pain, but was able to eat and drink. After talking with his specialist again by telephone it was decided to discharge him home to be monitored closely by the parents.
    His local physician agreed and as he lived close to the family said he would check on the patient at home to try to avoid precipitating another dysautonomic crisis.

    Discussion
    Familial dysautonomia was previously known as Riley-Day syndrome and classified as hereditary sensory autonomic neuropathy type III. It is caused by mutations on chromosome 9 and affects the sensory and autonomic nervous systems.
    It is an autosomal recessive disorder with a high carrier frequency in people of eastern European, Jewish ancestry. DNA testing is available.
    Clinical neurological manifestations vary and affect almost every organ system. Some manifestations include
    abnormal pain and temperature regulation, cardiovascular lability, hypotonia, poor coordination and balance, attention and learning problems, dysphagia, absent tears, and dysautonomic crisis.
    Individual patients may have normal or above normal intelligence, but as a group, patients with familial dysautonomia are skewed to toward lower IQ scores.

    Dysautonomic crisis can be precipitated by many causes including acute illness or emotional reactions such as the patient above.
    It is thought to be caused by misfiring of central autonomic neurons. The symptoms include retching/emesis, hypertension, tachycardia, diaphoresis, excessive salivation, skin blotching and piloerection, pupil dilatation and functional ileus.
    Treatment includes adequate hydration, stopping the crisis symptoms of retching and hypertension, and treatment of the precipitating cause.
    Fluids should be given to treat dehydration and maintain hydration. Hydration is best monitored by weight and BUN because usual assessment such as mucous membranes and urine output are not accurate in these patients.
    Diazepam is a fast-acting benzodiazepine that helps to calm the central autonomic nervous system. It can be given every 2-4 hours.
    Treatment of the underlying problem such as an infection or emotional problem is also necessary.

    Learning Point
    Children with special health care needs (CSHCN) should have a health care plan (HCP) developed that addresses the medical issues in the settings where the child lives, goes to school, works, recreates and travel.
    Obviously the HCP is individualized and maybe relatively simple (i.e. instructions for administration of asthma medication for a child with intermittent asthma) or complex (i.e. a patient with familial dysautonomia).
    The HCP should be developed, implemented and periodically reviewed by the patient (if appropriate), the parents and family members, healthcare professionals caring for the patient, school personnel, local emergency medical services, local emergency room personnel, pharmacist and other individuals.
    In order to ensure currency, a date and signature by the parent, healthcare provider, and other appropriate personnel should be at the beginning or end of the plan.

    Elements to consider having in a HCP include:

    • Date the HCP was put into place
    • Patient name, date of birth
    • Language spoken
    • Parent and/or legal guardian name, relationship to patient, home address, work address, telephone numbers and email addresses
    • Persons who can give consent
    • Other people who may give or receive information – home health care providers, nursing staff, social worker, teachers, child care provider, pharmacists, others
    • Brief/pertinent description of current health problems including:
      • Description of baseline status -
        • Overall description – i.e. non-communicative, ambulatory, mottled etc.
        • Base vital signs and physical findings
      • Allergies
        • To medication, foods, insects, etc. and what happens when this occurs
      • Immunization status – including dates, tuberculosis status
      • Current medication list
        • Drug name, strength, dose and frequency and time given – a log may be needed to record the medications, especially if initiating or discontinuing a medication for better monitoring
      • Medical equipment
        • Daily equipment used – name of home health care company and contact information, maintenance record, where stored
        • Emergency equipment available – home health care company, maintenance record, where stored
      • Current treatments/procedures needed
        • Type of procedure, who performs the procedure (patient or another person), frequency, positioning of patient during procedure, suggested venue for procedure, patient-specific techniques, any special precautions
      • Diet
      • Transportation needs including car seat
    • Brief/pertinent description of past health problems including dates and treatment of:
      • Hospitalizations
      • Surgeries
      • Injuries
      • Childhood illnesses
    • Emergency plan
      • Emergency contact numbers for fire, police, ambulance, gas company, electric company, home health care company, pharmacist etc.
      • Preferred hospital name and contact information
      • Local emergency room name and contact information (consider giving a copy of the HCP to local emergency medical services and the local emergency room)
      • Primary care physician name and contact information
      • Specialist physicians name and contact information
      • Dentist name and contact information
      • Other health care professionals name and contact information
      • List of who should be contacted for every emergency
      • Emergency consent for treatment including current insurance information
      • Telephone protocol – detailed information about how to contact and give information to emergency personnel by telephone
    • Anticipating possible problems and specific emergencies
      • A list of “XXX problem may arise for YYY reason and ZZZ is what should be done for it”
      • A list of “If you see XXX, you should do YYY”
    • List of trained care providers (especially for child care and school settings) – primary and backup staff name, type training done, date
    • Any other information that is important to convey

