Medical Journal of Zambia, Vol. 41, No. 1 (2014)

ORIGINAL ARTICLE Laboratory-confirmed Congenital Rubella Syndrome at the University Teaching Hospital in Lusaka, Zambia-Case Reports

* M.L. Mazaba-Liwewe1,2, A. Mtaja3, C. Chabala3, S. Sinyangwe4, O. Babaniyi5, M. Monze2, S. Siziya6, C. Michelo7 1EPI Unit, World Health Organization, Lusaka, Zambia 2Virology Unit, University Teaching Hospital, Lusaka, Zambia 3 Department of Paediatrics and Child Health, University Teaching Hospital, Lusaka, Zambia 4Department of Paediatrics and Child Health, School of Medicine, University of Zambia, Lusaka, Zambia 5WHO Country Office, World Health Organization, Lusaka, Zambia 6Clinical Sciences Department, Copperbelt University, Ndola, Zambia 7Department of Public Health, University of Zambia, Lusaka, Zambia

ABSTRACT have bilateral cataracts, congenital heart disease and microcephaly. Rubella Immunoglobulin M (IgM) results Background: Congenital rubella syndrome (CRS) were positive. The third case, a girl, was seen at twelve caused by rubella infection in uterine, is a major public weeks and brought in for slow growth rate. On health problem among women of child bearing age as it causes serious complications including foetal death or examination, the girl was found to have bilateral abnormalities including cardiovascular, ophthalmologic, cataracts, microcephaly and developmental delay. The respiratory and hearing impairment. Though there is fourth case is a girl who was brought to the hospital for evidence of rubella infection amongst the population failure to thrive, tachypnea and fever. On further under the expanded programme on immunization (epi) investigations there was evidence of cataracts, patent surveillance programme, there is no documented ductus arteriosus. At eight weeks, she tested positive for evidence of laboratory confirmed congenital rubella syndrome cases in Zambia. A report is given on four cases rubella IgM antibodies. of CRS that were identified and confirmed during routine Conclusion: The clinical symptoms and laboratory activities of the national measles surveillance program in Zambia. Clinical data on the symptomatic cases were evidence of rubella infection confirmed congenital collected and serum samples tested for rubella IgM to rubella syndrome in the four patients. There is an urgent confirm the cases. need for surveillance of congenital rubella syndrome and a baseline rubella sero-prevalence survey in Zambia in Case presentation: The first confirmed case was a baby order to determine the burden of the disease and use this girl presented to the Neonatal Intensive Care unit of the data to direct policy in terms of interventions for University Teaching Hospital for low birth weight and supportive treatment, control and possible elimination of hypothermia. At seven weeks, the girl was found to have rubella infection through immunization with measles- cataracts, spleno-hepatomegaly, microcephaly, and rubella vaccine. patent ductus arteriosus (PDA). The baby tested positive to rubella IgM antibodies. The second case was a baby BACKGROUND boy who was first seen at the University Teaching Hospital at three weeks and on examination was found to Congenital Rubella Syndrome (CRS) is a major public health problem among young women in *Corresponding author: Mazaba-Liwewe M L Virology Unit, University Teaching Hospital, Keywords: Congenital Rubella Syndrome; Confirmed; Lusaka, Zambia Measles-Rubella vaccine; Lusaka, Zambia

