SAJCH Vol 12, No 1 (2018)

CHILD HEALTH SOUTH AFRICAN JOURNAL OF

March 2018

Volume 12

Number 1

• Psychosocial disorders among overweight and obese Nigerian children • Hypernatraemic dehydration in infants • Paediatric splenectomy • Neonatal HIV-associated nephropathy • Persistent pulmonary hypertension of the newborn • Ultrasonographic assessment of renal length in Turkish children

CHILD HEALTH SOUTH AFRICAN JOURNAL OF

MARCH 2018

Volume 12

Number 1

CONTENTS Editorial 2

Hypernatraemic dehydration: Do we have consensus on its treatment?

J M Pettifor, S G Lala

Research

EDITOR Prof. J M Pettifor FOUNDING EDITOR Prof. N P Khumalo EDITORIAL BOARD Prof. M Adhikari (University of KwaZuluNatal, Durban) Prof. M Kruger (Stellenbosch University) Prof. H Rode (Red Cross War Memorial Children's Hospital, Cape Town) Prof. L Spitz (Emeritus Nuffield Professor of Paediatric Surgery, London) Prof. A Venter (University of the Free State, Bloemfontein) Prof. A Westwood (Red Cross War Memorial Children's Hospital, Cape Town) Prof. D F Wittenberg (University of Pretoria) HEALTH & MEDICAL PUBLISHING GROUP:

3 Pattern and predictors of psychosocial disorders among overweight and obese children in Enugu, Southeast Nigeria

CEO AND PUBLISHER Hannah Kikaya

N D Uleanya, E C Aniwada, C C Okeke, S O Nwaoha, C N Obionu

EXECUTIVE EDITOR Bridget Farham

10

Hypernatraemic dehydration in infants with acute gastroenteritis at King Edward VIII Hospital, Durban, South Africa

T Hariram, K L Naidoo, S Ramji

15 The profile of meningitis in a tertiary paediatric hospital in South Africa L Jansz, H Buys, M van Dijk, U Rohlwink

21

Paediatric splenectomy: The Johannesburg experience

MANAGING EDITORS Claudia Naidu Naadia van der Bergh TECHNICAL EDITORS Naadia van der Bergh Kirsten Morreira PRODUCTION MANAGER Emma Jane Couzens

N Patel, A Nicola, P Bennet, J Loveland, E Mapunda, A Grieve

DTP AND DESIGN Clinton Griffin

24

Neonatal mortality at Leratong Hospital

J C Moundzika-Kibamba, F L Nakwa

CHIEF OPERATING OFFICER Diane Smith | Tel. 012 481 2069 Email: dianes@hmpg.co.za

29

Retrospective review of neonates with persistent pulmonary hypertension of the newborn at Charlotte Maxeke Johannesburg Academic Hospital

I Harerimana, D E Ballot, P A Cooper

34

Ultrasonographic assessment of renal length in 310 Turkish children in the Eastern Anatolia region

M Özdikiçi

Case Report 38

Neonatal HIV-associated nephropathy

R Bhimma, E Naicker, B W Mzimela

41

CPD

ONLINE SUPPORT Gertrude Fani | Tel. 021 532 1281 Email: publishing@hmpg.co.za FINANCE Tshepiso Mokoena HMPG BOARD OF DIRECTORS Prof. M Lukhele (Chair), Dr M R Abbas, Mrs H Kikaya, Dr M Mbokota, Dr G Wolvaardt HEAD OFFICE Block F, Castle Walk Corporate Park, Nossob Street, Erasmuskloof Ext. 3, Pretoria, 0181 EDITORIAL OFFICE Suite 11, Lonsdale Building, Lonsdale Way, Pinelands, 7405 Tel. 021 532 1281 Email: publishing@hmpg.co.za ISSN 1999-7671

Use of editorial material is subject to the Creative Commons Attribution – Noncommercial Works Licence. http://creativecommons.org/licenses/by-nc/4.0

ublished by the Health and Medical Publishing Group, P Suite 11, Lonsdale Building, Lonsdale Way Pinelands 7405

Cover: Chevante, Red Cross War Memorial Children's Hospital Primary School

apers for publication should be addressed to the Editor, P via the website: www.sajch.org.za Tel | 021 532 1281 E-mail | publishing@hmpg.co.za ©Copyright: Health and Medical Publishing Group (Pty) Ltd

EDITORIAL

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

Hypernatraemic dehydration: Do we have consensus on its treatment?

Hypernatraemia occurs in some 10 - 20% of children with dehydrating gastroenteritis, and is more common in infants >6 months of age.

Of concern is the fact that hypernatraemia – rather than iso- or hyponatraemic dehydration – is associated with high mortality and morbidity rates. In this issue of SAJCH, Hariram et al.[1] report on the presentation of hypernatraemic dehydration among admitted infants and young children with acute gastroenteritis at King Edward VIII Hospital in Durban. They found a prevalence of just over 12%, using a serum Na level of >150 mmol/L as the defining characteristic. There is no universally accepted definition of hypernatraemia, and a number of researchers have used a lower Na threshold (>145 mmol/L) to define hypernatraemia. The prevalence among children admitted with dehydrating gastroenteritis in Durban is similar to the 16% reported in a convenience sample (aged <64 months) in Stellenbosch that used 145 mmol/L as the cut-off,[2] but is much lower than the 41% reported in another convenience sample (aged <2 years) in Johannesburg, also using the latter cut-off.[3] The higher incidence in the Johannesburg study might reflect the younger age of the sample studied. Despite the relatively common occurrence of hypernatraemia in acute dehydrating gastroenteritis, there is no consensus on how these children should be treated to reduce the risk of long-term sequelae. In the Durban cohort, >60% of children had neurological abnormalities during hospitalisation, but it is unclear if these neurological sequelae persisted following discharge.

Worldwide, there are no randomised controlled trials that have assessed the rate at which hypernatraemia should be corrected, or how this should be achieved. In a retrospective analysis of 62 patients with hypernatraemia (>155 mmol/L) in Israel, the researchers concluded that serum Na levels could be safely reduced by 0.65 mmol/L/h.[4] In the Durban study, the serum Na fell at a rate of between 0.5 and 1.0 mmol/L, with no evidence that the complication rate was any higher in those with higher rather than lower rates of fall. These figures are slightly higher than the rate of fall (<0.5 mmol/L/h) that has been recommended by the majority of researchers in the field. There is general agreement that shocked and dehydrated infants should be treated initially with rapid intravenous boluses of isotonic saline at a rate of 20 mL/kg of body weight, although there is concern about this recommendation following the Fluid Expansion as Supportive Therapy (FEAST) trial, which studied the use of bolus intravenous (IV) infusions in children with severe infection and impaired perfusion.[5] In this large trial, the mortality was higher in those children assigned to an IV bolus than those receiving continuous maintenance fluid. It should be pointed out, however, that children with acute gastroenteritis were specifically excluded from the trial, and so the relevance of the finding to this discussion is unknown.

Once adequate perfusion is achieved, there appears to be consensus that complete rehydration should take place slowly, at least over 48 to 72 hours. Furthermore, IV fluids should only be used when rehydration and fluid maintenance cannot be achieved orally. The most important aspect of slow rehydration is to ensure that the fall in serum Na is gradual; with frequent monitoring of the Na level, clinicians can further adjust the rate of replacement fluid to prevent

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a too-rapid fall in Na levels. To calculate the fluid requirement over this period, the free water deficit needs to be determined over and above the fluid requirements for maintenance and ongoing losses.[6] It is recommended that isotonic saline with 5% dextrose should be used routinely,[6] although regular monitoring of the hydration state and Na levels is required so that the volume and Na content of the infusate fluid can be adjusted as needed. Some centres recommend tailoring the fluid composition to the individual needs of the child (see the Durban protocol[1] and Schwaderer and Schwartz[8]). A recent systematic review of dysnatraemias in acute gastroenteritis has confirmed that the risk of developing hyponatraemia during the management of children with dehydrating gastroenteritis is greater if hypotonic saline solutions are used.[7] In conclusion, there is an urgent need for randomised controlled trials to be instituted, similar to the FEAST study but aimed at addressing the management of hypernatraemic dehydration in children with acute gastroenteritis. It is possible that, as was the case following the FEAST study, management may be turned on its head.

1. Hariram T, Naidoo K, Ramji S. Hypernatraemic dehydration in infants with acute gastroenteritis at King Edward VIII Hospital. S Afr J Child Health 2018;12(1):10-14. https://doi.org/10.7196/SAJCH.2018.v12i1.1424 2. Cooke ML, Nel ED, Cotton MF. Pre-hospital management and risk factors in children with acute diarrhoea admitted to a short-stay ward in an urban South African hospital with a high HIV burden. S Afr J Child Health 2013;7(3):84-87. https://doi.org/10.7196/SAJCH.2013.v7i3.472 3. Hoosain SBG. Hypernatraemic dehydration in acute gastroenteritis – a descriptive audit of prehospital management and predisposing factors. wiredspace.wits.ac.za/jspu/bitstream/10539/23167/1/Research%20report%20 final.pdf (accessed 9 April 2018).

4. Ben-Shalom E, Toker O, Schwartz S. Hypernatremic dehydration in young children: Is there a solution? IMAJ 2016;18:95-99.

5. Maitland K, Kiguli S, Opaka RO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med 2011;364:2483-2495. https://doi. org/10.1056/NEJMoa1101549 6. Anigilaje EA. Management of diarrhoeal dehydration in childhood: A review for clinicians in developing countries. Front Pediatr 2018;6:28. https://doi. org/10.3389/fped.2018.00028 7. Grisaru S, Xie J, Samuel S, Freedman SB. Iatrogenic dysnatremia in children with acute gastroenteritis in high-income countries: A systematic review. Front Pediatr 2017;5:210. https://doi.org/10.3389/fped.2017.00210 8. Schwaderer AL, Schwartz GW. Treating hypernatremic dehydration. Pediatr Rev 2005; 26:148 https://doi.org/10.1542/pir.26-4-148 S Afr J Child Health 2018;12(1):2. DOI:10.7196/SAJCH.2018.v12i1.1554

John M Pettifor

Editor, South African Journal of Child Health Department of Paediatrics, University of the Witwatersrand, Johannesburg, South Africa john.pettifor@wits.ac.za

Sanjay G Lala

Department of Paediatrics, University of the Witwatersrand and Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa sanjay.lala@wits.ac.za

MARCH 2018 Vol. 12 No. 1

ARTICLE

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

Pattern and predictors of psychosocial disorders among overweight and obese children in Enugu, Southeast Nigeria N D Uleanya,1 MB BCh, FMCPaed, MPH; E C Aniwada,2 MB BCh, MSc (Epid/Stat), MPH, FWACP, FMCPH; C C Okeke,2 MB BCh, MPH, FWACP; S O Nwaoha,3 MBBS, FWACP; C N Obionu,2 MBBS, FWACP, FMCPH, DTH Department of Paediatrics, Enugu State University Teaching Hospital, Enugu, Nigeria Department of Community Medicine, University of Nigeria Teaching Hospital, Enugu, Nigeria 3 Department of Medicine, Nnamdi Azikiwe University Teaching Hospital, Nnewi, Nigeria 1 2

Corresponding author: N D Uleanya (nulesa2001@yahoo.com) Background. Obesity in children is recognised as a public health problem worldwide. This is due to the high prevalence rate, as well as the associated adverse health and psychosocial effects. Psychosocial disorders negatively impact on children.

Objectives. This study aims to determine the pattern and predictors of psychosocial disorders among overweight and obese children in Enugu, Nigeria.

Methods. A descriptive cross-sectional study among adolescents attending secondary schools in Enugu was conducted. Sampling followed stratified and multi-staged methods. Participantsâ&#x20AC;&#x2122; weight and height were measured and their body mass index (BMI) determined.

Questionnaires were also used and the information obtained included psychometric measurements. Data was analysed using SPSS version 19. Ď&#x2021;2 and logistic regressions were carried out where a p-value â&#x2030;¤0.05 was considered significant.

Results. The mean age (standard deviation (SD)) of the 200 students included in the study was 12.9 (1.8) years. Most of the subjects suffered from depression (46%) and there was a significant association between anxiety and obesity in females (p=0.03), who were ~3 times more likely to be anxious than boys (OR 2.6; 95% confidence interval (CI) 0.78 - 8.36). Low self-esteem was also found to be closely associated with obese girls (p=0.002), who were about 3 times more likely to have a low self-esteem compared with males (OR 2.7; 95% CI 0.95 - 7.55).

Obesity was stigmatised (p=0.002) and obese students were almost 5 times more likely to feel stigmatised than overweight students (OR 5.01; 95% CI 1.80 - 13.9).

Conclusion. Obesity was directly associated with stigma and, while female gender predicts anxiety and low self-esteem, obesity itself was a predictor of stigmatisation among obese children.

S Afr J Child Health 2018;12(1):XX-XX. DOI:10.7196/SAJCH.2018.v12i1.1423

The burden of obesity has escalated over the last two decades in developing countries, while developed countries have reached pandemic levels.[1] The International Obesity Task Force (IOTF) reported that 1 in 10 children are overweight worldwide. In total, estimates show that there are ~155 million children and adolescents who are overweight and 30 - 45 million who are obese.[2,3] In fact, obesity in children and adolescents is now recognised as a major public health concern owing to alarming trends in the prevalence, severity and occurrence of adverse health and psychosocial consequences.[1] The developing world is likely to suffer a greater health and economic burden from obesity. For instance, it was estimated that between 1998 and 2025, diabetes caused by obesity would double to 300 million with ~225 million cases occurring in the developing world.[4] For nations whose economic and social resources are limited, the result could be disastrous. This is due to both the direct and indirect medical costs associated with obesity that would become a major burden for healthcare systems, including those in Nigeria.

Globally, the World Health Organization (WHO) estimates the economic cost of obesity to be ~2% to 7% of total healthcare costs per year.[4] Unfortunately, overweight children and adolescents are at increased risk of various psychological and social problems. These impact negatively on the economy of a nation, and may impair the psychological development, quality of life, academic and social performance of the overweight child, when compared with a child

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of normal weight.[5-7] It has been documented that weight-based stigma increases the susceptibility of children to depression, low self-esteem, poor body image, maladaptive eating behaviors and exercise avoidance.[8] The low self-esteem noted in children with paediatric obesity is said to be marked and often starts early in their life.[5,9,10] The weight-related stigma and discrimination could also be a mediating factor in the development of psychological ill-health as well as affect the academic performance of these children in their required age-specific developmental tasks.[5] The degree of obesity, though, appears to be an independent risk factor for common mental health disorders. Research has suggested that severe obesity puts individuals at greater risk of depression.[10,11] Many may not present with obvious depressive symptoms but with somatic symptoms which may confound the diagnosis. Depression in an obese child may also present in the form of oppositional defiant symptoms, aggressive behavior, anger, bullying (where the obese child is a bully rather than a victim), fatigue, poor academic performance, suicidal thoughts and attempted suicide.[9] These factors have been noted in this sample population at a frequency slightly greater than that of the general population.

In Nigeria, there are limited data on the pattern as well as predictors of psychosocial disorders among overweight and obese children. We are not aware of any study in Africa on the predictors of psychosocial disorders among overweight and obese children. We hypothesise that the overweight and obese children in Enugu will have psychological disorders as well as social problems. The aims

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ARTICLE of the study are to determine the pattern of psychological disorders and social problems among overweight and obese children and to determine the predictors of these disorders.

Methods

Study design

This was a descriptive cross-sectional study carried out among secondary schoolchildren aged 10 - 18 years in the Enugu metropolis of Nigeria from April to June 2015.

