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Congenital Syndrome

Congenital Rubella Syndrome

Vaccine-Preventable Diseases 1 SurveillanceWHO -Preventable Standards Diseases Surveillance Standards

Congenital Rubella Syndrome

DISEASE AND VACCINE CHARACTERISTICS

Rubella is an acute often affecting developmental disabilities (such as deafness) and have an susceptible children and young adults worldwide. increased risk for developmental delay (such as ) Although it causes only a mild clinical illness in these and autoimmune diseases (diabetes type 1, thyroiditis). groups, its public health importance is due to the In some cases of rubella during , teratogenic potential of the resulting in congenital particularly after 20 weeks of gestation, the fetus can rubella syndrome (CRS). From just before conception be infected but not develop the of through the first 8–10 weeks of gestation, rubella CRS. These infants are classified as congenital rubella infection of the pregnant woman can result in multiple infection (CRI), and also shed . fetal abnormalities in up to 90% of cases, and may result in or stillbirth. CRS defects can affect any Before introduction of rubella , epidemics organ system, including ophthalmic, auditory, cardiac, of rubella have resulted in rates of CRS of 0.8–4.0 per neurologic, hepatic and haemotologic. After 18 weeks 1,000 live births (1). has been highly of gestation, the risk of CRS is low. The most common effective at reducing the burden of CRS, and vaccination defects of CRS are hearing impairment and deafness, eye has led to elimination of rubella and CRS from several defects (, congenital glaucoma or pigmentary European and Western Pacific countries and the Pan retinopathy) and cardiac defects. Infected infants can American Health Organization Region. However, shed high amounts of rubella virus from body secretions insufficient population vaccination coverage can result for up to one year, thus potentially causing outbreaks. in a median age shift of rubella cases to young adults, Infants that survive the neonatal period may face serious which may result in more CRS cases.

RATIONALE AND OBJECTIVES OF SURVEILLANCE

Surveillance for CRS complements rubella surveillance. hh detect and isolate affected infants rapidly Rubella surveillance cannot capture every case of rubella hh mitigate the consequences of the disease for infants since it is frequently mild or . CRS is the and their families through early provision of most severe outcome of rubella, and the prevention of appropriate medical care CRS is the primary reason for rubella vaccination. Thus, h the goals for CRS surveillance are linked to national h demonstrate the elimination of CRS. goals for rubella vaccination, including monitoring The key global objective of CRS surveillance is to progress to achieve and maintain elimination. The provide data in support of rubella elimination in five of objectives for CRS surveillance are to: six WHO regions by 2020. hh document the burden of CRS prior to rubella vaccine introduction hh monitor the impact of rubella vaccine introduction in reducing the incidence of CRS

3 WHO Vaccine-Preventable Diseases Surveillance Standards BOX Complementary relationship between rubella surveillance 1 and CRS surveillance

CRS surveillance is addressed separately from clinical rubella surveillance in these surveillance standards because the surveillance systems for the two manifestations of rubella infection differ substantially in terms of case definitions, age groups of interest and sites of case detection. However, both rubella and CRS are manifestations of infection with rubella virus and are linked in terms of public health significance and implications for vaccination. As CRS is the most serious consequence of rubella virus infection, surveillance for CRS is important for monitoring the impact of rubella vaccination and progress towards rubella elimination.

TYPES OF SURVEILLANCE RECOMMENDED

MINIMAL SURVEILLANCE CASE DETECTION The minimal recommended standard is sentinel- hh Facility-based surveillance is preferred because site, case-based CRS surveillance with laboratory infants with the birth defects associated with CRS confirmation. The main target age group for CRS present to secondary, tertiary or specialty hospitals/ surveillance is infants < 12 months of age. All countries sites, and the case definition requires clinical that have introduced rubella vaccine should have evaluation. a CRS surveillance system that has the ability to hh If conducting sentinel-site CRS surveillance, capture the majority of infants with suspected CRS establish a programme at selected sentinel hospitals within the country. Because CRS is a constellation of and other sites that capture the majority of infants congenital abnormalities that may have other causes, with suspected CRS. Tertiary care and specialty CRS surveillance requires a high level of specificity, hospitals most likely to receive infants with cataracts, and thus laboratory confirmation is critical (see Case heart defects and hearing impairment should be definitions section). Surveillance systems based on prioritized as sentinel sites for establishing CRS aggregate reporting without laboratory confirmation are surveillance. Later, surveillance can be expanded to inadequate for CRS surveillance. Pregnancy registries include additional sites that have contact with more can complement CRS surveillance systems, but are of the population. insufficient for identifying the majority of CRS cases, as h rubella generally causes a mild or asymptomatic clinical h In most settings, a combination of passive and illness. active approaches should be employed to increase the likelihood that all CRS cases will be captured ENHANCED SURVEILLANCE by surveillance within the included health facilities. The recommendation for enhanced surveillance is Specialists in ophthalmology, , ear/nose/ national case-based, surveillance system (passive, active throat and paediatrics should be sensitized on the or both) with laboratory confirmation. process for reporting and investigating CRS cases.

