WEST NILE VIRUS: CLINICAL ASPECTS

Patrick F. Luedtke MD, MPHPatrick F. Luedtke MD, MPH

Deputy State EpidemiologistDeputy State Epidemiologist

Utah Department of HealthUtah Department of Health

University of UtahUniversity of Utah

pluedtke@utah.govpluedtke@utah.gov

A TALE OF TWO PATIENTS

On May 29 “Alex,” a 32 year On May 29 “Alex,” a 32 year old Caucasian male, old Caucasian male, developed a fever. Over developed a fever. Over the next 13 days he had the next 13 days he had sustained fever, excessive sustained fever, excessive thirst and diaphoresis, thirst and diaphoresis, abdominal pain, weak-abdominal pain, weak-

ness, delirium, flaccid ness, delirium, flaccid paralysis, encephalopathy paralysis, encephalopathy and finally, death on June and finally, death on June 1010thth. (1). (1)

On July 15On July 15thth, “Julie,” a 48 , “Julie,” a 48 year old female, presented year old female, presented to the emergency room to the emergency room because of progressive because of progressive unilateral leg weakness unilateral leg weakness following a mild upper following a mild upper respiratory syndrome. respiratory syndrome. Her URI resolved; but Her URI resolved; but seven months after seven months after discharge her leg discharge her leg weakness persists.weakness persists.

What is West Nile Virus (WNV)

1.1. WNV: Family---FlaviviridaeWNV: Family---Flaviviridae Genus----FlavivirusGenus----Flavivirus3.3. First isolated from a febrile woman in the First isolated from a febrile woman in the

West Nile district of Uganda in 1937West Nile district of Uganda in 19374.4. Single-stranded RNA virus within the Single-stranded RNA virus within the

Japanese Encephalitis Virus antigenic Japanese Encephalitis Virus antigenic complex which includes JEV, SLEV, complex which includes JEV, SLEV, MVEV, Kunjin virus (2)MVEV, Kunjin virus (2)

History of WNV

1.1. Largely confined to Africa, Asia, Middle East Largely confined to Africa, Asia, Middle East and Europe until the early 1990’sand Europe until the early 1990’s

2.2. Eight outbreaks in Israel between 1941 and Eight outbreaks in Israel between 1941 and 2000: No deaths in 1941 outbreak; 1957 2000: No deaths in 1941 outbreak; 1957 outbreak---single encephalitis case; in 2000 a outbreak---single encephalitis case; in 2000 a country-wide outbreak occurred with a case country-wide outbreak occurred with a case fatality rate of 8.4% and 58% of hospitalized fatality rate of 8.4% and 58% of hospitalized human cases having encephalitis (3)human cases having encephalitis (3)

3.3. ““Old world” WNV verses “New world” WNVOld world” WNV verses “New world” WNV

CLINICAL EPIDEMIOLOGY: I

1. Incubation period: variable (2-14 days)1. Incubation period: variable (2-14 days)

2. Patterns of infectivity (NYC experience) 2. Patterns of infectivity (NYC experience)

a.) 80% of infections not clinically apparenta.) 80% of infections not clinically apparent

b.) 20% develop “West Nile” fever (or worse) b.) 20% develop “West Nile” fever (or worse)

1.) One half (10%) of these see physician1.) One half (10%) of these see physician

2.) If hospitalized, 4-18% Case Fatality rate2.) If hospitalized, 4-18% Case Fatality rate

3.) Approximately 0.7% develop meningitis 3.) Approximately 0.7% develop meningitis

or encephalitis (or 1 in 150 infections)or encephalitis (or 1 in 150 infections)

CLINICAL EPIDEMIOLOGY: II

3. Advanced age (>75) is “by far the greatest 3. Advanced age (>75) is “by far the greatest risk factor for severe neurological disease, risk factor for severe neurological disease, long-term morbidity and death.” (3)long-term morbidity and death.” (3)

4. Clinical clues to WNV infection: onset of 4. Clinical clues to WNV infection: onset of meningitis or encephalitis in late summer meningitis or encephalitis in late summer or early fall; profound muscle weaknessor early fall; profound muscle weakness

CLINICAL PRESENTATIONS: I

WNV Clinical Syndromes:WNV Clinical Syndromes:

