Nonpolio enterovirus infections: A new era

By Janet Casey, MD, and Michael E. Pichichero, MD

The versatile nonpolio enteroviruses cause a broad spectrum of illness, ranging from mild to life-threatening. Developments have opened new vistas in diagnosing and treating these infections.

The enteroviruses include more than 70 serotypes and account for 10 million to 15 million illnesses each year in the United States.^1-3 Nonpolio enterovirus (NPEV) infections are responsible for most acute febrile illnesses in children and adolescents during the summer and fall months. They are costly in terms of direct medical expenses and indirect costs such as income lost by parents caring for sick children.⁴

LEARNING OBJECTIVES

After reviewing this article the physician should be able to:

The enteroviruses, members of the picornavirus family, include coxsackieviruses A and B, echoviruses, the newer numbered enteroviruses 68 to 71, and the polioviruses (Table 1). They are small, single-stranded RNA viruses that are grouped together because they have similar sites of infection and share many clinical manifestations. The majority of NPEV infections seen in private practice are self-limited, presenting with fever alone or clinically distinctive pictures such as hand-foot-and-mouth disease, herpangina, or pleurodynia.⁴ NPEVs also may cause serious illnesses such as meningitis, myocarditis, encephalitis, and neonatal sepsis.

Table 1
Tally of the enterovirus family

NPEV infections are often confused with bacterial infections and treated unnecessarily with antibiotics, a situation that could be prevented by more rapid identification of NPEVs. Recent advances in molecular biology have led to new diagnostic tests for NPEVs.⁵ These, along with anticipated new antiviral therapy, have greatly improved the outlook for diagnosis and treatment.

How NPEVs spread and cause illness

NPEVs are present throughout the world; infections from these viruses are very common. They cause disease in the summer and fall months in temperate climates and throughout the year in the tropics. Enteroviral infections spread predominantly from person to person by the fecal- oral route. Contaminated swimming pools also may serve as a source of transmission. (Foot-and-mouth disease currently affecting European livestock is also caused by a quick-spreading picornavirus that, while possibly lethal to animals, rarely affects humans.)

A large study of enteroviral infections, in our pediatric practice and others, found that children 4 to 12 years of age were most often infected. Infection commonly spread within families to both siblings and adults. Interestingly, clinical manifestations of the illnesses often differed among family members.⁴

After a person is exposed to a NPEV by the fecal-oral route, the virus colonizes the pharynx and the gastrointestinal tract. The infection spreads to the regional lymph nodes, where the virus replicates and an initial viremia occurs on approximately the third postexposure day. The initial viremia results in colonization and subsequent viral multiplication at many secondary sites (Figure 1). Replication at the secondary sites corresponds to the onset of clinical symptoms four to six days after exposure.

A second major viremia occurs during days 3 to 7 of infection, while the virus is multiplying at secondary sites. The end of viremia correlates with the appearance of antibody and the beginning of clinical recovery. The many clinical manifestations of NPEV infections result from the damage caused by the virus at the secondary sites of infection.

Milder clinical manifestations

One of the characteristics of NPEV infections is their amazing diversity of clinical manifestations (Table 2), which range from self-limited, nonserious infections to serious and sometimes fatal disease. Table 3 shows the prevalence of NPEV illnesses. The office-based practitioner most often encounters a child with benign NPEV infection, typically during the summer and fall months, although NPEV infection can occur year-round.⁴ The most common clinical syndromes are fever with rash, fever with myalgias and malaise, hand-foot-and-mouth disease, herpangina, and pleurodynia.

TABLE 2
Clinical manifestations of NPEV infection

TABLE 3
Prevalence of NPEV illnesses

Nonspecific febrile illness is the most common presentation of NPEV infection. The illness usually starts abruptly. Young children have only fever and malaise, but older children often report a headache. The fever usually lasts two to four days and is moderately high, ranging from 38.3° C to 40.0° C. It often has a biphasic pattern. The results of the physical examination are frequently benign with no overt findings. The illness usually lasts three to four days, but an occasional child may have symptoms for as long as a week.

Respiratory manifestations, most often pharyngitis, occur frequently with NPEV infections. Pharyngitis starts abruptly and is often accompanied by fever. Younger children may present with increased drooling, hands in the mouth, and refusal to eat. Older children complain of sore throat as well as headache, myalgias, and malaise. Mild vomiting and diarrhea commonly accompany the respiratory manifestations.

