# Presentation: 593112

## Rash Observations About West Nile Virus — Colorado, 2003

**Dayna Ferguson, MD**
**Colorado Dept of Public Health ****and Environment**
**Office of Workforce and ****Career Development, CDC**
** ****	****	****	****	****	****	**

**Notes:**
Good morning 

(I’m Dayna Ferguson – EIS Officer with the Colorado Department of Public Health and Environment)

It’s my pleasure today to present observations of the rash associated with West Nile Virus based on the 2003 outbreak in Colorado.   

## 2 Rash Investigations

**Clinical description of ****rash associated with WNV fever**
**Analysis of Colorado 2003 surveillance data**

**Notes:**
I’ll be presenting data from two studies.   
First, a small investigation to describe rash associated with WN fever.  

Second, an analysis of Colorado’s 2003 surveillance data to describe how rash is associated with WNV disease and death.

## WNV-Associated Rash Description

**Erythematous maculopapules**
**Neck, trunk, arms and legs**
**19%–57% of patients with****WNV disease**

**Notes:**
WNV-associated rash has been briefly described in the literature 

Most commonly as an erythematous maculopapular rash – or a combination small red flat and raised spots.

The distribution includes the neck, trunk, arms, and legs

The reported percentage of WNV patients who develop rash has varied widely from 19% in New York City in 1999 to 57% in a study of WN fever patients in Illinois in 2002

## Rash Investigation

**Goal – describe WNV-associated rash**
**Case definition**
**≥****18 years**
**New rash**
**Fever, headache or myalgias**
**Positive anti-WNV IgM **
**WNV fever**
**Clinicians described rash**
**Questionnaire**

**Notes:**
In Sept 2003, we set out to better describe WNV-associated rash

We investigated patients at CDC and clinics in the Fort Collins area who met the case definition 
>18 years,
With new rash, 
either fever, headache, or myalgias 
a positive anti-WNV IgM
And a diagnosis of WN fever

Clinicians described the rash and administered a questionnaire to patients

## Demographics(n=17)

**Median age, y (range)****	****    43      (24–65)**
** **
**Female, n (%)****	****	****    10      (59)**

**Notes:**
We had a convenience sample of 17 patients with WN fever and rash

The median age was 43 years

59% of patients  were female

No hospitalizations or death occurred

## Rash Timeline

**	****	****	****	****      ****	****    ****Median    Range **
**	****	****	****	**
**Illness duration, d****	****14****	****    (7–123)**
**Rash duration, d****	****	****  7****	****    (3–28)**
**Illness–Rash, d ****	****    ****	****  5****	****    (0–7)**
**  **

**Notes:**
The illness lasted a median of 14 days

The rash lasted a median of 7 days

Rash occurred a median of 5 days after illness onset

## Rash Description (n=17)

**Description****	****	****	****No.****	****     (%)**
**Maculopapular****	****	****13****	****     (76)**
**Macular****	****	****	****	****  3****	****     (18)**
**Vesicular****	****	****	****  1****	****       (6)**

**Notes:**
Most patients 76% had a maculopapular rash

18% had a macular rash (made up of only small flat lesions)

And 1 patient was described as having a vesicular rash

## Rash Distribution (n=17)

**Site****	****of rash****	****	****	****No.****	****	****(%)**
**Trunk****	****	****	****	****16****	****	****(94)**
**Upper extremities****	****15****	****	****(88)**
**Lower extremities****	****13****	****	****(76)**
**Head/neck****	****	****	****  9****	****	****(53)**

**Notes:**
Rash was located on the trunk in 94% of patients

upper extremities in 88%
lower extremities in 76%
And the head or neck in 53%

We also looked at sites of onset and spread to determine if there was a pattern that was characteristic for WNV disease.  
But we did not identify such a pattern

## Additional Findings (n=17)

**Characteristic****	****	****No.****	****	****(%)**
**Dysesthesia****	****	****	****6****	****	****(35)**
**Hyperesthesia****	****	****3****	****	****(18)**
**Pruritis****	****	****	****	****5****	****	****(29)**

**Notes:**
Some interesting findings were that 35% of patients reported dysesthesias where rash was associated with numbness or tingling of the skin

Of these patients, 3 also described hyperesthesia where it hurt to touch the skin.  One described it as feeling like a sunburn

29% of patients reported pruritis or itching

## Maculopapular Rash – Thigh

**Notes:**
The next three slides show pictures of the rash in patients with WN fever.

This picture shows a patient’s posterior thigh with a maculopapular rash – a combination of small, flat and raised red lesions.  