4 Congenital Rubella Syndrome Congenital Rubella Syndrome

hh During active surveillance visits to a site, conduct a Details on how to set up CRS surveillance can be found review of medical records (including admission and in Introducing Rubella Vaccine Into National discharge records) in units where infants who have Programmes: A Step-by-Step Guide (2). manifestations consistent with CRS are likely to be seen (for example, neonatal ward, paediatric surgical LINKAGES TO OTHER SURVEILLANCE ward, and eye, cardiac and ear clinics). CRS surveillance with laboratory confirmation can be hh As part of a comprehensive CRS surveillance system, incorporated into existing surveillance as test and follow up with pregnant women who were part of an enhanced birth defect surveillance system, detected through - surveillance either as or into other surveillance systems capturing congenital suspected -rubella cases or from exposure cataracts. Enhanced birth defect surveillance might to confirmed rubella cases. Rubella in pregnancy include expansion of existing birth defect surveillance registries can be used at the local level. These (3) to include ages up to 12 months and key CRS signs registries usually contain maternal demographic (such as congenital cardiac defects). Pregnant women information, test results, contact information and with rubella identified as part of integrated measles- pregnancy outcomes (delivery status of baby and rubella surveillance should be followed and birth birth defects). Infants identified as suspected or outcomes monitored to identify potential CRS cases confirmed CRS should be included in the CRS through rubella pregnancy registries. surveillance system. hh Clinicians should notify public health of suspected CRS cases immediately.

CASE DEFINITIONS AND FINAL CLASSIFICATION

SUSPECTED CASE DEFINITION FOR CASE FINDING B. Purpura, splenomegaly, microcephaly, developmental h h Any infant < 12 months of age that presents with delay, , radiolucent bone disease, any of the following: jaundice that begins within the first 24 hours after »» congenital heart disease birth.

»» suspicion of hearing impairment Using these clinical signs, one of the final classifications listed below may be made. » » one or more of the following eye signs: h (white pupil), congenital glaucoma (larger h Laboratory-confirmed CRS: A suspected CRS case eyeball) or pigmentary retinopathy. with at least one sign from group A and meets the laboratory criteria for confirmation of CRS (see h h Any infant < 12 months of age in whom a health Laboratory section). worker suspects CRS, even without apparent signs h of CRS, including maternal history of suspected or h Clinically compatible CRS: A suspected CRS case confirmed rubella during pregnancy. without an adequate specimen in whom a qualified clinician detects at least two of the complications FINAL CASE CLASSIFICATION from group A OR one from group A and one from group B. Final classification of CRS cases depends, in part, on identifying Group A or Group B clinical signs of CRS. hh Congenital rubella infection (CRI): An infant who has none of the clinical signs of CRS from group A, A. Cataract(s), congenital glaucoma, pigmentary but who meets the laboratory criteria for CRS. retinopathy, congenital heart disease (most commonly peripheral pulmonary artery stenosis, hh Discarded: A suspected CRS case with an adequate or ventricular septal defects), specimen not meeting the laboratory-confirmed case hearing impairment. definition, or a suspected case without an adequate laboratory specimen and not meeting the clinically compatible case definition.