Study area

The metropolis is made up of three local government areas – Enugu North, Enugu East and Enugu South, with a total of 123 registered secondary schools. This is comprised of 39 public (government) and 84 private secondary schools (based on information from Enugu State Ministry of Education).

Ethical consideration

Ethical clearance for the proposal was approved by the University of Nigeria Teaching Hospital Health Research and Ethics Committee (NHREC/05/01/2008B-FWA00002458 – IRB00002323).

Furthermore, approval was obtained from the Enugu State Ministry of Education, chairmen of private schools, principals and teachers as well as parents of the respondents. Informed consent – both verbal and written – were obtained from each child’s parents/guardian.

Following acquisition of consent, they were duly educated on the need and benefits of the study, the measurements required and how they would be collected. Confidentiality was maintained throughout and after the study.

Sampling technique

Multi-staged sampling involving stratified and simple random methods was used. The number as well as the ratio of public to private schools in the different local government areas were used to determine the number of students selected in the area. In each school selected, the participants were selected by simple random sampling using a statistical table of random numbers. Where the selected participant’s calculated body mass index (BMI)was either in the range of normal or underweight, after measurement of the weight and height, he/she was excluded from the study. The height of the subject was measured to the nearest centimetre (sensitivity of 0.5 cm) using a Seca stadiometer (Model 786 2021994 Seca GmbH & Co.) with the subject barefoot or wearing a pair of socks. The participant’s weight was measured using an electronic weighing scale with a sensitivity of 0.1 kg. Both the height and weight were measured twice and if there was disparity, a third measurement was taken and an average of the three measurements used. BMI was determined based on age and sex, using the Centers for Disease Control (CDC) BMI calculator for children and teens.[12] ‘Overweight’ was defined as a BMI between the 85th and 94th percentiles, while obesity was defined as a BMI ≥95th percentile.[12] All normal or underweight children, those on drugs with effects on weight and psychotherapy, all overweight and obese children who did not assent or consent and those whose parents or guardians did not consent to participate were excluded.

Data collection

A pretested, self-administered questionnaire was given to the selected students after obtaining informed assent/consent, and due explanation and education on the content, purpose and benefits of the study was provided. Some of the information required included biodata, socioeconomic class and psychometric measurements.

Socioeconomic class of a child was obtained by calculating the socioeconomic class of the parents using the method proposed by Oyedeji.[13] 4

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Psychometric measures

The psychometric scales used included Becks Depression Inventory II (BDI II), Revised Children Manifest Anxiety Scale (RCMAS), Rosenberg Self-Esteem Scale (RSES), and Internalized Stigma of Mental Illness Scale (ISMI). Both the BDI II and RCMAS have been validated in Nigeria using adolescents aged 13 - 18 years and primary schoolchildren respectively.[14,15] Beck’s Depression Inventory The BDI II was developed in response to the publication of the Diagnostic and Statistical Manual of Mental Disorders (DSM IV-TR) due to changes in the diagnostic criteria of major depressive disorders. It is a 21-item, multiple choice, self-rated inventory used to assess the cognitive, emotional and vegetative symptoms associated with depression in which the individual chooses 1 of 4 statements in each item that applies best to his/her feelings over the past 2 weeks. Each answer is scored on a scale of 0 - 3. Ratings are summed up to obtain total scores. The cut-offs used are 0 - 13 for minimal depression; 14 - 19 for mild depression; 20 - 28 for moderate depression; and 29 - 63 for severe depression. Higher total scores indicate increasingly severe depressive symptoms. The BDI II was designed to detect and analyse the intensity of depression in individuals. It correlates positively (r=0.71) with the Hamilton Depression Rating Scale (HAM-D) and has a high 1-week test-retest reliability (r=0.93).[16] The internal consistency of the HAM-D is high (α=0.91), with a sensitivity of 0.91 and specificity of 0.97 at a cut-off score of 18 and above. It has a positive predictive value of 0.88 and a negative predictive value of 0.98.[17] Revised Children Manifest Anxiety Scale (RCMAS) The RCMAS was designed to assess the degree and quality of anxiety in children and adolescents between 6 and 19 years. It was based on the Children Manifest Anxiety Scale of 1956 which was devised from The Manifest Anxiety Scale developed in 1951.[18,19] RCMAS is a 37-item self-report inventory used to measure anxiety in children and adolescents for clinical purposes – diagnosis and treatment evaluation, educational settings and research purposes.[20] The RCMAS consists of 28 Anxiety items and 9 Lie (social desirability) items. The 28 items relate to subjective, physiological and motoric indexes of anxiety that can be summed to form a total general anxiety score. These items can also be divided into physiological anxiety, worry/oversensitivity, and social concerns/concentration.

The remaining 9 items form a Lie scale, which can be used to assess a youth’s tendency to present themselves favourably. Each item is given a score of one for a ῾yes᾽ response, yielding a total anxiety score. Stallard et al.[21] recommended that an overall cut-off point of 19 out of 28 be used to identify children experiencing clinically significant levels of anxiety. This was the cut-off point employed in our study. The RCMAS has an internal consistency coefficient of r=0.8, a test-retest reliability of 0.6 - 0.88 and in terms of convergent validity, correlates with Screening for Children with Anxiety Related and Emotional Disorder (SCARED) (r=0.85), as well as the State Trait Anxiety Inventory for Children (STAIC) (r=0.85, p=0.05).[20,22-24] Rosenberg Self-Esteem Scale (RSES) The Rosenberg Self-Esteem Scale is the most widely used measure of global self-esteem. It is a 10-question Likert scale, designed to represent a continuum of self-worth statements.25 It is answered on a 4-point scale from strongly agree (3) to strongly disagree (0).

Total scores range from 0 to 30 with higher scores representing lower self-esteem.[26] The scale measures self-esteem by asking the respondents to reflect on their current feelings. Five of the items are positively worded while the remaining five have negatively worded statements. While some are scored as they are, others are scored in reverse order. Scores <15 suggest low self-esteem while scores ≥15

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ARTICLE suggest normal self-esteem. The scale has been translated into several different languages and used in cross-cultural studies involving at least 53 different countries. The RSES also has an adequate internal consistency of α=0.87, is highly reliable with a 2-week testretest correlation in the range of 0.82 to 0.88, and has a minimum coefficient of reproducibility of 0.9 with Cronbach’s alpha for various samples in the range of 0.77 to 0.88.[26-28] The RSES is closely related to the Cooper Smith Self-Esteem Inventory.

Internalized Stigma of Mental Illness Scale (ISMI) The ISMI is commonly used to measure internalised stigma and offers clinicians and clinical researchers a confirmable and viable target for general psychotherapeutic interventions.[29] The ISMI scale was developed to measure the internalised stigma of people diagnosed with a mental illness. Worldwide, the ISMI scale has been used as a measure of internalised stigma for people with diseases such as schizophrenia, depression, leprosy and AIDS. The ISMI contains 29 items which produce 5 subscale scores (including stigma and discrimination) and a total score. Each score is calculated by adding the item scores together and then dividing by the total number of answered items. If any item is unanswered, the total number to be divided by is reduced. The resulting score ranges from 1 - 4. A total score >2.5 signifies high internalised stigma. For calculating discrimination experience on this scale, the scores on the single items are summed and divided by the total number of questions. The higher the mean score, the greater the evidence of discrimination.[30] The ISMI has an internal consistency of reliability coefficient of α=0.90, with a test-retest reliability of r=0.92 and p=0.05.[27]

Data analysis

Data from 200 students were analysed using SPSS version 19. The mean was used to summarise quantitative variables while frequency and percentages were used for qualitative variables where applicable.

Tables were constructed as appropriate. χ2 tests were used to establish associations between sociodemographic variables (age, sex, social class) as well as BMI with presence or absence of psychological disorders and social problems while binary logistic regression was used to identify predictors of psychological disorders and social problems. Level of significance was at p-value ≤0.05.

Results

Of the 200 students studied, 33.5% (n=67) were overweight and 66.5% (n=133) obese. This total is made up of 136 (68.0%) females and 64 (32.0%) males, giving a male to female ratio of 1:2. Their mean (standard deviation (SD)) age was 12.9 (1.8) years old. Most of the students belonged to the upper social class (84.5%). A total of 157 students were in their early adolescence while 43 were in their late adolescence (Table 1).

There were essentially 2 major psychological disorders (depression and anxiety) and 3 major social problems (self-esteem, discrimination and stigmatisation) studied among the overweight and obese students. Among the 200 students, depression was found in 46% (n=92), anxiety disorder among 14% (n=28), 23% (n=46) had low self-esteem, 28% (n=56) suffered discrimination while 27% (n=54) were also stigmatised.

Depression among these children ranged from mild (21.5%; n=20/92) to severe (8.5%; n=8/92). The difference was not statistically significant. Those children in the middle class were about 3 times more likely (OR 2.96; 95% CI 1.18 - 7.43), while those in the lower class were about 1.3 times less likely to be depressed, compared with the upper class (OR 0.80; 95% CI 0.14 - 4.64) (Table 2). Anxiety disorder was more common among the females compared with the males and this was statistically significant (χ 2=4.695, p=0.030). On multivariate 5

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Table 1. Sociodemographic and BMI distribution of students Frequency, n (%) Age range (years) 10 - 14 15 - 19 Sex Male Female Social class Upper Middle Lower BMI (kg/m2) Overweight Obese

157 (78.5) 43 (21.5) 64 (32) 136 (68) 169 (84.5) 25 (12.5) 6 (3.0) 67 (33.5) 133 (66.5)

BMI = body mass index.

analysis, the females were about 2.6 times more likely to have anxiety disorder compared with the males (OR 2.56, 95% CI 0.78 - 8.36) (Table 2).

Among the major social problems, obesity was associated with stigmatisation and this was statistically significant (χ2=9.409; p=0.002). Those obese children were about five times more likely to feel stigmatised than the overweight (OR 5.01; 95% CI 1.80-13.90) (Table 3). Low self-esteem was more common among the females compared with males and this was statistically significant (χ2=9.866, p=0.002). On multivariate analysis, the females were ~3 times more likely to have low self-esteem than males (OR 2.68, 95% CI 0.95 - 7.55). The late adolescents were ~2 times more likely to feel discriminated against than the early adolescents (OR 0.43; 95% CI 0.16 - 1.15). Those children in the middle class were ~2 times less likely (OR 0.65; 95% CI 0.04 - 11.54) and those in lower class ~2 times more likely to feel discriminated against than those in the upper class (OR 1.78; 95% CI 0.09 - 36.84) (Table 3).

Discussion

For middle- and low-income countries, including Nigeria, public awareness and education on mental health is often inadequate due to limited resources. However, the most widespread consequence of childhood obesity is psychosocial, yet most paediatricians do not offer treatment to obese children and adolescents in the absence of comorbid conditions. The pattern of psychosocial disorders among overweight and obese children in Enugu is very worrisome. There is a high level of depression among these children. Depression is a common mental disorder presenting with depressed mood, loss of interest or pleasure, decreased energy, feelings of guilt or low self-worth, disturbed sleep or appetite and poor concentration and academic performance. This study found depression among these children higher than that of the general population (3% - 15%) and unfortunately it may persist into adulthood.[10,31] While 0.4% - 5% of the general population suffering with depression is classified as severe, it was found that as much as 8.5% of the participants in this study, primarily girls, were severely depressed. This is because depression and obesity have been found to have bidirectional associations and both are widespread problems with major public health implications.[10,11,32-34] This high level of depression may be related to body dissatisfaction, poor body image, discrimination, social isolation and weight-based teasing by peers and/or parent(s) experienced on a daily basis. Studies have shown that peer victimisation and body dissatisfaction predicts depression among adolescents.[35-37] Depression may be even worse among these young women, considering the fact that relationships and marriages are

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ARTICLE Table 2. Association between psychological disorders and sociodemographics and BMI (N=200) Bivariate analysis Anxiety Age range (years) 10 - 14 15 - 18 Sex Male Female Social class Upper Middle Lower BMI Overweight Obese Depression Age range (years) 10 - 14 15 - 18 Sex Male Female Social class Upper Middle Lower BMI (kg/m2) Overweight Obese

p-value

Multivariate analysis OR (95% CI for OR)

0.965

0.326

NA

60 (93.8) 112 (82.4)

4.695

0.030

22 (13.0) 6 (24.0) 0 (0.0)

147 (87.0) 19 (76.0) 6 (100)

3.189

0.203

NA

7 (10.4) 12 (15.8)

60 (89.6) 112 (84.2)

1.056

0.304

NA

69 (43.9) 23 (53.5)

88 (56.1) 20 (46.5)

1.237

0.266

NA

27 (42.2) 65 (47.8)

37 (57.8) 71 (52.2)

0.551

0.458

NA

74 (43.8) 16 (64.0) 2 (33.3)

95 (56.2) 9 (36.0) 4 (66.7)

3.982

0.137

35 (52.2) 57 (42.9)

32 (47.8) 76 (57.1)

1.579

Presence, n (%)

Absence, n (%)

20 (12.7)

137 (87.3)

8 (18.6)

35 (81.4)

4 (6.3) 24 (17.6)

Ď&#x2021;2

2.56 (0.78 - 8.36)

2.96 (1.18 - 7.43) 0.80 (0.14 - 4.64) 0.209 NA

OR = odds ratio; NA = not applicable; BMI = body mass index.

conceived during late adolescence in this environment. An association between obesity and depression has been found among obese women but not in men.[32,33,35] Unfortunately, though depression is common among these children, most doctors miss the diagnosis.