## Maculopapular Rash - Back

**Notes:**
This picture shows maculopapular rash on a patient’s back

## Maculopapular Rash - Flank

**Notes:**
This picture again shows a maculopapular rash on a patient’s flank

## IgM Test Results

**	****	****	****	****	****	****     ****Median, d    Range**
**Acute test pos (n=6)**** **
**    ****Onset–test 1    ****	****	****          17         (7–25)**
**Acute test neg (n=11)**
**    ****Onset–test 1****	****	****     ****	****     ****	****   5****	****     (0–8)**
**    ****Onset–test 2****	****   ****	****	****   ****	**** 23****	****     (11–42)**

**Notes:**
We found that only 6 or 35% of patients were positive on their initial test for anti WNV IgM antibodies  

Among the 6 that were positive, the median duration between illness onset and initial sera collection was 17 days

In contrast, in 11 patients with a negative initial test, sera were collected earlier in the disease with a median of 5 days between illness onset and sera collection

Among these patients the median duration between onset and a positive convalescent sera was 23 days.

So, in more than 1⁄2 of our patients rash was present before anti-WNV IgM antibodies were detectable.

## Summary of Rash Characteristics

_**New Findings**_
**Nonspecific pattern of onset and spread**
**Dysesthesia & hyperesthesia were somewhat common**
**Pruritis was somewhat common**
**Rash does not appear to be ****antibody mediated**

**Notes:**
New findings of this investigation are that WNV rash had a nonspecific pattern of onset and spread

Dysesthesia and hyperesthesia have not previously been associated WN fever.

Pruritis was also somewhat commonly associated with rash in this study. To my knowledge, pruritis has only been described with WNV rash once in the literature.
As rash occurred a median of 5 days after illness onset and the majority of patients in the study were IgM negative WNV-associated rash does not appear to antibody-mediated

## Analysis ofColorado 2003 Surveillance Data

**How common is rash in****WNV disease?**
**Is rash associated with outcome?**

**Notes:**
Now I am going to transition to an analysis of Colorado’s 2003 surveillance data.
I sought to answer the following questions:

How common is rash among patients with WNV disease?  

Is rash is associated with outcome?

## Surveillance Case Definition

**Colorado resident**
**2003**
**Compatible illness**
**Positive serum or CSF ****anti-WNV IgM**

**Notes:**
A  WNV patient was defined as a Colorado resident in 2003 with a compatible illness

And a Positive serum or cerebrospinal fluid anti WNV IgM

A person with a compatible illness (a non-specific, self-limited, febrile illness caused by infection with WNV, clinical disease generally occurs 2-6 days following the bite of an infected mosquito.  Typical cases are characterized by the acute onset of fever, headache, arthralgias, myalgias, and fatigue.  Maculopapular rash and lymphadenopathy generally are observed in less than 20% of cases.  Illness typically lasts 2-7 days.)

## WNV Disease Category

**Fever**
**Compatible illness**
**No evidence CNS disease**
**Meningitis**
**Evidence of CNS disease**
**Normal mental status**

**Notes:**
WNV Patients were categorized as having WN fever, meningitis or encephalitis.

A WN fever patient was defined as a patient with a compatible illness, 
And no clinical or laboratory evidence of central nervous system disease.

A meningitis patient was defined as a patient with clinical or laboratory evidence of central nervous system disease but normal mental status 

## WNV Disease Category

**Encephalitis**
**Evidence of CNS disease**
**Altered mental status**
**Acute flaccid paralysis**
**Not counted**

**Notes:**
An encephalitis patient was defined as a patient
with clinical or laboratory evidence of central nervous system disease, 
and specifically with altered mental status

Of note, we did not count acute flaccid paralysis cases

## Surveillance Data Collection

**Lab reportable condition**
**Standard interview**
**Chart review**
**Death certificates**

**Notes:**
WNV is a lab reportable condition in Colorado.

local health dept staff interviewed patients or family members using a standard interview to collect information about demographics, and symptoms