5 WHO Vaccine-Preventable Diseases Surveillance Standards OTHER DEFINITIONS FOR CRS CASES country during gestation, as supported by hh Source of infection epidemiological or genotyping evidence. » » CRI/CRS: A confirmed case whose »» Unknown source of CRI/CRS: A confirmed mother was exposed to endemic rubella case not meeting the above endemic or imported during gestation, as supported by CRI/CRS case definitions. epidemiological or genotyping evidence. A chain Figures 1a and 1b show how to classify suspected CRS of rubella virus transmission that is continuous cases by ELISA testing. Guidance for case confirmation for ≥ 12 months within a country is defined as an by virus detection is in the Specimen collection section endemic transmission. of this document. »» Imported CRI/CRS: A confirmed case whose mother was exposed to rubella outside of the

FIGURE Surveillance classification of suspected CRS case-patients 1a < 6 months of age

6 TO < 12 SUSPECTED CRS CASE FIGURE MONTHS 1b OF AGE →

< 6 MONTHS OF AGE

BLOOD SAMPLE BLOOD SAMPLE NOT OBTAINED* OBTAINED

DOES IgM- IgM+ MEETS NOT MEET CLINICAL CLINICAL CRITERIA CRITERIA FOR CRS FOR CRS WITHIN 1ST PRESENCE NO DISCARDED MONTH OF ≥ 1 DEFECTS OF LIFE, DEFECT FROM AND HIGH FROM CLINICALLY GROUP A DISCARDED SUSPICION GROUP A COMPATIBLE OF CRS

INFECTION ONLY CONFIRMED (CRI)

FOLLOW-UP TEST 1-2 MONTHS LATER

IgM- IgM+

*Every effort should be made to obtain a blood sample of adequate size (1ml) and that is kept cool DISCARDED CONFIRMED during transport.

6 Congenital Rubella Syndrome Congenital Rubella Syndrome

FIGURE Surveillance classification of suspected CRS case-patients 1b ≥ 6 months to < 12 months of age

< 6 SUSPECTED CRS CASE FIGURE MONTHS 1a OF AGE →

6 TO < 12 MONTHS OF AGE

BLOOD SAMPLE BLOOD SAMPLE NOT OBTAINED* OBTAINED

SECOND BLOOD IgG+ IgG+ IgG- & SAMPLE & IgM- & IgM+ IgM- / IgM+ NOT OBTAINED

SECOND BLOOD SAMPLE DISCARDED OBTAINED DOES MEETS NOT MEET CLINICAL CLINICAL CRITERIA CRITERIA IgG- IgG+ FOR CRS FOR CRS

CLINICALLY DISCARDED DISCARDED COMPATIBLE

PRESENCE NO OF ≥ 1 DEFECTS DEFECT FROM FROM *Every effort should be made to GROUP A GROUP A obtain a blood sample of adequate size (1ml) and that is kept cool during transport. INFECTION Note: For IgG+ sera, confirm that ONLY CONFIRMED suspected case has a low likelihood (CRI) of vaccination or of having postnatal rubella.

7 WHO Vaccine-Preventable Diseases Surveillance Standards CASE INVESTIGATION

Suspected CRS cases should be investigated within 48 infant is followed up with appropriate clinical and hours of detection. Use a standard case investigation laboratory evaluation, and placed under droplet and form for investigation of all suspected cases and include contact precautions to minimize potential spread. clinical examination for CRS-related signs, especially After rubella elimination, a single case of domestically those that benefit from early intervention. Specimens acquired CRS should lead to intensified rubella and should be taken for laboratory confirmation of all CRS surveillance and an investigation to determine suspected CRS cases. where the mother was exposed and the reason for Monitor the pregnancy outcomes for pregnant insufficient . women with suspected or confirmed rubella. For those that result in a live birth, ensure that the

SPECIMEN COLLECTION

SERUM SPECIMENS SPECIMENS FOR VIRAL DETECTION Serum specimens from infants for serological testing are Specimens for viral detection are also acceptable for the most common specimens used for CRS diagnosis. diagnosing CRS. The best results come from throat Collect specimens at first contact during the initial swabs, but nasal swabs, urine, serum or dried blood investigation; ideally, collect both a serum specimen for spots (in remote locations where serum transport is not serologic testing alongside a sample for viral detection. possible) may also be used. Other specimens such as As indicated below, additional samples may be needed in cerebrospinal fluid or cataracts are also possible sources infants < 1 month of age or individuals > 6 months of age. of virus detection depending on the clinical picture, though performance characteristics of viral detection hh If an infant is < 1 month of age with a high suspicion have not been established for these alternative specimen of CRS and a negative IgM , then a second types and negatives do not necessarily rule out a case. specimen should be collected after one month to Details on collection of these specimens can be found retest for IgM, as IgM seropositivity can be delayed elsewhere (4). until after the first month of life (false-negative for ages < 1 month). STORAGE AND TRANSPORT h h For infants ≥ 6 months of age but < 12 months with Whole blood/serum. Collection of whole blood is done an initial positive rubella IgG serology, a second by venipuncture using a sterile, plain collection tube or serum specimen for IgG should be collected after gel separator tube without additives. Whole blood can one month and tested in parallel with the initial be stored at 4−8°C (never freeze whole blood) for up to serum specimen to assess if there is a sustained 24 hours or for 6 hours at 20–25°C before the serum is rubella IgG response. separated from the clotted blood through centrifugation. If possible, 1 mL of blood in infants should be collected, After this time, whole blood must be transported to a although 0.5 mL can be acceptable in very small infants, facility equipped to separate the serum in order to avoid or dried blood spots (≥ 3 fully filled circles). haemolysis.

