Case 1 introduction

[34.1] Which of the following statements best describes an advantage of the oral polio vaccine when compared to the inactivated poliomyelitis vaccine?

[34.2] The primary pathologic effect of polioviral infection is a result of which of the following:

[34.3] The majority of nonimmunized patients infected with poliovirus would be expected to experience:

[34.1] C. The oral polio vaccine or "live" vaccine produces not only IgM and IgG antibodies in the blood but also secretory IgA antibodies in the intestine, resulting in intestinal immunity; the inactivated poliomyelitis vaccine produces humoral immunity, but not localized intestinal immunity. Answers A, B, D, and E are incorrect: (A) only the inactivated poliomyelitis vaccine is administered to immunocompromised patients; (B) the oral polio vaccine has been associated with transfer of live poliovirus to close contacts of immunized patients, and therefore, use of the inactivated poliomyelitis vaccine is currently recommended in the United States for childhood immunizations; (D) it is easily administered in multiple oral doses, not injections; (E) both the oral polio vaccine and the inactivated poliomyelitis vaccine can be given to young children with other scheduled immunizations.

[34.2] A. polioviruses are cytolytic and cause direct damage to infected cells; answers B, C, D, and E are incorrect: (B) paralysis results in less than 2 percent of patients infected with poliovirus and is a direct result of the destruction of infected neurons in the spinal cord and brain; (C) paralytic disease is caused by cytolytic damage because of the virus, not by the immune response; (D) aseptic meningitis is a result of poliovirus infection which occurs in less than 1-2 percent of patients infected, and is a result of the destruction of infected cells; (E) if not contained by the host antibody response, polioviral infection may result in "minor" and "major" viremic spread within the patient, however, the primary pathologic effect of poliovirus is still the cell lysis of infected cells.

[34.3] E. Greater than 90 percent of infections with poliovirus result in asymptomatic infections; answers A, B, C, and D are incorrect; all are potential outcomes of polioviral infections that remain uncontrolled by a host immune response, but are much less common outcomes of poliovirus infection.

A 3-year-old male infant is brought to the emergency room in the middle of January with fever, vomiting, and diarrhea for the past day. He has not been able to keep anything down by mouth and has had profuse, very watery stools. He attends day care, and several of his classmates have been out sick recently as well. No adult members of the household have been ill. He has no significant past medical history. On examination, his temperature is 37.9C (100.2F), and he has tachycardia. His mucous membranes are dry, and eyes appear somewhat sunken. His abdomen has active bowel sounds and is nontender. His stool is watery and pale. The stool tests negative for blood and fecal leukocytes.

 What is the most likely cause of this child's illness?

 How is this virus activated to form an infectious particle?

 Most likely cause of this child's illness: Rotavirus.

 How is this virus activated to form an infectious particle: Activation of Rotavirus occurs when the outer capsid layer is lysed by gastrointestinal (GI) proteases to create an infectious subviral particle (ISVP).

Summary: A 3-year-old boy who attends day care develops gastroenteritis in the winter.

CLINICAL CORRELATION

Introduction

Rotaviruses are ubiquitous worldwide and are estimated to cause more than 50 percent of gastroenteritis cases occurring in children less 2-3 years of age, resulting in approximately 4 billion annual cases. Infections typically occur in the cooler months and result in abrupt onset of vomiting followed with frequent watery diarrhea. Illness is typically self-limiting; however, severe infection can result in immunocompromised or malnourished children and may be fatal. Outbreaks are common in daycare, preschool, and hospital settings. Adults may also become infected but usually have few if any symptoms.

The mechanism by which rotaviral infection causes diarrhea is not entirely understood. Rotaviral particles infect the cells of the small intestinal villi and multiply in the cytoplasm of enterocytes. Damaged cells are sloughed off, releasing large numbers of viral particles into the stool. Virus can be excreted for days to weeks after infection. The infection prevents absorption of water, sodium, and glucose, resulting in a loss of water and electrolytes. A virally encoded nonstructural protein also acts as an enterotoxin, similar to those of Escherichia coli and Vibrio cholerae. Typical symptoms of rotaviral infection include fever, vomiting, abdominal pain, and watery diarrhea without blood or mucus. The net result is a profuse watery diarrhea that can cause dehydration without appropriate fluid and electrolyte replacement. Symptoms may last for approximately 1 week, with viral excretion lasting weeks longer. Severe and prolonged illness can occur in immunodeficient and malnourished children and without supportive therapy infection can be fatal. Infection with rotavirus stimulates a humoral response; however, protection against reinfection is temporary and incomplete. The presence of high levels of rotavirus IgA in the lumen of the intestine confers relative protection.