Based on the fact that these disorders are causally linked, the implication is that through dysregulated stress systems or through unhealthy lifestyle, these children may overeat regularly and become increasingly obese, leading to worsening depression.[33] The impact of this high rate of depression is alarming when one considers the medical and economic burden on a fragile economy. It may contribute significantly to the burden of mental ill-health in Enugu over time, poor academic performance of the children, musculoskeletal pains and increased risk of substance abuse and suicidal ideation compared with normal-weight peers. These medical implications, if they occur, burden the fragile Nigerian health system. Economically, the cost of illness due to depression would be enormous, depression being the leading cause of disability worldwide in terms of total years lost due to disability.[38]People who are obese and depressed are more likely to experience impairments in multiple domains including employment as well as physical and social functioning. Therefore, the high burden of depression among overweight and obese children portends a marked impediment in the future work force. Obviously, the coexistence of the disorders will be disastrous for poor nations such as Nigeria.[31] There was no significant association between anxiety disorder and children who are obese or overweight. This is similar to other studies.[39,40] However, between the genders, anxiety was more closely 6

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associated with girls. This may have resulted from weight-related discrimination, stigmatisation and teasing which may be very distressing for the young girls, especially in the adolescent stage of personality development in which they develop self-identity. This finding agrees with other studies that obesity may be more strongly related to anxiety disorders in women than in men.[8] Self-esteem relates with an individualâ&#x20AC;&#x2122;s social, emotional, behavioral and mental development â&#x20AC;&#x201C; how individuals perceive themselves and whether he or she feels that they are valued. Low self-esteem in children has been linked with negative consequences such as behavioral disorders including aggression, delinquency, depression, and other emotional concerns.[41]This study has documented a high prevalence of low self-esteem among overweight and obese Nigerian children similar to the findings by Wang et al.[42] This finding is found to be true as the literature has consistently shown an association between obesity and self-esteem according to sex and pubertal status, suggesting a more negative self-esteem among pubertal females.[43,44]In this study low self-esteem was also associated with the females, corroborating that female gender is a predictor of negative self-esteem. Although reports on selfesteem among overweight and obese children elsewhere has been inconsistent, this result agrees with the findings of Wang et al.,[42] and Friedlander.[44] Low self-esteem was also found to be more common among the late adolescents in this study. This is similar to the finding of Bodiba.[45] However, this might have been because during late adolescence, children become more aware of their body

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ARTICLE Table 3. Association between major social problems and sociodemographics and BMI Bivariate analysis Presence, n (%) Stigma Age range (years) 10 - 14 15 - 18 Sex Male Female Social class Upper Middle Lower BMI (kg/m2) Overweight Obese Discrimination Age range (years) 10 - 14 15 - 18 Sex Male Female Social class Upper Middle Lower BMI (kg/m2) Overweight Obese Self-esteem Age range (years) 10 - 14 15 - 18 Sex Male Female Social class Upper Middle Lower BMI (kg/m2) Overweight Obese

Absence, n (%)

40 (25.5) 14 (32.6)

117 (74.5) 29 (67.4)

Ď&#x2021;2

0.859

p-value

0.354

Multivariate analysis OR (95% CI for OR)

NA

17 (26.6) 37 (27.2)

47 (73.4) 99 (72.8)

0.009

0.924

NA

44 (26.0) 8 (32.0) 2 (33.3)

125 (74.0) 17 (68.0) 4 (66.7)

0.519

0.771

NA

9 (13.4) 45 (33.8)

58 (86.6) 88 (66.2)

9.409

0.002

40 (25.5) 16 (37.2)

117 (74.5) 27 (62.8)

2.304

21 (32.8) 35 (25.7)

43 (67.2) 101 (74.3)

1.081

0.298

43 (25.4) 12 (48.0) 1 (16.7)

126 (74.6) 13 (52.0) 5 (83.3)

5.890

0.053

16 (23.9) 40 (30.1)

51 (76.1) 93 (69.9)

0.848

0.357

NA

34 (21.7) 12 (27.9)

123 (78.3) 31 (72.1)

0.745

0.388

NA

6 (9.4) 40 (29.4)

58 (90.6) 96 (70.6)

9.866

0.002

2.68 (0.95 - 7.55)

38 (22.5) 7 (28.0) 1 (16.7)

131 (77.5) 18 (72.0) 5 (83.3)

0.514

0.773

NA

20 (29.9) 26 (19.5)

47 (70.1) 107 (80.5)

2.670

0.102

1.28 (0.53 - 3.12)

5.01 (1.80 - 13.90)

0.129 0.43 (0.16 - 1.15) NA

0.65 (0.04 - 11.54) 1.78 (0.09 - 36.84)

OR = odds ratio; NA = not applicable; BMI = body mass index.

and shape. It is at this stage that body dissatisfaction, weight-based teasing, social isolation, and exclusion based on weight may come into effect, ultimately promoting low self-esteem and poor social interaction that leads to poor development. Unfortunately, low selfesteem tends to linger into adulthood and predicts poor mental health.[41] The effect may be significant, especially in stressful environments. Low self-esteem coupled with overweight/obesity influences the performance of adolescents in their required agespecific developmental tasks and their well-being, leading to poor 7

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academic performance, aggression, poor development of social skills, early onset of substance abuse and low quality of life.[46,47] Furthermore, in this study obesity was found to be associated with stigma. Again, this must have resulted from poor body image and body dissatisfaction resulting from weight-based teasing, derogatory words from peers, teachers and parents, aggressive behavior and stereotyping.[48] This may have been more prevalent among the girls, considering that thin bodies are viewed as physically attractive.

The social consequences of being overweight and obese are serious

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ARTICLE and detrimental. These children are often targets of teasing, social isolation, prejudice and bullying and are susceptible to negative attitudes in multiple domains of living, including schools, their homes and interpersonal relationships.[48,49] This stigmatisation has the potential to affect the cognitive function of these children leading to lower educational attainment and lower self-esteem.[50] This effect is probably more prominent in the obese children compared with the children who are overweight, as people with obesity are stereotyped as lazy, less competent, lacking in self-discipline, non-compliant, sloppy and worthless.

Discrimination diminishes an individual’s self-worth.

Discrimination against obese individuals is a harmful, pervasive and significant social problem that needs to be addressed early, concretely, and as part of a child’s or teen’s obesity treatment regimen.[51]As much as 28% of the overweight and obese children in Enugu metropolis feel discriminated against as a result of their weight. This feeling of discrimination might have contributed to the social anxiety, lower self-esteem and depression that these children suffer. The findings in this study agree with findings of other studies.[52,53] Obese people, especially those who perceive themselves as overweight, often experience weight-related discrimination and have difficulty making friends.[51,52] This weight-related perceived discrimination might have been felt more by the late adolescents as they are more aware of their body image and eager to start relationships.[52,53] This perceived weight discrimination would have arisen from weight-related teasing by peers and relatives, social exclusion, stigmatisation and body dissatisfaction. The effect of this perceived weight discrimination is also hazardous as it has been found to contribute to maladaptive eating behaviours among obese individuals, leading to increases in the severity of obesity and is likely to increase vulnerability to depression, low self-esteem, low self-worth, guilt and poor body image.[10,54]

Study limitation

There was no control group for comparison with the overweight and obese children.

Conclusion and recommendations

Overweight children and childhood obesity are emerging problems within the African setting, especially among the upper socioeconomic class, and is associated with many psychosocial disorders. Depression is the most common disorder among obese and overweight children, and is higher compared with the general population. Female gender among obese children predicts anxiety and low self-esteem. Obesity predicts only stigmatisation but not depression, anxiety, discrimination or self-esteem but is significantly associated with stigma.

A comprehensive assessment of overweight and obese children both in the school and clinical setting is essential. In the school setting, the counselor should help form an obesity support group and discuss being overweight and obese with affected children, the challenges and impairments, the need and modalities to achieve weight loss with emphasis on physical activity and how to help each other overcome the psychological and social problems associated with obesity. Intense school health education should aim to mitigate isolation, exclusion, stereotyping, stigmatisation and discrimination against overweight and obese children. There is also an urgent need to enact laws in Nigeria enforcing private schools to provide physical recreation facilities and adequate time in the curriculum for physical activity. It was observed that private schools have little or no recreational facilities. In the clinical setting, paediatricians managing overweight or obese children for any condition should make time to assess for psychological disorders and refer appropriately.

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Acknowledgements: The authors wish to acknowledge all the children who participated in this research work who, in spite of their state of health, are ignorant of the dangers that their weight poses to them.

Author contributions. NDU conceived the study, contributed to questionnaire design, collected data and directed data analysis. ECA collected data and carried out data analysis. CCO and SON contributed toward the design of the questionnaire and data collection. CNO supervised questionnaire design, data collection and manuscript writing.

All authors participated in manuscript writing.

Funding. None.

Conflicts of interest. The authors hereby declare no conflict of interest among them.

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ARTICLE 24. Reynolds CR. Concurrent validity of what I think and feel: The Revised Children’s Manifest Anxiety Scale. J Consult Clin Psychol 1980;48(6):774-775. https://doi. org/10.1037//0022-006x.48.6.774 25. Franck E, De Raedt R, Barbez C, Rosseel Y. Psychometric properties of the Dutch Rosenberg Self-Esteem Scale. Psychol Belgica 2008;48:25-35. https://doi. org/10.5334/pb-48-1-25 26. Rosenberg M. Society and the Adolescent Self-Image. Princeton: Princeton University Press,1965:49-63.

27. Ritsher JB, Otilingam PG, Grajales M. Internalized stigma of mental illness: Psychometric properties of a new measure. Psychiatry Res 2003;121:31-49. https://doi.org/10.1016/j.psychres.2003.08.008 28. Gortmaker SL, Must A, Perrin JM, Arthur MS, Dietz WH. Social and economic consequences of overweight in adolescents and young adulthood. N Eng J Med 1993;329:1008-1012. https://doi.org/10.1056/nejm199309303291406 29. Tanabe Y, Hayashi K, Ideno Y. The Internalized Stigma of Mental Illness (ISMI) scale: Validation of the Japanese version. BMC Psychiatr 2016;16:116. https://doi. org/10.1186/s12888-016-0825-6 30. Boyd RJE. Internalized stigma of mental illness: Psychometric properties of a new measure. Psychiatry Res 2003;121:31-49.

31. Cesar J, Chavoushi F. Background paper 6.15 Depression. In: Sabate E. Depression in young people and elderly: Priority Medicine for Europe and the world. A public Health Approach to innovation. http://archives.who.int/prioritymeds/ report/background/depression.doc (accessed 5 June 2016).

32. De Wit LM, Luppino FS, van Straten A, Cuijpers P. Obesity and depression: A meta-analysis of community based studies. Psychiatry Res 2010;178:230-235. https://doi.org/10.1016/j.psychres.2009.04.015 33. Luppino FS, de Wit LM, Bouvy PF, et al. Overweight, obesity, and depression. Arch Gen Psychiatry 2010;67:220-229.https://doi.org/10.1001/ archgenpsychiatry.2010.2 34. Russell-Mayhew S, McVey G, Bardick A, Ireland A. Mental health, wellness and childhood overweight/obesity. J Obesity 2012(2012):Article ID 281801. https:// doi.org/10.1155/2012/281801 35. Nemiary D, Shim R, Mattox G, Holden K. The relationship between obesity and depression among adolescents. Psychiatr Ann 2012;42:305-308. https://doi. org/10.3928/00485713-20120806-09 36. Franklin J, Denyer G, Steinbeck KS, Caterson ID, Hill AJ. Obesity and risk of low self-esteem: A state-wise survey of Australian children. Pediatrics 2006;118:24812487. https://doi.org/10.1542/peds.2006-0511 37. Cash TF, Morrow JA, Hrabosky JI, Perry AA. How has body image changed?

A cross-sectional investigation of college women and men from 1983-2001.

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40. Gariepy G, Nitka D, Schmitz N. The association between obesity and anxiety disorders in the population: A systematic review and meta-analysis. Int J Obes 2010;34:407-419. https://doi.org/10.1038/ijo.2009.252 41. Lowry KW, Sallinen BJ, Janicke DM. The effects of weight management programs on self-esteem in pediatric overweight populations. J Pediatr Psychol 2007;32:1179-1195. https://doi.org/10.1093/jpepsy/jsm048 42. Wang F, Wild TC, Kipp W, Kuhle S, Veugelers PJ. The influence of childhood obesity on the development of self-esteem. Health Rep 2009;20(2):21-27 https:// www.ncbi.nim.nih.gov/pubmed/19728582 (accessed 4 May 2016).

43. Israel AC, Ivanova MY. Global and dimensional self-esteem in preadolescent and early adolescent children who are overweight: Age and gender differences. Int J Eat Disorder 2002;31:424-429. https://doi.org/10.1002/eat.10048 44. Friedlander SL, Larkin EK, Rosen CL, Palermo TM, Redline S. Decreased quality of life associated with obesity in school-aged children. Arch Pediatr Adolesc Med 2003;157(12):1206-1211. https://doi.org/10.1001/archpedi.157.12.1206 45. Bodiba P. The relationship between body mass index and self-concept among adolescent black female university students. Curationis 2008;31:77-84.https://doi. org/10.4102/curationis.v31i1.917 46. Donnellan MB, Trzesniewski KH, Robins RW, Moffitt TE, Caspi A. Low selfesteem is related to aggression, antisocial behavior and delinquency. Psychol Sci 2004;16:328-335. https://doi.org/10.1111/j.0956-7976.2005.01535.x 47. Schwimmer JB, Burwinkle TM, Varni JW. Health-related quality of life of severely obese children and adolescents. JAMA 2003;289:1813-1819. https://doi. org/10.1001/jama.289.14.1813 48. Lee PH, Lai HR,Chou YH, Chang LI, Chang WY. Perceptions of exercise in obese school-aged children. J Nurs Res 2009;70:110-116. https://doi. org/10.1097/jnr.0b013e3181b2554b 49. Stankov I, OldsT, Cargo M. Overweight and obese adolescents: What turns them off physical activity? Int J Behav Nut Physical Act 2012;9:53-68. https:// doi.org/10.1186/1479-5868-9-53 50. Muennig P. The body politic: The relationship between stigma and obesityassociated disease. BMC Pub Health 2008;8:128. https://doi.org/10.1186/14712458-8-128 51. Nieman P, LeBlanc CMA. Psychosocial aspects of child and adolescent obesity.

Pediatr Child Health 2012;17(4):205-206. https://doi.org/10.1093/pch/17.4.205 52. Guh DP, Zhang W, Bansback N, Amarsi Z, Laird Birmingham C, Anis AH. The incidence of co-morbidities related to obesity and overweight: A systematic review and meta-analysis. BMC Pub Health 2009;9:88. https://doi. org/10.1186/1471-2458-9-88 53. Jackson SE, Steptoe A, Beeken RJ, Croker H, Wardle J. Perceived weight discrimination in England: A population-based study of adults aged ≥50 years.

Int J Obes 2015;39:858-864. https://doi.org/10.1038/ijo.2014.186 54. Sutin AR, Terraciano A. Perceived weight discrimination and obesity. PLoS ONE 2013;8(7): e70048. https://doi.org/10.1371/journal.pone.0070048

Accepted 19 September 2017.

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RESEARCH

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

Hypernatraemic dehydration in infants with acute gastroenteritis at King Edward VIII Hospital, Durban, South Africa T Hariram, MB ChB, DCH (SA), FC Paed (SA); K L Naidoo, MB ChB, DCH (SA), FC Paed; S Ramji, MB ChB Department of Paediatrics and Child Health, University of KwaZulu-Natal, Durban, South Africa Corresponding author: T Hariram (terishiapillay@gmail.com) Background. Acute gastroenteritis (AGE) is a leading cause of infant mortality, with hypernatraemic dehydration contributing to increased morbidity and mortality.

Objectives. To determine the prevalence of hypernatraemia secondary to AGE in admitted infants in Durban, South Africa. To describe the feeding choices, nutritional status and outcomes of these patients. To determine the association between admission sodium (Na) level, the rate of Na correction and clinical outcomes Methods. A retrospective chart review was conducted on cases of hypernatraemic dehydration admitted in 2014 to a South African hospital.

Serum Na levels were corroborated with National Health Laboratory Services results. Descriptive and analytical statistics were done using Statistical Package for Social Sciences version 22.

Results. A 12.3% prevalence of hypernatraemia (n=41/334) was found. The majority of infants were formula-fed (76%) with a 21% incidence of malnutrition and 66% HIV exposure rate in this cohort. A high rate of neurological abnormalities (63%), and a 4.9% case fatality rate was found. Shock on admission was present in 92% of patients who developed severe neurological complications. The mean admission Na was higher in those with severe neurological complications (164.2 v. 158.4 mmol/L, p=0.08). The mean rate of Na change was not faster in those with severe neurological morbidity (0.61 v. 0.91 mmol/L/hr; p=0.1).

Conclusion. Hypernatraemic dehydration remains a significant problem in South Africa. High rates of formula feeding may be a contributory factor and the correlation with HIV infection needs investigation. Poor neurological outcomes were noted particularly in those patients presenting with hypernatraemia and shock. Although the mean admission Na level was higher in patients with severe neurological complications, this was not statistically significant in this sample. This study supports the hypotheses that neurological complications in diarrhoea-related hypernatraemia are largely associated with the severity of the dehydration that occurs prior to presentation rather than following rehydration.

