Togavirus: Rubella Longster Kemngang Rubella virus particles on a cellular surface http://www.sciencepicture.co/images/3643/Rubella-Virus.html

https://online.epocrates.com, 12 March 2015 Clinical Vignettes A 25-year-old man presents with a 3-day history of low-grade fever, malaise, headache, and aching knees. That morning he developed a rash on his face, which has now spread to his chest and arms. image His physical exam is notable for mild conjunctival injection, mild bilateral posterior auricular lymphadenopathy, and a discrete erythematous papular rash on his face, trunk, and upper arms. The patient is from Mexico, has lived in the US for 6 months, and is unaware of his immunization status. He reports that a coworker with whom he had close contact had a similar rash last week. A 2820-gram (6lbs 2 oz) female infant is born to a 22-year old primigravidas mother at approximately 38 weeks' gestation following an uncomplicated pregnancy. The baby has mild hepatosplenomegaly, numerous purplish firm nonblanching skin nodules, scattered petechiae, and a grade 3 continuous murmur audible at the left infraclavicular area. The baby's mother immigrated from Liberia during the sixth month of her pregnancy; she cannot recall having been immunized in childhood. primigravida —> first born https://online.epocrates.com, 12 March 2015

Rubella Rubivirus Togaviridae : Rubivirus : Rubella/German Measles DISEASE: GERMAN MEASLES (“3 DAY MEASLES”) Enveloped Icosahedral Capsid Positive Single Stranded RNA Rubella virus is the only member of the genus of Rubivirus and belongs to the family of Togaviridae The physicians who found it were german, so german measles The virus is covered by a lipid membrane (viral envelope), derived from the host cell membrane. There are prominent "spikes" (projections) of 6 nm composed of the viral envelope proteins E1 and E2 embedded in the membrane. The E1 glycoprotein is considered immunodominant in the humoral response induced against the structural proteins and contains both neutralizing and hemagglutinating determinants. E1 and E2 are targeting to the golgi apparatus. packaging and resembling proteins —> duh. E1 is targeting to rubella by addition of the GPI anchor Rubivirus

Virus Replication Cycle attachment, penetration, uncoating, replication, assembly, and release. The E1 glycoprotein is considered immunodominant in the humoral response induced against the structural proteins and contains both neutralizing and hemagglutinating determinants. E1 and E2 are targeting to the golgi apparatus. packaging and resembling proteins —> duh. E1 is targeting to rubella by addition of the GPI anchor

Acquired Rubella Host : Humans Virus enters body via respiratory route a) replicates asymptomatically in URT in the nasopharyngeal mucosa b) gains access to lymphatic system and subsequently enters bloodstream 2 week incubation period (12-18 days) transmitted by breathing in droplets that are sprayed into the air when an infected person sneezes, coughs or talks. Carrier is infectious for 7 days before appearance of rash and for 5-7 days after the appearance of the rash(2,3). Transmission requires close person-to-person contact(7). Medscape, 2015

Clinical Presentation Rubella production in the pharynx precedes the appearance of symptoms and continues through the course of the disease. Fever and rash occur later. Patients are infectious for 7 days before and after rash appears. The onset of lymphadenopathy coincides with viremia The person is infectious as long the virus is produced in the pharynx. Rash is the first symptoms to appear. Rash appears 2 weeks after infection The rash, if it occurs at all, occurs after the incubation period and begins on the face, lasting between 12 hours and 5 days.  Carrier is infectious for 7 days before appearance of rash and for 5-7 days after the appearance of the rash Following respiratory transmission of rubella virus, replication of the virus is thought to occur in the nasopharynx and regional lymph nodes. A viremia occurs 5 to 7 days after exposure with spread of the virus throughout the body.

Signs and Symptoms 70% of Adults: non-confluent —> there are not running together but they are fine, discrete erythematous rash The rash appears first on face and neck, then spread to the trunk and limbs The rash also fades after 48 hours or less Arthralgia or arthritis may occur in up to 70% of adult women who contract rubella, but it is rare in children and adult males. Fingers, wrists, and knees are often affected. Joint symptoms tend to occur about the same time or shortly after appearance of the rash and may last for up to 1 month; chronic arthritis is rare. Rare complications can include encephalitis in less than 1/5,000 cases, neuritis, orchitis, and panencephalitis.   Rash: maculopapular, non-confluent Rash extends from face to the trunk and limb 70% of Adults: Lymphoadenopathy (retroauricular and suboccipital), arthritis and arthralgias (adults) Mild Disease Signs/Symptoms: Fever Postauricular adenopathy Lymphadenopathy Arthralgias Fine truncal rash that starts at the head and moves down

Rubella Disease Timeline Prodrome — early symptom that may indicate the start of the disease Rubella production in the pharynx precedes the appearance of symptoms and continues through the course of the disease. The onset of lymphadenopaathy coincides with viremia Fever and rash occur later days later post viremia. And the only last about 48 hours maximum The person is infectious as long the virus is produced in the pharynx. We see that the virus remains in the pharynx the longest. So the symptoms can disappear but the pharynx still is carrying the virus Children and Adults: symptoms include low grade fever, sore throat, rash, and lymphoadenopathy. In extremely young children there is usually no prodrome. That is because it is usually congenital and pasted through the mother.People are usually infectious one week before the appearance of the rash to one week after the rash disappears. 

