Case 1 introduction

Cases of mumps are now relatively uncommon, but can be diagnosed primarily by clinical presentation along with a patient history that lacks mumps virus immunization. Clinical symptoms include acute onset of fever and malaise, followed with painful bilateral or unilateral swelling of the parotid or other salivary glands. 10-20 percent of cases may progress to more severe infections with CNS involvement, resulting in aseptic meningitis or meningoencephalitis. In adolescent children and adults, additional complications may occur including: orchitis, oophoritis, and pancreatitis. These more severe symptoms are more rare and occur primarily in immunocompromised hosts.

Laboratory diagnosis is not typically required; however, rapid confirmation of mumps infection can be obtained through direct viral antigen detection via immunofluorescence analysis. Appropriate clinical samples for analysis include saliva, CSF, and urine. Additionally, clinical specimens can be cultured in cells for observation of cytopathic effects such as cell rounding and syncytia formation. Alternately, serology can be used to detect a fourfold rise in mumps-specific IgM or IgG antibody in clinical samples.

Treatment and Prevention

There is no specific antiviral therapy for mumps. However, immunization with the live attenuated mumps virus vaccine provides effective protection against infection.

[32.1] A 6-year-old child presents to their pediatrician with symptoms of fever, fatigue, and swollen glands. Which of the following patient information would confirm a diagnosis of infection with the mumps virus?

[32.2] Which of the following statement regarding infection with the mumps virus is correct?

[32.3] Which of the following organs would most commonly exhibit signs of mumps infection?

[32.1] C. The detection of mumps-specific IgM antibody indicates active mumps virus infection; answers A, B, D, and E; are incorrect; (A) exposure to mumps does not necessarily cause infection, particularly if the child has been immunized; (B) symptoms of orchitis because of mumps infection occurs only in adolescent males; (D) encephalitis is a more rare complication of mumps infection and is not specific to the mumps virus.

[32.2] A. After initial replication in the upper respiratory tract and salivary glands, viral particles are also transmitted to distant organs such as the kidneys, testes, ovaries, and CNS through viremic spread; answers B, C, D and E are incorrect.

[32.3] D. Swollen parotid glands are a common symptom during infection with the mumps virus; answers A, B, C, and E are possible complications of infection with the mumps virus, but are less commonly occurring.

An 8-year-old boy is brought in to the office with a 3-day history of fever and a rash. He has also had a mild sore throat and felt somewhat fatigued. His mother is concerned that he could have "scarlet fever." The rash started on his face and then spread to his arms and legs. He has only been given acetaminophen for the fever. He takes no other medications, has no known allergies, has no significant medical history, and has had no contact with anyone known to be ill. On examination, his temperature is 37.7C (99.8F), and his other vital signs are normal. His cheeks are notably red, almost as if they had been slapped. His pharynx is normal appearing, and the remainder of his head and neck exam is normal. On his extremities there is a fine, erythematous, maculopapular rash but no vesicles or petechiae. A rapid group A streptococcal antigen test done in the office is negative.

 What virus is the likely cause of this illness?

 In which human cells does this virus cause lytic infections?

 Most likely viral cause of this illness: Infection with parvovirus B19.

 Human cells in which the virus causes lytic infections: Mitotically active erythroid precursor cells.

Summary: An 8-year-old boy with fever and "slapped cheek" appearance has erythema infectiosum or fifth disease.

CLINICAL CORRELATION

Introduction

Parvovirus B19 is the only parvovirus known to cause disease in humans. Infection occurs typically in school-age children resulting in a mild febrile upper respiratory illness followed by an exanthematous rash on the face or "slapped cheek" appearance which later spreads to the extremities. It is classically described as fifth disease because it was the fifth childhood exanthem to be described after varicella, rubella, roseola, and measles. Adults are less commonly infected, and primarily present with polyarthritis of the hands, knees, and ankles, occurring with or without rash. Chronic infection occurs in immunodeficient patients with more serious consequences, such as severe anemia and aplastic crisis. Additionally, infection occurring in pregnant seronegative mothers can lead to serious infection and fetal death.

Parvovirus B19 belongs to the Parvoviridae family and is the only parvovirus known to cause human disease. It is spread from person-to person by respiratory and oral secretions, replicating first in the nasopharynx, then spreading by viremia to the bone marrow. It binds to the erythrocyte blood group P antigen on erythroid precursor cells and is internalized through coated pits. After internalization, the viral DNA is uncoated and transported to the nucleus, where a complementary DNA strand is created by the host DNA polymerase. Inverted repeat sequences on the 5' and 3' ends of the viral DNA are used as primers to initiate DNA replication. The resultant double-stranded viral DNA is then further replicated and transcribed via host cell machinery, and newly formed virions are assembled in the nucleus. Additionally, other factors only available in the S phase of mitosis are required for parvoviral replication. The newly assembled infectious particles are then released by lysis of the host nuclear and cytoplasmic membranes, resulting in cell death. The major site for parvoviral replication is in adult bone marrow and fetal liver cells. Because replication in these cells results in cell lysis and death, there is a disruption of red cell production and resultant anemia that occurs with viral infection.