24 Medical Journal of Zambia, Vol. 41, No. 1 (2014) childbearing age causing serious consequences infection under the age of 15 years presenting including , foetal death or an with fever and rash for measles primarily then born with defects [1]. Although an effective rubella. Though there is evidence of rubella vaccine against rubella is available, CRS infection amongst this population under remains a major public health problem with a surveillance, there is no documented evidence total of 121,344 cases reported from 167 of laboratory-confirmed CRS cases in Zambia. countries to World Health Organisation (WHO) Using a model by Miller et al. [5] and data in 2009, showing a significant decrease from stemming from a study by Watts [6] on rubella 67,894 during 2000 in 102 WHO member antibodies in a sample of Lusaka mothers, Cutts states. The greatest part of the decrease was in et al. [3] estimated the incidence of CRS to be at the United States of America and Europe of 123/100 000 live births in Zambia [5-7]. nearly 100%, followed by the East Mediterranean Region (EMRO) at 35%. All Early diagnosis of infant rubella infection in these regions had set elimination goals and CRS cases may allow for the reversal of certain introduced a rubella containing vaccine (RCV) disabilities as well as the disruption of routine. In contrast, 20, 14 and 12 fold continued virus spreading as it has been increases were reported in the African region documented that children born with rubella (AFRO), as well as the South East Asia and infection may continue to shed the virus for Western Pacific regions (SEARO), even up to one year and hence should be respectively. In 2009,165 CRS cases were considered infectious. In order to monitor the reported from 75 WHO member states globally. presence of CRS and control the continued [2,3] Studies by Cutts et al. [3] indicating spread of rubella infection, laboratory-backed proportions of women susceptible to rubella routine surveillance is a necessity. (sero-negative) in the Africa region report less This article describes four case reports of CRS than 10% in 13, 10-25% in 20 and more than that were identified and confirmed during 25% in 12 countries. Zambia is estimated to be routine activities of the national measles in the 10-25%group. Cutts et al. [4] also surveillance programme in Zambia. Clinical document that 10% of 20 patients with data on the symptomatic cases were collected congenital cataracts and 12% of 34 with and serum samples tested for rubella IgM to congenital heart disease in Tanzania in 1980/81 confirm the cases. and 1985/86 had other symptoms compatible with CRS. Zimbabwe recorded 18 cases of Documenting the existence of CRS cases is CRS in 1978, and 10% of first legal abortions important and emphasizes the need to establish related to rubella infection were reported from the burden of disease in order to direct policy on South Africa. Tanzania, Senegal and Uganda control and possible elimination of this have also reported occasional cases of CRS [4]. devastating condition. In Zambia, there are no specific programmatic goals relating to the elimination or control of CASE PRESENTATION rubella disease and its consequences. The We present four confirmed cases of CRS seen at measles surveillance programme, a national the Teaching Hospital (UTH), Lusaka, Zambia case-based surveillance programme running between April 2012 and January 2013. since 2003 and supported by the WHO, has an Serological confirmation was performed using overall goal to investigate and document the number of children suspected of measles rubella–specific IgM (Immunoglobulin M) using ELISA. This was performed using the

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Siemens Enzygnost® Anti-Rubella Virus/IgM Further detailed inquiry of the mother antenatal assay, which is a qualitative and quantitative history reviewed that she had a minor rash at six based immune assay for the determination of weeks of which she 'contracted' from specific IgM antibodies to rubella virus in a neighbour's child. human serum or plasma. To prevent false positives due to rheumatoid factor (RF), pre- During follow-up, she was treated and discharged for and poor growth at 12 treatment with RF absorbent was implemented. weeks. She was notably microcephalic with The RF also binds specific IgG, thus increasing t h head circumference 34.5cm(below 5 sensitivity for detection of IgM. The difference percentile), weighed 2.34 kg and height 49cm in colour intensity/optical density between the (WHO weight-for-height z score <-2 standard antigen well and the control antigen well (? OD) deviation. At 12 weeks clinic review she had a gives the measure of the immunochemical cough, and tachypnoic (respiration rate at reactivity of the rubella virus specific IgM 84/minute) and fever (38.6oC) of 3 days antibodies in the sample. Any ? OD > 0.2 duration. Weight at this point was 2.43kg. She implies positive acute rubella infection, <0.1 is had course crepitations bilaterally. On the negative and otherwise is indeterminate. [8] cardiovascular system, S1 and S2 were heard and noted to be tachycardic but there were no Case 1 added sounds. Liver and spleen were both still palpable. Bilateral cataracts were also noted. A term low birth weight baby girl was seen and She was readmitted with a diagnosis of treated in the first week of life for hypothermia Pneumonia/viral pneumonitis secondary to and neonatal . Her birth weight was 1.7 kg congenital rubella syndrome. She was given and head circumference was 33cm. On physical Oxygen by nasal cannulae, and examination, she was noted to be in mild cloxacillin, the mother's expressed breast milk, respiratory distress with a hyperactive and normal saline nasal drops. Blood was collected for full blood count. The mother was precordium, marked tachycardia and a mild re-counseled and re-interviewed at which point systolic murmur in the left sternal border with she remembered that she had a rash at six weeks no hepatomegaly. Initial echocardiographic of pregnancy which she 'contracted' from a (ECHO) exam showed; patent ductus arteriosus neighbour's child. The full blood count results and peripheral pulmonary stenosis. The mother were as follows: HB – 11.9g/dl; Platelets – was a 28 year old, para 2 with unremarkable 360,000; White blood count – 23,000; antenatal history. At seven week, the baby Lymphocytes – 12,280; and Neutrophils – presented with generalised lymphadenopathy, 6,610. bilateral cataracts, conjunctivitis, tachycardia, hepatomegaly, splenomegaly and head At 7 days post admission, her cough had circumference of 34cm. She had gained weight subsided, probably a response to the treatment. to 2.4 kg. A clinical diagnosis of congenital She was well and her general TORCH infection possibly congenital rubella condition was good. Her physical examination revealed a head circumference of 34.5 cm – syndrome was entertained. The diagnosis was th confirmed with positive rubella IgM. Rapid way below the 5 centile; length 49 cm; weight for length