Herpangina is a specific syndrome of NPEV pharyngitis. Children with this syndrome have fever and a characteristic pharyngitis with papulovesicular lesions 1 to 2 mm in diameter on the anterior tonsillar pillars, soft palate, uvula, tonsils, and pharyngeal wall. The lesions are discrete and average five per patient. They do not appear in the anterior part of the mouth.

Hand-foot-and-mouth disease is well recognized by clinicians who care for young children. The child presents with fever and a specific enanthem and exanthem: papulovesicular lesions within the mouth that quickly become ulcerated and papulovesicular lesions on the palms and soles. The palms and soles are also puffy and red, and the child may act as though his hands and feet hurt, refusing to use his hands or walk. The fever accompanying herpangina and hand-foot-and-mouth disease usually lasts three or four days, but fever that persists for a week is not uncommon. The pharyngitis follows a pattern similar to the fever. Herpangina and hand-foot-and-mouth disease are usually benign illnesses, but an occasional child becomes dehydrated from decreased oral intake and requires IV hydration.

Pleurodynia (Bornholm disease) is an NPEV infection specific to the respiratory tract. It is characterized by sudden onset of pain in the chest or upper abdomen. The pain appears to be muscular in origin; its intensity varies. It can be excruciatingly severe and sudden and accompanied by profuse sweating, pallor, and apparent shock. In adults, it can be confused with a heart attack. Older children describe the pain as sharp and stabbing. It occurs in spasms that can last for a few minutes to a few hours. During spasms, the patient has rapid, shallow, grunting respirations that suggest pneumonia or pleural irritation. The symptoms usually last one or two days, but the illness can be biphasic, with symptoms resolving only to reappear a few days later. Pleurodynia was once epidemic in older children and adults, but appears sporadically today, usually in adolescents and adults.

Gastrointestinal manifestations are almost universal in NPEV infections. The most common symptoms are anorexia, nausea, vomiting, and diarrhea. They usually are not severe and often occur in combination with other symptoms, such as fever and sore throat. Abdominal pain may be the only manifestation of infection; when severe, it can mimic appendicitis.

Severe manifestations

The most severe manifestations of NPEV infections are neurologic disease (meningitis and encephalitis), cardiovascular complications (myocarditis and pericarditis), and neonatal sepsis. These conditions are rare and sometimes fatal.

Neurologic manifestations, which are common in NPEV infections, can range from mild, with headache as the only symptom, to severe brainstem meningoencephalitis and death. Aseptic meningitis is the most frequent neurologic manifestation of NPEVs. Others include encephalitis and acute flaccid paralysis.

The age of the patient strongly influences the clinical presentation of NPEV meningitis. Neonates present with nonspecific symptoms, such as irritability, poor feeding, and fever. Nuchal rigidity and a full fontanel are not often seen. Older children present with fever and headache. Photophobia, nausea, and vomiting are other common symptoms in older children. Nuchal rigidity occurs frequently. The child is usually brought to medical attention when a severe headache develops after a two or three day prodrome of fever, sore throat, and malaise.

The typical cerebrospinal fluid profile in NPEV meningitis is a mononuclear pleocytosis with 100 to 300 white blood cells/mL, normal or mildly elevated protein content, and normal glucose concentration. Illness usually lasts fewer than seven days, but adolescents, like adults, may be symptomatic for several weeks with persistent headache and photophobia.

NPEV meningitis typically has an excellent prognosis, but outbreaks of severe disease occur occasionally. One such outbreak, of hand-foot-and-mouth disease caused by enterovirus 71, affected thousands of children in Taiwan in 1998. Three hundred twenty children were admitted to hospitals with acute neurologic involvement, and at least 55 children died.^6,7

Cardiovascular manifestations of NPEV infections, myocarditis and pericarditis, are most often linked to the group B coxsackieviruses. Many patients present in congestive heart failure. The acute infection may go undiagnosed because symptoms are mild, so that the patient seeks medical attention only when the virus has infected the heart muscle or pericardial lining and led to reduced cardiac function.

Neonatal sepsis is most often caused by one of the echovirus serotypes. The most common route of infection is vertical transmission of the virus from mother to infant at birth. Nosocomial nursery outbreaks of NPEV also occur.