    Families may wish to use paper copies of the HCP which can be distributed to appropriate persons and also kept with the child in a backpack, at school or child care facility, at a home frequently visited, etc.
    Online personal health records are another way to ensure that current information about a child is available to those who need it when they need it.
    Another alternative is inexpensive magnetic media such as CD-ROMs or computer memory sticks.
    There are pros and cons to each recording method so it may be best to use more than one (i.e. paper print out of an online personal health record).
    The date the HCP was put into place should be documented so the most current version can be easily identified if two HCPs are presented.

    The American Academy of Pediatrics has a sample emergency information form (see To Learn More Below) but this is not a complete HCP and may not be suitable for other venues.

    Questions for Further Discussion
    1. Think about a specific CSHCN. What type of information would you put into the HCP?
    2. Think about a specific CSHCN. What type of information would you want if you were the treating physician in the emergency room when this child is having an emergency?

    Related Cases

    To Learn More
    To view pediatric review articles on this topic from the past year check PubMed.

    Information prescriptions for patients can be found at MedlinePlus for this topic: Autonomic Nervous System Disorders and Neurologic Diseases.

    To view current news articles on this topic check Google News.

    To view images related to this topic check Google Images.

    Haynie M, Porter SM, Palfrey JS. Children Assisted by Medical Technology in Educational Settings: Guidelines for Care. Project School Care, The Children’s Hospital, Boston, MA 1989;21-32.

    American Academy of Pediatrics Policy Statement.
    Emergency Preparedness for Children With Special Health Care Needs.
    Pediatrics 1999 104: e53. Available from the Internet at: http://aappolicy.aappublications.org/cgi/content/full/pediatrics;104/4/e53 (rev. 10/99, cited 2/1/08).

    Gold-von Simson G, Axelrod FB. Familial dysautonomia: update and recent advances.
    Curr Probl Pediatr Adolesc Health Care. 2006 Jul;36(6):218-37.

    ACGME Competencies Highlighted by Case

  • Patient Care
    1. When interacting with patients and their families, the health care professional communicates effectively and demonstrates caring and respectful behaviors.
    2. Essential and accurate information about the patients’ is gathered.
    3. Informed decisions about diagnostic and therapeutic interventions based on patient information and preferences, up-to-date scientific evidence, and clinical judgment is made.
    4. Patient management plans are developed and carried out.
    5. Patients and their families are counseled and educated.
    6. Information technology to support patient care decisions and patient education is used.
    7. All medical and invasive procedures considered essential for the area of practice are competently performed.
    8. Health care services aimed at preventing health problems or maintaining health are provided.
    9. Patient-focused care is provided by working with health care professionals, including those from other disciplines.

  • Medical Knowledge
    10. An investigatory and analytic thinking approach to the clinical situation is demonstrated.
    11. Basic and clinically supportive sciences appropriate to their discipline are known and applied.

  • Practice Based Learning and Improvement
    13. Information about other populations of patients, especially the larger population from which this patient is drawn, is obtained and used.
    15. Information technology to manage information, access on-line medical information and support the healthcare professional’s own education is used.

  • Interpersonal and Communication Skills
    19. The health professional works effectively with others as a member or leader of a health care team or other professional group.

  • Professionalism
    22. Sensitivity and responsiveness to patients’ culture, age, gender, and disabilities are demonstrated.

