Influenza is an acute respiratory disease of viral ...



Vinnytsya National Pirogov Memorial Medical University

Department of Children Infectious Diseases

“Approved”

at sub-faculty meeting

“_28_”_08 2012, protocol № 1

Head of Department

prof. _______I.I. Nezgoda

Study guide for practical work of students

Topic: “Meningococcal disease. Enteroviral infections (Poliomyelitis. Nonpolio Enteroviruses infections”.

Course V

English-speaking Students’ Medical Faculty

Duration of the class-180min

Composed by assoc. prof. L.M. Stanislavchuk

Vinnytsa 2012

Chapter 1. Meningococcal disease

I. The theme urgency.

The gram-negative diplococcus Neisseria meningitides is a major infectious cause of childhood death in developed countries. The mortality rate remains around 10%. Isolated meningococcal meningitis (5% mortality rate) has a better prognosis than meningococcal septicemia (10-40% mortality rate). Infection with N meningitides is highest in children aged 6 months to 2 years; these children have lost the maternal antibodies and have not yet developed mature humoral immunity.

II. Primary aims of the study.

To teach students major methods of meningococcal disease diagnosis and treatment.

A student should know:

1) Etiology of meningococcal disease.

2) Epidemiology of meningococcal disease.

3) Pathogenesis of meningococcal disease.

3) Classification and clinical manifestations of meningococcal disease.

4) Laboratory studies of meningococcal disease.

5) Complications of meningococcal disease.

6) Treatment of meningococcal disease.

7) Prevention.

A student should be able to:

1) Find out history

2) Interpret data of physical examination

3) Interpret data of laboratory studies

4) Formulate clinical diagnosis

5) Make differential diagnosis

6) Administer prehospital and in-patient treatment in meningococcal disease.

7) Prevention

III. Educative aims of the study.

To facilitate:

1) The formation of deontology concepts and practical skills related to patients with meningococcal disease.

2) To acquire the skills of psychological contact establishment and creation of trusting relations between the doctor and the patient and his parents.

3) The development of responsibility sense for timeliness and completeness of patient’s investigation.

IV. The contents of the theme.

Meningococcal disease, first described by Vieusseaux in 1805 as epidemic cerebrospinal fever, remains a significant health problem, particularly in the developing world. Although nasopharyngeal colonization rarely leads to disseminated disease, the fulminant, rapidly fatal course of meningococcemia is not soon forgotten.

ETIOLOGY.

Neisseria meningitidis is a gram-negative diplococcus that is often described as biscuit shaped. It is a common commensal organism of the human nasopharynx and has not been isolated from animal or environmental sources. The meningococcus is fastidious, and growth is facilitated in a moist environment at 35-37°C in an atmosphere of 5-10% carbon dioxide. It grows well on several enriched media, including supplemented chocolate agar. Mueller-Hinton agar, blood agar base, and trypticase soy agar. On solid media, colonies are transparent, nonpigmented, and nonhemolytic. N. meningitidis is identified by its ability to ferment glucose and maltose to acid and its inability to ferment sucrose or lactose. Indole and hydrogen sulfide are not formed. The cell wall contains cytochrome oxidase, which results in a positive oxidase test result.

The meningococci have been divided into serogroups based on antigenic differences in their capsular polysaccharides. Although 13 serogroups are currently recognized, groups A, B, C, W135, and Y account for most meningococcal disease. The other serogroups often colonize the nasopharynx but rarely disseminate. Lipooligosaccharides (e.g., endotoxin) and proteins found in the outer membrane complex are also used to serotype meningococcal strains.

EPIDEMIOLOGY.

Meningococcal dissemination occurs as endemic disease punctuated by outbreaks of cases that are often clustered geographically. True epidemics have become rare in developed countries but remain a significant problem in much of the developing world. Endemic disease appears to be caused by a heterogeneous group of meningococcal serotypes, and epidemics are caused by a single serotype. Analysis with multilocus enzyme genetic methods has confirmed that a meningococcal epidemic is caused by strains derived from a single clonotype.

The Centers for Disease Control (CDC) reported the results of a laboratory-based surveillance for meningococcal disease in a large United States population for the years 1989-1991. The average annual rate of invasive disease was 1.1/100,000 population, with an estimated 2,600 cases of meningococcal disease annually in the United States. The highest attack rates were during the winter and early spring months. Males accounted for 55% of the total cases, and 29% of the cases occurred in children younger than 1 yr, with the peak incidence of disease being 26/100,000 infants younger than 4 mo. Forty-six per cent of the cases occurred in children 2 yr of age or younger, and an additional 25% of the cases occurred in persons 30 yr of age or older. Serogroup B and serogroup C meningococci accounted for nearly equal proportions of disease (46% and 45%, respectively), but 69% of group C disease occurred in persons older than 2 yr. Fifty-eight per cent of the patients were reported to have meningitis. N. meningitidis was isolated from blood in 66% of cases, cerebrospinal fluid (CSF) in 51%, and joint fluid in 1%.

Subsequent data indicate that the proportion of cases caused by serogroup Y is increasing. The United States has also experienced an increased incidence of outbreaks of serogroup C disease. Eight outbreaks occurred during 1992-1993, and most of these outbreaks had attack rates exceeding 10 cases per 100,000 population.

Meningococcal disease, particularly group A, remains a major health problem in much of the developing world. Many areas, such as China and Africa, have an endemic rate of disease of 10-25/100,000 persons and major periodic epidemics (100-500/100,000). Epidemic disease typically involves individuals who are older than those with endemic disease.

PATHOGENESIS.

N. meningitidis is thought to be acquired by a respiratory route. Colonization of the nasopharynx with meningococci usually leads to asymptomatic carriage, and only rarely does dissemination occur. Colonization can persist for weeks to months. Carriage rates vary from 2-30% in a normal population during nonepidemic periods but are higher among children in daycare centers and in conditions of crowding. The carriage rate can approach 100% in a closed population during an epidemic.

Meningococcal nasopharyngeal colonization is facilitated by the secretion of proteases that cleave the proline-rich hinge region of secretory IgA and render it nonfunctional. Meningococci and gonococci produce this enzyme, but nonpathogenic Neisseria organisms do not. Meningococci then adhere selectively to nonciliated epithelial cells. Pili appear to be of major importance in the attachment of meningococci to the human nasopharynx. The bacteria enter nonciliated epithelial cells by endocytosis and are carried across the cell in membrane-bound vacuoles.

Meningococci disseminate from the upper respiratory tract through the bloodstream. Serum antibody leading to complement-mediated bacterial lysis has been shown to block this dissemination, and a deficiency of antimeningococcal antibody is associated with the development of meningococcemia. Bactericidal antibody is directed against the capsular polysaccharide, subcapsular protein, and lipooligosaccharide antigens. Newborn infants have protective antibody that is primarily IgG of maternal origin. As this antibody wanes, infants 3-24 mo of age experience the highest incidence of meningococcal disease. By adulthood, most individuals have developed natural immunity against N. meningitidis from nasopharyngeal colonization with N. meningitidis and colonization of the gastrointestinal tract with enteric bacteria that express cross-reactive antigens. Infants have a high carriage rate of an unencapsulated, nonpathogenic neisserial strain, N. lactamica, that leads to the development of bactericidal antibody against the meningococcus.