Some infants with NPEV infection are asymptomatic, but the risk of morbidity and mortality is high because of multiple system involvement including the CNS, lung, liver, and heart. Severe infection is associated with prematurity, male sex, and onset of maternal enteroviral infection within two weeks before delivery. The maternal infection is often identified only after a thorough history has been taken.

Neonatal infection most often presents in the first two weeks of life with fever, poor feeding, abdominal distention, lethargy, and hypotonia. The condition mimics neonatal bacterial sepsis and neonatal herpes simplex disease.

New findings about NPEV in outpatients

Physicians who care for pediatric patients are familiar with the common presentations of NPEV infections. Three predominant syndromes are seen in the outpatient setting: myalgias and malaise, stomatitis (herpangina), and hand-foot-and-mouth disease.⁴ Table 4 lists their presenting symptoms. Most patients have four to seven different symptoms at the time of presentation. Fever and sore throat are the symptoms most often seen in all three syndromes. Headache, fatigue, and muscle aches are also common in patients with the myalgias-malaise syndrome. NPEV stomatitis is most often characterized by fever, sore throat, and fatigue, while hand-foot-and-mouth disease syndrome has a very characteristic exanthem and enanthem, described previously, in addition to fever and sore throat.

TABLE 4
Symptoms at diagnosis in outpatients with the common NPEV syndromes

NPEV infections were once thought to be mild diseases that lasted two or three days. A recent study from private pediatric practices, including our own, found that illness is prolonged in most patients. We found the mean duration of illness to be 9.5 days for myalgias-malaise syndrome, 7 days for stomatitis, and 7.2 days for hand-foot-and-mouth disease.⁴ The illnesses caused significant symptoms, and their duration prompted parents to seek medical attention.

We also found that spread of NPEV infections within a household is common. More than 50% of patients we studied had a family member with NPEV illness.⁴ Half of siblings and 25% of adults within the household of the index case contracted an NPEV infection. Some had the same presentation as the index patient, but it was not uncommon for other household members to have quite different presentations—for example, an index patient with hand-foot-and-mouth disease, one sibling with myalgias-malaise, and a parent with pleurodynia. This creates a confusing picture both for clinicians and parents. Parents who seek medical attention for different symptoms among their children, only to be given the same diagnosis of NPEV infection for all the children, should be given an explanation.

NPEV illness is more costly to families of patients than previously realized, our study found (Figure 2). The costs are both direct and indirect. Direct costs include medical care, laboratory tests, and medication. The duration of the illness and the multitude of nonspecific symptoms lead to concern about a possible bacterial cause, which prompts a diagnostic workup, including laboratory tests, and empiric treatment with antibiotics. The direct costs vary with the syndrome; stomatitis and hand-foot-and-mouth disease are the least expensive to treat and aseptic meningitis is the most expensive.⁴

Indirect costs, including lost parental income from staying home with a sick child and expenses for sick-child care, are also considerable. Taken together, the direct and indirect costs for a case of NPEV illness range from $132 for hand-foot-and-mouth disease to $1,193 for aseptic meningitis.⁴

New findings about NPEV in ED patients

During the summer and fall, children with NPEV are often seen in the emergency department (ED) to rule out bacterial sepsis and meningitis since the symptoms of NPEV infections overlap with those of other pathogens, particularly bacteria. Distinguishing an NPEV infection from a bacterial infection can be difficult on clinical grounds alone, often leading to a laboratory workup and empiric antibiotic treatment. When Rotbart and colleagues studied children evaluated in the ED for serious febrile illnesses during one summer and fall, they found that 39% of children who were ill enough to have a blood culture or lumbar puncture had an NPEV infection. Among children without clear bacterial infection (urinary tract infection, for example), 46% had an NPEV infection.⁸

Symptoms and signs at presentation to the ED were similar among patients with, and those without, NPEV. As with outpatients, the most common presenting symptoms were fever, sore throat, and fussiness. Other symptoms seen often included lethargy, decreased appetite, vomiting, diarrhea, and rash.⁸ Characteristics of children seen in the ED who had an NPEV infection differed from those of children without an NPEV infection, however (Table 5). Patients with NPEV illness were younger than those without NPEV. Of patients infected with NPEV, 84% were younger than 3 months of age. Patients with NPEV also were more likely to have aseptic meningitis, be admitted to the hospital, and have antibiotics prescribed .⁸