8 Congenital Rubella Syndrome Congenital Rubella Syndrome

Serum should be stored at 4−8°C until shipment, but swabs with plastic shafts. Do not use calcium alginate ideally should not be held at 4-8°C for longer than swabs or swabs with wooden shafts as they may contain seven days. For longer periods, such as when a delay is substances that inactivate and/or inhibit PCR anticipated in shipping or testing, serum samples must testing. be frozen at –20°C or below and transported to the The throat swab is collected by swabbing the posterior testing laboratory on frozen ice packs in a sufficiently , avoiding the tongue. The NP swab has a insulated container. Avoid cycles of repeated freezing flexible shaft. Tilt the patient’s head back and insert the and thawing, as this can have detrimental effects on swab into the nostril parallel to the palate. The swab the integrity of IgM . Aliquots of important should contact the mucosal surface. Place the sample serum specimens should be prepared prior to freezing. in sterile tubes containing 2–3 mL of viral transport As a general rule, serum specimens should be shipped to media (VTM) or phosphate-buffered saline (PBS). It the laboratory as soon as possible, and shipment should is important to prevent the swabs from drying out. The not be delayed for the collection of additional specimens. throat and NP swabs may be refrigerated at 2–8°C for Blood can be dried onto filter paper (dried blood spots, up to 48 hours and shipped on ice/frozen ice packs. If or DBS) if venipuncture is not possible, or if a cold arrangements cannot be made for shipment within this chain or economical method to ship serum samples are timeframe, it is best to preserve the sample at -70°C. not available. While venous blood can be collected for After freezing at -70°C, the samples are shipped on DBS, normally DBS are prepared using capillary blood. dry ice. Avoid freeze/thaw cycles. If storage at -70°C Collect blood by finger- or heel-prick using a sterile is not available, store samples at -20°C; viral viability lancet, preferably a single-use disposable lancet. Allow will be lost, but the integrity of the viral RNA may be blood specimens that have been spotted on filter paper maintained and detected by RT-PCR. to air dry completely. Wrap individual cards in wax paper Urine. Urine is collected in a suitable sterile, leak-proof and place them in a sealable plastic bag with a desiccant container. The urine sample should be stored at 4–8°C pack. DBS should be stored at 4°C until they can be until the urine can be centrifuged. Do not freeze the shopped to the laboratory. It is acceptable to transport original urine sample prior to centrifugation. Whole DBS at ambient temperatures up to 42°C if the sample urine samples may be shipped in sealed containers at is delivered to the laboratory within three days. 4°C, but centrifugation within 24 hours of collection Oral fluid (OF). An adequate OF sample is one that is is recommended. The urine is centrifuged at 500 × g collected by gently rubbing along the base of the teeth (approximately 1500 rpm) for 5–10 minutes, preferably and gums for at least one minute, which should allow at 4°C and with the supernatant removed. Add sterile the sponge to absorb about 0.5 mL of crevicular fluid. VTM, tissue culture medium or phosphate-buffered If the daily ambient temperature is below 22°C, OF saline to the sediment to bring the final volume to 2 samples should be shipped to the laboratory within 24 mL. If a pellet is not visible, remove all but 1 mL at hours. At higher temperatures, the OF samples should the bottom of the centrifuge tube and mix with equal be kept at 4–8°C until the samples can be shipped to volume of VTM. Store the processed urine sample the laboratory on cold packs. The OF samples are not at 4°C and ship within 48 hours. Alternatively, the considered a biohazard and can be shipped without urine sample may be frozen at -70°C in viral transport special documentation from the site of collection to the medium and shipped on dry ice. If storage at -70°C laboratory. is not available, samples can be stored at -20°C; viral viability will be lost, but the integrity of the viral RNA Nasopharyngeal (NP), nasal or throat swabs. An may be maintained and detected by RT-PCR. oropharyngeal (throat swab) is the recommended sample for both viral detection and virus isolation for suspected Regardless of specimen type collected, all specimens cases. NP swabs will serve as good samples for both should arrive to the laboratory within five days of virus isolation and detection but are more difficult to collection, except in the case of oral fluids as noted collect. NP aspirates and nasal swabs are variations above. that have been used successfully to detect rubella virus. Swabs should be collected using only synthetic fiber