The importance of the complement system in host defense against N. meningitidis is underscored by the fact that individuals with primary or acquired complement deficiency have an increased risk of developing meningococcal disease, and 50-60% of individuals with properdin, factor D, or terminal-component deficiencies develop bacterial infections that are caused almost solely by N. meningitidis. Recurrent infection is common with terminal component deficiencies but is uncommon with properdin deficiency. Acquired complement deficiency also carries an increased risk and can be seen with systemic diseases that deplete serum complement. Examples are systemic lupus erythematosus, nephrotic syndrome, multiple myeloma, and hepatic failure.

The group B capsule is a homopolymer of sialic acid, which is known to inhibit alternative complement pathway activation. Antibody that activates the classic pathway can overcome this inhibition. The lack of specific antibody coupled with inhibition of the alternative pathway may explain the prevalence of serogroup B meningococcal disease in young children.

PATHOLOGY.

Disseminated meningococcal disease is associated with an acute inflammatory response. Hemorrhage and necrosis may be seen in any organ system and appear to be mediated by intravascular coagulation with deposition of fibrin in small vessels. The major organ systems involved in fatal cases of meningococcemia are the heart, central nervous system, skin, mucous and serous membranes, and adrenals. Myocarditis is found in more than 50% of patients who die of meningococcal disease. Cutaneous hemorrhages, ranging from petechiae to purpura, occur in most fatal infections and are associated with acute vasculitis with fibrin deposition in arterioles and capillaries. Diffuse adrenal hemorrhage may occur in patients with fulminant meningococcemia (i.e., Waterhouse-Friderichsen syndrome). Meningitis is characterized by acute inflammatory cells in the leptomeninges and perivascular spaces. Focal cerebral involvement is uncommon.

The interaction of endotoxin released by N. meningitidis and the complement system probably is key in the pathogenesis of the clinical manifestations of meningococcal disease. Complement activation correlates with the concentration of meningococcal lipooligosaccharide in the plasma. The concentration of circulating endotoxin is directly correlated with activation of the fibrinolytic system, development of disseminated intravascular coagulopathy (DIC), multiple organ system failure, septic shock, and death. The level of endotoxemia correlates with the concentration of circulating cytokines, which are released from endotoxin-stimulated monocytes and macrophages. The concentrations of tumor necrosis factor-alpha and interleukins have been directly associated with fatal meningococcal disease.

CLINICAL MANIFESTATIONS.

The spectrum of meningococcal disease can vary widely, from fever and occult bacteremia to sepsis, shock, and death. Recognized patterns of disease are bacteremia without sepsis, meningococcemic sepsis without meningitis, meningitis with or without meningococcemia, meningoencephalitis, and infection of specific organs.

A well-recognized entity is occult bacteremia in a febrile child. Upper respiratory or gastrointestinal symptoms or a maculopapular rash can be evident. The child often is sent home on no antibiotics or oral antibiotics for a minor infection. Spontaneous recovery without antibiotics has been reported, but some children have developed meningitis.

Acute meningococcemia initially can mimic a virus-like illness with pharyngitis, fever, myalgias, weakness, and headache. With widespread hematogenous dissemination, the disease rapidly progresses to septic shock characterized by hypotension, DIC, acidosis, adrenal hemorrhage, renal failure, myocardial failure, and coma. Meningitis may or may not develop. Concomitant pneumonia, myocarditis, purulent pericarditis, and septic arthritis have been described. More often, meningococcal disease is manifested as acute meningitis that responds to appropriate antibiotics and supportive therapy. Seizures and focal neurologic signs occur less frequently than in patients with meningitis caused by pneumococcus or Haemophilus influenzae type b. Rarely, meningoencephalitis can occur with diffuse brain involvement.

A review of 100 children with invasive meningococcal disease revealed that 71% presented with fever, 4% with hypothermia, and 42% with shock. Skin lesions occurred in 71% of the cases with petechiae and/or purpura and in 49% with both. Purpura fulminans developed in 16%. Other rashes described were maculopapular, pustular, and bullous lesions. Additional presenting symptoms and signs were irritability in 21%, lethargy in 30%, and emesis in 34%. Diarrhea, cough, rhinorrhea, seizure, and arthritis occurred much less frequently (6-10%). Leukopenia and low platelet counts affected 21% and 14%, respectively, and the white blood cell counts ranged from 900-46,000/mm3 . N. meningitidis was isolated in blood culture from 48% of the children, and meningitis was diagnosed in 55%. Six children had meningococci isolated from CSF in the absence of CSF pleocytosis, hypoglycorrhachia, or organisms detected by Gram stain. Five of eight children who presented with arthritis had N. meningitidis isolated from joint aspiration fluid. Eight per cent of the children had radiographic evidence of pneumonia on presentation.

Uncommon manifestations of meningococcal disease include endocarditis, purulent pericarditis, pneumonia, septic arthritis, endophthalmitis, mesenteric lymphodenitis, and osteomyelitis. Primary purulent conjunctivitis can lead to invasive disease. Sinusitis, otitis media, and periorbital cellulitis also can be caused by the meningococcus. Primary meningococcal pneumonia is associated with pleural effusions or empyema in 15% of cases. N. meningitidis is a rare isolate of the genitourinary tract in asymptomatic or symptomatic individuals and has been the causal organism in urethritis, cervicitis, vaginitis, and proctitis.

Chronic meningococcemia is a rare manifestation of meningococcal disease that can occur in children and adults. It is characterized by fever, nontoxic appearance, arthralgias, headache, and rash. The rash resembles that of disseminated gonococcal infection. Symptoms are intermittent, with the rash often appearing with fever. The mean duration of illness is 6-8 wk. Blood cultures may initially be sterile. Without specific therapy, complications such as meningitis can result.

DIAGNOSIS.

Definitive diagnosis of meningococcal disease is made by isolation of the organism from a usually sterile body fluid such as blood, CSF, or synovial fluid. Isolation of meningococci from the nasopharynx is not diagnostic for disseminated disease. Blood and CSF are the usual sources of organism isolation. The blood culture yields N. meningitidis in about half of the cases of disseminated disease, and culture or Gram stain usually reveals the organism in those with meningitis. Culture or Gram stain of petechial or papular lesions has been variably successful in identifying meningococci. Bacteria can occasionally be seen on Gram stain of the buffy coat layer of a spun blood sample.

In meningitis, the morphologic and clinical characteristics of CSF are those of acute bacterial meningitis. CSF cultures can be positive in patients with meningococcemia but without clinical evidence of meningitis or CSF pleocytosis. CSF cultures may be negative if the patient has received previous antibiotic treatment.

Particle agglutination using latex beads, which has replaced counterimmunoelectrophoresis, can detect meningococcal capsular polysaccharide in CSF, serum, joint fluid, or urine. This is especially useful when results are positive in the setting of partially treated infections with negative cultures. The available latex agglutination tests do not detect group B meningococcus, the most common cause of endemic meningococcal infections, and therefore have limited usefulness. Latex agglutination is not a substitute for proper Gram stain and culture techniques.

