Rubella

Communicable but often mild viral infections, which may be asymptomatic (without a rash and/or fever), are frequently associated with an exanthema of variable morphology, and exhibit a fairly characteristic tender enlargement of the retro-auricular, posterior cervical, and sub-occipital lymph nodes. Post-natally acquired rubella is usually mild and uncomplicated in infants and children, in contrast to adolescents and adults, in whom the infection might lead to arthropathy and purpuric lesions.

Rubella continues to be of significant concern in the pediatric context due to the severe embryopathy linked with congenital infection (in the fetus) resulting from the placental dissemination of viremia in an infected mother. This well-known condition is termed Congenital Rubella Syndrome, a prenatal disease characterized by a range of possible manifestations and varying degrees of severity (explained further below).

The Rubella virus is a pleomorphic single-stranded lipid-enveloped RNA virus with three structural proteins: a nucleocapsid protein and two glycoproteins (E1 and E2) present in the envelope.

It belongs to the Togaviridae family, genus Rubivirus.

The virus is sensitive to heat (thermosensitive) and UV-light, but it remains stable at cold temperatures below 4°C.

Humans are the exclusive known host and reservoir of the infection.

Growth of the virus can be sustained in African Green Monkey Kidneys cell lines. While no characteristic Cytopathic Effect (CPE) is observed (unlike the Warthin-Finkeldey Giant cells seen in Measles), indirect identification is possible by noting the resistance of rubella-infected cells to subsequent challenge with enteroviruses.

Transmission may occur through viral shedding in nasal and pharyngeal secretions, blood, and urine of the infected individuals.

The period of maximum communicability spans five days before the appearance of the rash and six days after. However, virus detection can continue up to about 14 days post-eruption. In cases of Congenital Rubella Syndrome (CRS), virus detection in body fluids may persist for one to one-and-a-half years.

• Worldwide, seroepidemiological surveys in most countries (except Trinidad and Tobago) indicate recent or past infection (sero-conversion) in 70 – 95% of females between adolescence and the end of reproductive life.
• Google data suggest that the disease is rare in Nigeria, with fewer than 10,000 cases reported annually, as stated by the College of Medicine of the University of Ibadan in South-West Nigeria.
• An earlier report from Trinidad highlighted very low seropositivity, indicating that sero-negative females are at a high risk of prenatal fetal infection and the associated embryopathy (congenital rubella).
• The risk of severe malformations in Congenital Rubella Syndrome (CRS) is highest during the first trimester of pregnancy, particularly before the 8th week of prenatal life. The first half of pregnancy in seronegative females carries a risk as high as 85%.
• The risk of malformation may be:
• 85 – 90% if maternal infection occurs before 11 weeks
• 33% between 11 – 12 weeks
• 11% between 13 – 14 weeks
• 24% between 15 – 16 weeks
• There is a low but definite risk if maternal infection occurs after 16 weeks. Late infections are associated with variable sensorineural hearing impairment.

• Rubella transmission occurs via:
• Droplet propagation and acquisition
• Direct or indirect contact with fomites contaminated by nasopharyngeal discharge, urine, and other body effluents
• It is less contagious compared to measles (rubeola), with contagiousness varying based on housing conditions, crowding, and ventilation adequacy.
• The incubation period is 14 – 21 days, similar to Mumps and varicella (chickenpox).
• Infectivity spans from the immediate post-incubation (prodromal period) to about one week after the rash appears. For Congenital Rubella Syndrome (CRS), body effluents remain infectious for about one to one-and-a-half years.
• CRS arises from severe virus infection in early pregnancy and is associated with:
• Virus interference with organ formation due to direct inhibition of mitosis, resulting in intrauterine growth restriction (IUGR)
• Fetal or embryonic cells providing an excellent tissue culture for the rubella virus
• Virus multiplication and spread in the fetus due to inadequate levels of virus-specific antibodies to limit spread
• Rubella virus inhibits cell growth via mitosis, causing prenatal IUGR and low birth weight (LBW). This inhibition appears to persist postnatally, leading to failure in acquiring adequate catch-up growth.
• Children with CRS have reduced ability to clear the virus post-birth. Despite persisting Hemagglutination Inhibition Antibodies (HIA), urine, Nasopharyngeal Aspirates (NPA), and stool of infants with CRS remain infective for the subsequent 12 – 18 months.
• Seizures, thrombocytopenia, and Disseminated Intravascular Coagulation (DIC) may be observed in children with CRS.