9 WHO Vaccine-Preventable Diseases Surveillance Standards LABORATORY TESTING

Laboratory confirmation of congenital rubella infection GENOTYPE TESTING or syndrome in an infant meets one of the following Genotyping plays a similar role in CRS as it does in criteria: rubella surveillance, providing information potentially on the source of the virus. In a post-elimination setting, h for infants < 6 months of age, rubella IgM antibody h genotype testing should be conducted on every CRS detected case < 12 months of age. In an endemic setting, genotype h h for infants ≥ 6 months but < 12 months of age, testing should be conducted at least once for every chain rubella IgM and IgG detected, OR a of rubella transmission. sustained rubella IgG antibody level, as determined on at least two occasions at least one month apart in LABORATORY NETWORKS the absence of receipt of rubella vaccine or exposure WHO coordinates the Global Measles and Rubella to wild-type rubella Laboratory Network (GMRLN). Regional and global hh for infants any age < 12 months, rubella virus reference laboratories can provide specialized testing detection by or PCR in an appropriate such as viral isolation with molecular techniques to clinical sample (throat, NP, or nasal swabs, blood, those countries that are unable to perform this in urine or cerebrospinal fluid specimens). their own laboratories. Ensure that samples are tested in a WHO accredited or proficient laboratory, or in Although IgM antibodies may persist for up to one year, laboratories with quality assurance support from national about 50% of CRS cases are IgM negative at 6 months labs in GMRLN. If this is not possible, then use a of age, depending on test sensitivity. Because IgM may laboratory that has an established a recognized quality not be detectable in some infants tested shortly after assurance programme such as ISO 15189 or ISO 17025 birth, IgM-negative infants with suspected CRS should accreditation, or Clinical Laboratory Improvement be retested at 1 month of age or shortly thereafter. Amendments (CLIA) certification. Laboratory confirmation of CRS in an infant older than 6 months of age should not rely on the IgM test alone if the IgM result is negative. In such cases, as mentioned, serial IgG testing should be done after at least one month to check for a sustained level of IgG antibody over several months.

10 Congenital Rubella Syndrome Congenital Rubella Syndrome

DATA COLLECTION, REPORTING AND USE

RECOMMENDED DATA ELEMENTS • Pigmentary retinopathy h h Demographic information • Purpura » » Child • Radiolucent bone disease • Name (if confidentiality is a concern the • name can be omitted so long as a unique • Meningoencephalitis identifier exists) • Microcephaly • Unique case identifier • Jaundice < 24h from birth • Place of residence (city, district, and province) • Other • Age/date of birth »» Outcome (patient survived, died, unknown) • Sex • Date of death • Age when case detected hh Laboratory methods and results (performed on • Race and/or ethnicity, if appropriate in infant) country setting »» Types of specimen(s) collected • Country of birth » »» Mother » Date(s) of specimen(s) collection » • Name (if confidentiality is a concern the » Date(s) specimen(s) sent to laboratory name can be omitted so long as a unique »» Date(s) specimen(s) received in laboratory identifier exists) »» Serology and/or viral detection results for each • Age at birth of affected child specimen type • Country of birth (for help determining »» Genotype mother’s rubella vaccination status) » hh Reporting Information » Follow up specimen collection #1: type, date, result »» Place of reporting (e.g., name of health facility, » county, district) » Follow up specimen collection #2: type, date, result »» Date of notification hh Maternal history »» Date of case investigation »» Gravida (number of pregnancies) h Clinical h » » » Para (number of pregnancies carried to viable » worker suspects CRS? gestational age) » » Signs and Symptoms »» History of rubella-like illness during pregnancy?

• Cataracts (unilateral, bilateral) • If yes, month (or weeks) of gestation • Hearing impairment • Was rubella diagnosed by a health care • Developmental delay worker at the time of illness? • (please specify) –– If yes, confirmed by laboratory? • Congenital glaucoma • Identified as part of pregnancy tracking register?