S Afr J Child Health 2018;12(1):XX-XX. DOI:10.7196/SAJCH.2018.v12i1.1424

Approximately 76% of deaths in children under 5 years of age occur within the first 12 months of life,[1] with diarrhoeal disease ranked as one of the leading causes of infant mortality in South Africa (SA).[1,2] Hypernatraemic dehydration as a complication of diarrhoeal disease, contributes to the morbidity and mortality of affected patients,[3] with a prevalence of 6.4% to 13.7%, respectively, reported in developing countries.[4,5] Diarrhoea-related hypernatraemic dehydration occurs as a result of a negative water balance, with water loss exceeding sodium (Na) loss.[6] Salt poisoning – commonly due to incorrect constitution of homemade oral rehydration therapy (ORT) and over-concentrated formula feeds – is also an important factor in the aetiology of hypernatraemia.[7] Acute onset hypernatraemia increases serum osmolality, causing fluid to shift from the intracellular to the extracellular space, leading to cerebral cell dehydration and shrinkage. This can perpetuate structural changes resulting in intracranial haemorrhages. As a means of adaptation to gradual onset hypernatraemia, the brain increases its intracellular content of idiogenic osmoles, thus regaining its cell volume.[3] In this event, rapid correction of the Na with hypotonic intravenous fluids can lead to cerebral oedema.

Thus, neurological abnormalities are common, ranging from irritability and tone disturbances to seizures and coma.[3] Mortality rates vary between 3% and 13%,[8] and hypernatraemic dehydration has been implicated as a predictor of death in children younger than 5 years old admitted with acute gastroenteritis (AGE). [9]

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Despite high morbidity and mortality rates, the management of hypernatraemic dehydration is still not standardised in national guidelines. Institutions and teaching hospitals have developed individually tailored protocols developed by clinicians over many years. In KwaZulu-Natal (KZN), where AGE rates remain high, such a protocol has been in place for the past decade in Durban hospitals, including King Edward VIII Hospital (KEH), which is the major teaching hospital in the province.[10] There are no published randomised controlled trials that clearly document the ideal choice of intravenous fluid, or the optimal rate of Na correction that can be undertaken without developing cerebral oedema, and there are conflicting results as to the correlation between the rate of fall of Na and clinical outcomes.[3,6] To reduce its impact on the neurological morbidity of infants in SA, there is a need to further understand this condition and the factors that may contribute to such adverse outcomes. The aim of this study was to describe the extent of hypernatraemic dehydration in an HIV-endemic province in SA and to clarify if the major contributor to these outcomes is the severity of the hypernatraemia itself, or complications arising from rapid fluid correction.

The objectives of the study were: (i) to determine the prevalence of hypernatraemia (Na ≥150 mmol/L) in all infants admitted with AGE at KEH from January until December 2014; (ii) to describe the feeding patterns, nutritional status and clinical outcomes of these infants; and (iii) to determine the association between admission Na level, rate of Na correction and clinical outcomes.

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RESEARCH Methods

This study was a retrospective chart review conducted at KEH, a regional hospital within the Durban Metropolitan area in KZN. Purposive sampling was used to identify cases of hypernatraemic dehydration in infants younger than 12 months old. Utilising a physician-verified institution database, all cases of AGE in infants admitted between January and December 2014 were identified.

The admission serum Na levels of these cases were traced via the National Health Laboratory Service (NHLS) Trakcare Web Results.

Those with an admission Na level â&#x2030;Ľ150 mmol/L were included in the study. This two-step process aimed to prevent any omission of cases of hypernatraemia that might have not been documented in the admission database. The inpatient charts of identified cases were retrieved from the KEH medical records department for detailed clinical review. Demographic characteristics of each patient, nutritional status, feeding choice, as well as clinical data, including documented neurological symptoms, signs and outcomes (length of stay or mortality) were captured. Nutritional status was based on the weight-for-height Z-score, the presence of oedema and visible severe wasting. A 10% adjustment in admission weight was made to correct for the degree of dehydration. The serum Na on admission and subsequent Na levels during the course of inpatient management, together with their sampling times, was used to calculate the average rate of Na reduction until correction (<150 mmol/L) within the first 24 hours of admission.

To improve accuracy and minimise inter-observer variability, the clinical examination findings of the attending specialist paediatrician

Results

There were 1 422 infants admitted to KEH in 2014, of whom 334 (23.5%) had an admission diagnosis of AGE. The prevalence of hypernatraemic dehydration secondary to AGE in infants was found to be 12.3% (n=41/334 cases). Three of the 41 patient files could not be traced, leaving 38 patients eligible for chart review. The sample population consisted of 84% infants under the age of 6 months (n=32/38) and 16% between 6 to 12 months of age (n=6/38); 55% were male (n=21/38) and 45% female (n=17/38). ORT had been used in 55% of patients (n=21) prior to presentation, 8% of patients (n=3) had not used ORT and 37% of the patient files (n=14) did not document whether ORT had been used or not. An initial clinical assessment of shock was present in 45% of the patients (n=17), of whom 65% also experienced a severe neurological complication. The HIV status of all infants with AGE is described in Table 1.

The hypernatraemic cohort was noted to have a 66% HIV exposure rate in comparison with 47% in those infants admitted for AGE without hypernatraemia, and this was a statistically significant difference (p=0.03). Table 2 lists the nutritional status and documented feeding choices and practices of the sampled cohort.

With regards to nutrition and feeding, 21% of hypernatraemic patients were classified as either moderate or severe acute malnutrition. The nutritional classification of patients admitted for AGE without hypernatraemia was recorded as 64% normal, 17% underweight and 19% severely underweight for age.

Seventy-six percent of the hypernatraemic cohort were exclusively formula fed with only 16% exclusively breastfed. Of those receiving

Table 1. HIV status of infants with AGE admitted to KEH in 2014 HIV status AGE with hypernatraemia (N=41),* n (%)

AGE without hypernatraemia (N=293), n (%)

Unexposed Exposed, HIV-uninfected Exposed, HIV-unknown Exposed, HIV-positive Unknown

151 (52) 91 (31) 33 (11) 16 (5) 2 (1)

14 (34) 20 (49) 4 (10) 3 (7) 0

*The HIV status of the three patients with missing files was obtained from the hospital admission database.

served as the primary source of data related to clinical symptoms and signs. For the purposes of this study, we recorded and classified the presence of irritability and/or abnormal muscle tone during the period of admission as a mild neurological abnormality. The occurrence of seizures and/or encephalopathy classified the patient as having a severe neurological abnormality.

It is plausible for a single patient to have more than one documented neurological abnormality during their admission; therefore, each patient was classified based on the most severe complication they developed, with encephalopathy considered most severe on the spectrum. This eliminated any duplication of results during the process of data analysis.

Data were captured on an Excel spreadsheet and subsequently analysed using the Statistical Package for Social Sciences version 22 (IBM Corp., USA). Descriptive statistics, including frequencies, percentages, means, medians and standard deviations (SD) were used to summarise results. Independent Samples t-test or the MannWhitney test was used to test for association between admission serum Na level, the rate of Na correction and outcomes. The level of significance was set at 0.05.

Ethics

Ethical approval was obtained from the Biomedical Research Ethics Committee of the University of KwaZulu-Natal (ref. no.

BE266/15).

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Table 2. Nutritional status and feeding practices n (%) Nutritional status (N=38) Normal nutrition Moderate acute malnutrition Severe acute malnutrition Feeding practices (N=38) Exclusive breastfeeding Exclusive formula feeding Mixed breast- and formula feeding Dilution of formula feeds (N=32) Correct Incorrect Not documented Reasons for not exclusively breastfeeding Scholar Returned to work HIV-positive mother Maternal or infant illness/medication Insufficient breastmilk Not documented

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30 (79) 3 (8) 5 (13) 6 (16) 29 (76) 3 (8) 3 (9) 3 (9) 26 (82) 3 (9) 5 (16) 10 (31) 2 (6) 5 (16) 7 (22)

RESEARCH formula feeds, 18% of patient caregivers were questioned about their formula dilution practices. Table 3 describes the clinical outcomes of the sampled cohort.

The majority (90%) of patients were discharged from KEH and 2 patients (4.9%) were transferred to an intensive care unit.

The mortality rate of infants with hypernatraemic dehydration at KEH was 4.9%. Both patients who demised had an initial clinical assessment of shock, as well as co-morbid conditions, one of which was severe sepsis with disseminated intravascular coagulation and the other was a chromosomal anomaly.

Neurological abnormalities were documented in 63% of reviewed infants, with 32% developing seizures and/or encephalopathy. Of those who developed seizures, 55% were preceded by irritability and/ or abnormal muscle tone. Of those wjo developed encephalopathy, 88% had preceding seizures. An initial clinical assessment of shock was present in 92% of patients who developed severe neurological complications. The association between admission serum Na level and neurological outcome is shown in Table 4.

The mean (SD) admission Na level for the sample population was 160.2 (9.49) mmol/L (range 150 to 181). A higher admission serum Na level was seen in those who developed severe neurological abnormalities; however, this association was not statistically significant.

There was no statistically significant difference between the median admission Na of those who died (n=2) and those who Table 3. Clinical outcomes Outcomes (N=41)*

n (%)

Discharged ≤7 days >7 days Transferred to PICU Demised Spectrum of neurological abnormalities (N=38) Nil Irritability and/or abnormal muscle tone only Seizures Seizures progressing to encephalopathy Encephalopathy

24 (58.5) 13 (31.7) 2 (4.9) 2 (4.9) 14 (37) 12 (31.5) 4 (10.5) 7 (18) 1 (3)

PICU = paediatric intensive care unit. *The outcomes of the three patients with missing files was obtained from the hospital admission database.

survived (n=36) (160.5 v. 157.5 mmol/L, p=1 using Mann-Whitney test).

The association between rate of Na correction and neurological outcome is shown in Table 5. The rate of Na correction ranged from –0.1 to 2.66 mmol/L/hr, with a mean (SD) of 0.81 (0.53) mmol/L/hr (n=37, as one patient had only an admission serum Na record with no subsequent measurements).

Severe neurological complications were not associated with a faster mean rate of Na correction. The sample population was also grouped into three categories according to rate of Na correction: <1 mmol/L/hr; 1 - 2 mmol/L/hr; and >2 mmol/L/hr. The categories were compared with outcomes. This showed that 70% of all patients had a rate of Na correction <1 mmol/L/hr. Of those with a rate of Na correction ≥1 mmol/L/hr, 18% developed a severe neurological complication. There was no statistically significant difference in the development of neurological complications between the groups (p=0.489 using Fisher’s exact test). Both patients who demised had severe neurological morbidity, and both had a rate of Na correction <1 mmol/L/hr.

Discussion

This study highlights the persistent burden of hypernatraemic dehydration secondary to AGE in SA. While the developed world now reports a decline in cases of hypernatraemic dehydration,[11] the prevalence rate of 12.3% in our study remains similar to that of earlier studies conducted in developing countries.[4,5] The incidence of hypernatraemia is said to increase with decreasing age,[4,5,10] as was the case in this study, with 84% of infants being under the age of 6 months. The decreased thirst response, as well as the inability to access adequate amounts of free water despite ongoing losses, contributes to this particular age group being identified as high-risk.[3] The hypernatraemic cohort in this study had a 66% HIV exposure prevalence, compared with 47% in those infants admitted for AGE without hypernatraemia, and this was a statistically significant difference. Both these results were also noted to be higher than the provincial HIV exposure prevalence of 40.1% in KZN.[12] It has been shown that HIV exposed uninfected infants have an increased risk of infectious morbidity, particularly when born to mothers with advanced disease,[13,14] and this could explain the increased prevalence among these infants with diarrhoeal disease. This study, however, describes a higher HIV exposure prevalence in relation to hypernatraemic dehydration, warranting further studies in this regard.

Table 4. Association between admission serum Na level (mmol/L) and severe neurological outcomes* Admission serum Na (mmol/L) Clinical outcome (N=38)

n (%)

Mean

SD

95% CI

No severe neurological abnormality noted Seizures and/or encephalopathy present

26 (68.4) 12 (31.6)

158.4 164.2

7.9 11.6

155.2 - 161.6 156.8 - 171.6

SD = standard deviation; CI = confidence interval. *p-value (two sample t-test) = 0.08.

Table 5. Association between rate of Na correction (mmol/L/hr) and severe neurological outcomes Clinical outcome (N=37)

n (%)

Rate of Na correction (mmol/L/hr) Mean SD 95% CI

No severe neurological abnormality noted Seizures and/or encephalopathy present

25 (67.6) 12 (32.4)

0.91 0.61

SD = standard deviation; CI = confidence interval. p-value (two sample t-test) = 0.1.

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0.58 0.37

0.67 - 1.14 0.38 - 0.84

RESEARCH Due to 31% of mothers using formula feeds indicating that their HIV status was the reason for their feeding choice, and as formula feeds are a recognised risk factor for the development of hypernatraemic dehydration,[7,8,15] we considered the effect of these feeding choices on HIV exposure prevalence and hypernatraemia; however, when we compared the HIV-exposed with the HIV-unexposed patients within the hypernatraemic cohort, we found an equally high number of patients who were exclusively formula-fed (76% v. 77%).

The use of formula feeds in developing countries is increasing, with only 8.3% of SA infants under the age of 6 months reported to be exclusively breastfed.[16] KEH advocates the current national infant feeding strategy, which recommends exclusive breastfeeding for all infants until 6 months of age, including those born to HIV-positive mothers. In keeping with this, the distribution of free formula feeds to HIV-positive mothers was discontinued in 2011.[17] Despite this, the low rate of exclusive breastfeeding was also apparent in our study at KEH, with 76% of infants being formula-fed and 8% mixed-fed with both formula and breastmilk.

Although the majority of patients were formula-fed, we noted that 82% of caregivers were not questioned about formula dilution practices. Over-concentration of formula feeds leads to a high osmotic load resulting in hypernatraemia,[7,15] so obtaining this information from caregivers is vital to identify such errors in feed dilution.

ORT serves as the first line management for the treatment of dehydration at the primary healthcare level; however, Dippenaar et al.[18]showed that 14% of caregivers added too much salt to the homemade sugar-salt solution, which is a known risk factor for the development of hypernatraemia. We noted that 37% of caregivers were not asked about the use of ORT prior to admission. This should be reinforced as an important component of the history-taking process for any patient admitted with AGE, to identify errors in ORT constitution and prevent recurrences.

Approximately 21% of our study population was found to have moderate and severe acute malnutrition. This was an unexpected finding, as hypernatraemic dehydration is classically described in the well-nourished infant[19] and its incidence is said to be inversely related to the degree of malnutrition.[4] A study by Chisti et al. [20] in Bangladesh reported that 28% of their hypernatraemic patients had severe wasting. This finding could be attributed to the higher rates of malnutrition in developing countries overall, as more than one-third of the infants admitted to KEH for AGE without hypernatraemia were also found to be underweight or severely underweight for age. Approximately two-thirds of patients in this study experienced abnormal neurological manifestations, of which 50% were seizures and/or encephalopathy. Robertson et al.[8] also reported a high incidence of seizures within their sample of hypernatraemic patients in Cape Town.

The mortality rate of 4.9% for hypernatraemic dehydration was similar to that of other studies.[8] However, it was higher in comparison to the age-matched mortality rate of 1% for infants admitted to KEH for AGE without hypernatraemia. This highlights the increased risk of mortality in patients with hypernatraemic dehydration, but is it a higher admission Na level or a rapid rate of Na correction that contributes to this increased risk?

Admission Na level and rate of Na correction

The management of hypernatraemic dehydration is based on providing adequate free water to correct the serum Na level;[3] however, the rate at which it is corrected remains a point of contention.