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Following the confirmation of the above CRS intrauterine infection with rubella virus. The case and sharing of information with clinicians signs and symptoms, commonly PDA and at the ' departmental meeting, three cataracts in the cases described in this article more cases described below with symptoms along with laboratory confirmation of rubella and signs suggestive of CRS were identified IgM (indicating active infection) support this and investigated. evidence. Confirmed CRS is defined as a clinically consistent case whose symptoms Case 2 include one or more specific signs and symptoms including cataracts or congenital A three week old boy was admitted to the glaucoma, congenital heart disease, hearing paediatrics ward with bilateral white papillary impairment, pigmentary retinopathy, purpura, reflex, congenital heart disease and hepatosplenomegaly, jaundice, microcephaly, microcephaly. ECHO showed patent ductus developmental delay, meningoencephalitis, or arteriosus. Ophthalmological examination radiolucent bone disease with a laboratory confirmed bilateral cataracts. Serum rubella evidence [4, 7, 9-10]. IgM was positive. Disease burden associated with Rubella Case 3 infection has continued to be of great public A twelve week old girl was brought to the health concern globally and is still a major and Paediatrics clinic for slow growth rate. On important cause of birth abnormalities. physical examination, the baby though Maternal infection during pregnancy can lead to generally active and in good condition, had CRS in the foetus [4, 6]. Identification of 4 bilateral cataracts, microcephaly and cases within a space of nine months in a developmental delay. A serum sample was defined/limited geographic area confirmed collected and tested in for rubella IgM. The circulation of rubella virus in Lusaka. In baby tested positive for rubella IgM. comparison to the other infections such as , Cytomegalovirus and Herpes Case 4 in the TORCH infection group, suggests it is an important cause of congenital abnormalities [7, A seven week old baby girl was seen at 11-13]. Many children born with CRS will Paediatrics outpatients' clinic for failure to demonstrate persistent neuromotor deficits later thrive, fever and difficulty in breathing. She in life. Pneumonitis, Diabetes mellitus, thyroid was treated for Pneumonia and Sepsis. Physical dysfunctions, and progressive panencephalitis examination showed poor growth, and heart are other late expressions of CRS [14-17]. murmurs and bilateral cataracts. Further Though the consequences of CRS are evaluation showed; Patent ductus arteriosus on devastating and long lasting, supportive ECHO, and bilateral cataracts on treatment can be given especially when detected ophthalmological evaluation. The rubella IgM early. [2, 17-18]. test was done at 8 weeks and revealed presence of rubella IgM antibodies. At the time of the There is scanty information on the evidence of report, the patient had an appointment CRS in Zambia or even the prevalence of scheduled a month later. Discussion susceptible women to rubella infection in pregnancy. Watts [6] documented an estimated The four cases that we have documented give 12%prevalence of vulnerable mothers in evidence of congenital rubella syndrome in Lusaka. These estimates were used by Cutts Zambia. CRS is a neonatal manifestation of and Vynnycky [5] to estimate a CRS incidence

27 Medical Journal of Zambia, Vol. 41, No. 1 (2014) rate of 123/100,000 live births. These statistics recommended by WHO and UNICEF and were reported more than a decade ago in one supported by GAVI [21-22] in national demographic area on a limited sample size. childhood immunization schedules. A clear and Data obtained through the measles surveillance well managed immunisation programme is program indicated that 21% of the rash and important in ensuring success in control and fever cases investigated were acutely infected eliminations of rubella as low vaccination with rubella virus in 2011 compared to 2.5% in coverage carries the theoretical risk of 2010 [19-20] suggesting an increase in the increasing the occurrence of congenital rubella. prevalence of CRS. After literature search, it [23] There is an urgent need for surveillance of was established that the four cases that we have congenital rubella syndrome and a baseline reported are the first laboratory-confirmed and rubella sero-prevalence survey in order to documented cases of CRS in Zambia. Since determine the burden of disease and use this CRS is a rare disease in immunized and non- data to direct policy in terms of interventions for outbreak communities [17], the incidence rate treatment, control and possible elimination of in Zambia in which vaccination against rubella rubella infection. has not been conducted may be underestimated. The cases described in this paper strongly CONSENT suggest evidence of rubella virus transmission Permission was granted by the Ministry of amongst pregnant women in Zambia. The Health after a waiver from the UNZA symptoms observed in three of the four cases, Biomedical Research Ethics Committee to particularly Patent Ductus Arteriosus are publish information relating to rubella infection suggestive of intra-uterine infection at <20 cases confirmed through the national measles weeks gestation [6-7, 9]. The observations surveillance programme. Letter attached. suggest presence of critical limitations in past and present surveillance efforts. List of abbreviations