11 WHO Vaccine-Preventable Diseases Surveillance Standards » » Was the mother directly in contact with someone hh Maternal characteristics including age group, race/ with confirmed rubella during pregnancy? If yes, ethnicity, country of birth, location of exposure, what month of gestation? vaccination status, gravida/para » » Vaccination history of mother hh Number of CRS cases with maternal history of rubella-like illness in pregnancy (including month • Number of doses of rubella containing or week of gestation during illness, whether this was vaccine given clinically compatible or laboratory-confirmed, and • Dates of vaccination whether she was included in a pregnancy registry) hh Location and exposure history hh Proportion of cases clustered or associated with a » » If location of exposure unknown, did mother rubella outbreak travel outside the country of residence during h Spot maps of confirmed CRS cases by year pregnancy? (If yes, list countries visited and h month of gestation) hh Age of CRS case at time of diagnosis (< 1 month, 1–5 months, 6–11 months) hh Classification h Number of infants with follow-up samples to »» Final case classification (laboratory-confirmed h confirm clearance of virus CRS, clinically compatible CRS, CRI, discarded) CRS surveillance data should be triangulated with »» Source (imported, endemic, unknown) rubella surveillance data. For instance, after a rubella

REPORTING REQUIREMENTS AND outbreak in women of childbearing age, there may be an RECOMMENDATIONS increase in CRS cases in the same area in the following months, typically 6–8 months later). CRS cases should be reported separately from clinical rubella cases. The clinician should transmit the case USING DATA FOR DECISION-MAKING notification form or set of core information to the local h epidemiologist or public health personnel. After case h Isolate infants in healthcare settings with CRS to investigation is completed, case-based data should be prevent further spread of rubella. transmitted from local levels to higher administrative hh Document the burden of CRS prior to rubella levels of the surveillance system, including to the vaccine introduction. national level/MOH. CRS should be reported annually h Monitor the impact of rubella vaccine introduction by every WHO Member State in the Joint Reporting h in reducing the incidence of CRS. Form ( JRF). CRS is not currently reportable under International Health Regulations (IHR 2005). hh Understand the epidemiology of CRS and its burden in the population in order to guide rubella RECOMMENDED DATA ANALYSES immunization strategies, including the need to fill hh Final case counts by final case classification, month/ immunity gaps in adolescents and young adults. year and geographic area (province, district, etc.); hh Determine risk factors for CRS, such as mothers confirmed cases by source of infection (endemic, who may have migrated from a country where imported/import-related, unknown) rubella vaccine is not yet introduced or recently hh CRS incidence (number of CRS cases per 1 000 live introduced. births) by year hh In conjunction with rubella surveillance data, help hh Clinical characteristics (types of birth defects) and demonstrate the status of achieving or maintaining outcome of CRS cases rubella elimination goals.

12 Congenital Rubella Syndrome Congenital Rubella Syndrome

SURVEILLANCE PERFORMANCE INDICATORS

CRS surveillance systems should be evaluated annually of all cases that meet the suspected CRS case definition. to assess completeness of CRS reporting at surveillance Review the indicators below at least annually. Data sites. This should include hospital record review to gathered from CRS surveillance system evaluations identify any missed cases. Missed cases can be identified should be included in National Verification Committee by comparing the list of reported CRS cases with the list (NVC) reports for measles/rubella/CRS.

TABLE 1 Surveillance performance indicators for CRS

HOW TO CALCULATE SURVEILLANCE INDICATOR TARGET (NUMERATOR / COMMENTS ATTRIBUTE DENOMINATOR) # of designated Percentage of reporting units in the designated units country reporting by TIMELINESS OF reporting to the At each level reports should be received ≥ 80% the deadline / # of national level on on or before the requested date. REPORTING designated reporting time, even in the units in the country x absence of cases 100 # of designated Percentage of reporting units in the designated units country submitting COMPLETENESS submitting 12 ≥ 80% 12 reports in the last monthly reports per OF REPORTING year / # of designated year, even in the reporting units in the absence of cases country x 100 An adequate CRS case investigation includes collection of all the following data elements: name and/or unique Percentage of all # of suspected cases identifier, place of residence, date of ADEQUACY OF suspected CRS of CRS for which an birth, sex, date of notification, date that have had adequate investigation of investigation, date of specimen INVESTIGATION an adequate ≥ 80% was initiated within 48 collection, history of rash illness of mother, investigation hours of notification / # travel history of mother, vaccination initiated within 48 of suspected CRS cases history of mother, age of mother, clinical hours of notification x 100 examinations for hearing impairment, cataract, and congenital cardiac (heart) defects and clinical outcome (alive/dead) at time of investigation. National annual # of suspected CRS ≥ 1/10 000 SENSITIVITY rate of suspected cases / live births x live births CRS cases 10 000