  • Systems Based Practice

    25. Quality patient care and assisting patients in dealing with system complexities is advocated.
    26. Partnering with health care managers and health care providers to assess, coordinate, and improve health care and how these activities can affect system performance are known.

    Author
    Donna M. D’Alessandro, MD
    Professor of Pediatrics, University of Iowa Children’s Hospital

    Date
    March 10, 2008

  • DRESS Syndrome in the Differential

    Patient Presentation
    A 10-year-old female was transferred to a children’s hospital with fever, lymphadenopathy and rash.
    She was placed on lamotrigine 6 weeks previously by an adult neurologist for absence seizures after an electroencephalogram was abnormal.
    Three weeks ago she developed a pruritic rash on the flexural areas of the knees that quickly spread over her body. The rash initially looked like welts.
    The lamotrigine was stopped and antihistamines and prednisone were begun. The rash became more flat but still continued to be erythematous and pruritic.
    Eight days prior to admission she began to have fever to 102° F. She also developed a cough and became more tired.
    She saw her primary care physician who felt this was a new cold and a chest radiograph was negative.
    On day 5 of the fever, she again saw her primary care physician. The cough had resolved.
    The physical examination was unchanged with no mucositis and screening laboratory testing including a complete blood count, erythrocyte sedimentation rate and urinalysis were normal.
    She had an equivocal rapid strep test and was started on penicillin for possible strep throat after a blood culture was drawn.
    On day 8, she had an acute increase in temperature to 106.7° F, and new multiple lymph nodes of 1-2.5 cm in size in the bilateral posterior cervical and anterior cervical chains.
    Her local physician transferred her for treatment for possible Kawasaki Disease.
    The past medical history revealed some bronchospasm as a preschooler.
    The family history was positive for hypothyroidism.
    The review of systems was unremarkable with no weight changes or mucositis at any time including dysuria.
    The pertinent physical exam showed her to be ill-appearing with a temperature of 39° C. Her other vital signs were normal and growth parameters were between 25-50% for age.
    HEENT showed mild generalized swelling of her face. She had no mucositis but her lips were minimally dry. She had no oral or eye changes.
    Lymphatic system had cervical lymphadenopathy noted previously, palpable axillary lymphadenopathy bilaterally 1-2.0 cm in size, and groin nodes bilaterally that were 0.5-1.5 cm in size.
    Lungs and abdominal examination were normal. Heart showed a Grade II/VI systolic ejection murmur best at lower left sternal border that was consistent with a flow murmur.
    Genitourinary examination showed no mucositis.
    Skin examination showed generalized erythema over the entire body, with areas that were papular on the trunk and extremities. The rash was pruritic. She had some very mild peeling of the skin on her cheeks but none on her hands.
    She had no nailbed or finger/foot changes.
    Neurologically she was normal.
    The work-up included a erythrocyte sedimentation rate of 33 mm/hr, hemoglobin of 11.6 mg/dl, hematocrit of 34%, and a white blood cell count of 9.7 x 1000/mm2 with 2640 segmented neutrophils, 2816 lymphocytes and 679 eosinophils.
    Platelets were 177 x 1000/mm2. The urinalysis was normal as were liver function tests. Testing for Epstein Barr virus, Hepatitis A, Cytomegalovirus, Adenovirus and Mycoplasma were initially sent.
    Blood and urine cultures were sent. Because of the significant fever for at least 8-9 days and new development of lymphadenopathy and no obvious cause for the constellation of symptoms, the patient was treated with intravenous immunoglobulin (IVIG) for Kawasaki Disease although the clinical picture and laboratory testing was not completely supportive of this diagnosis.
    She was also started on high dose aspirin therapy.
    The patient’s clinical course in the 36 hours after IVIG infusion showed continued fevers to 39.3° without resolution of the rash, nor development of mucositis.
    She also had a normal echocardiogram.
    At 1.5-2 days after IVIG infusion, she now had increasing erythrocyte sedimentation rate to 44 mm/hr, the complete blood count showed a platelet count of 98 x 1000/mm2, and a white blood cell count of 8.8 x 1000/mm2 but with eosinophilia of 2112. Liver function tests showed an aspartate aminotransferase of 1400 U/L, and a alanine aminotransferase of 857 U/L with normal synthetic function.
    Previous testing was now negative for all the viruses and cultures and the ASO was pending (later negative). Infectious disease was consulted who agreed not to give another dose of IVIG as her clinical picture looked less like Kawasaki Disease and recommended monitoring her laboratory testing and clinical condition.
    Other laboratories were sent to look for an autoimmune problem and other viruses.
    On day 3 she had decreased lymphadenopathy and her fever had decreased to 38.0°. Dermatology was consulted and felt her history, physical examination and laboratory testing was consistent with the diagnosis of DRESS syndrome caused by the lamotrigine.
    The patient was re-started on prednisone with a slow taper over 1 month time. The next day she was afebrile, her lymphadenopathy was almost gone, the eosinophilia was decreasing and her liver function tests were stable.
    She was discharged the following day to follow-up with dermatology in 2 weeks and her regular physician in 2 days. After discussions with her local physician, infectious disease consultant, and family, she was also continued on low dose aspirin treatment until she had a follow-up echocardiogram at 6 weeks.
    This was because she had been treated for Kawasaki Disease, and it was felt the aspirin therapy was a low risk compared to possibly undertreating the Kawasaki Disease.
    She also had an appointment with a pediatric neurologist to re-evaluate her for possible seizures and the need for continuing an anticonvulsant medication.

