# Presentation: 563376

## Surveillance among U.S. Children for Influenza-Related Mortality and Encephalopathy

**November 18, 2005**
**David K. Shay, MD, MPH**
**Influenza Branch**
**Centers for Disease Control and Prevention**

## Influenza Morbidity and Mortality

**Influenza causes annual epidemics**
**Major cause of morbidity and mortality: children aged <24 months, those aged >65, and those with underlying pulmonary, cardiac, and other conditions**** **
**Nationally available data has limitations**
**Relatively few respiratory illness cases tested  **
**Influenza has not been a reportable disease**
**Estimates of U.S. deaths and hospitalizations made by using statistical models**** **
**With retrospective death certificate, hospital discharge data, and viral surveillance data**

## Hospitalizations and Deaths from Influenza

**Modeling studies estimate an average of **
**>200,000 influenza-associated hospitalizations/year**
**~36,000 influenza-associated deaths/year**
**Highest rates of complications are in:**
**Persons with pulmonary and cardiac disease**
**Persons ********65 years**
**Children <5 years**
**Mortality data are limited for children**
**Estimated average of 92 influenza-related deaths among children aged <5 years annually**

- Izurieta HS, NEJM 2000; Neuzil KM, NEJM 2000; Thompson WW, JAMA 2004; Neuzil K, JID 2002; Thompson WW, JAMA 2003

##  Pertinent Features of the 2003-04 Influenza Season

**Began as early as October in some states**
**Influenza A (H3N2) predominant subtype**
**Historically associated with more severe seasons**
**Vaccine mismatch**
**CDC began receiving reports of influenza-related deaths in children in November 2003**
**No comparable historical data available**
**Public concern; spot vaccine shortages**
**On December 12, 2003, request to state, territorial, and local health departments for reports of pediatric influenza-associated deaths**

## Enhanced Surveillance Methods

**Surveillance period**
**September 28, 2003 - May 22, 2004**
**Case definition**
**U.S. resident**
**<18 years old**
**Death during surveillance period**
**Evidence of influenza virus infection by ****at least one laboratory**** test: rapid test, IFA, culture, RT-PCR, or immunohistochemistry on autopsy specimens **

## Results 2003-04 Season

**153 deaths reported from 40 states**
**Median age 3 years; range 2 weeks – 17 years**
**76 (50%) male**
**Race (n=146)**
**White 67%**
**Black 22%**
**Asian 6%**
**Ethnicity (n=134)**
**Hispanic 24%**

## Method of Diagnosis (n=153)

|  | Sole method
Number (%) | Total
Number |
| --- | --- | --- |
| Rapid antigen/EIA | 58 (38) | 117 |
| Viral Culture | 17 (11) | 54 |
| RT-PCR | 5 (3) | 11 |
| Fluorescent antibody (DFA, IFA) | 5 (3) | 25 |
| Immunohistochemical staining | 5 (3) | 27 |

***63 (41)***

***Multiple methods***

## Epidemic Curve and Virologic Activity  

**Epidemic Curve and Virologic Activity**** **** **

## Age Distribution (n=153)

## Age-specific Mortality Rates

| Age group | N (%) | Deaths/100,000
(95% CI) |
| --- | --- | --- |
|   <6 months | 18 (12) | 0.88 (0.52-1.39) |
|     6 - 23 months | 43 (28) | 0.71 (0.51-0.96) |
|     2 - 4 years | 35 (23) | 0.30 (0.20-0.42) |
|     5 - 17 years | 57 (37) | 0.11 (0.08-0.14) |
| All ages | 153 (100) | 0.21 (0.18-0.24) |

## Underlying Health Status

## Location at Time of Death (n=153)

##  Reported Clinical & Autopsy Diagnoses -1

|  | Clinical only | Autopsy only | Both | Total (n=146)  |
| --- | --- | --- | --- | --- |
| Pneumonia | 26 | 29 | 16 | 71 |
| Pneumonitis | 1 | 10 | 2 | 13 |
| Bronchiolitis | 1 | 10 | -- | 11 |
| ARDS | 9 | 1 | -- | 10 |
| Croup | 6 | -- | -- | 6 |
| Tracheitis/
bronchitis | -- | 27 | -- | 27 |
| Sepsis | 32 | 6 | 5 | 43 |
| Shock | 30 | 1 | 2 | 33 |