A study conducted in Cape Town found that rate of Na correction was not significantly associated with adverse outcomes.[8] In contrast, a Chinese study concluded that a faster rate of Na correction was a significant risk factor for the development of cerebral oedema.[21] In the face of these conflicting study results, no definitively safe rate of correction has yet been advocated. Moritz and Ayus[3] recommend that, 13

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unless symptoms of hypernatraemic encephalopathy are already present, a rate of correction not exceeding 1 mmol/L/hr is reasonable.[19] Another recommendation by Duggal et al.[22] is to factor in the rate of development of the hypernatraemia. A gradual onset requires slower correction at 0.5 mmol/L/hr, while an acute onset can tolerate faster correction, with a rate of 1 mmol/L/hr deemed acceptable.

The experience at KEH has been to aim for a rate of Na correction between 0.5 and 1 mmol/L/hr using a standardised hospital protocol that guides the fluid management of hypernatraemic dehydration. This protocol was developed by senior clinicians using their collective experience in the management of such cases over a number of years.

Standard ORT is used in cases of mild hypernatraemic dehydration.

Where intravenous rehydration is required, fluids containing a Na concentration of approximately two-thirds that of the patientâ&#x20AC;&#x2122;s Na level is used, at an initial rate of 10 mL/kg/hr. This accounts for maintenance requirements, deficit and ongoing losses, and is continued until the level of hydration improves and the patient is able to tolerate adequate amounts of ORT.[10] In this study, we found that 70% of hypernatraemic patients had a rate of Na correction <1 mmol/L/hr, in keeping with recommendations in the literature.

Our study showed no statistically significant correlation between a faster rate of Na correction within the first 24 hours and adverse neurological outcomes and mortality. Of those with a rate of Na correction â&#x2030;Ľ1 mmol/L/hr, only 18% developed a severe neurological complication.

In the light of these findings, it appears that the hypernatraemia itself would be the more likely cause for adverse outcomes in these patients. This study showed that the mean admission Na level was higher in those with severe neurological morbidity and mortality; however, this association did not reach statistical significance.

We postulate that the development of neurological complications could be related to an interaction of factors prior to presentation, including the severity of the hypernatraemia together with the clinical presence of shock. In this study, 92% of patients with severe neurological complications were in shock on presentation, highlighting it as an important factor in those with adverse outcomes.

It is known that the degree of dehydration is often underestimated in hypernatraemic patients due to the relatively well-preserved intravascular volume.[6] Thus, the signs of severe dehydration and shock occur late, and may initially be missed by caregivers. This leads to inadequate provision of ORT and delayed presentation, while intracellular cerebral dehydration prevails. Hypernatraemia and increasing plasma arginine vasopressin concentrations have also been shown to affect haemostatic function, thus promoting a hypercoaguable state, although the mechanism of this effect remains unclear.[23] This association with an increased risk of thrombosis, together with the haemo-concentrated state induced by hypovolaemic shock, are risk factors for the development of cerebral sinus venous thrombosis, which can present with seizures and neurological abnormalities.[24] The use of neuroimaging would ideally differentiate between intracranial haemorrhages, thrombosis and cerebral oedema in patients who experience severe neurological complications during admission; however, this is not always feasible in resource-limited settings.

Study limitations

As this was a retrospective study, data were obtained from information documented in patient files, which were often poorly recorded with regard to ORT use and formula dilution.

There was a small sample size. There was a lack of definite timebased data for all neurological signs. There was no case control group in this study with which to make clear comparisons with the hypernatraemic group.

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RESEARCH Conclusion and recommendations

This study confirms that hypernatraemic dehydration related to AGE remains a significant challenge in South Africa, with a prevalence of 12.3% in a high HIV-exposed infant cohort. The predominant use of formula feeds, with low breastfeeding rates noted in these patients, may be a contributory factor. We also reaffirm the high rate of neurological morbidity and increased risk of mortality in hypernatraemic patients in this study. Mean admission Na was higher in cases with severe neurological complications and mortality, although this finding did not reach statistical significance. A faster rate of Na correction within the first 24 hours was not significantly associated with adverse outcome. This study suggests that the development of neurological complications could be related to an interaction of factors prior to presentation, including the severity of the hypernatraemia together with the clinical presence of shock. Larger multicentre trials are needed to further delineate these associations, to assist with management guidelines and reduce complications.

We recommend that greater emphasis should be placed on the pre-hospital management of patients with AGE, including educating caregivers on the correct use and constitution of ORT, appropriate practices and quick referral for help, to prevent the development of hypernatraemia and shock. Formula-fed infants should be identified as at risk for hypernatraemia. This study highlighted the poor documentation of ORT use and constitution, as well as formula dilution practices in patient records at the institution where the study took place. We suggest that existing admission templates be altered to remind staff to enquire about the relevant history in AGE cases.

In the management of infants with hypernatraemia following AGE, healthcare workers should aim for a reduction in serum Na between 0.5 and 1 mmol/L/hr, as per recommendations in the literature[3,22] to prevent any added risk of cerebral oedema.

Acknowledgements. Catherine Connolly for her assistance with data analysis.

Author contributions. TH was responsible for study design, data collection, data analysis and drafting of the manuscript. KN and SR supervised the study and reviewed the manuscript.

Funding. None.

Conflicts of interest. None.

1. South African Medical Research Council (SAMRC). Under-5 Mortality Statistics in South Africa: Shedding Some Light on the Trends and Causes 1997-2007.

Pretoria: SAMRC, 2012. http://www.mrc.ac.za/bod/MortalityStatisticsSA.pdf (accessed on 22 May 2017).

2. Statistics South Africa (SSA). Mortality and Causes of Death in South Africa, 2015: Findings from Death Notification. Pretoria: SSA, 2016. http://www. statssa.gov.za/publications/P03093/P030932015.pdf (accessed 22 May 2017).

3. Moritz ML, Ayus JC. Preventing neurological complications from dysnatremias in children. Pediatr Nephrol 2005;20(12):1687-1700. https://doi.org/10.1007/ s00467-005-1933-6 4. Samadi AR, Wahed MA, Islam MR, Ahmed SM. Consequences of hyponatraemia and hypernatraemia in children with acute diarrhoea in Bangladesh. Br Med J (Clin Res Ed) 1983;286(6366):671-673. https://doi. org/10.1136/bmj.286.6366.671 5. Eke F, Nte A. A prospective clinical study of patients with hypernatraemic dehydration. Afr J Med Med Sci 1996;25(3):209-212.

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6. El-Bayoumi MA, Abdelkader AM, El-Assmy MM, Alwakeel AA, El-Tahan HM. Normal saline is a safe initial rehydration fluid in children with diarrhea-related hypernatremia. Eur J Pediatr 2012;171(2):383-388. https://doi.org/10.1007/ s00431-011-1559-6 7. Abu-Ekteish F, Zahraa J. Hypernatraemic dehydration and acute gastroenteritis in children. Ann Trop Paediatr 2002;22(3):245-249. https://doi. org/10.1179/027249302125001624 8. Robertson G, Carrihill M, Hatherill M, Waggie Z, Reynolds L, Argent A. Relationship between fluid management, changes in serum sodium and outcome in hypernatraemia associated with gastroenteritis. J Paediatr Child Health 2007;43(4):291-296. https://doi.org/10.1111/j.1440-1754.2007.01061.x 9. Chisti MJ, Pietroni MA, Smith JH, Bardhan PK, Salam MA. Predictors of death in under-five children with diarrhoea admitted to a critical care ward in an urban hospital in Bangladesh. Acta Paediatr 2011;100(12):e275-279. https:// doi.org/10.1111/j.1651-2227.2011.02368.x 10. Naidoo KL, Ramji S. Acute gastroenteritis with hypernatraemic dehydration in children â&#x20AC;&#x201C; a guide to management. S Afr Pediatric Rev 2007;4(2):19-21.

11. Moritz ML, Ayus JC. The changing pattern of hypernatremia in hospitalized children.

Pediatrics 1999;104(3):435-439. https://doi.org/10.1213/ ane.0b013e3181f70826 12. National Department of Health (NDoH). The 2013 National Antenatal Sentinel HIV Prevalence Survey South Africa. Pretoria: NDoH, 2014. https:// www.health-e.org.za/wp-content/uploads/2016/03/Dept-Health-HIV-HighRes-7102015.pdf (accessed 22 May 2017).

13. Cooke ML, Nel ED, Cotton MF. Pre-hospital management and risk factors in children with acute diarrhoea admitted to a short-stay ward in an urban South African hospital with a high HIV burden. S Afr J Child Health 2013;7(3):84-87. https://doi.org/0.7196/SAJCH.472 14. Marinda E, Humphrey JH, Iliff PJ, et al. Child mortality according to maternal and infant HIV status in Zimbabwe. Pediatr Infect Dis J 2007;26(6):519-526. https://doi.org/10.1097/01.inf.0000264527.69954.4c 15. Taitz LS. Solute and calorie loading in young infants: Short- and longterm effects. Arch Dis Child 1978;53(9):697-700. https://doi.org/10.1136/ adc.53.9.697 16. Republic of South Africa Department of Health/Medical Research Council.

South African Demographic Health Survey 2003. http://www.mrc.ac.za/bod/ sadhs.htm (accessed 22 May 2017).

17. Ijumba P, Doherty T, Jackson D, et al. Free formula milk in the prevention of mother-to-child transmission programme: Voices of a peri-urban community in South Africa on policy change. Health Policy Plan 2013;28(7):761-768. https://doi.org/10.1093/heapol/czs114 18. Dippenaar H, Joubert G, Nel R, Bantobetse ML, Opawole AA, Roshen KS. Homemade sugar-salt solution for oral rehydration: Knowledge of mothers and caregivers. SA Fam Pract 2005;47(2):51-53. https://doi.org /10.1080/20786204.2005.10873188 19. Diedericks RJ. Fluid therapy in the emergency unit. CME 2013;31(1):21-23.

20. Chisti MJ, Ahmed T, Ahmed S, et al. Hypernatraemia in children with diarrhea: Presenting features, management, outcome, and risk factors for death. Clin Pediatrics 2016;55(7):654-663. https://doi.org/10.1177/0009922815627346 21. Fang C, Mao J, Dai Y, et al. Fluid management of hypernatraemic dehydration to prevent cerebral oedema: A retrospective case control study of 97 children in China. J Paediatr Child Health 2010;46(6):301-303. https://doi.org/10.1111/ j.1440-1754.2010.01712.x 22. Duggal AK, Yadav P, Agarwal AK, Rewari BB. Clinical approach to altered serum sodium levels. JIACM 2006;7(2):91-103.

23. Grant PJ, Tate GM, Hughes JR, Davies JA, Prentice CR. Does hypernatraemia promote thrombosis? Thromb Res 1985;40(3):393-399.

24. Hashmi M, Wasay M. Caring for cerebral venous sinus thrombosis in children.

J Emerg Trauma Shock 2011;4(3):389-394. https://doi.org/10.4103/09742700.83870 25. Chouchane S, Fehri H, Chouchane C, et al. Hypernatremic dehydration in children: Retrospective study of 105 cases. Arch Pediatr 2005;12(12):16971702.

Accepted 7 August 2017.

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RESEARCH

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

The profile of meningitis in a tertiary paediatric hospital in South Africa L Jansz,1 BSc; H Buys,2 FCP; M van Dijk,1 PhD; U Rohlwink,3 PhD Department of Paediatric Surgery, Erasmus MC-Sophia Children’s Hospital, Rotterdam, the Netherlands Department of Paediatrics and Child Health, Faculty of Health, University of Cape Town, and Red Cross War Memorial Children’s Hospital, South Africa 3 Division of Neurosurgery, Faculty of Health, University of Cape Town, and Red Cross War Memorial Children’s Hospital, South Africa 1

2

Corresponding author: L Jansz (lucajansz@gmail.com) Background. Meningitis in children is a major health problem worldwide, leading to high rates of mortality and morbidity.

Objectives. To describe the profile of patients treated for meningitis at a leading tertiary paediatric hospital (Red Cross War Memorial Children’s Hospital) in South Africa.

Methods. This study describes all patients treated for suspected meningitis at our hospital from 2010 to 2012. Data were retrospectively collected from patient folders.

Results. A total of 706 patients with meningitis were divided into definite bacterial (n=42), probable bacterial (n=113), partially treated bacterial (n=100), viral (n=412), and tuberculous meningitis (TBM, n=39)) infections. Fever (74.7%), headache (66.4%), vomiting (52.1%) and irritability (34.5%) were common symptoms in all patients; TBM patients presented more often with weight loss, neck stiffness, lethargy and abnormal neurological signs. Symptoms were usually present for 1 - 2 days in viral and bacterial meningitis, and 8 days in TBM. The median duration of hospitalisation was 1 day for viral meningitis, 2 days for all three groups of bacterial meningitis and 22 days for TBM, before referral to primary or secondary hospitals.

Conclusion. Patients with meningitis in this study often presented with nonspecific symptoms, making it difficult to clinically differentiate between types of meningitis. TBM patients presented more often with neurological fallout, and had a longer duration of symptoms. Patients often received antibiotics before a lumbar puncture was performed, further compounding the difficulty of diagnosis. Swift, sensitive and specific novel diagnostic tools would aid clinicians in making timeous and accurate diagnoses and treatment decisions.

S Afr J Child Health 2018;12(1):15-20. DOI:10.7196/SAJCH.2018.v12i1.1428

Meningitis is an major health problem worldwide, including in South Africa (SA), which has an annual incidence of 4 per 100 000 cases in the general population, and it occurs commonly in infants (with an incidence of 40 per 100 000). This incidence rate is probably an underestimate, because the rate of positive cerebrospinal fluid (CSF) culture results is low, and negative cultures are excluded in these numbers.[1] Furthermore, owing to the rising incidence of tuberculosis in SA, the increasing number of patients with tuberculous meningitis (TBM) is of great concern.[2] Symptoms of meningitis may be nonspecific, differ between age groups and have little diagnostic value.[3-5] Presenting symptoms include fever, irritability, poor feeding, vomiting, seizures, headaches, photophobia and confusion. Older children (>3 years) tend to present more similarly to adults, with classical signs such as headaches, neck stiffness and photophobia.[1] Signs of meningeal irritation are present in 75% of children with bacterial meningitis.[5] Seizures may occur in meningitis, but should not be confused with the common febrile seizures in the age range of 6 months - 6 years.[4] Fever occurs regularly, but is less common in infants.[3] Since the diagnostic value of clinical features in children with meningitis is limited, a low threshold for the use of diagnostic tools such as lumbar puncture (LP) for suspected meningitis in infants and young children is recommended.[1,4] Typical CSF findings for bacterial meningitis are an elevated white blood cell count (WCC), with polymorph predominance, decreased glucose and increased protein.[6,7] TBM is associated with elevated lymphocytes and protein; glucose may be decreased.[8] Viral meningitis occurs with CSF findings closer to normal ranges, but a slightly elevated WCC is common.[9] Usually there is lymphocyte predominance, but early in the disease course, CSF may show polymorph predominance.[6,9] Although CSF findings may confirm the presumptive diagnosis of meningitis, laboratory results are 15

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not always easy to interpret, since immediate administration of antibiotics in suspected meningitis is recommended in SA at primary care level, and CSF may be sterilised a few hours after antibiotics are given.[1,7] Pretreatment with antibiotics is also associated with fewer positive CSF culture results, and affects CSF profiles, as glucose may increase and protein may decrease.[10] Complete sterilisation may already occur within 2 - 4 hours after administering antibiotics.[11] Furthermore, there are also discrepancies in the normal values used in different studies, and the CSF criteria used to distinguish between viral and bacterial aetiologies may also differ between studies.