Because the symptoms of rotaviral infection resemble those of other viral diarrhea producing agents, the definitive diagnoses of rotaviral infection requires the detection of viral antigens in stool samples. Enzyme immunoassay and latex agglutination are two easy, rapid assays used to confirm rotaviral infection. Additionally, PCR can be used for genotyping viral nucleic acid in stool specimens. Viral culture is both difficult and unreliable and therefore is not used for diagnoses.

An attenuated recombinant Rotavirus vaccine was developed and used in children for several years. However, its approval was withdrawn, and its use stopped because of concerns with the development of intussusception among vaccine users. Another difficulty with the production of such a vaccine is that a single vaccine may not protect against all Rotavirus serotypes.

[35.1] You isolate a virus from the stool of a 1-year-old infant with signs of fever, vomiting, and diarrhea. Laboratory results show that the viral genome is composed of multiple segments of double-stranded RNA, which leads you to suspect that rotavirus is the causative agent of infection. Which of the following statements is true regarding rotavirus replication?

[35.2] Similar to Rotavirus, which of the following viral agents is also a nonenveloped RNA virus known to cause gastroenteritis diarrhea in young children?

[35.1] C. The segmented genome of Rotaviruses, allows for the assembly of new virions with mixed genomes in cells multiply infected as a result of reassortment; answers A, B, D, and E are incorrect: (A) the rotaviral genome consists of double-stranded RNA and replicates in the cytoplasm and thus does not integrate into the host chromosome; (B) as an RNA virus that replicates in the cytoplasm, the rotoviral genome is replicated by a viral RNA polymerase; (D) the high genetic variability of rotaviruses because of reassortment results in multiple viral serotypes, at least nine different serotypes have currently been classified in human illness; (E) newly assembled nonenveloped rotaviral particles are released by cell lysis.

[35.2] A. Like Rotaviruses, Caliciviruses are nonenveloped RNA viruses that cause watery diarrhea, especially in children; answers B, C, D, and E are incorrect: (B) paramyxoviruses are enveloped RNA viruses that cause childhood respiratory and exanthemous infections; (C) parainfluenza viruses are enveloped RNA viruses which cause respiratory infections such as croup, bronchiolitis, and pneumonia in children; (D) Coxsackie viruses are nonenveloped RNA viruses that cause nonspecific respiratory tract infections, febrile rashes, and meningitis.
CASE 36

INTRODUCTION

A 10-month-old female is brought to the pediatric emergency room in late December with a cough and fever. She started getting sick with a mild cough and runny nose about 3 days prior, but has progressively worsened. She is now coughing frequently and has vomited after coughing. She has no history of asthma or other respiratory illness. She was born after an uncomplicated, full-term pregnancy and has no significant medical history. She attends daycare 3 days a week. On examination, her temperature is 38.3C (100.9F), pulse is 110 beats per minute, respiratory rate is 30 breaths per minute, and her oxygen saturation is low at 91 percent by pulse oximetry. Her head and neck examination shows her to have a right otitis media but is otherwise normal. Her cardiac exam is notable only for tachycardia. Her pulmonary examination shows her to be in moderate respiratory distress. She has prominent nasal flaring and subcostal retractions on inspiration. She has loud expiratory wheezes in all lung fields. The remainder of her examination is normal. A chest x-ray shows hyperaeration but no infiltrates.

 What is the likely infectious cause of her respiratory illness?

 Following resolution of this illness, her mother asks whether she is protected from getting this disease again. How do you respond?

 Likely infectious cause of her respiratory illness: Respiratory syncytial virus (RSV).

 Is she protected from getting this disease again: The immunity developed with an RSV infection is incomplete, and reinfections are common. However, the severity of disease with repeat infections appears to be reduced, especially in older children and adults.

Summary: A 10-month-old female presents with bronchiolitis. A chest x-ray shows hyperaeration but no infiltrates.

CLINICAL CORRELATION

Introduction

RSV is a ubiquitous and highly contagious viral infection and is the single most common cause of fatal respiratory tract infections in infants under 12 months of age. It accounts for approximately 25 percent of pediatric hospitalizations of this age group, resulting in severe respiratory illnesses such as bronchiolitis, pneumonia, and respiratory failure. It is also highly prevalent in childcare settings, with 70-95 percent of children attending daycare being infected by 3-4 years of age. Less severe illness occurs in older children and adults and may present as a common cold.

