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During late January 2003, the Michigan Department of Community Health
(MDCH) received reports of severe unexplained illnesses and deaths in children
and young adults aged <21 years residing in Michigan. Subsequently, two
of the deaths were found to be associated with influenza, including one with
neurologic complications. To identify cases of severe influenza in otherwise
healthy children and young adults aged <21 years, MDCH conducted enhanced
surveillance for influenza-associated illness. This report summarizes the
findings of this ongoing investigation, which indicate the need to better
define the frequency of serious complications from influenza in healthy children
and to incorporate such findings into evaluations of current vaccine recommendations
Enhanced surveillance for influenza-associated severe illnesses and
deaths focused on children and young adults aged <21 years at low risk*
for influenza complications who had illness onset or death after January 1,
2003. Severe influenza-associated illnesses included nonrespiratory complications
requiring hospital admission (e.g., myocarditis, rhabdomyolysis, encephalitis,
encephalopathy, and prolonged seizures) or any complications requiring intensive
care unit (ICU) admission. Influenza infections were confirmed by viral culture,
rapid antigen test, immunofluorescence, or immunohistochemical staining (IHC).
Surveillance for unexplained deaths also was conducted because of the possibility
that such deaths were associated with influenza infection. An unexplained
death was defined as a fatal, community-acquired illness in a person aged
<21 years with evidence of an infectious process† but for which
no specific etiology had been identified.
MDCH performed case finding by contacting local health departments,
infection-control practitioners, health-care providers, and clinical laboratory
directors through the Michigan Health Alert Network, broadcast fax, and e-mail
listservs. Medical charts and medical examiner reports were reviewed, health-care
providers were interviewed, and clinicians were asked to perform influenza
testing on children who were experiencing severe complications from influenza-like
illness (ILI). In addition, one Michigan county initiated active emergency
department (ED) surveillance in two large tertiary care hospitals by laboratory
testing all patients with ILI and evaluating all hospitalized children testing
positive for influenza to determine if they had illness consistent with the
case definition for influenza-associated severe illness. Available respiratory
specimens were obtained and cultured for influenza and other respiratory viruses
at local clinical and MDCH laboratories. CDC characterized influenza isolates
and evaluated available autopsy specimens by using IHC.
Enhanced surveillance identified 14 influenza cases, comprising four
deaths and 10 severe illnesses with onset during January 17–February
21 among children and young adults aged <21 years in Michigan. Of these
14 cases, eight (57%) had evidence of encephalopathy,‡ including two
deaths, and one case had evidence of myocarditis. In addition, four other
unexplained deaths are under investigation. This report describes the four
influenza-associated deaths and the 10 severe influenza illnesses.
Case 1. In January, a previously healthy male
teenager had onset of fever, nasal congestion, cough, nausea, vomiting, and
leg pain. He took over-the-counter (OTC) medications containing pseudoephedrine
and acetaminophen that evening and the following morning. On that morning,
he was found unresponsive and was transported to an ED, where he could not
be resuscitated. ED laboratory tests showed a markedly elevated white blood
cell count (WBC) of 34, 000 cells/mm3, (normal range: 4,000-10,500
cells/mm3) with a neutrophilic predominance, a substantially elevated
troponin of 98.5 ng/ml (normal range: 0-0.39 ng/ml), and a negative toxicology
screen. Evaluation of autopsy specimens indicated interstitial pneumonia and
focal myocyte necrosis without frank myocarditis. IHC of respiratory epithelial
cells of bronchi from centrally located lung tissue was positive for influenza
A virus. Review of available records revealed no history of influenza vaccination.
Case 2. In January, a previously healthy girl
aged 6 years with a 1-day history of fever, sore throat, and cough was examined
by her primary-care physician and noted to have harsh upper airway sounds.