Meningitis as a cause of death is more common in developing countries (24.0 deaths per 100 000 children) than in the developed world (1.6 deaths per 100 000 children),[12] yet little has been published on paediatric meningitis in developing countries, where the profile of meningitis differs from that in the developed-world context.[13] Previous studies have reported a decrease in meningitis caused by Haemophilus influenzae type B (Hib) since the introduction of the Hib vaccine; however, there has been an increase in paediatric TBM cases in the last 30 years in the Western Cape province of SA, and meningitis remains a major cause of death in SA children.[2,8,14,15] The aim of this study is to describe the profile of patients treated for bacterial and viral meningitis at a tertiary paediatric hospital in SA.

Methods

All patients who underwent a diagnostic LP between 1 July 2010 and 30 June 2012 at the Red Cross War Memorial Children’s Hospital (RCWMCH) were included for record review. Patients were identified using the laboratory database of all CSF analyses over this period. Records were thoroughly examined to identify all patients treated for meningitis. Normal values for CSF used by the hospital

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RESEARCH laboratory are described as there being no polymorphonucleocytes, ≤5 lymphocytes, protein ≤0.8 g/L or ≤0.45 g/L (for <1 year of age or >1 year of age, respectively) and glucose ≥2.3 mmol/L. Chloride values were not considered in categorising meningitis patients.

Patients were categorised as belonging to one of five types of meningitis. ‘Viral meningitis’ was diagnosed when CSF showed elevated WCC (>5 lymphocytes, or any polymorphonucleocytes), with CSF chemistry (protein and glucose) within the normal range.

Bacterial meningitis was divided into subgroups: ‘definite bacterial meningitis’, ‘probable bacterial meningitis’ and ‘partially treated bacterial meningitis’. A definite bacterial meningitis categorisation was assigned when CSF culture or Gram stain was positive for a bacterial pathogen, ‘probable bacterial meningitis’ if CSF showed any polymorphonucleocytes in combination with elevated protein or decreased glucose, and ‘partially treated bacterial meningitis’ when a patient received antibiotics prior to LP, and CSF results showed predominantly polymorphonucleocytes, or elevated protein or decreased glucose. For the purposes of this study, the categorisation of TBM was based on a published consensus statement, which combines laboratory, clinical and radiological criteria.[16] Patients falling into the ‘definite’ and ‘probable TBM’ groups were analysed as a single group. Uncategorised patients were defined as ‘uncertain pathology’ in the case of a normal WCC, but abnormal chemistry and no history of antibiotics prior to LP. ‘Partially treated meningitis or misdiagnosed’ was assigned when the patient received antibiotics prior to LP, but showed normal CSF, and ‘misdiagnosed’ when CSF was normal and there was no history of antibiotics prior to LP. The CSF studies were processed by the National Health Laboratory Service, using standard laboratory methods. CSF was not routinely processed for viral culture or polymerase chain reaction (PCR). All CSF studies were processed for Gram stain and culture. In cases of suspected TBM, acid-fast stain was added.

Data collection

Demographic and clinical data, including history, presenting signs and symptoms, diagnostic and laboratory tests, treatment and inhospital death, were retrieved from patient folders. Outcome was not recorded, as the RCWMCH is a tertiary hospital, and most patients were referred to primary or secondary hospitals for further management after the initial diagnosis and stabilisation. Follow-up at other hospitals was beyond the reach of this study.

Statistics

Normally distributed variables were summarised using mean (standard deviation), and non-normally distributed variables as median (interquartile range (IQR)). Statistical comparisons between groups for continuous variables were performed using Kruskal-Wallis tests, and χ2 and Fisher’s exact tests in the case of categorical variables.

This study was approved by the Human Research Ethics Committee of the University of Cape Town (ref. no. HREC 177/2012).

Results

Between 1 July 2010 and 30 June 2012, a total of 7 410 LPs were performed in the RCWMCH, and 805 patients were treated for meningitis. The bacterial meningitis group consisted of 42 definite cases (5.9%), 113 probable cases (16.0%) and 100 partially treated cases (14.1%). The confirmed bacterial cases group contained 31 (73.8%) positive CSF cultures, and another 11 (26.2%) positive Gram stains. Cultured organisms (n=31) were Streptococcus pneumonia (n=9; 29.0%), Group B Streptococcus (n=6; 19.4%), Neisseria meningitides (n=5; 16.1%), Haemophilus influenzae (n=4; 12.9%), Escherichia coli (n=2; 6.5%), Staphylococcus epidermidis (n=2; 6.5%), Enterobacter cloacae complex (n=1; 3.2%), Streptococcus pyogenes (n=1; 3.2%) and a nontyphoidal Salmonella (n=1; 3.2%). A total of 39 patients met the criteria for definite (n=20) or probable 16

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TBM (n=19) (5.5%). Viral meningitis cases made up the largest group, with 412 cases (58.4%). There were 99 patients who did not meet any of the meningitis criteria, and were categorised as ‘possible TBM’ (n=36), ‘uncertain pathology’ (n=9), ‘partially treated/misdiagnosed’ (n=37) or ‘misdiagnosed’ (n=17). These patients were not included in the results (see Fig. 1).

Table 1 gives an overview of the background characteristics for the total sample; Table 2 provides an overview on presenting symptoms, signs, diagnostics and treatment.

LP between July 2010 and June 2012 (n=7 410)

Treated for meningitis (n=805)

Did not meet criteria (n=99): Possible TBM (n=36) Uncertain pathology (n=9) Partially treated/misdiagnosed (n=37) Misdiagnosed (n=17)

Met meningitis criteria (n=706)

Definite bacterial meningitis (n=42)

Probably bacterial meningitis (n=113)

Partially treated bacterial meningitis (n=100)

TBM (definite and probable; n=39)

Viral meningitis (n=412)

Fig. 1. Flowchart of patient inclusion and categorisation (LP = lumbar puncture; TBM = tuberculous meningitis.)

Table 1. Demographic characteristics of patient population in children with meningitis (N=706) Demographic characteristic n (%) Gender Male Female Age group Neonate (<1 month) 1 month - 1 year >1 year - 6 years >6 years Language spoken at home English IsiXhosa Afrikaans Other/unknown HIV status (n=510)* Positive HIV-exposed, PCR-negative Immunisations UTD† Previous meningitis‡ Diagnosis Bacterial (definite) Bacterial (probable) Bacterial (partially treated) TBM Viral In-hospital deaths Discharge destination§ Home Other healthcare facility

436 (61.8) 270 (38.2) 39 (5.5) 268 (38.0) 264 (37.4) 135 (19.1) 296 (41.9) 235 (33.3) 110 (15.6) 65 (9.2) 50 (9.8) 66 (12.9) 436 (90.3) 20 (3.2) 42 (5.9) 113 (16.0) 100 (14.2) 39 (5.5) 412 (58.4) 16 (2.3) 330 (48.0) 358 (52.0)

PCR = polymerase chain reaction; UTD = up to date, TBM = tuberculous meningitis. *HIV status was known in 510 patients (72.2%). † Immunisation status was known in 483 patients (68.4%). ‡ Previous meningitis status was known in 621 patients (88.0%). § Discharge status was known in 688 patients (97.5%).

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RESEARCH Table 2. Symptoms, signs, diagnostics and treatment in patient population in children with meningitis (N=706) Meningitis type, n (%)

Symptom Fever Vomiting Irritability Headache (n=345)* Neck stiffness Loss of appetite Lethargy Seizures Failure to thrive Not walking (n=399)† Duration of symptoms, (days; median (IQR)) Sign GCS <15 (n=130)‡ Focal neurology (n=512)§ Signs of raised ICP (n=283)¶ CN palsy (n=59)|| Diagnostic LP before treatment Raised OP (>25 cm H2O) on first LP (n=41)** CT brain CT before LP (n=156) Treatment Antibiotics (including pre-hospital) Prehospital antibiotics Antibiotics duration (days, median (IQR)) Viral therapy Steroids Surgery EVD Shunt Hospitalisation (days; median (IQR))

Bacterial (definite), n=42

Bacterial (probable), n=113

Bacterial (partially treated), n=100

TBM, n=39

Viral, n=412

p-value

34 (81.0) 12 (28.6) 20 (47.6) 3 (33.3) 10 (23.8) 26 (61.9) 11 (26.2) 12 (28.6) 2 (4.8) 1 (8.3) 2 (1 - 3)

77 (68.1) 55 (48.7) 38 (33.6) 22 (40.7) 36 (31.9) 27 (23.9) 19 (16.8) 27 (23.9) 17 (15.0) 1 (1.6) 1 (1 - 3)

70 (70.0) 50 (50.0) 38 (38.0) 28 (65.1) 23 (23.0) 24 (24.0) 14 (14.0) 19 (19.0) 10 (10.0) 1 (2.0) 1 (1 - 2)

20 (51.3) 20 (51.3) 10 (25.6) 14 (50.0) 26 (66.7) 17 (43.6) 19 (48.7) 9 (23.1) 18 (46.2) 8 (24.2) 8 (4 - 15)

326 (79.1) 230 (55.8) 137 (33.3) 162 (76.8) 123 (29.9) 122 (29.6) 60 (14.6) 57 (13.8) 27 (6.6) 5 (2.0) 1 (1 - 2)

<0.001 0.012 0.265 <0.001 <0.001 <0.001 <0.001 0.023 <0.001 <0.001 <0.001

7 (100.0) 11 (32.4) 14 (51.9) 2 (40.0)

13 (68.4) 19 (21.8) 6 (14.3) 3 (42.9)

3 (21.4) 6 (9.2) 4 (9.8) 1 (11.1)

20 (71.4) 24 (64.9) 7 (30.4) 11 (55.0)

9 (14.5) 21 (7.3) 17 (11.3) 3 (16.7)

<0.001 <0.001 <0.001 0.057

19 (45.2) 0 19 (45.2) 15 (78.9)

51 (45.1) 3 (30.0) 37 (32.7) 32 (86.5)

0 1 (33.3) 17 (17.0) 13 (76.5)

11 (28.2) 10 (55.6) 39 (100) 34 (87.2)

287 (69.7) 1 (14.3) 44 (10.7) 38 (86.4)

<0.001 0.209 <0.001 0.747

39 (92.9) 8 (19.0) 7.5 (5 - 14) 10 (23.8) 16 (38.1) 3 (7.1) 1 (2.4) 1 (2.4) 2 (1 - 10.5)

108 (95.6) 29 (25.7) 7 (5 - 10) 23 (20.4) 23 (20.4) 3 (2.7) 1 (0.9) 0 2 (1- 9)

100 (100) 43 (43.0) 7 (5 - 7) 9 (9.0) 5 (5.0) 3 (3.0) 2 (2.0) 0 2 (1 - 4.5)

39 (100) 11 (28.2) 7 (7 - 9) 9 (23.1) 36 (92.3) 26 (66.7) 20 (51.3) 19 (48.7) 22 (12 - 35)

346 (84.0) 49 (11.9) 5 (2 - 7) 22 (5.3) 14 (3.4) 2 (0.5) 2 (0.5) 1 (0.2) 1 (1 - 2)

<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001

IQR = interquartile range, GCS = Glasgow Coma Scale; ICP = intracranial pressure; CN = cranial nerve; CT = computed tomography; EVD = external ventricular drain; LP = lumbar puncture; OP = opening pressure (OP). *Headache assessed in verbal patients (>1.5 years old, n=345 (48.8%)). † Not walking assessed in patients >1 year (n=399 (56.4%)). ‡ GCS assessed in 130 patients (18.4%) § Focal neurology assessed in 512 patients (72.5%). ¶ Signs of raised ICP assessed in 283 patients (40.1%). || CN palsy assessed in 59 patients (8.4%), **Opening pressure of first LP assessed in 41 LPs (5.8%).

The majority of the patients were male (61.8%), and the median (IQR) age was 1.45 (0.3 - 4.9) years. The age distribution was different between diagnosis groups (p<0.001), ranging from a median (IQR) age of 0.46 (0.1 - 1.1) years in the definite bacterial group, to a median (IQR) age of 3.1 (1.3 - 5.2) years in TBM patients (Fig. 2). HIV infection was diagnosed in 50 (7.1%) patients, 460 (65.1%) patients were not infected, and in 196 (27.8%) patients, HIV status was not tested, recorded or known.

Most (75.1%) patients had been referred from another health facility, and just over half (52.0%) of the patients were discharged to another hospital after initial hospitalisation.

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Signs and symptoms

Common presenting symptoms were fever (n=527, 74.7%), headache (n=229, 66.4%), vomiting (n=367, 52.0%) and irritability (n=243, 34.4%). Weight loss, neck stiffness, altered level of consciousness and lethargy were more common in TBM than in all other groups (p<0.001). Fever was less common (51.3%) in the TBM group than in the others (68.1% - 81.0% (p=0.001). Patients with TBM also had the longest duration of symptoms: the median (IQR) was 8 (4 - 15) days, compared with 2 (1 - 3) days for definite bacterial meningitis, 1 (1 3) day for probable bacterial meningitis and 1 (1 - 2) day for partially treated bacterial and viral meningitis (p<0.001) (Fig. 3).

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RESEARCH Signs were not consistently recorded in patient records, with missing values ranging from 27.5% for focal neurology, up to 81.6% for Glasgow Coma Scale (GCS). A GCS <15 was more common in definite bacterial (100%), probable bacterial (68.4%) and TBM (71.4%) than viral (14.5%) and partially treated bacterial meningitis (21.4%) (p<0.001). Neurological signs and symptoms of raised intracranial pressure (ICP) were common in definite bacterial meningitis and TBM.

Diagnostics

All patients in this study underwent one or more LPs. The majority (69.7%) of patients with viral meningitis received their LP before antibiotic treatment, in contrast with TBM patients (28.2%) (p<0.001), who were more likely to be given antibiotics prior to LP. 12.5 *

* *

Discussion

5 * 2.5

l Vi ra

Diagnosis

Fig. 2. Age distribution of meningitis patients according to diagnosis (TBM = tuberculous meningitis.) *

25

60

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Duration of hospitalisation (days)

Age (years)

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In this study, 706 paediatric patients with meningitis were evaluated with respect to signs, symptoms, diagnostics and treatment. These patients may be a fair representation of the paediatric meningitis population of the Western Cape, as RCWMCH was the primary paediatric hospital in this area during the study period, and many children were referred from primary care units. This study showed that it was difficult to differentiate between bacterial and viral meningitis based on clinical symptoms, which could account for 84.0% of the patients with viral meningitis receiving antibiotics. However, the durations of antibiotics and of hospitalisation were shorter in the viral meningitis group compared with other groups, which might indicate cautious initial use of antibiotics and hospitalisation, with a cessation of antibiotics once the clinical picture had been fully reviewed. Given the threat of increasing drug resistance, faster reliable diagnostic tools for bacterial meningitis are urgently needed. Several studies are looking into promising diagnostic tools, such as procalcitonin in CSF, real-time PCR, multiplex PCR-based reverse line blot and matrix-assisted laser desorption/ionisation time of flight mass spectrometry.[17-20] Interestingly, the viral meningitis group received the lowest amount of viral therapy. This might be explained by the use of

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Antibiotics were given to the majority of patients, from 84.0% in the viral group to 100% in partially treated bacterial meningitis and TBM. The duration of antibiotics is defined as the number of days for which they were prescribed. The viral cohort received antibiotics for a median (IQR) duration of 5 (2 - 7) days, which was 2 - 2.5 days fewer than the other groups (p<0.001). The duration of hospital stay varied between groups (p<0.001). The median duration ranged from 1 (viral meningitis) to 22 (TBM) days (Fig. 4). After hospitalisation, 48.0% of all patients were sent home, and 52.0% to another healthcare facility.