Post-natal Rubella:

• Biopsy specimens and rare autopsy material of post-natal rubella reveal:
• Non-specific lymphoreticular inflammation
• Mononuclear perivascular and meningeal cellular infiltration

CRS (Congenital Rubella Syndrome):

• Pathological findings are observed in nearly every organ/system in affected infants, particularly those infected early. Late fetal affectation is less severe due to the placenta acting as a better barrier and cells being less vulnerable to infection.
• In infants with CRS, cellular and tissue damage are common pathological events leading to dysmorphogenesis and intrauterine growth restriction (IUGR).
• The fundamental cause of pathological events in CRS is tissue necrosis resulting from:
• Ischemia or vascular insufficiency
• Reduced cellular multiplication time
• Chromosomal 'fractures' or breaks
• Production of a protein inhibitor responsible for causing mitotic arrests in specific cell types
• CRS is characterized by the chronicity of these pathological events, with the virus persisting in fetal cells. Once infected in early embryonic life, cellular-level infection continues well beyond delivery, leading to ongoing tissue damage and virus reactivation.

Diagnostic Essentials (of Postnatally Acquired Rubella):

• Variable symptomatic expression ranging from absence of fever and rash (asymptomatic viral shedding) to the typical case.
• The typical case presents with:
• Incubation period of 14 – 21 days
• Non-specific prodromal period, including malaise, low-grade fever, headache, poor appetite, conjunctivitis (usually without discharge but associated with eye pain)
• Towards the end of the prodromal period, the typical appearance and distribution of lymph node enlargement become evident
• Irregular pink macular or discrete maculopapular rash, occasionally coalescing with rapid cranio-caudal centrifugal progression:
• Rash appears first on the face as faint but discrete macules (unlike measles), then rapidly spreads to the trunk, torso, and proximal extremities
• The rash typically evolves over about 2 – 3 days, after which facial lesions disappear
• Fading of the rash is rarely, if ever, associated with desquamation, unlike measles
• Characteristic distribution of lymphadenopathy:
• Lymphadenopathy involves anterior cervical, retro-auricular, and sub-occipital nodes
• Lymphadenopathy typically precedes and outlasts the presence of the rash
• Minimal systemic symptoms, including low-grade fever
• Little or no coryza or respiratory symptoms

Diagnostic Essentials of Congenital Rubella Syndrome (CRS)

• IUGR/Symmetrical SGA and subsequent growth retardation;
• Thrombocytopenic purpura, with or without petechial lesions (ranging from mild to severe), occasionally presenting as blue 'berry muffin lesions' with bleeding evidence;
• CNS-related manifestations:
• Microcephaly (may be minimally evident), associated with poor brain development
• Psychomotor retardation with delayed milestone acquisition
• ADHD (previously called MBD)
• Movement disorders
• Behavioral disorders and specific learning disorders
• Progressive rubella panencephalitis (PRPE), a slowly progressive degenerative CNS lesion similar to SSPE in chronicity
• Joint lesions including arthritis and tendonitis, more common and severe in young adults;
• Sensorineural deafness associated with defective development of the cochlear organ and/or the organ of Corti;
• Ophthalmic manifestations:
• Micro-ophthalmia
• Cataract
• Cloudy cornea
• Congenital glaucoma
• Peculiar retinopathy ('salt and pepper retinitis') with scattered or diffuse discrete black pigmentary lesions on the retinae
• Congenital cardiac lesions, including:
• Pulmonary arterial stenosis
• PDA (Patent Ductus Arteriosus)
• VSD (Ventricular Septal Defect)
• Specific organ defects including:
• Massive hepatosplenomegaly with jaundice
• CNS signs (lethargy or convulsions)
• Petechiae
• Alimentary tract and adnexal lesions:
• Hepatitis with significant biliary tract affectation
• Splenitis
• Pancreatitis
• Malabsorption syndromes
• Diabetes mellitus
• Osteomyelitis with characteristic circular radiolucent metaphyseal areas and associated metaphysitis;
• Immunological Defects:
• Range from hypogammaglobulinemia to cell-mediated immune disorders
• Persistently high levels of rubella-specific IgM of fetal origin
• Characteristic admixture of fetal and maternal rubella-specific IgG
• Fetal IgM eventually replaced by rubella-specific IgG produced by the child

Abnormalities Compatible with Congenital Rubella Syndrome (CRS) – Diagnostic Suspicion

LIST A:

• Cataract
• Congenital glaucoma
• Congenital heart disease
• Hearing loss
• Pigmentary retinopathy

LIST B:

• Purpura, growth retardation
• Hepatomegaly, splenomegaly, jaundice
• Meningoencephalitis, bone radiolucencies
• Microcephaly, mental retardation

(Note: Presence of two features/complications in List A, or any of the complications in List A combined with another complication in List B)

• Measles
• Chickenpox (Varicella)
• Fifth Disease (Erythema Infectiosum)
• Scarlet Fever
• Roseola Infantum (Exanthem Subitum)
• Hand, Foot and Mouth Disease
• Dengue Fever
• Enterovirus Infections
• Kawasaki Disease
• Rocky Mountain Spotted Fever
• Stevens-Johnson Syndrome
• Toxic Shock Syndrome
• Drug Reactions
• Secondary Syphilis
• Lyme Disease

Other Differential Diagnoses of Exanthematous Febrile States

• Rocky Mountain Spotted Fever (RMSF)
• Serum Sickness / Blood or Blood Product Transfusion
• Post-Allergen Exposure Eruptions
• Tick or Insect Bites
• Drug Allergy (Especially Aminopenicillins)