Most common congenital manifestations Congenital TORCHES Most common congenital manifestations Toxoplasma gondii Other (varicella-zoster, parvovirus B19) Rubella CMV HIV Herpes simplex virus-2 Syphilis microbes that pass from mother to fetus. transmission is transplacental in most cases or via delivery . esp in the HSV-2. non specific abnormalities. Infection with rubella virus is most severe in early gestation. The virus may affect all organs and cause a variety of congenital defects. Infection may lead to fetal death, spontaneous abortion, or premature delivery.

Congenital Rubella Crosses placenta when mother has acute infection. The earlier the fetus is infected -> more serious disease. May result in serious congenital abnormalities Intrauterine growth retardation Hepatosplenomegaly Cataracts Mental retardation Sensorineural hearing loss Heart- Patent ductus arteriosis Pulmonary stenosis Thrombocytopenic purpura The severity of the effects of rubella virus on the fetus depends largely on the time of gestation at which infection occurs. As many as 85% of infants infected in the first trimester of pregnancy will be found to be affected if followed after birth. While fetal infection may occur throughout pregnancy, defects are rare when infection occurs after the 20th week of gestation. The overall risk of defects during the third trimester is probably no greater than that associated with uncomplicated pregnancies. Congenital infection with rubella virus can affect virtually all organ systems. Deafness is the most common and often the sole manifestation of congenital rubella infection, especially after the fourth month of gestation. Eye defects, including cataracts, glaucoma, retinopathy, and microphthalmia may occur. Cardiac defects such as patent ductus arteriosus, ventricular septal defect, pulmonic stenosis, and coarctation of the aorta are possible. Neurologic abnormalities, including microcephaly and mental retardation, and other abnormalities, including bone lesions, splenomegaly, hepatitis, and thrombocytopenia with purpura may occur. * In Pediatrics , these is a classic triad for the congenital manifestations blueberry muffin rash —distrubuted purpura—bleeding under the skin .3-1cm (skin lesions are sites of extra medullary hematopoesis—> differential. This rash is seen in CMV and Rubella. Cataracts Classic triad: PDA Cataracts, and deafness +/- “blueberry muffin” rash Blueberry Muffin Rash PDA

Pattern of Viral Excretion and Infant’s Antibody Response in Congenital Rubella viral excretion (+) Transplacental infection of the fetus occurs during viremia. Fetal damage occurs through destruction of cells as well as mitotic arrest. The risk of severe disease in neonates is the highest if the mother is infected within the first few weeks of pregnancy and declines as the pregnancy progresses. So here we see that during the first trimester, the mother has the virus and IgM is fighting the infection. By birth, the mother has IgG fighting off the infection and the child’s IgM is high as the longevity pairing up with the longevity of the infection due to the time the virus occurred in the mother. Viremia, 1st trimested. Virus from congenital infections persists after birth. Those with congenital infections can infect others after birth for several months. The virus occurs in naso-pharyngeal secretions, urine and feces.

Clinical Laboratory Findings/Diagnosis Isolation of rubella virus from clinical specimen (e.g., nasopharynx, urine) Positive serologic test for rubella IgM antibody Significant rise in rubella IgG by any standard serologic assay (e.g., enzyme immunoassay) Treatment: No treatment, just supportive care Prevention: MMR vaccine (Measles/Mumps/Rubella)

Treatment, Prevention & Control MMR vaccine: live attenuated virus Measles/Mumps/Rubella Dramatic decline in the incidence of the disease since introduction of vaccine Periodic epidemics affect unvaccinated populations.  Pro — induces strong, often life-long immunity Con — may revert to virulent form USA Vaccination schedule: at 12-15 months and at 4 to 6 years Immunize at 9 months in endemic areas Administer 1 dose of MMR vaccine to infants aged 6 through 11 months before departure from the United States for international travel Efficiency: 95% lifelong immunization with a single dose live attenuated vaccine —> the microorganism loses its pathogenicity but retains capacity for transient growth within the inoculated host. the vaccine mainly induces a cellular response Rubella vaccine is very safe. Most adverse reactions reported following MMR vaccination (such as fever and rash) are attributable to the measles component. The most common complaints following rubella vaccination are fever, lymphadenopathy, and arthralgia. These adverse reactions only occur in susceptible persons and are more common in adults, especially in women. Joint symptoms, such as arthralgia (joint pain) and arthritis (joint redness and/or swelling), are associated with the rubella component of MMR. Arthralgia and transient arthritis occur more frequently in susceptible adults than in children and more frequently in susceptible women than in men. Acute arthralgia or arthritis is rare following vaccination of children with RA 27/3 vaccine. By contrast, approximately 25% of susceptible postpubertal females develop acute arthralgia following RA 27/3 vaccination, and approximately 10% have been reported to have acute arthritis-like signs and symptoms. Rarely, transient peripheral neuritic complaints, such as paresthesias and pain in the arms and legs, have been reported. Rubella Vaccine Vaccine Trade Name Licensure HPV-77:DE5 Meruvax 1969 HPV-77:DK12 Rubelogen 1969 GMK-3:RK53 Cendevax 1969 RA 27/3* Meruvax II 1979 *Only vaccine currently licensed in U.S. CDC, 2015