TBM patients were more often referred to another healthcare facility after initial hospitalisation than other groups (p=0.006) â&#x20AC;&#x201C; only 20.6% of TBM patients were sent home directly.

TB

7.5

Treatment

(p Bac ro te ba ria bl l e)

Age (years)

10

The opening pressure (OP) on the first LP was documented in only 41 (5.8%) of all LPs, but more often in patients with TBM (46.2%, p<0.001). A raised OP >25 cm H2O was present in 10 TBM patients (55.6% of documented OPs in TBM; 25.6% of all TBM patients).

Of these 10 patients, 9 were diagnosed with hydrocephalus on head computed tomography (CT) scans.

(p

Diagnosis

Diagnosis

Fig. 3. Duration of symptoms in days at presentation in the hospital, according to diagnosis (not shown: 2 tuberculous meningitis (TBM) outliers (>2 standard deviations at 49 and 60 days.)).

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Fig. 4. Duration of hospitalisation in days, according to diagnosis (not shown: 2 tuberculous meningitis (TBM) outliers (+1 standard deviation at 86 and 79 days.)).

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RESEARCH acyclovir (in addition to antibiotics) only when herpes simplex encephalitis was suspected or difficult to rule out immediately, or more likely because most viral meningitis cases are actually caused by enteroviruses, in which case acyclovir would not be indicated.[1] Fever, headache, vomiting and irritability were common symptoms.

However, these symptoms are not specific to meningitis. This is in accordance with previous studies that have demonstrated the limited diagnostic value of these symptoms in meningitis.[3,4,21] More specific symptoms such as neck stiffness or focal neurology were less common; neck stiffness occurred in less than one-third of patients with viral (29.9%) and bacterial meningitis (23.0 - 31.9%). Focal neurology was present in only 7.3% in viral meningitis but went up to 32.4% in definite bacterial meningitis. Although bacterial and viral meningitis seemed to present quite similarly, TBM tended to present differently, with more severe and prolonged symptoms, such as weight loss, neck stiffness and an altered level of consciousness, in keeping with the more insidious nature of TBM. Given that clinical presentation and history form an important component of the presumptive diagnosis of this potentially devastating disease, the presence of these symptoms could alert clinicians to prioritise TBM in their differential diagnosis. Rapid diagnosis of TBM remains challenging, but research into novel diagnostic tests is on going. Some potential candidates include GeneXpert and the LAM-ELISA assay.

GeneXpert is an additional test for CSF with reported sensitivity and specificity of 59.3% and 99.5%, respectively.[22] The test is fairly easy to operate, and provides results within 2 hours, making it a valuable asset for diagnosing TBM.[23] LAM-ELISA is a urinary test, providing a simple diagnostic test for TBM, but its sensitivity is suboptimal.[24] The difficulty in interpreting clinical signs and CSF results emphasises the need for better diagnostic tools, to avoid not only missing an important diagnosis, but also administering treatment unnecessarily, in the case of viral meningitis. Multiple clinical decision scores have been developed and validated, with sensitivities ranging from 0.83 to 1.00, and specificity from 0.36 to 0.85.[25] The bacterial meningitis score (BMS) is the most promising, with a sensitivity of 99.3% and specificity 62.1% in a recent meta-analysis.[26] This suggests that the BMS could serve as a valuable additional tool in the clinical assessment of children with suspected meningitis, although some false positives would probably occur. The BMS consists of five criteria (CSF Gram stain positive, CSF protein >0.8 g/L, blood absolute neutrophil count >10 000 cells/mm3, history of seizures during current illness and CSF neutrophil count >1 000 cells/mm3) to determine the risk of bacterial meningitis in children with CSF pleocytosis. Patients with a BMS of 0 points are likely to have aseptic meningitis, and can be considered for outpatient management.[26] Tygerberg Hospital, another tertiary hospital in the Western Cape, has carried out 3 studies of its meningitis patients in the past 30 years.[2,27,28] The median age of our study population (1.45 years) is similar to that found in the most recent Tygerberg study (1.4 years), and the majority of meningitis diagnoses were also of viral meningitis.[2] However, the proportion of TBM patients was much higher in the Tygerberg study (22% v. 5.5% in this study). This might be explained by differences in the diagnostic protocols across the two hospitals, or it may be a reflection of time, as the Tygerberg study included patients over a 20-year period, when TBM might have been more common.

HIV results were available in 72.2% of our patients, and the number of patients who tested positive was low (9.8% of tested patients), which reflects favourably on SAâ&#x20AC;&#x2122;s proactive mother-tochild antiretroviral roll-out programme.

The tertiary nature of our hospital is demonstrated by the large number of patients referred from other healthcare facilities (75.1%) and discharged to another hospital (52.0%). This referral pattern could explain why many patients had received antibiotics before they arrived at RCWMCH, where the diagnostic LP was performed.

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The World Health Organization (WHO) Integrated Management of Childhood Illness approach is widely used in SA, and nurses at primary care facilities give an immediate single dose of ceftriaxone in the case of suspected meningitis, prior to referring the child to a hospital.[29] Therefore the interpretation of our CSF results is challenging, given that the CSF can be sterilised and parameters can normalise within hours after antibiotics have been started. This might have contributed to the low number of culture-positive CSF results (4.4% of all patients) that we found. Most TBM patients had received treatment before having an LP. Firstly, this may be owing to strong concerns about poor outcomes of untreated TBM. Secondly, it may be due to the increased risk of raised ICP in TBM, which is a contraindication for LP. Therefore antibiotic treatment may be commenced before a head CT can be performed to identify the risk of non-communicating hydrocephalus and the safety of an LP.[8] However, despite this risk, about one in six TBM patients was not scanned before an LP. This may be a result of uncertainty regarding the diagnosis, the absence of obvious clinical signs of raised ICP and poor access to a CT scanner. In this study population, 25.6% of TBM patients had a raised opening pressure on their LP, and 84.6% had hydrocephalus, which is similar to what has been found in previous studies.[8] Two important limitations of this study are the subjectivity of defining the different meningitis groups, and the retrospective nature of this study. To our knowledge, there is no consensus in the literature regarding exact case definitions or cut-off points in CSF values for different meningitis aetiologies. For instance, bacterial meningitis usually shows polymorphonucleocyte predominance and viral meningitis shows lymphocytosis, but in early viral meningitis there may be polymorphonucleocyte predominance too.[6] Probable bacterial meningitis has been described as >5 leucocytes in CSF, up to >10 leucocytes, combined with a positive blood culture.[1,2,10,11] The WHO defines probable bacterial meningitis as suspected meningitis with turbid CSF, leucocytosis >100 or leucocytosis >10 combined with elevated protein or decreased glucose.[30] However, a case definition for viral meningitis is lacking, other than clinically suspected meningitis. Research definitions for viral meningitis range from any suspected case of meningitis where another cause has been ruled out, to CSF with predominantly lymphocytes and normal chemistry or confirmed viral pathogen using PCR.[2,31] Uniform case definitions for bacterial and viral meningitis without a confirmed pathogen would be beneficial for future research. Defining the type of meningitis uses a combination of clinical signs and symptoms and the supporting information from CSF analysis, and is prone to subjective interpretation by clinicians. This made it difficult to retrospectively define the type of meningitis, when treatment was given based on the discretion of the treating clinician, and where variability in management choices may exist among clinicians due to the lack of standardised guidelines for patient management.

However, this is also indicative of the challenges facing paediatricians daily: which child with fever, vomiting and headache has meningitis, and which child does not? Moreover, which child with meningitis should receive antibiotics and which child can be safely sent home after a short hospitalisation?

Another limitation of this study is that some data from the patient folders were missing. Some patient folders could not be located, many folders lacked detailed information, and there was variability in the history-taking of the clinicians, and their notes on the physical examination. This might have led to an underestimation of signs and symptoms. To ensure complete notes on history and clinical examination, a patient-folder template would be very useful. A final limitation of this study is the lack of detailed outcome and follow-up data, as many patients were sent to other health facilities to complete their treatment. Important complications of meningitis such as hearing loss and other neurological outcomes were therefore

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RESEARCH not documented in this study. Designing a prospective study on signs, symptoms, diagnostics and treatment in patients with meningitis would be valuable, to document the thinking behind clinical decisions when treating patients. This could provide insight into the difficult process of clinically assessing acutely sick children.

Paediatric meningitis remains challenging to diagnose and treat, given the nonspecific nature of the signs and symptoms, the lack of rapid and reliable diagnostic tests and the high frequency of immediate antibiotic administration. Although progress has been made, and new diagnostic test candidates are being investigated, further research is needed. This study provides a baseline of meningitis at this paediatric institution, and the clinical and treatment data presented may inform future studies that prospectively address some of the challenges of managing and diagnosing these patients.

Conclusion

Patients with meningitis in this study often presented with nonspecific symptoms such as fever, headache, vomiting and irritability, which make it difficult to clinically differentiate between different types of meningitis. However, patients with TBM presented more often with neurological signs and symptoms and had a longer duration of symptoms. Most patients received antibiotics, including the patients with viral meningitis, often before the LP was performed, further compounding the difficulty of diagnosis. Swift, sensitive and specific novel diagnostic tools would aid clinicians in making timeous and accurate diagnoses and treatment decisions.

Acknowledgements. The authors thank Selma Jaspers for contributing to data collection for this study.

Author contributions. LS: data collection, analysis and interpretation, revising; HB: interpretation of data, revising; MvD and UL: study design, analysis and interpretation of data, revising Funding. None.

Conflicts of interest. None.

1. Boyles TH, Bamford C, Bateman K, et al. Guidelines for the management of acute meningitis in children and adults in South Africa. South Afr J Epidemiol Infect 2013;28(1):5-15. https://doi.org/10.1080/10158782.2013.11441513 2. Wolzak NK, Cooke ML, Orth H, van Toorn R. The changing profile of pediatric meningitis at a referral centre in Cape Town, South Africa. J Trop Pediatr 2012;58(6):491-495. https://doi.org/10.1093%2Ftropej%2Ffms031 3. Best J, Hughes S. Evidence behind the WHO guidelines: Hospital care for children – what are the useful clinical features of bacterial meningitis found in infants and children? J Trop Pediatr 2008;54(2):83-86. https://doi. org/10.1093%2Ftropej%2Ffmn013 4. Curtis S, Stobart K, Vandermeer B, Simel DL, Klassen T. Clinical features suggestive of meningitis in children: A systematic review of prospective data.

Pediatrics 2010;126(5):952-960. https://doi.org/10.1542%2Fpeds.2010-0277 5. Kim KS. Acute bacterial meningitis in infants and children. Lancet Infect Dis 2010;10(1):32-42. https://doi.org/10.1016%2Fs1473-3099%2809%2970306-8 6. Negrini B, Kelleher KJ, Wald ER. Cerebrospinal fluid findings in aseptic versus bacterial meningitis. Pediatrics 2000;105(2):316-319. https://doi. org/10.1542%2Fpeds.105.2.316 7. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004;39(9):1267-1284. https://doi.org/10.1086%2F425368 8. Van Well GT, Paes BF, Terwee CB, et al. Twenty years of pediatric tuberculous meningitis: A retrospective cohort study in the Western Cape of South Africa.

Pediatrics 2009;123(1):e1-8. https://doi.org/10.1542%2Fpeds.2008-1353 9. Logan SA, MacMahon E. Viral meningitis. BMJ 2008;336(7634):36-40. https:// doi.org/10.1136%2Fbmj.39409.673657.ae 10. Nigrovic LE, Malley R, Macias CG, et al. Effect of antibiotic pretreatment on cerebrospinal fluid profiles of children with bacterial meningitis. Pediatrics 2008;122(4):726-730. https://doi.org/10.1542%2Fpeds.2007-3275

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12. Whiteford HA, Degenhardt L, Rehm J, et al. Global burden of disease attributable to mental and substance use disorders: Findings from the Global Burden of Disease study 2010. Lancet 2013;382(9904):1575-1586. https://doi.or g/10.1016%2Fs0140-6736%2813%2961611-6 13. Furyk J, Swann O, Molyneux E. Systematic review: Neonatal meningitis in the developing world. Trop Med Internat Health 2011;16(6):672-679. https://doi. org/10.1111%2Fj.1365-3156.2011.02750.x 14. Ntuli ST, Malangu N, Alberts M. Causes of deaths in children under five years old at a tertiary hospital in Limpopo province of South Africa. Glob J Health Sci 2013;5(3):95-100. https://doi.org/10.5539%2Fgjhs.v5n3p95 15. Von Gottberg A, de Gouveia L, Madhi S, et al. Impact of conjugate Haemophilus influenzae type b (Hib) vaccine introduction in South Africa. Bull World Health Organ 2006;84(10):811-818. https://doi.org/10.2471%2Fblt.06.030361 16. Marais S, Thwaites G, Schoeman JF, et al. Tuberculous meningitis: A uniform case definition for use in clinical research. Lancet Inf Dis 2010;10(11):803-812. https://doi.org/10.1016%2Fs1473-3099%2810%2970138-9 17. Konstantinidis T, Cassimos D, Gioka T, et al. Can procalcitonin in cerebrospinal fluid be a diagnostic tool for meningitis? J Clin Lab Anal 2015;29(3):169-174. https://doi.org/10.1002/jcla.21746 18. Khumalo J, Nicol M, Hardie D, Muloiwa R, Mteshana P, Bamford C. Diagnostic accuracy of two multiplex real-time polymerase chain reaction assays for the diagnosis of meningitis in children in a resource-limited setting. PLOS ONE 2017;12(3):e0173948. https://doi.org/10.1371/journal.pone.0173948 19. Wang Y, Guo G, Wang H, et al. Comparative study of bacteriological culture and real-time fluorescence quantitative PCR (RT-PCR) and multiplex PCRbased reverse line blot (mPCR/RLB) hybridization assay in the diagnosis of bacterial neonatal meningitis. BMC Pediatr 2014;14(1):224-231. https://doi. org/10.1186/1471-2431-14-224 20. Segawa S, Sawai S, Murata S, et al. Direct application of MALDI-TOF mass spectrometry to cerebrospinal fluid for rapid pathogen identification in a patient with bacterial meningitis. Clinica Chimica Acta 2014;435:59-61. https:// doi.org/10.1016/j.cca.2014.04.024 21. Amarilyo G, Alper A, Ben-Tov A, Grisaru-Soen G. Diagnostic accuracy of clinical symptoms and signs in children with meningitis. Pediatr Emerg Care 2011;27(3):196-199. https://doi.org/10.1097%2Fpec.0b013e31820d6543 22. Nhu NT, Heemskerk D, Thu DDA, et al. Evaluation of GeneXpert MTB/RIF for diagnosis of tuberculous meningitis. J Clin Microbiol 2014;52(1):226-233. https://doi.org/10.1128/jcm.01834-13 23. Lawn SD, Nicol MP. Xpert MTB/RIF assay: Development, evaluation and implementation of a new rapid molecular diagnostic for tuberculosis and rifampicin resistance. Fut Microbiol 2011;6(9):1067-1082. https://doi. org/10.2217/fmb.11.84 24. Minion J, Leung E, Talbot E, Dheda K, Pai M, Menzies D. Diagnosing tuberculosis with urine lipoarabinomannan: Systematic review and meta-analysis. Eur Respir J 2011;38(6):1398-1405. https://doi.org/10.1183/09031936.00025711 25. Kulik DM, Uleryk EM, Maguire JL. Does this child have bacterial meningitis?