Note 1: An adequate specimen is a blood Percentage of sample by venipuncture in a sterile tube suspected cases # of suspected cases with a volume of at least 0.5 mL. SPECIMEN with adequate with an adequate A proficient laboratory is one that COLLECTION blood specimens for specimen tested in a Note 2: ≥ 80% is WHO accredited or has established AND TESTING detecting rubella proficient laboratory/ a recognized quality assurance ADEQUACY infection collected # of suspected cases programme such as International and tested in a x 100 Organization for Standards (ISO) or proficient laboratory Clinical Laboratory Improvement Amendments (CLIA) certification.

13 WHO Vaccine-Preventable Diseases Surveillance Standards HOW TO CALCULATE SURVEILLANCE INDICATOR TARGET (NUMERATOR / COMMENTS ATTRIBUTE DENOMINATOR) Percentage of # confirmed cases with An adequate specimen is a throat swab, ADEQUACY OF confirmed cases an adequate specimen NP swab or aspirate, nasal swab, serum, SPECIMENS with adequate for viral detection urine or clinical specimen based on ≥ 80% FOR VIRAL specimens tested tested in a proficient symptoms (e.g. cataracts, cerebrospinal DETECTION for virus detection/ laboratory/ # of fluid specimen). Usual specimen is throat isolation confirmed cases x 100 swab. # of confirmed CRS cases aged ≤ 12 COMPLETENESS Percentage of months with at least 2 confirmed CRS negative tests for virus OF MONITORING cases demonstrated ≥ 80% detection and samples FOR VIRAL to no longer be collected at least a SHEDDING shedding virus month apart / # of confirmed CRS cases aged ≤ 12 months # of confirmed Percentage of CRS and CRI cases This should include individuals found TIMELINESS OF CRS and CRI cases detected within 3 ≥ 80% through active case search in both the detected within 3 months of birth / # of CASE DETECTION numerator and denominator months of birth confirmed CRS or CRI cases x 100 Percentage of # of specimens TIMELINESS specimens (serologic received within 5 or virologic) received days of collection Indicator only applies to public OF SPECIMEN ≥ 80% at the laboratory at laboratory / # of laboratories. TRANSPORT within 5 days of specimens collected collection x 100 Percentage of # of serologic results TIMELINESS serologic results reported within 4 days OF REPORTING reported by the Indicator only applies to public ≥ 80% of specimen receipt / # laboratory within 4 laboratories. LABORATORY of specimens received days of specimen RESULTS by laboratory x 100 receipt

CLINICAL CASE MANAGEMENT

No current treatment is available for CRS beyond CRI; if exposed, pregnant contacts should be tested for clinical management of related congenital abnormalities. rubella. In areas where follow-up testing of confirmed Infants with CRS and CRI shed live rubella virus for CRS and CRI cases is not feasible, emphasis must long periods (60% shed for the first four months of life), be placed on ensuring close contacts and health care therefore appropriate infection control measures should workers are vaccinated for rubella. be applied. In health care settings, contact precautions Note: Infants with confirmed CRS or CRI should be should be implemented for every detected CRS and followed by public health until two consecutive clinical CRI case. Infants should be considered infectious until specimens, obtained one month apart, are negative for two clinical specimens, obtained one month apart, are rubella virus detection/isolation. negative for rubella virus detection/isolation. Pregnant women should not be exposed to infants with CRS or

14 Congenital Rubella Syndrome Congenital Rubella Syndrome

CONTACT TRACING AND MANAGEMENT

Contact tracing is recommended among mothers of further transmission, protective immunity should be infants with CRS or CRI to identify the source of the assured among contacts of CRS cases, including health rubella virus in the mother. Infants with CRS or CRI care workers and family members. Persons in contact shed rubella virus for long periods (60% for the first with the infant should be immune to rubella either four months of life), and appropriate infection control through vaccination or natural infection (serological measures should be applied. It is particularly important evidence of immunity). Non-pregnant persons who that pregnant women who are not rubella-immune lack documentation of immunity should be vaccinated. should not be exposed to infants with CRS or CRI. Pregnant contacts should be tested as outlined in the To prevent further infection with rubella virus and rubella surveillance chapter.