In additions I performed chart review on two groups:
Encephalitis patients who weren’t interviewed
and Patients listed as dying from WN fever or meningitis
Deaths were recorded during interviews and
supplemented with death certificate review, counting cases where WNV disease was listed as the underlying condition or a significant contributing condition

## 2003 Surveillance Results(n=2626)

**Characteristic****	****No.****	****	****	****(%)**
**Rash****	****	****	****1564****	****	****(60)**
**Female****	****	****	****1344****	****	****(51)**
**≥****65 years****	****	****  455****	****	****(17)**
**Died****	****	****	****    63****	****	****  (2)**

**Notes:**
We interviewed 89% of 2947 patients identified as  having WNV disease in 2003
Of these 2626 patients, 60% reported rash

51% were female

17% were aged ≥65 

And 2% died

## Rash by Disease Category

**  ****64%**

**  ****55%**

** ****33%**

**Notes:**
This slide shows that the percentage of patients reporting rash differed by disease category

64% of WN fever patients reported rash 
Vs 55% of meningitis patients
And only 33% of encephalitis patients

## Rash by Age Group

**Notes:**
Similarly, the percentage of patients reporting rash differed by age group.

67% of patients <65 reported rash 

as compared with 25% of patients >65

## Rash by Sex

**Notes:**
Although not as great, there was also a difference in reported rash by sex.

65% of female patients reported rash 
vs 54% of male patients

## Association betweenDisease Category and Rash  

**Disease category****	****  AOR*  ****	****  (95% CI)**
**Fever  ****	****	****	****   1****	****    ****	****   Ref**
**Meningitis****	****	****   0.7****	****   (0.6–0.9)**
**Encephalitis ****	****	****   0.5****	****   (0.3–0.6)**
***Adjusted for age group, sex, and ****age group by sex**

**Notes:**
This table shows results of our multivariable logistic regression model 

and the adjusted odds ratios for patients comparing meningitis and encephalitis with WN fever, 

adjusted for age group, sex, and an interaction term between age group and sex.

Meningitis patients were 0.7 times as likely to report rash as fever patients.  

Encephalitis patients were 0.5 times as likely to report rash as fever patients

## Risk Factors for Death

**63 total deaths**
**61 (97%) WNV encephalitis**

**Notes:**
I’m going to transition now and look at death as the outcome 
with rash, age group, and sex as potential risk factors for death

There were 63 total death associated with WNV in 2003

61 or 97% were associated with encephalitis
So, therefore the following analysis was limited to patients with WN encephalitis

## Encephalitis Deathsby Age Group and Rash

**Notes:**
This graph demonstrates the % of patients with encephalitis who died stratified by age-group and rash

The two bars on the left represent patients <65.  
The two bars on the right patients >65 
The yellow bars represent patients with rash.  The blue bars patients without rash

Younger Patients with rash had the lowest risk of death with 4% dying
Younger Patients without rash had a greater risk of death with 10% dying

Older Patients with rash had an even greater risk of death with 25% dying
Finally, older patients without rash had the highest risk of death with 48% dying

So although age had the largest association with death.  Within each age group, the presence of rash was associated with a lower risk of death.
(2/55	7/67		6/24		46/96)

## Association between Age Group, Rash, Sex, and Death

**Variable****	****	****	****AOR****	****	****  95% CI**
**<65 years****	****	****0.1****	****	**** (0.05–0.3)**
**Rash****	****	****	****0.3****	****	**** (0.1–0.8)**
**Female****	****	****	****0.8****	****	**** (0.4–1.6)**

**Notes:**
This table shows results of exact logistic regression modeling for the association between age group, rash, sex and death. 

encephalitis patients <65 had 0.1 times the likelihood of death as older patients

Encephalitis patients who reported rash had 0.3 times the likelihood of death as patients without rash

## Rash is Protective

_**New Finding**_
**Rash associated with 70% reduction in likelihood of death among encephalitis patients**

**Notes:**
I think that the most important new findings of this analysis 

was that the presence of rash was associated with a 70% reduction in the likelihood of death in patients with encephalitis

