• E-mail
• Print
• Comment
• Font Size
• Digg
• del.icio.us
• Discuss article

Spectrum of Clinical Manifestations of West Nile Virus Infection in Children

Posted on: Thursday, 16 December 2004, 03:00 CST

ABSTRACT. Reports of clinical manifestations of West Nile virus (WNV) infections in children have been relatively rare. Four cases of WNV infection in children are described: the first report of prolonged encephalitis and fulminant hepatitis caused by WNV, and 3 other presentations of WNV, including the first report of ocular involvement in a child. Pediatrics 2004;114:1673-1675; West Nile virus, hepatitis, vitritis, encephalitis, meningitis, child.

ABBREVIATIONS. WNV, West Nile virus; CNS, central nervous system; CBC, complete blood count; WBC, white blood cell; CSF, cerebrospinal fluid; CPK, creatine phosphokinase; HSV, herpes simplex virus; CT, computed tomography; Ig, immunoglobulin; ELISA, enzyme-linked immunosorbent assay.

West Nile virus (WNV) has become a significant cause of arboviral infection of the central nervous system (CNS) in the United States since it was first identified in 1999.1 Although clinical manifestations of WNV infections in adult patients have been well documented, pediatric cases have been relatively rare. We describe 4 cases of WNV infection in children: the first report of prolonged encephalitis and fulminant hepatitis caused by WNV, and 3 other presentations of WNV, including the first reported case of ocular involvement in a child.

CASE REPORTS

Patient 1

An 11-year-old white girl with a history of complex partial seizures initially presented to an outside hospital with prolonged generalized tonic-clomc seizure (80 minutes) that started several minutes after she began playing soccer. The patient's seizure disorder began at the age of 7 years and was well controlled previously with lamotrigine. She was developmentally normal and studying at an appropriate grade level. She had no prodromal illness before the new seizure. There was no history of sick contacts, recent travel, tick bites, or pets. She lived in a wooded area and reported multiple mosquito bites within the past 2 weeks. On examination, her temperature was 106F, which quickly decreased to 103F with antipyretics. There was no rash, nuchal rigidity, lymphadenopathy, or hepatosplenomegaly. Her Glasgow Coma Scale score was 3 with no eye movements or response to verbal or painful stimuli. The remainder of the physical examination was normal.

The patient required 18 mg of lorazepam and 750 mg of phenytoin to control her seizure. She then was intubated for deteriorating mental status and imminent respiratory failure from her anticonvulsant medications. No preintubation arterial blood gas was noted, although a postintubation gas revealed a pH of 7.4, arterial partial pressure of carbon dioxide of 27, arterial partial pressure of oxygen of 462, and HCO^sub 3^ of 17. After receiving ceftriaxone, the patient was transferred to Children's Hospital of Pittsburgh for additional treatment. Acyclovir and vancomycin were started, and ceftriaxone was continued. The patient was extubated on day 4 and defervesced by day 6 of her hospital course.

Initial complete blood count (CBC) showed a white blood cell (WBC) count of 9.4 10^sup 3^ per L, hemoglobin of 11.3 g/dL, and platelet count of 178 10^sup 3^ per L. Cerebrospinal fluid (CSF) revealed no white blood cells, glucose of 72 mg/dL, and an elevated protein of 62 mg/dL. Bacterial cultures of blood, urine, and CSF were negative. Initial alanine transaminase and aspartate transaminase values were normal but then increased to 3959 and 4270 U/L, respectively, by day 2 of hospitalization. Prothrombin time had risen from 14.1 to 18.6 seconds. Total bilirubin, γ-glutamyl- transferase, and ammonia levels were normal. Renal function was normal with blood urea nitrogen (BUN) of 8 mg/dL and creatinine of 1.2 mg/dL. A follow-up creatinine level obtained ~3 hours later was 0.9 mg/dL. Urine toxicology was negative for illicit drugs. Anticonvulsant drug levels were in the therapeutic range and did not account for the elevation of liver enzymes. Creatine phosphokinase (CPK) levels were elevated at 3400 U/L, although cardiac enzymes and CPK fractionation were normal. Amylase and lipase were also elevated at 114 and 682 U/L, respectively. The patient's liver transaminases, CPK, prothrombin times, and pancreatic enzymes normalized by 8 days after admission.