Other Differential Considerations for Congenital Rubella Syndrome (CRS):

1. Toxoplasmosis:
   • Sabin-Feldman dye test, antibody titre (serological conversion with a 4-fold rise in the specific titre)
   • Diffuse cranial calcification
2. Cytomegalovirus (CMV):
   • Periventricular calcification
   • Virological confirmation
3. Congenital Herpes (HSV):
   • Vesicular skin lesions
   • Absence of intracranial calcifications

The diagnosis of rubella is primarily based on clinical presentation and supported by laboratory tests. Here are some diagnostic clues and laboratory findings:

• Clinical Presentation: The clinical symptoms and characteristic rash are essential diagnostic clues.
• Laboratory Tests:
  • Throat swab, NPA, urine, and feces samples are suitable for viral identification in the initial phase.
  • Serology: Detection of rubella-specific IgM or IgG using ELISA is commonly used for diagnosis.
  • Paired sera: A four-fold rise in IgG or IgM antibody levels between acute and convalescent phases is characteristic.
  • CSF Analysis: Cerebrospinal fluid analysis may show nonspecific pleocytosis and a modest rise in protein levels.
  • False Negative in CRS: In cases of congenital rubella syndrome (CRS), serology tests may give false-negative results due to competing circulating IgG.
  • Advanced Testing: In some cases, advanced tests like RT-PCR or viral culture in African Green Monkey Kidney (AGMK) cell lines may be necessary.

Rubella infection can lead to various complications, and the prognosis depends on the timing of infection and the presence of congenital rubella syndrome (CRS). Here are some key points:

• Complications:
  • Encephalitis: Rare in post-natally acquired cases, occurring in approximately 1 out of 6000 cases.
  • Arthritis and Arthralgia: Seen more commonly in adolescent girls, involving several joints and may resemble juvenile rheumatoid arthritis (JRA).
  • Encephalitis: Encephalitis is usually mild, but progressive rubella panencephalitis (PRPE) may occur, resembling subacute sclerosing panencephalitis (SSPE).
• Prenatal Infections: The major concern is prenatal rubella infections, especially during the first trimester of pregnancy, as this is associated with a high risk of congenital rubella syndrome (CRS).
• Prognosis:
  • Postnatal Rubella: The prognosis for self-limiting postnatal rubella infections is generally good, with recovery expected.
  • Congenital Rubella Syndrome (CRS): In cases of CRS, the prognosis is more serious, and there is a higher risk of death or prolonged handicaps.

The treatment approach for rubella depends on the specific situation. Here are some considerations:

• Postnatal Rubella:

  Postnatal rubella infection is usually self-limiting and does not require specific treatment in many cases. Complications are rare in most individuals, except for certain groups:

  • Pregnant Adolescents, Young and Older Adults: In pregnant individuals, especially adolescents and young or older adults, rubella infection can have more severe implications. These groups are at a higher risk of complications and adverse outcomes.
• Adolescent Females and Young Adults:

  Adolescent females and young adult females who have not been previously exposed to the rubella virus or immunized against it are particularly vulnerable. If they contract rubella infection during the first trimester of pregnancy, there is a high risk of congenital rubella syndrome (CRS).

  For individuals in these high-risk groups, appropriate management and counseling are essential to ensure the best possible outcomes.

  (Reference: "Management of Probable Rubella Exposure and Possible Pregnancy")

Rubella is a vaccine-preventable disease with the following preventive measures:

• Rubella Vaccine:

  The rubella vaccine, known as RA 27/3, is a live vaccine that is often administered in combination with measles and mumps vaccines as MMR, or with varicella vaccine as MMRV. The vaccine is given in a 2-dose regimen:

  • First Dose: Administered between 12 and 15 months of age.
  • Second Dose: Given shortly before school entry, between 4 and 6 years of age.
• Post-Exposure Prophylaxis:

  The rubella vaccine can also provide potential preventive value for post-exposure prophylaxis. If given within 3 days of suspected exposure, it can help prevent infection.

• Contraindications:

  The rubella vaccine is contraindicated in pregnant females due to the risk of vaccine-induced congenital rubella syndrome (CRS). However, if a patient becomes pregnant within 4 weeks of immunization, the potential risk of CRS should be explained to the patient and family. Therapeutic abortion is rarely needed in such cases due to the very small risk from recent studies.

  It is also contraindicated in immunocompromised individuals, especially children with HIV/AIDS. Fever is not a contraindication to receiving the vaccine.

• Adverse Reactions:

  Adverse reactions to the RA 27/3 vaccine may include:

  • Fever
  • Rash
  • Arthritis and/or Arthralgia: More common among post-pubertal girls, with around 10% experiencing these symptoms. Tendonitis may also occur occasionally.
  • Rarely, Peripheral Neuropathies
  • Transient Thrombocytopenia: Occasional occurrence in vaccine recipients.