SURVEILLANCE, INVESTIGATION AND RESPONSE IN OUTBREAK SETTINGS

An increase in CRS cases generally occurs six to eight enhanced with active case finding in facilities located months after outbreaks of rubella infection. Detecting in outbreak areas. This can help identify infants with an increase in CRS cases can be a signal for wider CRS or CRI who are shedding live rubella virus and rubella virus circulation in the population, indicating the prolonging the outbreak. CRS surveillance should possible occurrence of a past or current rubella outbreak. continue for a minimum of nine months after the last rubella case. During rubella outbreaks, CRS surveillance should be established or strengthened in maternity hospitals, During rubella outbreaks, a pregnancy registry should paediatric hospitals, neonatal intensive care units and be established, if not already in place, to document all amongst specialists who treat infants with cardiac, pregnancy outcomes of infected and exposed women. hearing or eye deficits. If not already a sentinel site, Outcomes include , fetal deaths, CRS cases, hospitals located in the area where the outbreak is infants with congenital rubella infection, and unaffected occurring should become a sentinel site. If a passive infants. surveillance system for CRS is in place, it should be

15 WHO Vaccine-Preventable Diseases Surveillance Standards SPECIAL CONSIDERATIONS FOR CRS SURVEILLANCE

RETROSPECTIVE REVIEW OF MEDICAL RECORDS SEROLOGICAL SURVEYS OF REPRODUCTIVE-AGE WOMEN Retrospective medical record review should be used to monitor the sensitivity of CRS surveillance systems Serological assessments of rubella IgG antibody levels annually. For countries unable to establish or maintain among reproductive-age women in a survey setting CRS surveillance, retrospective record review can be may help evaluate population immunity against rubella conducted to identify CRS cases. Medical records and protection against CRS in newborns. Rubella review in itself is not considered surveillance, but can IgG can be acquired through both vaccination and inform disease burden estimates or provide baseline data natural infection, therefore serosurveys are not purely a for measuring the impact of vaccine introduction for reflection of vaccination coverage. A serological survey a country. It also can be used in special circumstances is not a substitute for conducting CRS surveillance, but (for example, countries with a small population) where can provide complimentary information. it is believed that CRS elimination has already been achieved. However, a limitation of this approach is that retrospectively identified cases usually lack laboratory confirmation, and therefore lack a definitive diagnosis. Details can be found in the Introducing Rubella Vaccine Into National Immunization Programmes: A Step-by-Step Guide (2).

REFERENCES

REFERENCES CITED 1. World Health Organization. Rubella : WHO position paper. Wkly Epidemol Rec. 2011;86(29):301–16 (http://www.who.int/wer/2011/wer8629.pdf?ua=1). 2. World Health Organization. Introducing rubella vaccine into national immunization programmes: a step-by-step guide. Geneva: World Health Organization; 2015 (http://www.who.int/immunization/documents/who_ivb_15.07/en/). 3. World Health Organization, Centers for Disease Control and Prevention & International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). Birth defects surveillance: a manual for programme managers. Geneva: World Health Organization; 2014 (http://www.who.int/nutrition/publications/birthdefects_manual/en/). 4. World Health Organization. Manual for the laboratory-based surveillance of measles, rubella, and congenital rubella syndrome, 3rd edition. Geneva: World Health Organization; 2018 (http://www.who.int/immunization/monitoring_surveillance/ burden/laboratory/manual/en/)

ADDITIONAL REFERENCES 5. Centers for Disease Control and Prevention. Control and prevention of rubella: evaluation and management of suspected outbreaks, rubella in pregnant women, and surveillance for congenital rubella syndrome. MMWR Morb Mortal Wkly Rep. 2001;50(RR12):1–23 (https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5012a1.htm). 6. World Health Organization. Framework for verifying elimination of measles and rubella. Wkly Epidemiol Rec.2013;88(9): 89-99 (http://www.who.int/wer/2013/wer8809.pdf). 7. World Health Organization. Roadmap to elimination standard measles and rubella surveillance. Wkly Epidemiol Rec. 2017;92(9-10): 97–105 (http://apps.who.int/iris/bitstream/10665/254652/1/WER9209-10.pdf?ua=1).

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