Serologies for cytomegalovirus, adenovirus, Coxsackie, hepatitis A, hepatitis B surface antigen and core antibody, hepatitis C, Lyme, Saint Louis encephalitis virus, and herpes simplex virus were negative. Serologies for Epstein-Barr virus revealed past infection. Polymerase chain reaction testing of the CSF was negative for HSV. Chest radiograph, head computed tomography (CT), and brain magnetic resonance imaging were normal. An electroencephalogram, performed twice, showed diffuse slowing and medication effect; there were no paroxysmal lateralized epileptiform discharges to indicate HSV involvement. Because of epidemiologic evidence of 2 clinical cases of WNV in the patient's county (patients 2 and 3), serologies for WNV were sent on day 2 of illness and were positive for WNV immunoglobulin M (IgM) and negative for WNV IgG. CSF was not tested for antibody to WNV.

Twelve days after admission, the patient had a Glasgow Coma Scale score of 10; she had no apparent motor deficits but did not respond to commands or have intelligible speech. One month after her initial presentation, she could repeat single words and walk with assistance but still had little response to commands. Six months later, the patient has improved significantly but has not returned to her baseline function. She was able to walk unassisted and respond to basic commands and has limited purposeful speech.

Patient 2

A 14-year-old previously healthy white boy presented to the emergency department of an outside hospital with a 4-day history of frontal headaches accompanied by photophobia, vomiting, neck discomfort, and fever to 102.5F. There was no history of recent travel or sick contacts. On examination, there was mild posterior cervical lymphadenopathy but no rash, nuchal rigidity, or hepatosplenomegaly. Neurologic examination including evaluation of mental status was normal. After a lumbar puncture was performed and bacterial cultures were obtained, the patient was started on ceftriaxone.

Initial CBC showed a WBC count of 9.8 10^sup 3^ per L, hemoglobin of 13.0 g/dL, and platelet count of 285 103 per L. CSF showed a WBC count of 158 cells per L with 67% polymorphonuclear leukocytes and 30% lymphocytes, 2 red blood cells per L, protein of 42.6 mg/dL, and glucose of 60 mg/dL. Bacterial cultures of the CSF and throat were negative. Polymerase chain reaction testing of the CSF was negative for HSV. A viral culture of the throat was positive for enterovirus; no viral cultures were obtained from other sites. Head CT was normal. The patient was hospitalized for presumed viral meningitis; a serum sample sent on the first day of hospitalisation was negative for Lyme but positive for WNV IgM and negative for WNV IgG. A CSF sample obtained concurrently was positive for WNV IgM. The patient demonstrated full improvement in his clinical symptoms by the fifth day after presentation.

Patient 3

An 8-year-old previously healthy white girl presented to her primary physician with a 4-day history of severe headache accompanied by low-grade fever, anorexia, vomiting, and cough. There was no nuchal rigidity, lymphadenopathy, rash, or organomegaly. Neurologic examination, including mental status, was normal by the time of examination by the physician. CBC showed a WBC count of 4.99 10^sup 3^ per L, hemoglobin of 13.2 g/dL, and platelet count of 281 10^sup 3^ per L; tests of liver function were normal. Head CT was normal. The patient did not undergo a lumbar puncture because her symptoms seemed to be improving. A viral culture from the throat was positive for enterovirus. Because the patient lived in an area endemic for WNV and had a history of recent mosquito bites, serologies for WNV were sent on day 5 of her illness and were positive for WNV IgM and negative for WNV IgC. The patient demonstrated improvement in her clinical symptoms by the sixth day after presentation.