    Discussion
    Kawasaki Disease (KD) is an acute, self-limited vasculitis of unknown etiology.
    It is a clinical diagnosis as the etiology is unknown currently.

    KD is defined as:

    • Fever of at least 5 days

    • Plus 4 or more of the following:
      • Polymorphous exanthem

      • Bilateral bulbar conjunctival injection without exudate
      • Changes in lips and oral cavity – erythema, cracked lips, strawberry tongue, diffuse injection
      • Cervical lymphadenopathy – more than 1.5 cm, usually unilateral
    • Exclusion of other diseases with similar findings
      • Viral infections – especially adenovirus, enterovirus, Epstein-Barr virus and measles

      • Scarlet fever
      • Staphylococcal scalded skin syndrome
      • Toxic Shock Syndrome
      • Bacterial cervical lymphadenitis
      • Drug hypersensitivity reactions
      • Stevens-Johnson syndrome
      • Juvenile rheumatoid arthritis
      • Rocky Mountain spotted fever
      • Leptospirosis
      • Mercury hypersensitivity reaction
    • Laboratory findings associated with KD include:
      • Leukocytosis with neutrophilia and immature forms

      • Elevated C-reactive protein
      • Elevated erythrocyte sedimentation rate
      • Thrombocytosis after week 1
      • Sterile pyuria

    Some patients do not fulfill the full criteria for KD and/or have unusual presentations. The American Heart Association has a scientific statement to assist in evaluation and treatment for these patients. See To Learn More below.

    Learning Point
    DRESS syndrome, or drug rash with eosinophilia and systemic symptoms was first described by Bocquet et. al. in 1996.
    The systemic findings can include lymphadenopathy, abnormal liver or kidney function, pulmonary or cardiac infiltrates and hematological problems (especially eosinophilia and activated lymphocytes).
    It was first described with anticonvulsants, especially carbamazepine, phenytoin and phenobarbital, but later described associated with other anticonvulsants and other drugs such as allopurinol, dapsone, lamotrigine, mexiletine, minocycline, nevirapine, sulfasalazine and zonisamide.
    It has also been associated with reactivated human herpes virus 6 (HHV-6).

    DRESS symptoms begin usually 2-6 weeks after beginning drug therapy and despite discontinuing the medication may continue to have evolving symptoms.
    “[C]linical criteria for this syndrome are not present on any given day and that the severity of these clinical symptoms at onset provides only a guide to prognosis and is not absolute: usually patient initially develops two or three features of this syndrome followed by a step-wise development of other symptoms.”Thankfully most symptoms resolve without sequelae over time. Interestingly, lamotrigine is always reported to cause fever in the literature.