Other laboratory findings may include elevated sedimentation rate and C-reactive protein, leukocytopenia or leukocytosis, thrombocytopenia, proteinuria, and hematuria. Patients with DIC coagulation have decreased serum concentrations of prothrombin and fibrinogen.

Differential Diagnosis.

This includes acute bacterial or viral meningitis, Mycoplasma infection, leptospirosis, syphilis, acute hemorrhagic encephalitis, encephalopathies, serum sickness, collagen vascular diseases, Henoch-Schonlein purpura, hemolytic-uremic syndrome, and ingestion of various poisons. The petechial or purpuric rash of meningococcemia is similar to that in any patient with a disease characterized by generalized vasculitis. These diseases include septicemia due to many gram-negative organisms; overwhelming septicemia with gram-positive organisms; bacterial endocarditis; Rocky Mountain spotted fever; epidemic typhus; Ehrlichia canis infection; infections with echoviruses, particularly types 6, 9, and 16; coxsackievirus infections, predominantly of types A2, A4, A9, and A16; rubella; rubeola and atypical rubeola; Henoch-Schonlein purpura; Kawasaki's disease; idiopathic thrombocytopenia; and erythema multiforme or erythema nodosum due to drugs or infectious or noninfectious disease processes. The morbilliform rash occasionally observed may be confused with any macular or maculopapular viral exanthem.

TREATMENT.

Aqueous penicillin G is the drug of choice and should be given in doses of 250,000-300,000 U/kg/24 hr, administered intravenously in six divided doses. Cefotaxime (200 mg/kg/24 hr) and ceftriaxone (100 mg/kg/24 hr) are acceptable alternatives. Chloramphenicol sodium succinate (75-100 mg/kg/24 hr IV in four divided doses) provides effective treatment for patients who are allergic to beta-lactam antibiotics. Therapy is continued for 5-7 days.

Isolates of N. meningitidis have been reported from Spain, South Africa, and Canada as being relatively resistant to penicillin, defined as having a minimal inhibitory concentration of penicillin of 0.1-1.0 mu/mL. Moderate resistance is caused, at least in part, by altered penicillin-binding protein 2. High-level resistance due to beta-lactamase production has been reported from South Africa. The CDC estimated that about 4% of meningococcal disease in 1991 in the United States was caused by N. meningitidis strains that were relatively resistant to penicillin. None of the strains isolated produced beta-lactamase. The clinical significance of moderate penicillin resistance is unknown. The CDC decided that routine susceptibility testing of clinical meningococcal isolates is probably not indicated in the United States at this time, but continued surveillance is necessary.

Patients with acute meningococcal infections should be monitored carefully.

COMPLICATIONS.

Acute complications are related to the inflammatory changes, vasculitis, DIC, and hypotension of invasive meningococcal disease. These can include adrenal hemorrhage, arthritis, myocarditis, pneumonia, lung abscess, peritonitis, and renal infarcts. The vasculitis can lead to skin loss with secondary infection, tissue necrosis, and gangrene. Skin sloughing can necessitate the use of skin grafts. Bone involvement can lead to growth disturbance and late skeletal deformities secondary to epiphyseal avascular necrosis and epiphyseal-metaphyseal defects. Limb amputation has been reported for patients with purpura fulminans.

Meningitis rarely is complicated by subdural effusion or empyema or by brain abscess. Deafness is the most frequent neurologic sequela, but the reported incidence varies from 0-38%. Other rare sequelae include ataxia, seizures, blindness, cranial nerve palsies, hemiparesis or quadriparesis, and obstructive hydrocephalus.

The late complications of meningococcal disease are thought to be immune complex mediated and become apparent 4-9 days after the onset of illness. The usual manifestations are arthritis and cutaneous vasculitis. The arthritis is usually monarticular or oligoarticular. Effusions are usually sterile and respond to nonsteroidal anti-inflammatory agents. Permanent joint deformity is uncommon. Because most patients with meningococcal meningitis are afebrile by the 7th hospital day, the persistence or recrudescence of fever after 5 days of antibiotics warrants an evaluation for immune complex-mediated complications.

PROGNOSIS.

Despite the use of appropriate antibiotics, the mortality rate for disseminated meningococcal disease remains at 8-13% in the United States. Poor prognostic factors include hypothermia, hypotension, purpura fulminans, seizures or shock on presentation, leukopenia, thrombocytopenia, and high circulating levels of endotoxin and tumor necrosis factor. The presence of petechiae for less than 12 hr before admission, hyperpyrexia, and the absence of meningitis reflect rapid progression and poorer prognosis.

Screening for complement deficiency after resolution of the acute infection is recommended for individuals with meningococcal disease. In one series of 20 patients with a first episode of meningococcal meningitis, meningococcemia, or meningococcal pericarditis, three had a deficiency of a terminalpathway component and three had deficiencies of multiple complement components associated with underlying systemic diseases.

PREVENTION.

Close contacts of patients with meningococcal disease are at increased risk of infection and should be carefully monitored and brought to medical attention if fever develops. Prophylaxis is indicated as soon as possible for household, daycare, and nursery school contacts. Prophylaxis is also recommended for persons who have had contact with patients' oral secretions. Prophylaxis is not routinely recommended for medical personnel except those with intimate exposure, such as with mouth-to-mouth resuscitation, intubation, or suctioning before antibiotic therapy was begun. Rifampin is given (10 mg/kg; maximum dose, 600 mg) orally every 12 hr for 2 days (total of four doses). The dose is reduced to 5 mg/kg for infants younger than 1 mo. Other effective antimicrobial agents are ciprofloxacin (500 mg orally as a single dose for adults) and ceftriaxone as a single intramuscular dose (125 mg for children < 15 yr and 250 mg for adults). Penicillin does not eradicate nasopharyngeal carriage, and patients treated with penicillin should receive chemoprophylactic antibiotics before hospital discharge.

Vaccine.

A quadrivalent vaccine composed of capsular polysaccharide of meningococcal groups A, C, Y, and W135 is licensed in the United States. The vaccine is immunogenic in adults but is unreliable in children younger than 2 yr. The group B polysaccharide is poorly immunogenic in children and adults, and no vaccine is available against this serogroup. Routine immunization of the United States population is not recommended at this time, but the vaccine is routinely given to all American military recruits.

Immunization is useful to control outbreaks of meningococcal disease of the serogroups represented in the quadrivalent vaccine. It is also recommended for travelers to countries with a high incidence of meningococcal disease. Immunization of close contacts of individuals with A, C, Y, or W135 disease should be considered, because it has been useful in the prevention of secondary cases. Individuals with anatomic or functional asplenia and those with complement component deficiencies should be immunized.

Polysaccharide-protein conjugate vaccines are being developed for the prevention of meningococcal disease, and subcapsular proteins and detoxified lipooligosaccharides are being investigated as possible vaccines.