Clinical symptoms caused by parvovirus B19 are related to the immune system response to the infection. The most common clinical illness associated with parvovirus B19 is erythema infectiosum, or fifth disease. It is commonly seen in children and usually causes a biphasic infection with mild upper respiratory symptoms, low-grade or no fever, and a rash. The initial stage lasts for approximately 1 week and involves the infection and killing of erythroid cells followed by viremic spread. This stage is the infectious stage and produces flu-like symptoms with mild fever and upper-respiratory symptoms. The second stage of infection is immune-mediated, with the formation of host antibody-virus immune complexes, a reduction in viremia, and the emergence of a lacy skin rash. The rash usually starts on the face and is classically described as causing a "slapped cheek" appearance. A maculopapular rash will then frequently develop on the extremities. Adults may get a rash, but more often develop arthralgias or frank arthritis. The production of rash, arthralgias, and arthritis are all results of circulating antibody-virus immune complexes. These symptoms are usually self-limited; however, persistent infections can occur in immune-compromised hosts who fail to produce virus-neutralizing antibodies, because host antibody-mediated immunity is necessary for defense against the infection and prevention of reinfections.

More rare but potentially life-threatening complications of parvovirus B19 infection can occur. Aplastic crisis can occur in hosts with a chronic hemolytic anemia, such as sickle cell disease or other acquired hemolytic anemias. In this setting, the combination of viral replication in red cell precursors along with the reduced circulatory life span of existing red cells may result in a profound anemia. Additionally, parvoviral B19 infection in immunodeficient patients can result in persistent infections with chronic bone marrow suppression and anemia. There is also an increased risk of fetal loss because of anemia caused by transplacental infection of the fetus when a seronegative mother becomes infected during pregnancy. Fetal parvoviral infection can result in hydrops fetalis, severe anemia, and often, fetal death before the third trimester. The fetus of a seropositive mother is protected from infection by maternal circulating antibodies.

Definitive diagnosis of parvovirus B19 infection relies on the detection of viral DNA via PCR or DNA hybridization assays using patient serum, blood or tissue samples. Additionally, serologic detection of viral IgM or IgG antibodies via ELISA (enzyme-linked immunosorbent assay) can be used for diagnoses.

At present, there is no specific treatment for parvovirus B19 infections. Infection control measures are used in hospitals to avoid parvoviral spread, such as rigorous hand washing and isolation of infected patients. Although vaccines are available for dogs and cats, there is currently no parvoviral B19 vaccine available for humans.

[33.1] Which of the following statements is most accurate regarding infection with parvovirus B19?

[33.2] A normally healthy 7-year-old girl is sent home from school with a suspected case of fifth disease as a result of her presenting with the initial symptoms of the infection. After being at home for a few days, her symptoms change indicating her transition into the second phase of the illness. Which of the following symptoms is the girl most likely experiencing during the second phase of parvoviral infection?

[33.3] Which of the following conditions would put an individual at increased risk for serious chronic illness following an infection with parvovirus B19?

[33.1] B. Parvovirus B19 binds preferentially to the erythrocyte blood group P antigen on erythroid precursor cells; answers A, B, C, and E are incorrect: (A) after entry the single-stranded viral DNA genome is transported to the cell nucleus where the host DNA polymerase synthesizes the complimentary DNA strand; (C) Parvovirus B19 infection can be diagnosed by direct detection of viral DNA not RNA; (D) the fetus of a seropositive mother is protected from infection by maternal circulating antibodies; (E) Parvovirus B19 is transmitted primarily by respiratory secretions and is prevalent in school-age children.

[33.2] D. The second stage of parvoviral B19 infection is immune-mediated, and results in formation of a lacy skin rash occurring first on the face and then moves to the extremities; answers A, B, C, and E are incorrect: (A) aplastic crisis occurs in hosts with sickle cell disease or other acquired hemolytic anemias, not in normally healthy individuals; (B) parvoviral infection does not cause gastrointestinal symptoms; (C) mild fever, not high fever, is a symptom that occurs in the initial stage of fifth disease; (E) parvoviral infection does not result in swollen glands.

[33.3] B. More serious complications of parvoviral B19 infection, such as aplastic crisis, can occur in hosts with sickle cell disease or other chronic hemolytic anemias; answers A, C, D, and E are incorrect as they are not associated with serious complications of parvovirus B19 infection.