TABLE 5
Comparison of ED patients with and without NPEV infection

New diagnostic tests for NPEVs

The benign forms of NPEV infection seen most often by the primary care physician do not usually warrant specific diagnosis. The more severe infections that lead to hospitalization, empiric use of antibiotics, and multiple diagnostic tests would, however, benefit from rapid diagnosis and more targeted treatment.⁹ The recent advent of specific therapy for NPEV infection requires rapid, accurate diagnosis to start appropriate treatment promptly. Three diagnostic methods are available to detect NPEV in patient samples: viral culture, serologic testing, and the polymerase chain reaction (PCR) assay.

Viral culture was the only diagnostic test for NPEV infection for many years. NPEVs can be cultured from the oropharynx, stool, blood, urine, CSF, and tissues in severe disease. The best viral samples are obtained from the oropharynx and stool. The viruses grow quickly in cell culture and can be identified in four to seven days. Results are not available to the clinician, however, in time to affect care. Viral culture does play an important role in serologic identification of NPEVs during an epidemic, however.

Serologic analysis is of limited clinical value because it is slow and requires acute and convalescent samples. It cannot be used to tailor treatment of NPEV infections.

The polymerase chain reaction assay can rapidly identify NPEV in patient samples and is ideal for diagnosing such infections. PCR assays are performed in the laboratories of university or community hospitals. Their availability varies from community to community. Results are available in less than 24 hours. The many different NPEVs share common genomic sequences—a fact that has been exploited to develop PCR-based assays that can now identify almost all NPEVs. The PCR can work on small clinical samples and is rapid, sensitive, and specific. Enterovirus PCR has been thoroughly studied with many different clinical samples and found superior to viral culture for diagnosing NPEV infection, especially aseptic meningitis.^10,11 Rapid diagnosis has been shown to decrease costs by shortening the hospital stay and reducing unnecessary use of antibiotics.^12,13

New treatments on the horizon

Until recently, specific treatments were not available for NPEV infection. The benign, self-limited illnesses are treated symptomatically, and patients usually recover uneventfully. It is patients with serious and sometimes fatal NPEV illness who stand to benefit from specific therapy.

Pleconaril is a new drug, not yet approved by the Food and Drug Administration, that interferes with NPEV attachment and uncoating by binding to the virus protein capsid. Pleconaril has broad antiviral effects on many NPEV serotypes. It is absorbed well from the gastrointestinal tract and has a long half-life, allowing oral dosing three times daily.¹⁴ Several studies show improvement in children, adolescents, and adults with NPEV meningitis after treatment with pleconaril.^15,16 They suggest that specific antiviral therapy for NPEV infections is effective, thereby establishing a new category of common viral infections that can be considered treatable. Pleconaril is also being studied in neonates with enteroviral sepsis.

The development of antibodies heralds the beginning of recovery from NPEV infection. This fact has led to the use of immunoglobulin to treat serious disease. Although immunoglobulin therapy has had some limited success, one study of newborns with severe NPEV infection demonstrated no clear benefit of immunoglobulin.¹⁷

Good news for patients

NPEV infections are commonly seen by primary care physicians. Their clinical manifestations are many and varied, and they cause a spectrum of disease ranging from asymptomatic to fatal. The development of rapid diagnostic tests and specific antiviral therapies heralds a new era in the care of patients with NPEV infections.

REFERENCES

1. Spigland I, Fox JP, Elveback LR, et al: The Virus Watch Program: A continuing surveillance of viral infections in metropolitan New York families: II. Laboratory methods and preliminary report on infections revealed by virus isolation. Am J Epidemiol 1966;83:413

2. Fox JP, Hall CE, Cooney MK, et al: The Seattle Virus Watch: II. Objectives, study population and its observation, data processing and summary of illnesses. Am J Epidemiol 1972;96:270

3. Strikas RA, Anderson LJ, Parker RA, et al: Temporal and geographic patterns of isolates of nonpolio enterovirus in the United States, 1970-1983. J Infect Dis 1986;153:346

4. Pichichero ME, McLinn S, Rotbart HA, et al: Clinical and economic impact of enterovirus illness in private pediatric practice. Pediatrics 1998;102:1126