A rapid test of a throat swab for Group A Streptococcus was negative. The
patient received oral prednisone for the treatment of croup and an OTC cold
medicine containing acetaminophen without salicylates. Later the same day,
she complained of leg pain. The next morning, she was found apneic. When paramedics
arrived, the patient was in cardiopulmonary arrest and was intubated, resuscitated,
and transported to an ED. Her WBC count was 15,900 cells/mm3. She
was transferred to the pediatric ICU, where she died the same day. A viral
culture of an endotracheal aspirate was positive for influenza A virus that
was antigenically similar to the vaccine strain A/New Caledonia/20/99 (H1N1)-like.
A bacterial culture of a throat swab taken at her primary-care physician's
office was positive for Group A Streptococcus. Evaluation of autopsy specimens
indicated bronchopneumonia with numerous intracellular bacteria in the intra-alveolar
infiltrate. IHC of bronchiolar epithelial cells from lung tissue was positive
for influenza A virus but negative for Group A Streptococcus. Review of available
records revealed no history of influenza vaccination.
Case 3. In February, a girl aged 5 years with
no underlying health conditions had onset of a low-grade fever. During the
evening, she became disoriented and lethargic and vomited at least seven times.
She had recently completed a course of amoxicillin for treatment of streptococcal
pharyngitis. The patient received medications containing ibuprofen; no information
about aspirin exposure was available. On arrival to an ED the next day, she
had a temperature of 104.1°F (40.05°C) and a WBC count of 13,100 cells/mm3 and again vomited. Antibiotics were administered. A nasopharyngeal
swab was positive for influenza A virus by a rapid antigen test, and treatment
with oseltamivir was initiated. Liver function tests showed an elevated aspartate
transaminase of 494 U/L (normal range: 20-45 U/L) and elevated alanine aminotransferase
of 383 U/L ( normal range: 5-25 U/L). The patient's neurologic status deteriorated
rapidly, and she progressed to respiratory arrest. After intubation, a computerized
tomography scan indicated uncal herniation. The patient died 19 hours after
admission. Autopsy was declined. A viral culture of the nasopharyngeal specimen
obtained during the hospitalization was positive for influenza A virus that
was antigenically similar to the vaccine strain influenza A/ New Caledonia/20/99
(H1N1)-like. The patient's illness was consistent with influenza-associated
encephalopathy; however, Reye syndrome could not categorically be ruled out
because no autopsy was performed. Review of available records revealed no
history of influenza vaccination.
Case 4. In February, a boy aged 2 years with
a history of resolved reactive airway disease had onset of a fever and cough.
The next evening and on the third morning, the patient received a children's
formulation of an OTC combination cold medication. After several hours of
lethargy, the boy was found unresponsive at home. Paramedics transported the
child to the hospital, where attempts to resuscitate were unsuccessful. A
postmortem lung swab was positive for influenza A virus by a rapid antigen
test, but viral culture was negative. Evaluation of autopsy specimens indicated
tracheobronchitis and massive brain edema without evidence of inflammation.
IHC of respiratory epithelial cells of trachea and bronchi from centrally
located lung tissue was positive for influenza A virus. The patient had not
been vaccinated against influenza.
Surveillance identified 10 children with severe illnesses that were
likely complications of influenza. The median age of these children was 2.5
years (range: 14 months–9 years); eight patients were female. Nine patients
were influenza A virus–positive, and one was influenza B virus–positive.
Of the nine influenza A virus cases, eight were confirmed by culture and one
by rapid antigen test. Three influenza A virus isolates were H1N1, four were
H1N2, and one was H3N2. Of those antigenically characterized, the H1N1 virus
isolates and H3N2 virus isolates were similar to the 2002-03 influenza vaccine
strains A/New Caledonia /20/99 (H1N1) and A/Panama/2007/99 (H3N2). Of the
H1N2 isolates, the H1 antigen was similar to that from the A/New Caledonia/20/99
(H1N1) vaccine strain, and the N2 antigen was similar to that from the A/Panama/2007/99
(H3N2) vaccine strain; the vaccine should provide protection against influenza
A(H1N2) virus. The influenza B isolate was most similar antigenically to the
reference strain B/Brisbane/32/2002, a minor variant of the B/Hong Kong/330/2001
vaccine strain. Vaccination history of these 10 children is unknown.