V. Sources of information.

Basic literature:

|№ |Author(s) |Name of the source |City, |Year of |Number of pages |

|№ | |(textbook, manual, monograph, etc) |Publish-ing house |edition, vol.,| |

| | | | |issue | |

|1 | Mikhailova A.M., Minkov | | Odessa | | |

| |I.P., Savchuk A.I. |Infection diseases in children | |2003 |124-131 |

| | | | | | |

|2 |E. Nikitin, | | | | |

| |M. Andreychin |Infectious diseases |Ukrmedkniga |2004 | |

Additional literature:

|№ |Author(s) |Name of the source |City, |Year of |Number of |

|№ | |(textbook, manual, monograph, etc) |Publishing house |edition, vol.,|pages |

| | | | |issue. | |

|1 |Robert M. Kliegman, MD, | |W.B.Saunders |2007, 18 th |826-829 |

| |Richard E. Behrman, MD, |Nelson Textbook of pediatrics |company |edition | |

| |Hal B. Jenson, MD and | | | | |

| |Bonita F. Stanton, MD | | | | |

Chapter 2. Enteroviral infections (Poliomyelitis. Nonpolio Enteroviruses infections)

The theme urgency.

Enteroviruses are a large group of viral agents that inhabit the intestinal tract and are responsible for significant and frequent human illnesses that produce protean clinical manifestations.

Enteroviruses are RNA viruses belonging to the Picornaviridae family. The original enteroviral subgroups-- Coxsackieviruses, echoviruses, and polioviruses--were differentiated by their effects in tissue culture and animal. Coxsackieviruses are named after the town of Coxsackie, New York, where they were first isolated in 1948, as nonpolio enteroviruses causing paralysis in children. Echoviruses (enteric cytopathogenic human orphan viruses) were not recognized initially to cause any disease in animals or humans. The Coxsackieviruses consist of two groups, A and B. Since 1970 new enteroviral types (68-72) have been classified by enteroviral numbers. Hepatitis A virus is classified as enterovirus 72 but is antigenically distinct from all other enteroviruses.

Enteroviruses retain activity for several days at room temperature and can be stored indefinitely at ordinary freezer temperatures (-20°C). They are rapidly inactivated by heat (>56°C), formaldehyde, chlorination, and ultraviolet light. Enteroviruses, except for most members of Coxsackie group A, grow well in many cell cultures and cause cytopathic effects that are different from those caused by herpesvirus, adenoviruses, and reoviruses. Coxsackie A viruses are identified by their pathologic effects in suckling mice.

Chapter 2.1 Poliomyelitis

I. Primary aims of the study.

To teach students major methods of poliomyelitis diagnosis and treatment.

A student should know:

1) Etiology of poliomyelitis.

2) Epidemiology of poliomyelitis.

3) Pathogenesis of poliomyelitis.

4) Laboratory studies of poliomyelitis.

5) Classification and clinical manifestations of poliomyelitis.

6) Treatment of poliomyelitis.

7) Prevention.

A student should be able to:

1) Find out history

2) Interpret data of physical examination

3) Interpret data of laboratory studies

4) Formulate clinical diagnosis

5) Make differential diagnosis

6) Administer treatment in poliomyelitis.

7) Prevention

II. Educative aims of the study.

To facilitate:

1) The formation of deontology concepts and practical skills related to patients with poliomyelitis.

2) To acquire the skills of psychological contact establishment and creation of trusting relations between the doctor and the patient and his parents.

3) The development of responsibility sense for timeliness and completeness of patient’s investigation.

III. The contents of the theme.

ETIOLOGY.

There are three antigenically distinct serotypes of poliovirus (types 1, 2, and 3).

EPIDEMIOLOGY.

In 1952 there were more than 57,879 cases of polio in the United States, including 21,269 cases of paralytic polio that resulted in more than 3,000 deaths. The use of poliovirus vaccine has eliminated, since 1979, wild poliovirus in the United States. The last case of wild poliovirus in the Americas occurred in Peru, in 1991. In 1994 the World Health Organization declared that polio had been eradicated from the Western hemisphere.

However, poliomyelitis still occurs in many regions of the developing world. In countries where vaccines are not available and economic conditions are poor, poliomyelitis remains a significant disease of infants and young children, with several thousand cases annually worldwide. A changing epidemiologic pattern is emerging in some underdeveloped countries as economic standards improve. Significant outbreaks occasionally occur in these countries where paralytic poliomyelitis had become rare.

From 1980 to 1994, 133 cases of paralytic poliomyelitis were reported in the United States. Of these, 125 cases were associated with oral poliovirus vaccine, six cases were imported, and two cases were indeterminate. Approximately four to eight cases of vaccine-associated paralytic poliomyelitis (VAPP) occur annually in the United States.

PATHOGENESIS.

The neuropathy of poliomyelitis and other paralytic diseases caused by nonpolio enteroviruses is due to direct cellular destruction. Secondary damage may be due to immunologic mechanisms. In poliomyelitis, neuronal lesions occur in the (1) spinal cord (chiefly in the anterior horn cells and to a lesser degree in the intermediate and dorsal horn and dorsal root ganglia); (2) medulla (vestibular nuclei, cranial nerve nuclei, and the reticular formation, which contains the vital centers controlling respiration and circulation); (3) cerebellum (nuclei in the roof and vermis only); (4) midbrain (chiefly the gray matter but also the substantia nigra and occasionally the red nucleus); (5) thalamus and hypothalamus; (6) pallidum; and (7) cerebral cortex (motor cortex). Areas that are spared include (1) the entire cerebral cortex except the motor area; (2) the cerebellum except the vermis and deep midline nuclei; and (3) the white matter of the spinal cord.

Infants acquire immunity transplacentally from their mothers. This immunity is usually complete during the first 4-6mo of life and disappears at a variable rate. Active immunity, after natural infection, probably lasts for life. Neutralizing antibodies against polioviruses develop within several days after exposure, often before the onset of illness. The early production of immunoglobulin (Ig) G antibodies is a result of replication of the virus in the intestinal tract and deep lymphatic tissues, which occurs before the central nervous system is invaded. Local (mucosal) immunity, conferred mainly by secretory IgA, is an important defense against polioviral infection.

CLINICAL MANIFESTATIONS.

Poliovirus infections may follow one of several courses: inapparent infection, which occurs in 90-95% of cases and causes no disease and no sequelae, abortive poliomyelitis, nonparalytic poliomyelitis, or paralytic poliomyelitis.

Abortive Poliomyelitis.

Abortive poliomyelitis is a brief febrile illness with one or more symptoms of malaise, anorexia, nausea, vomiting, headache, sore throat, constipation, and diffuse abdominal pain. Coryza, cough, pharyngeal exudate, diarrhea, and localized abdominal tenderness and rigidity are uncommon. The fever seldom exceeds 39.5°C (103°F), and the pharynx appears normal despite the frequent complaint of sore throat.

Nonparalytic Poliomyelitis.