Patient 4

A 9-year-old white girl presented for ophthalmologic consultation with a 10-day history of decreased vision in her left eye. Ten days before, she was diagnosed to have acute otitis media and streptococcal pharyngitis; oral amoxicillin and topical ofloxacin ear drops were prescribed. There was no history of pet exposures, fevers, diarrhea, arthralgias, or eye pain. On examination, the patient was afebrile and had no rash or hepatosplenomegaly. There was modest enlargement of her submandibular and anterior cervical lymph nodes.

Ophthalmic examination showed visual acuity of 20/20 OD and 20/ 40 OS with full extraocular movements and visual fields. Anterior segment examination of both eyes was normal. Posterior segment examination of the right eye showed 1+ vitreous haze, 1+ vitreous cells with 2 snowballs, and a small infratemporal area of snowbanking. Vitreous examination of the left eye revealed 2 to 3+ haze with 2 to 3+ cells with vitreous hemorrhage and possible snowbanking infratemporally. These findings were consistent with vitritis or a possible pars planitis.

A systemic workup for vitritis was conducted. CBC showed a WBC count of 7.26 10^sup 3^ per L, hemogl\obin of 12.7 g/dL, and platelet count of 447 10^sup 3^ per L. Angiotensin converting enzyme level was negative for sarcoidosis with a value of 43 U/L. Antinuclear antibody screen was initially positive; however, a follow-up Antinuclear antibody titer was <1:40. Serologies for syphilis and Lyme were negative. Skin testing for tuberculosis was negative. The patient had no known risk factors or illnesses consistent with human immunodeficiency virus. A serum sample for WNV was sent 20 days after onset of her illness and was positive for WNV IgM and negative for WNV IgG. A convalescent serum sample for WNV obtained 14 days later was negative for WNV IgG. Plaque reduction neutralization testing on the convalescent serum sample performed by the Centers for Disease Control and Prevention is pending.

The patient was treated with 1 drop of 1% prednisolone acetate per eye every 2 hours while awake. One week later, she reported some clinical improvement in her vision. Vitreous examination revealed increased inflammation in the right eye with 2+ haze and 2 to 3+ cells and decreasing inflammation on the left with 2 to 3+ haze and 1+ cells. The patient demonstrated slow improvement with complete recovery of her vision 6 months after initial presentation.

DISCUSSION

As of March 3, 2004, the Centers for Disease Control and Prevention reported 9306 human cases of WNV in the United States.2 Of those cases, 2757 (30%) were reported as West Nile meningitis or encephalitis. In the 2 counties adjacent to where these patients reside, there were 12 confirmed cases of WNV in 2003 compared with only 1 during 2002.3 In the 10 counties surrounding the patients' homes, there were an additional 10 confirmed cases of WNV in 2003 compared with none the previous year.3

Reports of pediatric WNV infections, particularly the neurologic manifestations, have been rare. Age is a significant risk factor for the development of serious WNV infection of the CNS. From analysis of the 1999 New York City outbreak, the incidence of severe WNV disease of the CNS was 10 times higher in people 50 to 59 years old and 43 times higher in those at least 80 years old compared with people 0 to 19 years old.4 In 2002, only 4% of reported cases with neurologic manifestations occurred in people <18 years old.5

Manifestations of infection with WNV in adults commonly include fever, weakness, gastrointestinal symptoms, headaches, changes in mental status, and myalgias.4 Whereas patients 1 and 4 did not present with these classic symptoms, patients 2 and 3 demonstrated the fever, headache, and vomiting more typical of WNV infection in adults. CNS involvement can include ataxia with extrapyramidal signs, cranial nerve abnormalities, myelitis, optic neuritis, polyradiculitis, and seizures.1 Severe mental status changes are rare, and the history of epilepsy in our first patient may have contributed to her prolonged seizure. The presentation of patient 1 is unusual because of age, serious neurologic manifestations, and the development of a fulminant hepatitis.