A 62-year-old man presents to the emergency room after suddenly losing the use of his right leg. He reports that he had a few days of headache, fever, and sore throat, which was treated with oral antibiotics and resolved about 4 days ago. He was feeling fine until this morning, when he could not lift his right leg to get out of bed. All of his other limbs are functioning normally, and he has normal sensation in them. He has a medical history significant for lung cancer for which he is receiving chemotherapy, with his most recent cycle having been completed a few days prior to the onset of his febrile illness. He denies having any recent falls, injuries, current headache, or neurologic symptoms other than in the right leg. He has not traveled outside of the United States. His only current medication is amoxicillin/clavulanic acid, which was prescribed for his recent febrile illness. He lives with his son, daughter-in-law, and two young grandchildren. The children are healthy, and each had their routine well-child checkups and vaccinations about a month ago, including an oral vaccine. On examination, he is anxious appearing but has normal vital signs and has unremarkable head and neck, cardiovascular, pulmonary, and abdominal examinations. He has flaccid paralysis with normal sensation of the right leg, with normal movement and strength in all other extremities and a normal cranial nerve examination. A head CT scan and lumbar magnetic resonance imaging (MRI) are also normal.

 What is the most likely infectious cause of this man's flaccid paralysis?

 Assuming that he was infected at home, what is the most likely source of his infection?

 Most likely infectious cause of this man's flaccid paralysis: Poliomyelitis, caused by poliovirus.

 Most likely source of his infection: fecal-oral transmission of viral particles shed from one of his grandchildren recently vaccinated with live attenuated poliovirus vaccine.

Summary: A 62-year-old man with flaccid paralysis of the right leg. He lives with his grandchildren, who were recently given an oral vaccine.

CLINICAL CORRELATION

Introduction

Poliovirus is an exclusive human pathogen, which causes an acute infectious disease that can result in flaccid paralysis from the destruction of motor neurons in the spinal cord. Although most childhood infections tend to be subclinical, the risk of more serious paralytic disease increases with age. Infections are spread through fecal-oral transfer and poor sanitation and crowded conditions help to promote viral spread. Both attenuated live and inactivated oral viral vaccines have been available for over 40 years, and most industrialized countries have been free from wild poliovirus infections since the late 1990s or early 2000s. Use of the killed-virus vaccine for childhood immunizations is currently recommended in the United States because of safety issues with the live-attenuated vaccine, including possible transfer of live virus to close contacts. Efforts are being continued to globally eradicate poliovirus from residual areas such as Africa and India.

As with other Enteroviruses, poliovirus is transmitted primarily by the fecal-oral route. Viral particles enter through the mouth and primary replication is thought to occur in the oropharynx, tonsils, and lymph nodes or in the intestinal epithelium and adjacent lymphoid tissue. The virus is resistant to a wide range of pH levels, allowing it to survive the acidity of the stomach. Depending on the host immune response and the ability of the virus to spread, infection with poliovirus can result in one of four different types of infection: asymptomatic illness, abortive poliomyelitis, nonparalytic poliomyelitis, or paralytic poliomyelitis. After initial viral replication, an immune competent host will make specific antibodies to the virus, and if the infection is limited to this stage the infection remains asymptomatic. Host antibodies provide the major immune response to poliovirus infections. However, if infection is not contained by the host antibody response, there may be a "minor" viremic spread to cells containing a specific receptor recognized by the capsid VP proteins. The specificity of poliovirus infection via these receptors restricts the tropism for poliovirus to cells such as the anterior horn cells of the spinal cord, dorsal root ganglia, motor neurons, skeletal muscle cells, and lymphoid cells.

After binding to the receptor, the RNA genome is inserted into the host cytoplasm through a channel created in the cell membrane. Viral transcription and replication occur in the cytoplasm, and new virions are released by cell lysis. Replication in these cells can then lead to a "major" viremia that, when controlled by host antibody response, produces the "minor" illness of abortive poliomyelitis. Abortive poliomyelitis causes nonspecific symptoms that include fever, sore throat, and headache. In a small percentage of infected people, the virus may continue to spread to involve the central nervous system (CNS) or the meninges. This can occur either as a result of viremic dissemination or ascending infection through peripheral nerves into the CNS. This can then result in nonparalytic poliomyelitis, aseptic meningitis, or, when anterior horn cells of the spinal cord or motor cortex are involved, paralytic poliomyelitis. Paralytic poliomyelitis is the least common complication of poliovirus infection and appears less than a week following initial symptoms of abortive poliomyelitis. Paralytic disease is caused by cytolytic damage caused by the virus, not by the immune response.

Diagnosis

In addition to the presentation of the above clinical findings, a suspected poliovirus infection can be diagnosed by the recovery and culture of the virus from clinical samples. The best clinical specimens include throat swabs if collected shortly after the onset of infection or rectal swabs and stool specimens collected up to 30 days post onset. Cells inoculated with poliovirus will show cytopathic effects of viral infection in less than a week of culture. Even when there is CNS and meningeal involvement, poliovirus is rarely recovered from CNS fluid. RT-PCR can also be used to detect RNA sequences in tissues and body fluids, increasing the sensitivity and speed of diagnosis.