The symptoms in this form of poliovirus infection are the same as those enumerated for abortive poliomyelitis except that headache, nausea, and vomiting are more intense, and there is soreness and stiffness of the posterior muscles of the neck, trunk, and limbs. Fleeting paralysis of the bladder is not uncommon, and constipation is frequent. Approximately two thirds of these children have a short symptom-free interlude between the first phase (minor illness) and the second phase (central nervous system disease or major illness). This two-phase course is less common in adults, in whom the evolution of symptoms is more insidious. Nuchal and spinal rigidity are the basis for the diagnosis of nonparalytic poliomyelitis during the second phase.

Physical examination reveals nuchal-spinal signs and changes in superficial and deep reflexes. In cooperative patients the nuchal-spinal signs are first sought by active tests. The child is asked to sit up unassisted. If this causes undue effort and if the knees flex upward and the patient writhes a bit from side to side in sitting up and uses the hands on the bed to assume the tripod supporting position, there is unmistakable spinal rigidity. Still sitting, the patient is asked to flex the chin to the chest and is observed for nuchal rigidity. Alternatively, in the supine position, with the knees held down gently, the patient is asked to sit up and kiss his or her knees.

If the knees draw up sharply or if the maneuver cannot be adequately completed, there is stiffness of the spine as a result of muscle spasm. If the diagnosis is still uncertain, attempts should be made to elicit the Kerning and Brudzinski signs. Gentle forward flexion of the occiput and neck will elicit nuchal rigidity, which may precede spinal rigidity. Head drop may be demonstrated by placing the hands under the patient's shoulders and raising the trunk. Normally the head follows the plane of the trunk, but in poliomyelitis it often falls backward limply. The head-drop sign is not due to true paresis of the neck flexors. In struggling infants it may be difficult to distinguish voluntary resistance from clinically important involuntary nuchal rigidity. One may place the infant's shoulders flush with the edge of the table, support the weight of the occiput in the hand, and then flex the head anteriorly. Nuchal rigidity that persists during this maneuver may be interpreted as involuntary. When not closed, the anterior fontanel may be tense or bulging as in meningitis.

In the early stages the reflexes are normally active and remain so unless paralysis supervenes. Changes in reflexes, either an increase or depression, may precede weakness by 12-24hr; hence, it is important to detect them, especially in nonparalytic patients managed at home. The superficial reflexes, that is, the cremasteric and abdominal reflexes and the reflexes of the spinal and gluteal muscles, are usually the first to be diminished. The spinal and gluteal reflexes may disappear before the abdominal and cremasteric ones do. Changes in the deep tendon reflexes generally occur 8-24hr after the superficial reflexes are depressed and indicate impending paresis of the extremities. Tendon reflexes are absent with paralysis. Sensory defects do not occur in poliomyelitis.

Paralytic Poliomyelitis.

The manifestations are those enumerated for nonparalytic poliomyelitis plus weakness of one or more muscle groups, either skeletal or cranial. These symptoms may be followed by a symptom-free interlude of several days and then a recurrence of disease culminating in paralysis. Bladder paralysis lasting 1-3 days occurs in approximately 20% of patients, and bowel atony is common, occasionally to the point of paralytic ileus. In some patients muscular paralysis may be the initial presentation.

Flaccid paralysis is the most obvious clinical expression of the neuronal injury. The ensuing muscular atrophy is due to denervation plus the atrophy of disuse. The pain, spasticity, nuchal and spinal rigidity, and hypertonia early in the illness are probably due to lesions of the brain stem, spinal ganglia, and posterior columns. Respiratory and cardiac arrhythmias, blood pressure and vasomotor changes, and the like reflect damage to the vital centers in the medulla.

On physical examination the distribution of paralysis is characteristically spotty. To detect mild muscular weakness, it is often necessary to apply gentle resistance in opposition to the muscle group being tested. In the spinal form there is weakness of some of the muscles of the neck, abdomen, trunk, diaphragm, thorax, or extremities. In the bulbar form there is weakness in the motor distribution of one or more cranial nerves with or without dysfunction of the vital centers controlling respiration and circulation. Components of both the preceding forms occur together in bulbospinal poliomyelitis. In the encephalitic form irritability, disorientation, drowsiness, and coarse tremors not explained by inadequate ventilation are noted; peripheral or cranial nerve paralysis coexists or ensues. Hypoxia and hypercapnia caused by inadequate ventilation due to respiratory insufficiency may produce disorientation without true encephalitis.

A number of components acting together may produce insufficiency of ventilation, resulting in hypoxia and hypercapnia, which may produce profound effects on many other systems. Because respiratory insufficiency may develop rapidly, continued clinical evaluation is essential. Despite weakness of the respiratory muscles, the patient may respond with so much respiratory effort (associated with anxiety and fear) that overventilation may occur at the outset, resulting in respiratory alkalosis. Such effort is fatiguing and soon leads to respiratory failure.

There are certain characteristic patterns of disease. Pure spinal poliomyelitis with respiratory insufficiency involves tightness, weakness, or paralysis of the respiratory muscles (chiefly the diaphragm and intercostals) without discernible clinical involvement of the cranial nerves or vital centers that control respiration, circulation, and body temperature. The cervical and thoracic spinal cord segments are chiefly affected. Pure bulbar poliomyelitis involves paralysis of the motor cranial nerve nuclei with or without involvement of the vital centers. Involvement of the 9th, 10th, and 12th cranial nerves results in paralysis of the pharynx, tongue, and larynx with consequent airway obstruction. Bulbospinal poliomyelitis with respiratory insufficiency affects the respiratory muscles and results in coexisting bulbar paralysis.

The clinical findings associated with involvement of the respiratory muscles include (1) anxious expression; (2) inability to speak without frequent pauses, resulting in short, jerky, "breathless" sentences; (3) increased respiratory rate; (4) movement of the alae nasi and of the accessory muscles of respiration; (5) inability to cough or sniff with full depth; (6) paradoxical abdominal movements caused by diaphragmatic immobility due to spasm or weakness of one or both leaves; (7) relative immobility of the intercostal spaces, which may be segmental, unilateral, or bilateral. When the arms are weak, and especially when deltoid paralysis occurs, there may be impending respiratory paralysis because the phrenic nerve nuclei are in adjacent areas of the spinal cord. Observation of the patient's capacity for thoracic breathing while the abdominal muscles are splinted manually indicates minor degrees of paresis. Light manual splinting of the thoracic cage will help to assess the effectiveness of diaphragmatic movement.