Fulminant hepatitis has been observed in WNV infections that occurred before 1990 but not in recent outbreaks.4 A Medline database search using the words "West Nile virus,""hepatitis," and "liver failure" yielded very few descriptions of hepatic injury resulting from WNV. With patient 1, we present a detailed clinical report of hepatitis caused by WNV and the first in a pediatric patient. Hepatic injury as a result of hypoxia from a prolonged seizure, druginduced side effects, or hyperpyrexia could cause a fulminant hepatitis. However, patient 1 had no evidence of accompanying renal failure to suggest hypoxic injury, and anticonvulsant drug levels remained therapeutic. Given these normal findings and the temporal association of her hepatic failure and diagnosis of WNV, we concluded that hepatitis as a direct result of her WNV infection is most likely.

Our fourth case is also atypical because of the ocular manifestations. Recent reports have described vitritis and chorioretinal lesions in adult patients with WNV infection.6,7 However, a search of the Medline database using the search terms "West Nile virus,""ocular,""pars planitis," and "vitritis" did not yield any reports of intraocular manifestations of WNV infection in children. With patient 4, we present a presumptive diagnosis of an ocular finding of WNV infection in a child. Screening for systemic causes of vitritis, including sarcoidosis, syphilis, Lyme disease, tuberculosis, and autoimmune disease, all were negative. Patient 4 has no history of risk factors to suggest ocular manifestations of human immunodeficiency virus infection. Serologies for cytomegalovirus and toxoplasmosis were not performed. Given the temporal association of the vitritis, the serologic diagnosis of WNV, and her negative systemic workup, her ocular findings are most likely attributable to WNV infection.

Diagnosis of WNV infection is based on clinical suspicion of viral encephalitis and on specific laboratory tests for WNV. The most common method for diagnosis uses the IgM antibody capture enzymelinked immunosorbent assay (ELISA). In these 4 cases, all WNV IgM and IgG testing was performed at the Pennsylvania State Department of Health using the Food and Drug Administration- approved WNV capture ELISA (PANBIO; Windsor, Australia). Sensitivities of 90% to 100% have been demonstrated, whereas specificity has been reported at 92% with some cross-reactivity among flaviviruses and enteroviruses.

The most compelling laboratory support for the diagnosis of West Nile infection is the documentation of positive IgM serologies followed by the development of IgG antibodies in convalescent sera. The finding of IgM antibody in the CSF is also convincing for WNV infection of the CNS as IgM does not cross the blood-brain barrier.4 Although all 4 patients had positive IgM serologies for WNV, the weakness of our report is the failure to collect convalescent specimens in patients 1 and 3.

Cross-reactivity of some flaviviruses and enteroviruses can potentially affect WNV testing. St. Louis encephalitis virus, a flavivirus, is a possible source for ELISA cross-reactivity in this geographic area. However, patient 1 had a negative test for this virus, making the possibility of a false-positive result less likely. Patients 2 and 3 each were found to have a positive throat culture for enterovirus in addition to positive serologies for WNV. Enteroviruses commonly circulate at the end of the summer and may be present in throat cultures for 5 to 15 days after infection.8 Although patient 2 had a concurrent positive test for enterovirus, he also had a confirmatory positive test for WNV IgM in the CSF indicative of WNV infection of the CNS. Patient 3 may have had a concurrent enteroviral infection contributing to her symptoms.

Given the presence of positive serum WNV IgM, negative acute serologies for WNV IgG, and geographic clustering of cases, acute WNV infection is likely for these 4 patients. Seventy-five percent of patients with encephalitis caused by flavivirus will have a positive serum or CSF IgM during the first 4 days of illness, with nearly all tests positive by 7 to 8 days after illness.9 All of our patients' serologies appropriately matched this time frame. WNV IgG may be present 7 to 14 days after initial infection. The WNV IgM antibody may be present in the serum for 6 months or longer after initial infection.4 However, each of these patients had negative concurrent serologies for WNV IgG, indicating that recent infection is most likely. The clustering of cases with neurologic manifestations in a geographic area also suggests a common cause.