## Rash Associated with Disease Category, Age Group and Sex

_**New Finding**_
**Rash reported more frequently by specific patients with WNV disease**
**Fever > Meningitis > Encephalitis**
**Younger age > Older age**
**Females > Males**

**Notes:**
The other new finding of this analysis was that rash was reported more frequently by specific patient groups

Patients with WN fever reported rash more frequently than meningitis and encephalitis patients

Younger patients more than older patients

And females more than males

## Possible Interpretation

**Host immune factors associated with rash**
**Protective against severe disease**
**Protective against death**

**Notes:**
So what do we make of this?
A possible hypothesis is that host immune factors associated with rash 
Are more likely to be present in younger patients and  seem to be protective against developing severe disease such as encephalitis 
Additionally, these factors appear to be protective against death in patients who do develop encephalitis

. 

## Limitations

**Interviews of sickest patients through family members**
**Rash might influence****healthcare-seeking behavior**
**Potential misclassification of disease categories**

**Notes:**
There were at least 3 limitations to this investigation
First, we conducted interviews with family members for the sickest patients.  They might have been unaware of rash resulting in underreporting of rash in the encephalitis group.  

Second, rash might have influenced healthcare-seeking behavior making patients with rash more likely to seek medical care.  This might inflate rash reporting in the WN fever group.  

Third, there was potential for misclassification of patient’s disease category. Some disease categories were changed after chart review. Since not all charts were reviewed, there are still potentially mislabeled patients

## Summary – 1st Study

**WNV can cause generalized erythematous, maculopapular rash**
**Might be associated with dysesthesia and pruritis**
**Nonspecific pattern of onset and spread**
**Febrile rash illness during WNV season can facilitate diagnosis**

**Notes:**
To summarize findings of the 1st study:
WNV can cause a generalized, erythematous, maculopapular rash

Rash may be associated with dysesthesia and pruritis

Although onset and spread are nonspecific, 

Febrile rash illness during WNV season can direct testing and aid in making the diagnosis

## Summary – 2nd Study

**Rash is common symptom of ****WNV disease – 60% of patients**
**Rash occurs more frequently in specific subgroups**
**WNV fever**
**Younger patients**
**Females**
**Rash associated with decreased risk of death **

**Notes:**
To summarize findings of the second study
Rash occurs commonly in WNV disease occurring in up to 60% of patients in our study

Rash appears to occur more commonly in specific subgroups

WV fever patients
younger patients 
And female patients 

Additionally, The presence of rash is associated with decreased risk of death in patients with encephalitis

## Recommendations

**Confirm findings with other surveillance data**
**Study pathogenesis of rash**

**Notes:**
Some recommendations for additional study include:
To confirm these finding with other surveillance data

And begin to study the pathogenesis of rash in WNV.  Skin biopsies on patients with rash would be a potential place to start.	

## Acknowledgments

_**Local Health Dept Staff**_
_**CDPHE**_
**Steve Burnite**
**Ken Gershman**
**Nicole Haubert**
**John Pape**
_**LCDHE**_
**Adrienne Lebailly**

_**DVBID – CDC**_
**Ned Hayes**
**Lyle Petersen**
_**OWCD – CDC**_
**Anindya De**
**Tom Török**
_**Family Practice Assoc**_
**James Sprowell**

**Notes:**
There were many people I would like to acknowledge without whose help I could not have done this analysis

THANK YOU.

## Surveillance Results – Colorado, 2003

**Disease****	****      **
**Category****	****     Interviewed/Total****	****  (%)**
**Fever****	****	****2002 / 2280****	****  ****	****  (88)**
**Meningitis****	****  379 / 420****	****	****  (90)**
**Encephalitis****	****  244 / 246****	****	****  (99)**
**Unknown****	****	****      1 / 1****	****	****	****(100)**
**Total****	****	****	****2626 / 2947****	****	****  (89)**

**Notes:**
Based on these surveillance data, we interviewed or reviewed records of 2002 of 2280 patients or 88% of patients with WNV fever, 

379 of 420 patients or 90% of patients with WNV meningitis
and 244 of 246 or 99% patients with WNV encephalitis.

There was an additional patient whose disease category was unknown

So a total of 2626 of 2947 or 89% of case patients with WNV disease were interviewed or had their chart reviewed.