The clinical findings seen with bulbar poliomyelitis with respiratory difficulty (other than paralysis of extraocular, facial, and masticatory muscles) include (1) nasal twang to the voice or cry caused by palatal and pharyngeal weakness (hard-consonant words such as "cookie" or "candy" bring this out best); (2) inability to swallow smoothly, resulting in accumulation of saliva in the pharynx, indicates partial immobility (holding the larynx lightly and asking the patient to swallow will confirm such immobility); (3) accumulated pharyngeal secretions, which may cause irregular respirations because each inspiration must be "planned" to avoid aspirating; the respirations may thus appear interrupted and abnormal even to the point of falsely simulating intercostal or diaphragmatic weakness; (4) absence of effective coughing, shown by constant fatiguing efforts to clear the throat; (5) nasal regurgitation of saliva and fluids as a result of palatal paralysis, with inability to separate the oropharynx from the nasopharynx during swallowing; (6) deviation of the palate, uvula, or tongue; (7) involvement of vital centers in the medulla, which are manifested by irregularities in rate, depth, and rhythm of respiration; by cardiovascular alterations including blood pressure changes (especially increased blood pressure), alternate flushing and mottling of the skin, and cardiac arrhythmias; and by rapid changes in body temperature; (8) paralysis of one or both vocal cords, causing hoarseness, aphonia, and ultimately asphyxia unless this is recognized by laryngoscopy and managed by immediate tracheostomy; and (9) the "rope sign," an acute angulation between the chin and larynx caused by weakness of the hyoid muscles (the hyoid bone is pulled posteriorly, narrowing the hypopharyngeal inlet).

DIAGNOSIS.

Poliomyelitis should be considered in any unimmunized or incompletely immunized child with nonspecific febrile illness, aseptic meningitis, or paralytic disease. The combination of fever, headache, neck and back pain, asymmetric flaccid paralysis without sensory loss, and pleocytosis is not regularly seen in any other illness.

The cerebrospinal fluid, while often normal during the minor illness, demonstrates a pleocytosis between 20-300 cells/mm3 with central nervous system involvement; the cells may be polymorphonuclear early in the disease but shift to mononuclear cells soon afterward. By the second week of the major illness, the total WBC count falls to near-normal values. In contrast, the cerebrospinal fluid protein is normal or only slightly elevated at the outset of central nervous system disease but usually rises to between 50-100mg/dL by the second week of illness.

Serologic testing demonstrates seroconversion or a fourfold or greater increase in antibody titers. Poliovirus is easily cultured from the stool and nasopharynx and infrequently from the cerebrospinal fluid. Isolates should be submitted to the Centers for Disease Control and Prevention for DNA sequence analysis, which can distinguish wild poliovirus from the strains used in the oral poliovirus vaccine.

Differential Diagnosis.

Several other conditions of muscular weakness should be considered. Guillain-Barre syndrome is the most common disease and the most difficult to distinguish from poliomyelitis. Paralysis is characteristically symmetric, and sensory changes and pyramidal tract signs are common in Guillain-Barre syndrome absent in poliomyelitis. Fever, headache, and meningeal signs are less notable, and there are few cells but an elevated protein level in the cerebrospinal fluid. Peripheral neuritis may be due to lead toxicity, cranial nerve herpes zoster, or postdiphtheritic neuropathy. Arthropod-borne viral encephalitis, rabies, and tetanus have been confused with bulbar poliomyelitis. Botulism may closely simulate bulbar poliomyelitis, but nuchal-spinal rigidity and pleocytosis are absent. Demyelinating types of encephalomyelitis are associated with or follow the exanthems and other infections or occur as an untoward sequel of antirabies vaccination. Neoplasms originating in and around the spinal cord rarely have a fairly abrupt onset. Familial periodic paralysis, myasthenia gravis, and acute porphyria are uncommon causes of muscle weakness. Hysteria and malingering are rare in children.

Conditions causing pseudoparalysis do not present with nuchal-spinal rigidity or pleocytosis. These causes include unrecognized trauma, transient (toxic) synovitis, acute osteomyelitis, acute rheumatic fever, scurvy, and congenital syphilis (pseudoparalysis of Parrot).

TREATMENT.

The broad principles of management are to allay fear, to minimize ensuing skeletal deformities, to anticipate and meet complications that may occur in addition to the neuromusculoskeletal problems, and to prepare the child and family for the prolonged treatment that may be required and for permanent disability if this seems likely. Patients with the nonparalytic and mildly paralytic forms of poliomyelitis may be treated at home.

Abortive Poliomyelitis.

Supportive treatment with analgesics, sedatives, an attractive diet, and bed rest until the child's temperature is normal for several days is usually sufficient. Avoidance of exertion for the ensuing 2wk is desirable, and there should be a careful neuromusculoskeletal examination 2mo later to detect any minor involvement.

Nonparalytic Poliomyelitis.

Treatment for the nonparalytic form is similar to that for the abortive form; in particular, relief is indicated for the discomfort of muscle tightness and spasm of the neck, trunk, and extremities. Analgesics are more effective when they are combined with the application of hot packs for 15-30min every 2-4hr. Hot tub baths are sometimes useful. A firm bed is desirable and can be improvised at home by placing table leaves or a sheet of plywood beneath the mattress. A footboard should be used to keep the feet at a right angle to the legs. Because muscular discomfort and spasm may continue for some weeks, even in the nonparalytic form, hot packs and gentle physical therapy may be necessary. Such patients should also be carefully examined 2mo after apparent recovery to detect minor residual effects that might cause postural problems in later years.

Paralytic Poliomyelitis.

Most patients with the paralytic form require hospitalization. A calm atmosphere is desirable. Suitable body alignment is necessary to avoid excessive skeletal deformity. A neutral position with the feet at a right angle to the legs, knees slightly flexed, and hips and spine straight is achieved by use of boards, sandbags, and, occasionally, light splint shells. Active and passive motions are indicated as soon as the pain has disappeared. Opiates and sedatives are permissible only if no impairment of ventilation is present or impending. Constipation is common, and fecal impaction should be prevented. When bladder paralysis occurs, a parasympathetic stimulant such as bethanechol (5-10mg orally or 2.5-5.0mg subcutaneously) may induce voiding in 15-30min; some patients do not respond, and others respond with nausea, vomiting, and palpitations. Bladder paresis rarely lasts more than a few days. If bethanechol fails, manual compression of the bladder and the psychologic effect of running water should be tried. If catheterization must be performed, care must be taken to prevent urinary tract infections. An appealing diet and a relatively high fluid intake should be started at once unless the patient is vomiting. Additional salt should be provided if the environmental temperature is high or if the application of hot packs induces sweating. Anorexia is common initially. Adequate dietary and fluid intake can be maintained by placement of a central venous catheter. An orthopedist and a physiatrist should see these patients as early in the course of the illness as possible and should assume responsibility for their care before fixed deformities develop.

The management of pure bulbar poliomyelitis consists of maintaining the airway and avoiding all risk of inhalation of saliva, food, or vomitus. Gravity drainage of accumulated secretions is favored by using the head-low (foot of bed elevated 20-25 degrees) prone position with the face to one side. Aspirators with rigid or semirigid tips are preferred for direct oral and pharyngeal aspiration, and soft, flexible catheters may be used for nasopharyngeal aspiration. Fluid and electrolyte equilibrium is best maintained by intravenous infusion because tube or oral feeding in the first few days may incite vomiting. In addition to close observation for respiratory insufficiency, the blood pressure should be taken at least twice daily because hypertensionis not uncommon and occasionally leads to hypertensive encephalopathy. Patients with pure bulbar poliomyelitis may require tracheostomy because of vocal cord paralysis or constriction of the hypopharynx; most patients who recover have little residual impairment, although some exhibit mild dysphagia and occasional vocal fatigue with slurring of speech.