##  Reported Clinical and Autopsy Diagnoses - 2

|  | Clinical only | Autopsy only | Both | Total (n=146)  |
| --- | --- | --- | --- | --- |
| Encephalopathy/ encephalitis | 8 | 2 | 3 | 13 |
| Stroke | 4 | 1 | 1 | 6 |
| Seizures | 14 | -- | -- | 14 |
| Myo/pericarditis | 1 | 5 | -- | 6 |
| Myocardial infarction | -- | 2 | -- | 2 |
| Myositis/
rhabdomyolysis | 4 | 1 | -- | 5 |
| DIC | 15 | 2 | 1 | 18 |
| Hemophagocytosis | 1 | 1 | 1 | 3 |

***On review, 9 met the case definition for probable or suspected influenza-associated encephalopathy**

## Antiviral Medication Use 

**Median 1 day**
**Mean 2.6 days**

## Limitations

**Request for case reports was made near the peak of the season in December**
**Passive surveillance**
**Variations in testing practices, clinical, and pathologic diagnoses**
**Incomplete medical records**
**Limited information for non-hospitalized cases**
**Lack of comparable historical data**

## 2004-05 Influenza Season

**Lab-confirmed pediatric influenza-associated death became a nationally notifiable condition in June 2004**
**Reporting began October 2004**
**Data reported weekly in MMWR Table 1 and weekly influenza update**
**43 cases reported from 18 states during the 2004-05 season**
**26 received oseltamivir**

## Influenza-Associated Acute Encephalopathy in Children – United States, 2003-04 Influenza Season 

## Background

**Influenza-associated encephalopathy (IAE) is an uncommon complication of influenza**
**Can result in serious neurologic sequelae**
**IAE most commonly reported in young Japanese children**
**I48 Japanese cases reported during 1998-99 **
**25 U.S. cases identified during 1999-2003**

## Enhanced Surveillance Methods

**Surveillance period**
**September 28, 2003 - May 22, 2004**
**Case definition**
**U.S. resident **
**<18 years of age**
**Febrile illness**
**Laboratory-confirmed Influenza virus infection**
**Altered mental status  **

## Case Classification

_**Probable **_
**Altered mental status >24 hours**
**And**
**Onset of altered mental status within 5 days of fever onset**
**And**
**No other cause for altered mental status identified****	**

## Case Classification

_**Suspect **_
**Duration of altered mental status unknown**
**Or**
**Altered mental status ******** 24 hours, but unable to rule out another cause**
**Or**
**Altered mental status  < 24 hours, or other cause for altered mental status identified**
**	****And Status Epilepticus**
**Or Objective findings of cerebral inflammation (CT, MRI, EEG, CSF)****	**

## Results 2003-04 Season

**42 IAE cases reported from 22 states**
**22 Probable**
**20 Suspect**
**20 Males (48%)**
**Probable:****	****54% Male**
**Suspect:****	****40% Male**

## Results 2003-04 Season

**White**
**Probable:****	****9 (50%)**
**Suspect:****	****12 (67%)**
**Black**
**Probable:****	****6 (33%)**
**Suspect:****	****6 (33%) **
**Asian**
**Probable:****	****3 (17%)**
**Suspect:****	****0**

## Ethnicity information available for some probable and suspect cases
6 Hispanic (23%)
Probable: N=13
1 Hispanic (8%)
Suspect: N=13
5 Hispanic (38%)

**6 Hispanic (23%)**
**Probable: N=13**
**1 Hispanic (8%)**
**Suspect: N=13**
**5 Hispanic (38%)**

**Results 2003-04 Season**

## Age Distribution (N=42)

**Age Distribution (N=42)**

**Median:  5 years**
**Mean:     6.9 years**
**Range:  6 months - 17 years**

**Number**

**Age (Years)**

## Underlying High Risk Medical Conditions

**42 Suspect and Probable Cases**
** ****27 had no prior medical conditions**
** ****15 had at least 1 chronic medical conditions**
**7 Probable**
**8 Suspect**
**5 had a condition for which ACIP recommended influenza immunization for the 2003-04 influenza season**