## Rash by Age Group and Sex

**Notes:**
In analyzing these data, we noted that the percentage of rash reported by men and women varied by age group

This shows the percentage of patients reporting rash stratified for Age Group and Sex.  

Patients <65 years are shown on the left two bars. And, patients >65 years are shown in the right two bars
Females are shown in yellow and males in blue

There was a difference in the percentage of women and men <65 years who reported rash. 73% of younger women reported rash as compared with 60% of younger men

In comparison, there was minimal difference in the % of females and males reporting rash in the older age-group 26% vs. 25%

## Association betweenAge Group, Sex and Rash

**	****	****	****	****      ****Male****	****  ****	****       Female**
**Age Group     AOR*    (CI)****	****     AOR*  (CI)**
**<65 years   ****	**** 4****	****   (3–6)****	****    7****	****   (5–10)****	****    **
**≥****65 years****	**** ****1        Ref****	****    1****	****   (0.6–2)**
***Adjusted for disease category**

**Notes:**
This table shows the adjusted odds ratio for patients reporting rash based on age group and sex, adjusted for disease category 

These odd’s ratio are reported separately for males and females because of the interaction term between age group and sex

Males >65 were made the reference group shown in yellow

Females >65 were equally likely to report rash.

Males <65 were 4 times as likely to report rash as older males

Females <65 were 7 times as likely to report rash as older males

## Encephalitis Deaths by Age Group

**Notes:**
Not surprisingly, as this has been reported in the literature,

 increased age was associated with an increased risk of death among patients with WNV disease

Only 7% of patients <65 years with encephalitis died as compared with 43% of patients >65 years with encephalitis

## Encephalitis Deaths by Rash

**Notes:**
It was surprising that rash also appeared to be associated with outcome.

Among WNV encephalitis patients with rash, 10% died as compared with 32% of patients who had encephalitis without reported rash

## Encephalitis Deaths by Sex

**Notes:**
On the other hand,the risk of death was not significantly different between female and male patients with WNV encephalitis

## Discussion – Rash Frequency

**	****	****	****           ****	****	****	****	****Median age**
**Outbreak****	****	****   % Rash     % Fever      (years)**
**NYC (1999)****	****      19****	****        ****	****  8               71**
**Israel (2000)****	****      22****	****        ****	****24            ****	****  65**
**Israel (1950)****	****      50       ****	**** ****	****98****	****        18–20**
**Illinois (2002)****	****      57****	****       100****	****        <65**
**Colorado (2003)    60       ****	****	****77 ****	****      ****	****  47**

**Notes:**
If you recall from earlier in this talk, the frequency of rash associated with WNV disease has varied substantially in the literature.  This is the same list of  studies I showed earlier to which I have added our data shown in yellow

Looking at WNV disease category and age group might help explain different frequencies of rash reported in the literature

In NYC in 1999 and Israel in 2000 only 19-22% of patients had rash.  In those outbreak, however, only 8-24% of patients had WNV fever and patients were older with median ages of 65 – 71

In comparison, in Israel in 1950, 50% of patients had rash, a much higher %,  98% had WNV fever and patients were much younger, most between 18 and 20 years

In Illinois in 2002, 57% of patients reported rash.  In this study, which was specifically focused on WNV fever, 100% had WNV fever and the median age was <65 years

In our data 60% of patients reported rash and again a higher % of patients 77% had WNV fever and patients were relatively younger with a median age of 47

These combined studies are consistent with our conclusion that rash is more common in WNV fever and younger patients

## Percentage with Rash byAge Group

## Patients who Died by Age Group

**Notes:**
This slide shows the percentage of patients who died by age group

Unlike the other slides in this part of the analysis, it shows the percentage of patients who died with WNV disease not just WNV encephalitis

We looked at the frequency of death by 5 year intervals.  You could make the argument that we should use ≥60 years as the older age group based on the slope of the curve.  To be consistent with the rash analysis we elected to use ≥65 years

## Duration Between Illness Onset and Death 

**	****	****	****	****	****  ****Median****	****    ****	****	****	****	****	****               Duration, d        Range**
**No rash (N=54)  ****	****      29  ****	****          (1–248)**
**Rash (N=8)****	****	****      29  ****	****	****  (4–210)**