Impaired ventilation must be recognized early; mounting anxiety, restlessness, and fatigue are early indications for preemptive intervention. Tracheostomy is indicated for some patients with pure bulbar poliomyelitis, spinal respiratory muscle paralysis, and bulbospinal paralysis because these patients are generally unable to cough, sometimes for many months. Mechanical respirators are often needed.

COMPLICATIONS.

Paralytic poliomyelitis may be associated with numerous complications. Melena severe enough to require transfusion may result from single or multiple superficial intestinal erosions; perforation is rare. Acute gastric dilatation may occur abruptly during the acute or convalescent stage, causing further respiratory embarrassment; immediate gastric aspiration and external application of ice bags are indicated. Mild hypertension of a few days or weeks duration is common in the acute stage, probably related to lesions of the vasoregulatory centers in the medulla and especially to underventilation. In the later stages, because of immobilization, hypertension may occur along with hypercalcemia, nephrocalcinosis, and vascular lesions. Dimness of vision, headache, and a lightheaded feeling associated with hypertension should be regarded as premonitory of a frank convulsion. Cardiac irregularities are uncommon, but electrocardiographic abnormalities suggesting myocarditis are not rare. Acute pulmonary edema occurs occasionally, particularly in patients with arterial hypertension. Pulmonary embolism is uncommon despite the immobilization. Skeletal decalcification begins soon after immobilization and results in hypercalciuria, which in turn predisposes the patient to urinary calculi, especially when urinary stasis and infection are present. A high fluid intake is the only effective prophylactic measure. The patient should be mobilized as much and as early as possible.

PROGNOSIS.

Mortality in poliomyelitis epidemics in the United States prior to vaccine use was 5-7%. Most deaths occur within the first 2wk after onset. Mortality and the degree of disability are greater after the age of puberty. In general, the more extensive the paralysis in the first 10 days of illness, the more severe is the ultimate disability. Unexpected improvement may appear soon after defervescence and again about 6wk after onset, a time that corresponds to functional restoration of temporarily inactive neurons. The degree of functional recovery also depends upon the adequacy and promptness of supportive therapy: proper body positioning, active motion, use of assistive devices, and, of great importance, the psychologic motivation of the patient to return to as full and normal a life as possible.

Postpolio Syndrome.

After an interval of 30-40yr, as many as 30-40% of persons who survived paralytic poliomyelitis in childhood may experience muscle pain and exacerbation of existing weakness, or they may develop new weakness or paralysis. This entity, which is referred to as postpolio syndrome, has been reported only in persons who were infected in the era of wild poliovirus circulation. Risk factors for postpolio syndrome include increasing length of time since acute poliovirus infection, presence of permanent residual impairment after recovery from acute illness, and female sex.

PREVENTION.

Vaccination is the only effective method of preventing poliomyelitis. Hygienic measures help limit the spread of the infection among young children, but immunization is necessary to control transmission among all age groups. Both the inactivated polio vaccine (IPV), which is currently produced using improved methods compared to the original vaccine and is sometimes referred to as enhanced IPV, and the live, attenuated, orally administered polio vaccine (OPV) have established efficacy in preventing poliovirus infection and paralytic poliomyelitis. Both vaccines induce production of antibodies against the three strains of poliovirus. IPV elicits higher serum immunoglobulin (Ig)G antibody titers, but OPV also induces significantly greater mucosal IgA immunity in the oropharynx and gastrointestinal tract that limits replication of the wild poliovirus at these sites. Transmission of wild poliovirus by fecal spread is limited in OPV recipients. The immunogenicity of IPV is not affected by the presence of maternal antibodies.

IPV has no adverse effects. Live vaccine may undergo reversion to neurovirulence as it multiplies in the human intestinal tract and may cause vaccine-associated paralytic poliomyelitis (VAPP) in vaccinees or in their contacts. This risk is very low, but since 1979 VAPP accounts for all of the four to eight cases of paralytic poliomyelitis that have occurred annually in the United States. The overall risk of VAPP is low (1 case/2.4million doses) but is higher after the first dose for children (1/750,000 first doses) and for all first-dose recipients (1/1.2 million first doses). Based on doses distributed, the overall risk for recipients is 1 case/6.2million doses.

Many countries rely on OPV, whereas Sweden, Finland, and Holland use only IPV as the standard vaccine preparation. IPV and OPV are used in a combined regimen in Denmark and Israel.

In the United States, the Centers for Disease Control and the American Academy of Pediatrics in 1999 revised poliomyelitis vaccine recommendations to increase reliance on IPV. The relative benefits of OPV on the United States population have diminished because of the elimination of wild poliovirus in the Western hemisphere and the reduced threat of poliovirus importation into the United States. Thus, the risk of vaccine-associated poliomyelitis caused by OPV is now judged less acceptable. A transition policy has been implemented that will increase the use of IPV and decrease the use of OPV; recommendation of an IPV-only immunization schedule for children is anticipated by 2001.

As of January, 2000, the IPV-only schedule is recommended for routine polio vaccination in the United States. All children should receive four doses of IPV at 2 mo, 4 mo, 6-18 mo, and 4-6 yr of age. OPV should be used only for (1) mass vaccination campaigns to control outbreaks; (2) unvaccinated children who will be traveling within 4 wk to areas where polio is endemic; and (3) children of parents who do not accept the recommended number of vaccine injections; these children may receive OPV only for the third or fourth dose or both. Health care providers should administer OPV only after discussing the risk of VAPP with parents or caregivers. OPV is contraindicated for use in immunocompromised persons as well as in all their household contacts, because of the risk of VAPP; these persons should receive only IPV. OPV remains the vaccine of choice in countries where polio is endemic.

IV. Sources of information.

Basic literature:

|№ |Author(s) |Name of the source |City, |Year of |Number of pages |

|№ | |(textbook, manual, monograph, etc) |Publish-ing house |edition, vol.,| |

| | | | |issue | |

|1 | Mikhailova A.M., Minkov | | Odessa | | |

| |I.P., Savchuk A.I. |Infection diseases in children | |2003 |114-123 |

| | | | | | |

|2 |E. Nikitin, | | | | |

| |M. Andreychin |Infectious diseases |Ukrmedkniga |2004 |7-77 |

Additional literature:

|№ |Author(s) |Name of the source |City, |Year of |Number of |

|№ | |(textbook, manual, monograph, etc) |Publishing house |edition, vol.,|pages |

| | | | |issue. | |

|1 |Robert M. Kliegman, MD, | |W.B.Saunders |2000, 18 th |956-959 |

| |Richard E. Behrman, MD, |Nelson Textbook of pediatrics |company |edition | |

| |Hal B. Jenson, MD and | | | | |

| |Bonita F. Stanton, MD | | | | |

Chapter 2.2 Nonpolio Enteroviruses infections

I. Primary aims of the study.

To teach students major methods of enteroviruses infections diagnosis and treatment.

A student should know:

1) Etiology of enteroviruses infections.

2) Epidemiology of enteroviruses infections.