CONCLUSION CRS: Congenital rubella Syndrome; WHO: World Health Organisation; EMRO: East Congenital Rubella Syndrome (CRS) is a major Mediterranean Regional; RCV: Rubella public health problem among young women in Containing Vaccine; AFRO: Africa Region; childbearing age causing serious consequences SEARO: South East Asia and Western Pacific including miscarriage, foetal death or an infant Region; UTH: University Teaching Hospital; born with abnormalities. The clinical OD: Optical Density; NICU: Neonatal symptoms and laboratory evidence of rubella Intensive Care Unit; PDA: Patent Ductus infection confirmed congenital rubella Arteriosus; IgM: Immunoglobulin M; RPR: syndrome in our four patients. Although the R a p i d P l a s m a R e a g i n ; T O R C H : disease is mild and probably missed, this To x o p l a s m o s i s , O t h e r s , R u b e l l a , requires urgent strategic public health Cytomegalovirus and Herpes; Competing responses especially that the effects and defects interests associated with infection are severe and mostly irreversible in children affected. Though few All authors have approved the submission and cases are seen, the devastating consequences in declare that they have no competing interests. the new-born are long lasting [9]. We suggest Authors' contributions testing different interventions, one of which could be the use of a combined Measles- AM, CC, SS4 made substantial contributions to Rubella vaccine (MR vaccine), a vaccine highly clinical care. MLML, AM, CC collected the

28 Medical Journal of Zambia, Vol. 41, No. 1 (2014) patient data. MLML, MM, CM interpreted data. ACKNOWLEDGEMENTS MLML drafted the manuscript. MLML, AM, CC, SS, CM, OB, WJM, MM, SS revised and We acknowledge the contributions of the edited the manuscript. All authors read and approved the final manuscript. following individuals and institutions for their Authors' information contribution to this article:

MLML: MSc Epi candidate. Department of Ministry of Health – Zambia; University Community Medicine, School of Medicine, Teaching Hospital (Virology Laboratory); University of Zambia, Lusaka, Zambia. World Health Organisation; EPI National Laboratory scientist. EPI laboratory, Virology Laboratory team (I Ndumba, T Msiska, J Laboratory, University Teaching Hospital, Lusaka, Zambia. Chibumbya, T Bwalya & E Banda); EPI Surveillance Team (Zambia); Chris Kapp and AM: Paediatrics Registrar. School of Medicine. Medewerkers/Associates for much guidance in University of Zambia. Registrar. Neonatal unit. the manuscript development; Barbara Otaigbe University Teaching Hospital. for the invaluable input; We acknowledge the 4 SS : School of Medicine. University of Zambia. support provided by the Research Support Centre at Neonatal unit. University Teaching Hospital. the University of Zambia, School of Medicine CC: Paediatrician, Senior Registrar, University (UNZA-SoM) through the Southern African Teaching Hospital, Lusaka, Zambia. Consortium for Research Excellence (SACORE), which is part of the African Institutions Initiative OB: WHO representative. WHO country office, Grant of the Wellcome Trust (company no. Lusaka, Zambia. 2711000), a charity (no. 210183) registered in WJM: Professor. Department of Epidemiology, England; The National Institutes of Health (NIH) International Health & Molecular Microbiology through the Medical Education Partnership and Immunology. Bloomberg School of Public Initiative (MEPI) programmatic award No. Health, Johns Hopkins University, Baltimore, Maryland, USA. 1R24TW008873 entitled “Expanding Innovative Multidisciplinary Medical Education in Zambia” at MM: Virologist/Head of unit. Virology UNZA-SoM; We also acknowledge the various laboratory, University Teaching Hospital, contributions made by the following people for this Lusaka, Zambia. work: The members of the UNZA-SoM SACORE 7 SS : Professor – Medical Biostatistics. Clinical Steering Committee (Dr Margret Maimbolwa, Dr Sciences Department, Copperbelt University, Paul Kelly, Dr Hellen Ayles, & Dr Charles Michelo) Ndola, Zambia as well as Mr Maxward Katubulushi, Ms Choolwe CM: Head of department. Department of Nkwemu Jacobs, Ms Mutanti Simonda and Ms Community medicine. School of Medicine, Mulemwa Mwangala arranging analytical support. University of Zambia, Lusaka, Zambia.

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