2.2. West Nile Fever (WNF)West Nile Fever (WNF)

3.3. West Nile Meningitis (WNM)West Nile Meningitis (WNM)

4.4. West Nile Encephalitis (WNE)West Nile Encephalitis (WNE)

5.5. West Nile Virus Associated-Acute Flaccid West Nile Virus Associated-Acute Flaccid Paralysis (AFP)Paralysis (AFP)

CLINICAL PRESENTATIONS: II

1. 1. West Nile FeverWest Nile Fever (20% of NYC infections?) (20% of NYC infections?)

a.) Mild illness lasting 3-6 days.a.) Mild illness lasting 3-6 days.

b.) Sudden onset of malaise, anorexia, b.) Sudden onset of malaise, anorexia,

nausea, vomiting, eye pain, headache, nausea, vomiting, eye pain, headache,

myalgia, rashmyalgia, rash

c.) May include fever, URI symptoms andc.) May include fever, URI symptoms and

non-specific rash non-specific rash

CLINICAL PRESENTATIONS: III

• West Nile MeningitisWest Nile Meningitis(0.2% of NYC infx?)(0.2% of NYC infx?) a.) Fever present in > 90% (T>37.8)a.) Fever present in > 90% (T>37.8) b.) Weakness, nausea, vomiting inb.) Weakness, nausea, vomiting in

approx. 50% approx. 50% c.) Meningismus:c.) Meningismus: fever, headache and nuchal ridigity; fever, headache and nuchal ridigity;

clinically indistinguishable from other clinically indistinguishable from other non-WNV viral meningitis cases non-WNV viral meningitis cases

CLINICAL PRESENTATIONS: IV

• West Nile EncephalitisWest Nile Encephalitis(0.4% of NYC infx?)(0.4% of NYC infx?) a.) Fever present in > 90%a.) Fever present in > 90% b.) GI tract symptoms, headache and severe b.) GI tract symptoms, headache and severe

weakness common weakness common c.) Encephalitic changes:c.) Encephalitic changes: (altered level of consciousness, abnormal (altered level of consciousness, abnormal

mental state, focal or diffuse neurological mental state, focal or diffuse neurological signs---cranial nerves, deep tendon reflexes, signs---cranial nerves, deep tendon reflexes, seizures) seizures)

CLINICAL PRESENTATIONS: V

• Acute Flaccid ParalysisAcute Flaccid Paralysis (?% of NYC infections) (?% of NYC infections) a.) Asymmetric weakness affecting upper or a.) Asymmetric weakness affecting upper or

lower limbs lower limbs b.) Can occur without menigoencephalitis!b.) Can occur without menigoencephalitis! c.) Concomitant bowel/bladder dysfunctionc.) Concomitant bowel/bladder dysfunction and sensory deficits commonand sensory deficits common d.) Polio-like destruction of anterior horn cells d.) Polio-like destruction of anterior horn cells

of spinal cord; also axonal or de-myelinating of spinal cord; also axonal or de-myelinating neuropathy described neuropathy described

MAKING THE DIAGNOSIS:

1.1. Clinical suspicion: consistent presentation Clinical suspicion: consistent presentation during appropriate time of yearduring appropriate time of year

2.2. Lab testing: CSF or serum “MAC-ELISA” (IgM Lab testing: CSF or serum “MAC-ELISA” (IgM antibody capture-ELISA). IgM serum and IgG antibody capture-ELISA). IgM serum and IgG testing requires acute and convalescent sera! testing requires acute and convalescent sera! (CSF?, Case definition: probable/confirmed)(CSF?, Case definition: probable/confirmed)

3.3. Beware recent YF/JEV vaccinees or SLEV infx Beware recent YF/JEV vaccinees or SLEV infx 4.4. Nucleic Acid Amplification (PCR) available at Nucleic Acid Amplification (PCR) available at

Utah State LaboratoryUtah State Laboratory

WNV TESTING: I

1. Who to test?1. Who to test?a.) Encephalitis cases of unknown etiologya.) Encephalitis cases of unknown etiologyb.) Non-enteroviral meningitis casesb.) Non-enteroviral meningitis casesc.) Patients with flaccid paralysis or neurological c.) Patients with flaccid paralysis or neurological

symptoms following a febrile illnesssymptoms following a febrile illnessd.) Pregnant womend.) Pregnant women

---If compatible febrile syndrome with---If compatible febrile syndrome with exposure historyexposure history---No indication to screen asymptomatic ---No indication to screen asymptomatic womenwomen

WNV TESTING: II

2. What to Test?2. What to Test?a.) Serum & CSFa.) Serum & CSF

---IgM ELISA---IgM ELISA• 4 commercial labs, state labs4 commercial labs, state labs