MJ Wilkins, DVM, ML Boulton, MD, GA Stoltman, PhD, SA Bidol, MPH, KS
Enger, MPH, JJ Lai, MPH, Michigan Dept of Community Health. T Uyeki, MD, S
Harper, MD, Div of Viral and Rickettsial Diseases; M Fischer, MD, SP Reagan,
MPH, Div of Bacterial and Mycotic Diseases; J Jones, MD, P Terebuh, MD, SD
Stonecipher, DVM, EIS officers, CDC.
Nationally, the 2002-03 influenza season was mild; however, this investigation
documented severe influenza-associated morbidity and mortality, including
encephalopathy, among children and young adults aged <21 years in Michigan.1 In Japan, influenza-associated acute encephalopathy among children
is a substantial public health problem; in the winter of 1998-99, for example,
a total of 148 cases of encephalitis/encephalopathy associated with influenza
were reported.2 Few such cases have been reported in the United
States.3,4 The reasons for these differences are unclear.
Influenza-associated deaths and severe illnesses in children might be
underreported in the United States. Because baseline data on such events are
not generally available, whether the cases described in this report represent
an increase or are the result of enhanced surveillance is unknown. In addition,
because influenza is not a nationally reportable disease, the estimated numbers
of annual deaths from influenza are derived from modeling techniques.5
Of the four deaths associated with influenza, none were in children
considered to be at high risk for influenza, nor were they in the age group
for which influenza vaccination is encouraged by the Advisory Committee on
Immunization Practices (ACIP).6 The risk factors for severe complications
and death from influenza in previously healthy children have not been well
described. The viruses isolated from these cases were of different types and
subtypes and were antigenically similar to viruses in circulation throughout
the United States during 2002-03.
Vaccination for influenza is recommended for persons at high risk for
complications from influenza. Young, otherwise healthy children aged 6-23
months are at increased risk for influenza-related hospitalization. For this
reason, influenza vaccination of healthy children aged 6-23 months is encouraged
when feasible.6 The results of this ongoing investigation indicate
the need for further studies to better define the frequency of serious complications
from influenza in children and young adults and to incorporate such findings
into evaluations of current vaccine recommendations for children.
This report is based on data contributed by LE Bauman, S Reedy, Washtenaw
County Public Health Dept, Ypsilanti; Newaygo County Health Dept, Cadillac;
Oakland County Health Dept, Pontiac; MG Stobierski, DVM, T Bolen, MS, J Beggs,
MPH, B Carlson, MPH, H Kapoor, MD, PA Somsel, DrPH, P Clark, MPH, VM Vavricka,
MS, A Casey, DS Wilkinson, Michigan Dept of Community Health. K Fukuda, MD,
S Zaki, MD, WJ Shieh, MD, J Guarner, MD, C Paddock, MD, Div of Viral and Rickettsial
Diseases, National Center for Infectious Diseases; K Kurpel, VMD, Epidemiology
Program Office, CDC.
References: 6 available
*Not a member of a high-risk group (i.e., residents of chronic care
facilities; persons with chronic disorders of the circulatory or respiratory
system, including asthma; persons with chronic metabolic disorders, renal
dysfunction, hemoglobinopathies, or immunosuppression; children on aspirin
therapy for chronic conditions; and women who are pregnant.1
†Includes any of the following: fever, leukocytosis or leukopenia,
histopathologic evidence of acute infection or inflammation, inflammation
of usually sterile fluids, or imaging studies consistent with infection or
‡Defined as altered mental status of any duration, including
seizure but not including simple febrile seizures.
Severe Morbidity and Mortality Associated With Influenza in Children and Young Adults—Michigan, 2003. JAMA. 2003;290(23):3058–3060. doi:10.1001/jama.290.23.3058
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