    DRESS syndrome is a clinical diagnosis and there is some controversy in the literature on what criteria should be used to diagnose it. Some dermatologists believe it would better be called Drug-induced Hypersensitivity Syndrome (DIHS).
    A Japanese consensus group developed criteria for what they call DIHS
    which includes:

    • Maculopapular rash that occurs more than 3 weeks after starting certain drugs
    • Prolonged clinical symptoms 2 weeks after stopping the drug
    • Fever more than 38° C.
    • Liver enzyme abnormalities (alanine aminotransferase > 100 U/ L), or other organ involvement.
    • At least one leukocyte abnormality = leukocytosis > 11 x 1000/mm2, atypical leukocytosis > 5%, or eosinophilia > 1.5 x 1000/mm2
    • Lymphadenopathy
    • HHV-6 reactivitation

    Treatment is usually with IVIG and steroids.

    The case patient met 6 of these criteria. HHV-6 was not tested for and therefore could not be used as a criterion.
    This patient appeared to be at the intersection of two clinical entities, both of which progress over time.
    Therefore it was difficult for the physicians to arrive at the diagnosis of DRESS syndrome early on; in the end it is also difficult to totally exclude the possible diagnosis of Kawasaki Disease.

    Questions for Further Discussion
    1. What other consultations may be helpful in establishing the diagnosis of Kawasaki Disease or DRESS syndrome?
    2. What are the pros and cons of continuing to treat or not treat this patient for Kawasaki Disease?

    Related Cases

    To Learn More
    To view pediatric review articles on this topic from the past year check PubMed.

    Information prescriptions for patients can be found at MedlinePlus for these topics: Medicines and Allergy.

    To view current news articles on this topic check Google News.

    To view images related to this topic check Google Images.

    PeyriËre H, Dereure O, Breton H, Demoly P, Cociglio M, Blayac J-P, Hillaire-Buys D. and the Network of the French Pharmacovigilance Centers.
    Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?.. British Journal of Dermatology, 2006;155(2); 422-428.

    Shiohara T, Iijima M, Ikezawa Z, Hashimoto K. The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations.
    Br J Dermatol. 2007 May;156(5):1083-4.

    Newberger JW, Takahasi M, Gerber MA, et. al. Diagnosis, Treatment and Long-term Management of Kawasaki Disease. Circulation 2004;110:2747-2771.Available from the Internet at: http://circ.ahajournals.org/cgi/content/full/110/17/2747 (cited 3/28/05).

    ACGME Competencies Highlighted by Case

  • Patient Care
    1. When interacting with patients and their families, the health care professional communicates effectively and demonstrates caring and respectful behaviors.
    2. Essential and accurate information about the patients’ is gathered.
    3. Informed decisions about diagnostic and therapeutic interventions based on patient information and preferences, up-to-date scientific evidence, and clinical judgment is made.
    4. Patient management plans are developed and carried out.
    5. Patients and their families are counseled and educated.
    7. All medical and invasive procedures considered essential for the area of practice are competently performed.
    8. Health care services aimed at preventing health problems or maintaining health are provided.
    9. Patient-focused care is provided by working with health care professionals, including those from other disciplines.

  • Medical Knowledge
    10. An investigatory and analytic thinking approach to the clinical situation is demonstrated.
    11. Basic and clinically supportive sciences appropriate to their discipline are known and applied.

  • Practice Based Learning and Improvement
    12. Evidence from scientific studies related to the patients’ health problems is located, appraised and assimilated.
    13. Information about other populations of patients, especially the larger population from which this patient is drawn, is obtained and used.
    14. Knowledge of study designs and statistical methods to appraisal clinical studies and other information on diagnostic and therapeutic effectiveness is applied.
    15. Information technology to manage information, access on-line medical information and support the healthcare professional’s own education is used.
    16. Learning of students and other health care professionals is facilitated.

  • Systems Based Practice
    24. Cost-effective health care and resource allocation that does not compromise quality of care is practiced.
    25. Quality patient care and assisting patients in dealing with system complexities is advocated.
    26. Partnering with health care managers and health care providers to assess, coordinate, and improve health care and how these activities can affect system performance are known.

    Author
    Donna M. D’Alessandro, MD
    Professor of Pediatrics, University of Iowa Children’s Hospital

    Date
    March 3, 2008