---IgG not useful acutely ---IgG not useful acutely 3. When to test?3. When to test?

a.) Clinically compatible cases during a.) Clinically compatible cases during transmission seasontransmission season---June to September with highest risk August ---June to September with highest risk August

to mid Septemberto mid September

WNV TREATMENT

1.1. In general treatment is supportiveIn general treatment is supportive

2.2. No controlled studies have assessed the No controlled studies have assessed the efficacy of ribavirin, interferon, gamma-efficacy of ribavirin, interferon, gamma-globulin, steroids, anticonvulsants or globulin, steroids, anticonvulsants or osmotic agents---but research continues!osmotic agents---but research continues!

3.3. Vaccine: no human vaccine exists; an Vaccine: no human vaccine exists; an equine vaccine is in useequine vaccine is in use

DIFFERENTIAL DIAGNOSES

1.1. JEV group (JEV, SLEV, MVEV, Kunjin JEV group (JEV, SLEV, MVEV, Kunjin virus)virus)

2.2. Other viral infections e.g., Herpes, Other viral infections e.g., Herpes, enteroviruses, VEE, WEE, etc.enteroviruses, VEE, WEE, etc.

3.3. Bacterial infections e.g., N. meningitidisBacterial infections e.g., N. meningitidis4.4. Presentation dependent (e.g., Polio for the Presentation dependent (e.g., Polio for the

acute flaccid paralysis patient; Guillain-acute flaccid paralysis patient; Guillain-Barre---viral/Campylobacter)Barre---viral/Campylobacter)

CLINICAL OUTCOMES (4-7)

1/16

(6%)

33/233

(14%)

40/826

(5%)

16/393

(4%)Deaths

8/16

(50%)

134/233

(58%)

84/826

(10%)

236/393

(60%)

Enceph

+

5/16

(31%)

37/233

(15.9%)

308/826

(37%)

157/393

(40%)

Mening

+

16/39

(37%)

326/417

(78%)

480/826

(58%)

393/835

(47%)Hosp

+

Louisiana

2002

Israel

2000

Russia

1999

Romania

1996

SYNDROME PROGNOSES (8)

• WNFWNF: infected persons in “New World” : infected persons in “New World” appear to fully recover to pre-morbid appear to fully recover to pre-morbid functioning following a short illness.functioning following a short illness.

• WNMWNM: nearly everyone has full recovery : nearly everyone has full recovery (in Louisiana follow-up study, 5/5 had full (in Louisiana follow-up study, 5/5 had full recovery and no discernable neurological recovery and no discernable neurological deficit after 8 months) deficit after 8 months)

SYNDROME PROGNOSES II

3. 3. WNEWNE: 6/8 returned to pre-morbid level of : 6/8 returned to pre-morbid level of functioning at 6 months (2 required initial functioning at 6 months (2 required initial discharge to LTC, 1 ultimately died); 5/8 had discharge to LTC, 1 ultimately died); 5/8 had postural and/or kinetic tremor at 8 months (one postural and/or kinetic tremor at 8 months (one severe); most had persistent fatigue and myalgiassevere); most had persistent fatigue and myalgias

4. 4. AFPAFP: 3/3 had no resolution of limb weakness after : 3/3 had no resolution of limb weakness after one year; all had persistent fatigue and myalgias; one year; all had persistent fatigue and myalgias; bladder symptoms resolved.bladder symptoms resolved.

RISK FACTORS (9)

1. For severe disease (WNE & AFP):1. For severe disease (WNE & AFP):

a.) Age > 75 (RR=2.7; 95%CI=1.3-5.8)a.) Age > 75 (RR=2.7; 95%CI=1.3-5.8)

b.) Diabetes mellitus (age adjusted b.) Diabetes mellitus (age adjusted RR=5.1; 95%CI=1.5-17.3) RR=5.1; 95%CI=1.5-17.3)

c.) Anemia?c.) Anemia?

d.) Immunosuppression? (malignancy, d.) Immunosuppression? (malignancy, chemotherapy, other medications) chemotherapy, other medications)

TRANSMISSION ISSUES (9)

a.) Blood transfusion (peak <21/10,000 a.) Blood transfusion (peak <21/10,000 donations in severely affected cities) donations in severely affected cities)

b.) Organ transplantation from infected b.) Organ transplantation from infected donor donor

c.) Bone marrow/stem cell transplantsc.) Bone marrow/stem cell transplants d.) Maternal-fetal: intrauterine? breast d.) Maternal-fetal: intrauterine? breast feeding?feeding?