## Specific High Risk Medical Conditions

**Chronic GI: 1**
**Arthritis: 1**
**Chronic lung disease: 1**
**Cerebral palsy: 2**
**Seizure disorder: 2**
**ENT abnormality: 2**
**Asthma: 3**
**Developmental delay: 6**

## Time from fever to onset of encephalopathy 

## Clinical Presentation - 1

**33 (78%) presented with altered mental status**
**Duration: median 3 days (range 1-31) among 28 patients with available data**
**20 (48%) Seizures: 9 Probable & 11 Suspect**
**8 Status Epilepticus: 3 Probable & 5 Suspect**
**16 Multiple seizures: 8 Probable & 8 Suspect**

## Clinical Presentation - 2

**17 (40%) Movement Disorder/Ataxia**
**8 Probable**
**9 Suspect**
**Decreased strength/Flaccid weakness**
**Hypotonicity/Hypertonicity**
**Slow movements**
**Unable to hold trunk/head properly**

## Neuroimaging Studies - 1

**17 (65%) Abnormal **
**17 Probable**
**11 Abnormal**
**  ****9 Suspect**
** ****6 Abnormal**
**Abnormalities included**
**Cerebral edema (most common)**
**Evidence of infarct**
**Tonsilar herniation**
**Focal cerebritis**

**Neuroimaging Studies - 1**

## Neuroimaging Studies - 2

**3 Probable**
**1 Abnormal**
**8 Suspect**
**3 Abnormal**
**All 4 abnormal CTs showed cerebral edema**
**2 with herniation**

**Neuroimaging Studies - 2**

## Diagnostic Testing

**18 Probable cases**
**7 with > 5 WBCs/mm****3**
**Range 8-69 cells**
**13 Suspect cases**
**1 with > 5 WBCs/mm****3**** (13 cells)**
**Influenza CSF Cultures (N=17)**
**1 positive (Suspect case)**

**Diagnostic Testing**

## Antiviral Treatment

**18 Received antivirals**
**9 Probable**
** ****9 Oseltamivir**
** ****1 Rimantadine**
**9 Suspect**
** ****3 Oseltamivir**
** ****5 Amantadine**
** ****1 Not Reported**

## Outcomes (N=39)

**18 fully recovered: 10 Probable & 8 Suspect**
**12 had neurologic sequelae: 8 Probable & 4 Suspect**
**9 died: 4 Probable & 5 Suspect**

## Outcomes by Age (N=39)

## Limitations

**Passive surveillance**
**May have missed cases **
**Selection or referral bias**
**Differential reporting by states**
**Timing of surveillance **
**Limited clinical data**
**No national baseline data on laboratory confirmed cases**

## Summary

**At least 42 IAE cases occurred**
**22 Probable**
**20 Suspect**
**Asian-Americans were not prominent **
**50% were <5 years old, but older children also affected**
**21 had severe outcomes, including death or neurologic sequelae**

## Recommendations

**Further surveillance for IAE needed**
**Studies needed to assess prevention and treatment interventions for IAE**
**Educate physicians and public about influenza-associated encephalopathy**

## Acknowledgments

**State and Local Health Departments**
**Local Clinicians**
**CSTE**
**EPO**
**Anna Likos**
**Tim Uyeki**
**Karen Broder**
**Michael Greenberg**
**Drew Posey**
**Niranjan Bhat**
**Erin Murray**
**Alicia Postema**
**Laura Podewils**

**Keiji Fukuda**
**Ermias Belay**
**Marc Fischer**
**Stephanie Schrag**
**Scott Harper**
**Matt Kuehnert**
**Cynthia Whitney**
**David Shay**
**Tonya Farris**
**James Sejvar**
**Sherif Zaki**
**Wun-Jun Shieh**
**Chris Paddock**
**Jeanette Guarner**
**Alexander Klimov**

**Kathryn Teates**
**Thea Fischer**
**Cynthia Whitney**
**Stephanie Schrag**
**Matt Kuehnert**
**Brittany Baughman**
**Michelle Oberlin**
**Melissa Amundson**
**Jeevan Sekhar**
**Tonya Farris**
**Irene Shui**
**James Sejvar**
**Craig Borkowf**
**Mitesh Patel**