5. Abzug MJ, Loeffelholz M, Rotbart HA: Diagnosis of neonatal enterovirus infection by polymerase chain reaction. J Pediatr 1995;126:447

6. Ho M, Chen ER, Hsu KH, et al: An epidemic of Enterovirus 71 infection in Taiwan. N Engl J Med 1999;341:929

7. Huang CC, Liu CC, Chang YC, et al: Neurologic complications in children with Enterovirus 71 infection. N Engl J Med 1999;341;936

8. Rotbart HA, McCracken GH Jr, Whitley RJ, et al: Clinical significance of enteroviruses in serious summer febrile illnesses of children. Pediatr Infect Dis J 1999;18:869

9. Ramers C, Billman G, Hartin M, et al: Impact of a diagnostic cerebrospinal fluid enterovirus polymerase chain reaction test on patient management. JAMA 2000;283:2680

10. Sawyer M: Enterovirus infections: Diagnosis and treatment. Pediatr Infect Dis J 1999;18:1033

11. Ahmed A, Brito F, Goto C, et al: Clinical utility of the polymerase chain reaction for diagnosis of enteroviral meningitis in infancy. J Pediatr 1997;131:393

12. Hamilton MS, Jackson MA, Abel D: Clinical utility of polymerase chain reaction testing for enteroviral meningitis. Pediatr Infect Dis J 1999;18:533

13. Nigrovic LE, Chiang VW: Cost analysis of enteroviral polymerase chain reaction in infants with fever and cerebrospinal fluid pleocytosis. Arch Pediatr Adolesc Med 2000;154:817

14. Kearns GL, Abdel-Rahman SM, James LP, et al: Single-dose pharmacokinetics of a pleconaril (VP63843) oral solution in children and adolescents. Antimicrob Agents Chemother 1999;43:634

15. Sawyer MH et al: Oral pleconaril reduces the duration and severity of enteroviral meningitis in children (Abstract 1012). Presented at the Pediatric Academic Societies' Annual Meeting, San Francisco, Calif, May 1-4, 1999

16. Shafran SD et al: Pleconaril is effective for enteroviral meningitis in adolescents and adults: A randomized placebo-controlled multicenter trial (Abstract 1904) in, 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Calif, 1999. Washington, D.C., American Society for Microbiology, 1999, p 436

17. Abzug MJ, Keyserling HL, Lee ML, et al: Neonatal enterovirus infection: Virology, serology, and effects of intravenous immune globulin. Clin Infect Dis 1995;20:1201

DR. CASEY is a partner in the Elmwood Pediatric Group, Rochester, N.Y., and clinical instructor, department of pediatrics, University of Rochester Medical Center.

DR. PICHICHERO is a partner in the Elmwood Pediatric Group, Rochester, N.Y., and professor of microbiology and immunology, pediatrics, and medicine, University of Rochester Medical Center.

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Jefferson Medical College of Thomas Jefferson University, as a member of the Consortium for Academic Continuing Medical Education, is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical education for physicians. All faculty/authors participating in continuing medical education activities sponsored by Jefferson Medical College are expected to disclose to the activity audience any real or apparent conflict(s) of interest related to the content of their article(s). Full disclosure of these relationships, if any, appears with the author affiliations at the beginning of the article.

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Jefferson Medical College designates this continuing medical educational activity for a maximum of one hour of Category 1 credit towards the Physician's Recognition Award (PRA) of the American Medical Association. Each physician should claim only those hours of credit that he/she actually spent in the educational activity.

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FACULTY DISCLOSURES

Jefferson Medical College, in accordance with accreditation requirements, asks the authors of CME articles to disclose any affiliations or financial interests they may have in any organization that may have an interest in any part of their article. The following information was received from the author of "Nonpolio enterovirus infections: A new era."

Janet Casey, MD, has nothing to disclose.

Michael E. Pichichero, MD, has nothing to disclose.

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Date of publication: June 2001
Title: "Nonpolio enterovirus infections: A new era"
Authors: Janet Casey, MD, and Michael E. Pichichero, MD
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Michael Pichichero, Janet Casey. CME: Nonpolio enterovirus infections: A new era.

Contemporary Pediatrics

2001;6:82.