Differential Dx Rubella: Enveloped Icosahedral Capsid Positive Single Stranded RNA Measles: Paramyxoviruses Enveloped negative linear non segmented helical Single Stranded RNA Rubella has NO desquamation (different from Measles) Rash: maculopapular, non-confluent (different from Measles: Rash presents last and spreads from head to toe. Koplik spots—not present in Rubella). Crucial Symptom: Lymphoadenopathy (retroauricular and suboccipital), arthritis and arthralgias — 70% of Adults viral exanthems —> a wide spread rash measles —> triple C and P —-> cough, conjuctiva, coryza (runny nose) and photophobia … multinucleated giant cells and inclusion bodies but koplik spots are the definite diagnosis .. rash measles —-> it appears in 1-2 days then leaves in 1-2 days so its hard to tell still —> desqaumation= to come off as flakes rubella and measles are both rare in vaccinated children so independent of the “con” of the vaccine, the chances are you were not vaccinated. In Exanthem Roseola: The rash begins as the fever goes away. There is a sudden "surprise" appearance of the rash after the fall of the fever. Numerous pale pink, almond-shaped macules appear on the trunk and neck. They become confluent, and then fade in a few hours to 2 days without scaling or pigmentation.vomiting, running nose, cough, and hepatomegaly The hallmark of rubella is the generalized tender lymphadenopathy which involves all nodes, but which is most striking in the suboccipital, postauricular, and anterior and posterior cervical nodes. Swelling of the lymph nodes most prevalent at the time of appearance of the exanthem but may precede it by a week. The tenderness that accompanies this lymphadenopathy subsides rapidly, however the enlargement may last days or weeks. Extend from face to the trunk and limb (different from Exanthem roseola: surprise “almond-shaped” macule rash post fever on the trunk and neck) Viral exanthems : Varicella (VZV) , Rubella, Measles Congenital: Rubella and CMV are the only TORCH viruses that have been documented by skin biopsies to cause dermal erythropoiesis Parvo B19 (Slap cheek) no vaccine; EASY to mistake for rubella Look for Anemia and NO Teratogenic properties if congenital in Parvo B19

https://online.epocrates.com, 12 March 2015 Clinical Vignettes A 25-year-old man presents with a 3-day history of low-grade fever, malaise, headache, and aching knees. That morning he developed a rash on his face, which has now spread to his chest and arms. image His physical exam is notable for mild conjunctival injection, mild bilateral posterior auricular lymphadenopathy, and a discrete erythematous papular rash on his face, trunk, and upper arms. The patient is from Mexico, has lived in the US for 6 months, and is unaware of his immunization status. He reports that a coworker with whom he had close contact had a similar rash last week. A 2820-gram (6lbs 2 oz) female infant is born to a 22-year old primigravidas mother at approximately 38 weeks' gestation following an uncomplicated pregnancy. The baby has mild hepatosplenomegaly, numerous purplish firm nonblanching skin nodules, scattered petechiae, and a grade 3 continuous murmur audible at the left infraclavicular area. The baby's mother immigrated from Liberia during the sixth month of her pregnancy; she cannot recall having been immunized in childhood. https://online.epocrates.com, 12 March 2015

References http://www.cdc.gov/rubella/index.html Chantler, J., Wolinsky, J. S., & Tingle, A. (2001). Rubella Virus. In D. M. Knipe, & P. M. Howley (Eds.), Fields Virology (4th ed., pp. 963-990). Philidelphia: Lippincott Williams & Wilkins. Edlich, R. F., Winters, K. L., Long, W. B.,3rd, & Gubler, K. D. (2005). Rubella and congenital rubella (German measles). Journal of Long-Term Effects of Medical Implants, 15 (3), 319-328. De Santis, M., Cavaliere, A. F., Straface, G., & Caruso, A. (2006). Rubella infection in pregnancy. Reproductive Toxicology (Elmsford, N.Y.), 21 (4), 390- 398. doi:10.1016/j.reprotox.2005.01.014 Murray, Patrick R. PhD , Ken S. Rosenthal PhD. Medical Microbiology: with Student consult Online Access, 7e Paperback – November 28, 2012