3) Pathogenesis of enteroviruses infections.

4) Classification and clinical manifestations of enteroviruses infections.

5) Laboratory studies of enteroviruses infections.

6) Treatment of enteroviruses infections.

7) Prevention.

A student should be able to:

1) Find out history

2) Interpret data of physical examination

3) Interpret data of laboratory studies

4) Formulate clinical diagnosis

5) Make differential diagnosis

6) Administer treatment in enteroviruses infections

7) Prevention

II. Educative aims of the study.

To facilitate:

1) The formation of deontology concepts and practical skills related to patients with enteroviruses infections.

2) To acquire the skills of psychological contact establishment and creation of trusting relations between the doctor and the patient and his parents.

4) The development of responsibility sense for timeliness and completeness of patient’s investigation.

III. The contents of the theme.

EPIDEMIOLOGY.

Humans are the only known reservoir for the human enteroviruses. Viruses related to human enteroviruses have been isolated from dogs and cats, but there is no evidence of spread from animals to humans. These viruses are spread from person to person by fecal-oral and possibly oral-oral (respiratory) routes. The enteroviruses infect the human gastrointestinal tract, but they do not colonize it. Even during the season of greater prevalence, very few strains circulate, probably as a result of interference among the virus types.

Children are immunologically susceptible, and their unhygienic habits facilitate spread. Transmission occurs from child to child (via feces to skin to mouth) and then within family groups. Even when an enterovirus is spreading through a community, it is often confined to households with young children. Rapid and extensive spread occurs in other similar environments such as summer camps and day-care centers. Recovery of enteroviruses is inversely related to age, and prevalence of specific antibodies is directly related to age. The incidence of infections and the prevalence of antibodies do not differ between boys and girls, but significant disease is more common in boys. Enteroviruses are often isolated from sewage and survive for up to 6mo in wet soil, but person-to-person spread is the primary mode of transmission. Environmental contamination is probably the result rather than the cause of human infection.

Enteroviruses have a worldwide distribution. In tropical and semitropical areas, they are found year round. In temperate climates, they are detected during winter and spring but are more common during summer and fall, with peaks from August to October. Winter outbreaks are rare. Infection and acquisition of postinfection immunity occur with greater frequency and at earlier ages in crowded, economically deprived populations. Under such conditions, the incidence of infection with one or more enterovirus serotypes may exceed 50%; mixed infections are common.

Although there are 68 identified enteroviruses, most illness in the United States is due to about a dozen nonpolio enteroviral types. Recently, the most prevalent types have been echoviruses 4, 6, 9, 11, and 30, Coxsackieviruses A9, A16, and B2-B5, and enteroviruses 70 and 71.

PATHOGENESIS.

Following the acquisition of virus by the oral or respiratory route, initial viral replication occurs in the pharynx and the lower gastrointestinal tract. Cell surface macromolecules serve as virus receptors in the gastrointestinal tract for several enteroviruses: poliovirus receptor (PVR) and integrin (VLA-2) for echoviruses 1 and 8; decay accelerating factor (DAF, CD55) for echovirus 7 and Coxsackie B viruses. Virus receptors for enteroviruses appear to be expressed on both the apical and the basolateral surfaces of intestinal epithelial cells.

The environmental conditions of the gastrointestinal tract, low pH, the presence of proteolytic enzymes, and bile salts favor the viability and local infection of certain viruses over some others. The detergent-like action of bile salts is especially detrimental to enveloped viruses and explains the fact that intestinal infections are mainly due to nonenveloped viruses (e.g., enteroviruses and rotaviruses). Two or more enteroviruses may invade and replicate at the same time in the gastrointestinal tract, but replication of one type often interferes with the growth of the heterologous type. Interference has been documented between echovirus, Coxsackievirus, and poliovirus, including vaccine strains. Within 1 day the infection extends to the regional lymph nodes. On about the third day minor viremia occurs, involving many secondary sites. Multiplication of virus in these sites coincides with the onset of clinical symptoms. Illness can vary from minor to fatal infections. Major viremia occurs during the period of multiplication of virus in the secondary sites and usually lasts from the 3rd to the 7th day of infection. In many enteroviral infections central nervous system involvement occurs at the same time as other secondary organ involvement, but the occasional delay in appearance of central nervous system symptoms suggests that seeding occurred later in association with the major viremia or by another pathway such as autonomic nerve fibers. Cessation of viremia correlates with the appearance of serum antibody. The viral concentration in secondary sites begins to diminish on about the 7th day. However, infection continues in the lower intestinal tract for prolonged periods.

Enteroviruses have been detected in some cases of myopericarditis. The pathogenesis of enterovirus-associated nephritis, myositis, polyradiculitis, pancreatitis, hepatitis, pneumonitis, and other syndromes is unclear; these disorders may be due to the inflammatory response to viral antigens or to virus-induced tissue damage. Enteroviral RNA sequences have been demonstrated in cardiac tissues from patients with cardiomyopathies, but a causal relationship has not been established. Some peptide sequences that constitute viral epitopes are shared by host tissues, which may provide a mechanism for autoimmune reactions in enteroviral infection.

Certain viral infections, most notably Coxsackievirus B and other enterovirus infections, have been implicated in the pathogenesis of childhood (insulin-dependent) diabetes mellitus. These viruses can induce beta cell damage in mice, but their causal role remains undefined. There is no conclusive evidence to support an association of enteroviral infection with chronic fatigue syndrome.

Neutralizing antibodies against enteroviruses form within several days after exposure, often before the onset of illness. This early production of IgG antibodies is a result of replication of the virus in the intestinal tract and deep lymphatic tissues, which occurs before the target organs, such as the central nervous system, are invaded. Mucosal immunity, conferred mainly by secretory immunoglobulin IgA, is an important defense against enteroviral infection, mediating protection against intestinal reinfection after recovery from natural infection.

CLINICAL MANIFESTATIONS.

Coxsackieviral and echoviral infections are exceedingly common, and their spectrum of disease is protean. Because many of the clinical-virologic associations are based on a limited number of cases and because enteroviruses are frequently carried asymptomatically in the gastrointestinal tract for relatively long periods of time, some of the observed illnesses and coincidentally recovered viruses may represent a causal relationship. However, repeated observations have confirmed many virus-illness associations, even though their occurrence has been sporadic. More than 90% of infections caused by nonpolio enteroviruses are asymptomatic or result in undifferentiated febrile illnesses. Some clinical syndromes are highly but not exclusively associated with certain serotypes.

Asymptomatic Infection.

Coxsackieviruses and echoviruses are frequently recovered from the stools of healthy children, but there are few data on the rate of asymptomatic infection with nonpolio enteroviruses. The isolation of enteroviruses from the stool cannot be equated with asymptomatic infection because illness, if it occurs, happens shortly after the virus is acquired and is of short duration, whereas viral shedding may continue for 1-3 mo. In general, the more carefully clinical symptomatology is sought, the lower the percentage of truly asymptomatic infections that is found. Clinical expression is also inversely related to age and varies by viral type. Overall, probably ................
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