RSV is initially transmitted to the nasopharynx through contact with infected secretions and fomites, resulting in localized infections of respiratory epithelium. Although viremia is rare, progressive infections can extend to the middle and lower airways. Disease caused by RSV is primarily the result of the host immune system mediating damage to infected respiratory epithelial cells. In adults and older children, mild upper respiratory tract symptoms such as a runny nose or mild cough usually develop with clinical symptoms lasting for 1-2 weeks. In infants or younger children, more serious illness such as bronchiolitis can occur. This occurs when there is inflammation and plugging of the bronchi and bronchioles with mucous and necrotic tissue from immune-mediated cellular damage. The smaller airways of infants and young children are especially susceptible and may result in cough, tachypnea, respiratory distress, wheezing, and hypoxia.

In addition to the presenting clinical symptoms, RSV can be diagnosed more definitively through viral isolation and antigen detection. Direct identification of RSV antigens is performed via immunofluorescence analysis on exfoliated epithelial cells or with ELISA (enzyme-linked immunosorbent assay) testing on nasal secretions. Large amounts of viral particles are present in nasal washings, particularly from infected children, making it a good clinical specimen for viral isolation. Because of the labile nature of RSV, clinical samples should be inoculated immediately into cell cultures. The presence of RSV can be recognized by the formation of giant cells or syncytia formation in inoculated cultures in 1-2 weeks.

Treatment of RSV infections relies mainly on supportive care including oxygenation, ventilatory support, IV fluids, and nebulized cold steam. These modalities are used in an effort to remove or reduce mucus secretions in the airways and allow for adequate oxygen exchange. The antiviral agent ribavirin has been approved for use via aerosolization in high-risk infants exposed to RSV and in severe lower respiratory tract illnesses caused by RSV infection. Additionally, close observation of severe cases is critical. Currently there is no vaccine approved for RSV.

Additionally, preventative measures are particularly important in hospital and specifically neonatal intensive care units, because RSV is highly contagious. Prevention of nosocomial spread requires strict enforcement of the following precautions: hand washing; isolation of RSV infected infants; and changing of gloves, gowns, and masks between patients.

COMPREHENSION QUESTIONS

[36.1] Which of the following paramyxoviruses lacks an envelope viral attachment protein with hemagglutinin activity?

[36.2] An 8-month-old infant is brought to the emergency room with a suspected RSV infection. Which of the following clinical illnesses would you be most concerned about this child having as a result of infection with this virus?

[36.3] Which of the following statements most accurately describes the chemical and physiologic properties of RSV?

[36.1] D. Respiratory syncytial virus, differs from other paramyxoviruses in that it does not have a hemagglutinin protein in its viral envelope; answers A, B, and C all have viral envelope proteins with hemagglutinin activity.

[36.2] A. Bronchiolitis is a common clinical manifestation of RSV infection in infants, which results from inflammation and plugging of the bronchi and bronchioles with mucous and necrotic tissue; answers B, C, D, and E are incorrect as they are not symptoms specific to infection with RSV.

[36.3] E. RSV is an enveloped virus and is inactivated by many detergents as well as changes in temperature and pH.; answers A, B, C, and D are incorrect: (A) RSV is an enveloped virus with a single-stranded, negative-sense RNA genome; (B) RSV virions are released by budding from the host cell membrane, not by cell lysis; (C) RSV infects respiratory epithelial cells, not erythroid precursor cells, via fusion with the host membrane; (D) RSV is an RNA virus, and transcription, protein synthesis, replication, and assembly of new virions occurs in the cytoplasm of the host cell.

You are asked to consider being vaccinated with smallpox vaccine to serve as a first-responder in the event of a biological warfare attack. After considering the risks and benefits, you consent. You are given the vaccine by the standard techniquea small, bifurcated needle is used to create multiple punctures in the skin overlying your deltoid. The area is covered, and you are instructed not to touch the actual site. In two days, a small papule and erythema appear at the vaccine site. A few days later, multiple vesicles are noted. These progress to form larger pustules. In about two weeks, the whole vaccine site has formed a scab and this subsequently falls off in another week. When complete recovery has occurred, you have a scar left at the vaccine site.

 What is the actual virus used as the smallpox vaccine?

 Why must variola carry or encode its own enzymes for DNA and mRNA synthesis?