A tale of two patients---revisited

On May 29 “Alex,” a 32 year On May 29 “Alex,” a 32 year old Caucasian male, old Caucasian male, developed a fever. Over developed a fever. Over the next 13 days he had the next 13 days he had sustained fever, excessive sustained fever, excessive thirst and diaphoresis, thirst and diaphoresis, abdominal pain, weak-abdominal pain, weak-

ness, delirium, flaccid ness, delirium, flaccid paralysis, encephalopathy paralysis, encephalopathy and finally, death on June and finally, death on June 1010thth. (1). (1)

On July 15On July 15thth, “Julie,” a 48 , “Julie,” a 48 year old female, presented year old female, presented to the emergency room to the emergency room because of progressive because of progressive unilateral leg weakness unilateral leg weakness following a mild upper following a mild upper respiratory syndrome. respiratory syndrome. Her URI resolved; but Her URI resolved; but seven months after seven months after discharge her leg discharge her leg weakness persists.weakness persists.

A tale of two patients---revisited

Alexander the Great:Alexander the Great:

Died June 10, 323 BC in Died June 10, 323 BC in Babylon (90 km south Babylon (90 km south of Bagdhad)of Bagdhad)

West Nile Encephalitis?!West Nile Encephalitis?!

Intermountain West Pt.Intermountain West Pt.

MRI: normal brain and MRI: normal brain and spinal cord; CE +spinal cord; CE +

CSF IgM +++CSF IgM +++

Acute Flaccid Paralysis!Acute Flaccid Paralysis!

IT’S COMINGBACK!

Bibliography

1.1. Marr J, Calisher C. Alexander the Great and Marr J, Calisher C. Alexander the Great and West Nile Virus Encephalitis. Emerg Infect Dis. West Nile Virus Encephalitis. Emerg Infect Dis. 2003;9:1599-1603.2003;9:1599-1603.

2.2. Petersen L, Marfin A. West Nile Virus.Petersen L, Marfin A. West Nile Virus. JAMA. 2003;290:524-528.JAMA. 2003;290:524-528.3. Petersen L, Marfin A. West Nile Virus: A Primer 3. Petersen L, Marfin A. West Nile Virus: A Primer

for the Clinician. Ann Intern Med. for the Clinician. Ann Intern Med. 2002;137:173-179.2002;137:173-179.

Bibliography II

1.1. Tsai T, Popovici F. West Nile encephalitis Tsai T, Popovici F. West Nile encephalitis epidemic in southeastern Romania.Lancet. epidemic in southeastern Romania.Lancet. 1998;352:767-771.1998;352:767-771.

2.2. Platonov A, Shipulin G. Outbreak of West Platonov A, Shipulin G. Outbreak of West Nile Virus Infection in Volgograd Region, Nile Virus Infection in Volgograd Region, Russia, 1999. Emerg Infect Dis. Russia, 1999. Emerg Infect Dis. 2001;7:128-132.2001;7:128-132.

Bibliography III

1.1. Weiss D, Carr, D. Clinical Findings of Weiss D, Carr, D. Clinical Findings of WNV Infection in Hospitalized Patients, WNV Infection in Hospitalized Patients, NY and NJ, 2000. Emerg Infect Dis. NY and NJ, 2000. Emerg Infect Dis. 2001;2001;

7:654-658.7:654-658.3.3. Chowers M, Lang R. Clinical Chowers M, Lang R. Clinical

Characteristics of the West Nile Fever Characteristics of the West Nile Fever Outbreak, Israel, 2000. Emerg Infect Dis. Outbreak, Israel, 2000. Emerg Infect Dis.

2001;7:675-678.2001;7:675-678.

Bibliography IV

1.1. Sejvar J, Haddad M. Neurological Sejvar J, Haddad M. Neurological Manifestations and Outcome of WNV Manifestations and Outcome of WNV Infection. JAMA. 2003;290:511-515.Infection. JAMA. 2003;290:511-515.

2.2. Nash D, Mostashari F. The Outbreak of Nash D, Mostashari F. The Outbreak of WNV Infection in the NYC Area in 1999. WNV Infection in the NYC Area in 1999. N Engl J Med. 2001;344:1807-1814.N Engl J Med. 2001;344:1807-1814.