Infections caused by WNV are usually subclinical and self- limited; however, ~1 in 150 infected people will develop serious neurologic disease.1 Patients 2 and 3 presented with self-limited symptoms that began to resolve within 5 to 6 days after presentation. Patient 1, however, had prolonged mental status changes that have persisted for >6 months. Although she has made significant progress with her speech and purposeful actions, she is still far from her baseline function and will require additional long-term evaluation to assess her outcome. Patient 4 also demonstrated prolonged symptoms that required 6 months for complete recovery of her vision.

These 4 patients each demonstrated different manifestations of WNV infection. Patient 1 did not present clinically with the lymphadenopathy, rash, vomiting, weakness, or myoclonus that has been characteristic of the previous WNV outbreak in New York.4 Patients 2 and 3, however, each presented with symptoms more typical of previously reported WNV infections and aseptic meningitis. Patient 4 presented with ocular manifestations, a rare finding of WNV disease. These cases illustrate the importance of considering WNV as an cause for unexplained encephalitis, fulminant hepatitis, aseptic meningitis, or vitritis in a child during arbovirus season.

REFERENCES

1. Romero JR, Newland, JG. Viral meningitis and encephalitis: traditional and emerging viral agents. Semin Pediatr Infect Dis. 2003;14:72-82

2. Centers for Disease Control and Prevention. West Nile Virus 2003 Human Cases as of March 3, 2004 [CDC West Nile Virus Web site]. Available at: www.cdc.gov/ncidod/dvbid/westnile/ surv&controlCaseCount03_ detailed.htm. Accessed March 4, 2004

3. United States Geological Survey (USGS). West Nile Virus maps- 2003 and 2002 [USGS West Nile Virus National and State Maps Web site]. Available at: westnilemaps.usgs.gov. Accessed February 11, 2004

4. Petersen LR, Marfin AA. West Nile virus: a primer for the clinician. Ann Intern Med. 2002;137:173-179

5. Centers for Disease Control and Prevention. Epidemic/ Epizootic West Nile Virus in the United States: Revised Guidelines for Surveillance, Prevention, and Control. 3rd Rev. Atlanta, GA: Centers for Disease Control and Prevention; 2003

6. Bains HS, Jampol L\M, Caughron MC, Parnell JR. Vitritis and chorioretinitis in a patient with West Nile virus infection. Arch Ophthalmol. 2003; 121:205-207

7. Hershberger VS, Ausberger JJ, Hutchins RK, Miller SA, Horwitz JA, Bergmann M. Chorioretinal lesions in nonfatal cases of West Nile virus infection. Ophthalmology. 2003;110:1732-1736

8. Cherry JD. Enteroviruses: Coxsackieviruses, Echoviruses, and Polioviruses. In Feigin RD, Cherry JD, eds. Textbook of Pediatric Infectious Diseases. 4th ed. Philadelphia, PA: W. B. Saunders; 1998:1793

9. Petersen LR, Hughes JM. West Nile virus encephalitis. N Engl J Med. 2002;347:1225-1226

Robert Yim, MD; Klara M. Posfay-Barbe, MD; Dawn Nolt, MD, MPH; George Fatula, MD; and Ellen R. Wald, MD

From the Division of Allergy, Immunology and Infectious Diseases, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.

Accepted for publication May 26, 2004.

doi:10.1542/peds.2004-0491

No conflict of interest declared.

Reprint requests to (E.R.W.) Division of Allergy, Immunology and Infectious Diseases, Children's Hospital of Pittsburgh, 3705 Fifth Ave, Pittsburgh, PA 15213-2583. E-mail: ellen.wald@chp.edu

PEDIATRICS (ISSN 0031 4005). Copyright 2004 by the American Academy of Pediatrics.

Copyright American Academy of Pediatrics Dec 2004

Source: Pediatrics

More News in this Category