A systematic review of clinical prediction rules for children with suspected bacterial meningitis. J Emerg Med 2013;45(4):508-519. https://doi. org/10.1016%2Fj.jemermed.2013.03.042 26. Nigrovic LE, Malley R, Kuppermann N. Meta-analysis of bacterial meningitis score validation studies. Arch Dis Child 2012;97(9):799-805. https://doi.org/10 .1136%2Farchdischild-2012-301798 27. Donald P, Burger P, Becker W. Paediatric meningitis in the Western Cape. A 3-year hospital-based prospective survey. S Afr Med J 1986;70(7):391-395.

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Accepted 19 September 2017.

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RESEARCH

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

Paediatric splenectomy: The Johannesburg experience N Patel,1 BA Hons, MA, MB BCh; A Nicola,1 MBBCh; P Bennet,1 MB ChB; J Loveland,1 MB BCh, FCS (SA), Cert Paed Surg (SA); E Mapunda,1 MB ChB, FCS (SA), Cert Paed Surg (SA); A Grieve,1 MB BCh, MMed (Surg), FC Paed Surg (SA) 1

Department of Paediatric Surgery, University of the Witwatersrand, Johannesburg, South Africa

Corresponding author: N Patel (niravpatel44@gmail.com) Background. Splenectomy is an uncommon procedure in children, and data on children who underwent splenectomy in South Africa are sparse.

Objective. To describe the profile, operative management and outcomes of children undergoing splenectomy.

Methods. The records for all children aged 0 to 16 years who underwent splenectomy at Charlotte Maxeke Johannesburg Academic (CMJAH) and Chris Hani Baragwanath Academic (CHBAH) hospitals between 2000 and 2015 were reviewed. Student’s t-tests and χ2 tests were used to analyse the data.

Results. The mean age at surgery was 9.9 years (range 3-16). Most splenectomies (91%; n=30/33) were performed for haematological disorders and were open (67%; n=22/33). The mean post-operative length of stay (LOS) was shorter in the laparoscopic (4.5 days) than the open (7.1 days) groups (p<0.05). Surgical complications were more common in the laparoscopic (36%, 4/11) than open (9%; n=2/22) group, and in children older than the mean age at time of surgery. No cases of overwhelming post splenectomy infection (OPSI) were noted. At study completion, 61% (n=20/33) of patients were alive, 9% (n=3/33) had demised, and 30% (n=10/33) were lost to follow-up.

Conclusion. Local indications for paediatric splenectomy mirror those found in international literature. Mean and median postoperative lengths of stay (LOS) were shorter in the laparoscopic than open group, but relatively longer for both groups than reported internationally.

Laparoscopy is not currently the preferred technique for splenectomy in our setting. All mortalities were due to progression of underlying disease and no cases of OPSI were recorded. The high loss-to-follow-up rate in this study is a significant barrier to accurate data collection, analysis and reporting.

S Afr J Child Health 2018;12(1):XX-XX. DOI:10.7196/SAJCH.2018.v12i1.1431

Splenectomy is a well-described procedure in children. As opposed to the adult literature, trauma is an uncommon indication for splenectomy in children. Frequently, failure of medical therapy to control the splenic sequelae of haematological disorders, e.g. splenomegaly, hypersplenism and massive infarction, necessitates splenectomy.[1-4] Common examples of haematological disorders that necessitate splenectomy in children are hereditary spherocytosis (HS), sickle cell disease (SCD) and idiopathic thrombocytopaenic purpura (ITP). Although the pre-, peri- and postoperative management of paediatric patients undergoing elective and emergency splenectomy is well described within the international literature, there is a paucity of such literature in the South African (SA) context.[1,4] The objective of our study was to describe the demographic profile, operative management and outcomes of children undergoing splenectomy in the largest academic paediatric surgical centres in South Africa between 2000 and 2015.

Methods

A retrospective record review of paediatric patients undergoing splenectomy at Chris Hani Baragwanath Academic Hospital (CHBAH) and Charlotte Maxeke Johannesburg Academic Hospital (CMJAH) between 2000 and 2015 was conducted. Ethics approval was obtained from the University of the Witwatersrand Human Research Ethics Committee (ref. no. M160643). All patients between the ages of 0 and 16 years who underwent splenectomy were included in the study. All candidates for inclusion were identified by means of the splenectomy specimens submitted to the National Health Laboratory Services (NHLS) during the study period. Demographic data, data on pre- and postoperative medical management, surgical technique, postoperative complications and postoperative length of hospital stay were collected. Descriptive statistics were performed using Microsoft Excel. Analytical statistics were performed using 21

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Student’s t-test and χ2 test. Complete records were retrieved for 33 of the 41 eligible patients.

Results

A total of 41 splenectomies were performed on children between January 2000 and December 2015. Complete records were found for 33 of the patients; 48% (n=16/33) patients undergoing splenectomy were male, while 52% (n=17/33) were female. The mean age at surgery was 9.9 years (median 9; range 3 - 16). The majority of the splenectomies (91%; n=30/3) were performed for haematological disorders and the remainder (9%; n=3/33) were performed due to malignancy or trauma. Table 1 describes the specific indications for surgery in our series; 67% (n=22/33) of splenectomies in our series were performed open, with 33% (n=11/33) performed laparoscopically. In a single case, laparoscopy was abandoned due to uncontrolled intra-abdominal haemorrhage. The mean postoperative hospital length of stay (LOS) was significantly shorter (p<0.05) in patients who underwent laparoscopic splenectomy (4.5 days) than in those who had open surgery (7.1 days). The median postoperative Table 1. Indications for surgery Indication

n

ITP HS SCD CHA Malignancy Trauma

13 12 3 2 2 1

HS = hereditary spherocytosis; ITP = idiopathic thrombocytopaenic purpura; CHA = congenital haemolytic anaemia; SCD = sickle cell disease.

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RESEARCH hospital LOS was also shorter in the laparoscopic (4.0 days) relative to the open (6.5 days) group. All patients in our series underwent total splenectomy. The incidence of postoperative complications was higher in the laparoscopic (36%; n=4/11) than the open group (9%; n=2/22). These data and the relevant complications are summarised in Table 2. All patients undergoing splenectomy received immunisations against Streptococcus pneumoniae, Haemophilus influenzae, and Meningococcus as per departmental protocol. Booster immunisations were given at follow-up where necessary. All patients received postoperative life-long antibiotic prophylaxis (Pen VK or erythromycin) as per the departmental protocol. At a two-year followup, 20 patients (61%) were alive, 3 (9%) had died, and 10 (30%) had been lost to follow-up. These data are summarised in Table 3.

Discussion

The role of the spleen has long been disputed. Splenomegaly was associated with poor health and poor athletic ability in the ancient Roman, Egyptian and Babylonian eras.[5] Hippocrates considered the spleen the seat of black cholera and melancholy.[5] It was this perception of splenomegaly as a source of physical and mental disability that led ancient physicians to seek out ways in which to remove the spleen or at least decrease its size.[5] The first recorded splenectomy in Western medicine occurred in 1549, but it was not until the 19th century that elective splenectomies for splenomegaly were regularly performed.[6] Due to advances in anatomical knowledge and surgical technique, splenectomy became increasingly feasible. Fortunately, this improvement in surgical capability was accompanied by the knowledge that splenectomy performed for the wrong indication often had disastrous consequences.[5] Currently, the most common indication for splenectomy in children is to treat the splenic effects of haematological conditions, e.g. hypersplenism, splenomegaly or splenic sequestration.[5] The Table 2. Complications of open and laparoscopic splenectomy (n=6)

n

Open splenectomy (n=2) Minor complications Superficial wound sepsis Major complications Right pneumothorax

1 1

Laparoscopic splenectomy (n=4) Major complications Infected haematoma Port-site hernia Conversion to open surgery

2 1 1

Table 3. Postoperative management and outcome Candidates receiving antibiotic prophylaxis Antibiotic prophylaxis Penicillin VK Erythromycin Intermediate outcomes Alive at follow-up 1 year post splenectomy Alive at follow-up 2 years post splenectomy Lost to follow-up at 1 year post splenectomy Lost to follow-up 2 years post splenectomy Deceased at 1 year post splenectomy Deceased at 2 years post splenectomy

33 31 2 25 20 6 10 2 3

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first splenectomy for haematological disorders in children was performed in the early 20th century, more than 400 years after the first recorded splenectomy in adults.[5] Notwithstanding significant improvements in the post-operative haematological profiles of these patients, splenectomised patients were also found to be especially prone to immediate and late postoperative sepsis. By the 1970s, this phenomenon and the associated role of encapsulated bacteria, such as S. pneumoniae, H. influenzae type B and Neisseria meningitidis types A and C, had been labelled as overwhelming causes of postsplenectomy infection (OPSI).[7] OPSI is a devastating consequence of splenectomy in children, with mortality rates of up to 50% in high-risk groups, i.e. young children, those with haematological disease and with malignancy.[8] Although at highest risk within the first two years post-splenectomy, the risk of OPSI is lifelong.

Appropriate pre- and postoperative management with vaccination, antibiotic prophylaxis and immediate management of suspected sepsis in splenectomised patients have enabled modern surgeons and physicians to safely perform splenectomies in children under the age of 4 in some centres.[7] The indications for splenectomy in our series were similar to those found in the international literature, with the majority of cases performed for haematological disorders (namely ITP and HS). In total, 39% (n=13/33) of all cases were for ITP and 36% (n=12/33) for HS. Although laparoscopy is now the standard surgical approach for splenectomy in children, only 33% (n=11/33) of cases were performed laparoscopically in our series.[4,5,9] In a single instance, open conversion was necessary due to excessive intra-abdominal haemorrhage. The high rate of open splenectomy in our series could possibly be due to the lack of appropriate equipment during the early years of the study, lack of the necessary laparoscopic skills, and the fact that patients who present with massive splenomegaly are not amenable to laparoscopy.

The complication rate for laparoscopic splenectomy in our series was 36% (n=4/11); 2 patients developed infected haematomas, 1 had a port-site hernia, and 1 required open conversion due to haemorrhage.

Both haematomas required open drainage and antibiotic treatment.

The complication rate in our series of laparoscopic splenectomy contrasts with international rates of 1 - 5%,[4,5] and may be expected, given our relative inexperience with laparoscopic splenectomy in the early study period and the relatively low sample size. The complication rate for open splenectomy was 9% (n=2/22), with major complications accounting for 4.5% (n=1/22) and minor complications 4.5% (n=1/22) of the overall rate. The discrepancy in the complication rate for open splenectomy in our series and the rate of 1% reported in the international literature[4,5] may again be due to the low sample size. Postoperative complications were more common in patients who were older than the mean age of 9.9 years (n=16) â&#x20AC;&#x201C; 25% (n=4/16) of them suffered a significant postoperative complication. The complication rate was only 6% (n=1/17) in the 17 patients who were younger than the mean age of 9.9 years at the time of surgery. This finding may be due to numerous factors including the severity of the underlying disease process at the time of surgery and may suggest that earlier splenectomy may decrease the complication rate in our setting. Further study with a prospective and larger sample size is required in order to examine this relationship.

The mean postoperative LOS was significantly lower in the laparoscopic group (4.5 days) compared with the open group (7.1 days) (p<0.05). Thus, our data reaffirm the conclusions of international literature with regards to the benefit of laparoscopic over open splenectomy in terms of postoperative LOS.[3,4,9-11] This said, the postoperative LOS in both the open and laparoscopic groups was considerably longer in our series relative to international studies in which postoperative LOS ranges from 1.4 - 1.8 days for laparoscopic splenectomy and 2.5 - 4.0 days for open splenectomy.[9,10] In the local setting, access to quality healthcare is a significant

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RESEARCH concern and may prompt managing physicians to prolong hospital admission once patients are discharged from surgical care. This assertion is supported by the similar postoperative LOS for patients who experienced operative complications (mean 7.6 days) and those who did not (mean 6.2 days).

The mortality rate in our series was 9% (n=3/33) at 2 years post splenectomy. All mortalities were due to progression of underlying diseases, with one death due to progression of metastatic papillary serous adenocarcinoma of the ovary, another to an intracerebral bleed secondary to ITP and the last due to the cardiac sequelae of systemic lupus erythematosus. No case of OPSI was recorded. Mortality data and the incidence of OPSI in our setting are difficult to compare with the international literature due to the short follow-up period and the high number of patients who were lost to follow-up.

Conclusion

Indications for splenectomy were similar locally to those noted internationally, with haematological disorders accounting for the majority of cases. Laparoscopy, the standard surgical approach internationally, trails open surgery as the technique of choice in our setting. Postoperative lengths of hospital stay and complication rates (for both open and laparoscopic techniques) are longer and higher in our setting. This may be influenced by the late presentation of our patients, a skills shortfall in laparoscopic surgery of the spleen, prolonged post-surgical admission due to patient difficulties in reaccessing appropriate quality care once discharged from a tertiary centre, and the low sample size. Although no patients experienced OPSI in our series, the short follow-up period and high rate of loss to follow-up limit our ability to infer long-term outcomes in our patients. Further inquiry may centre on long-term patient outcomes, possible changes in surgical technique, given the knowledge and skills acquired in the past 15 years, and a comparison between the various academic paediatric surgical centres in South Africa.

Acknowledgements. The authors acknowledge the contributions of the Department of Paediatrics, Division of Haematology and Oncology, University of the Witwatersrand, for permitting access to their patient records.

Author contributions. NP, AN, PB, JL, EM and AG participated in concept/design, data analysis/interpretation, drafting and critical revision of the article, and data collection.

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Funding. All research for this article was self-funded by the principal investigator and the Department of Paediatric Surgery, University of the Witwatersrand.

Conflicts of interest. None.

1. Al-Salem AH. Indications and complications of splenectomy for children with sickle cell disease. J Pediatr Surg 2006;41(11):1909-1915. https://doi. org/10.1016/j.jpedsurg.2006.06.020Â 2. Davies JM, Barnes R, Milligan D. Update of guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen. Clin Med 2002;2(5):440-443. https://doi.org/10.7861/clinmedicine.2-5-440 3. Luoto TT, Pakarinen MP, Koivusalo A. Long-term outcomes after pediatric splenectomy. Surgery 2015;159(6):1583-1590. https://doi.org/10.1016/j. surg.2015.12.014 4. Park A, Heinford BT, Hebra A, Fitzgerald P. Pediatric laparoscopic splenectomy.

Surg Endosc 2000;(14):527-531. https://doi.org/10.1007/s004640000152 5. Wilkins BS. The spleen. Br J Haematol 2002;117:265-274. https://doi. org/10.1046/j.1365-2141.2002.03425.x 6. Sherman R. Perspectives in management of trauma to the spleen. J Trauma 1980;20(1):1-13. https://doi.org/10.1016/s0022-3468(80)80830-x 7. Lesher AP, Kalpatthi R, Glenn JB, Jackson SM, Hebra A. Outcome of splenectomy in children younger than 4 years with sickle cell disease. J Pediatr Surg 2009;44(6):1134-1138. https://doi.org/10.1016/j.jpedsurg.2009.02.016 8. Salvadori MI, Price VE. Preventing and treating infections in children with asplenia or hyposplenia. Paediatr Child Health 2014;19(5):271-274. https://doi. org/10.1093/pch/19.5.271 9. Rescorla FJ, Breitfeld PP, West KW, Williams D, Engum SA, Grosfeld JL. A case controlled comparison of open and laparoscopic splenectomy in children.

Surgery 1998;124(4):670-676. https://doi.org/10.1067/msy.1998.91223 10. Minkes RK, Lagzdins M, Langer JC. Laparoscopic versus open splenectomy in children. J Pediatr Surg 2000;35(5):699-701. https://doi.org/10.1053/ jpsu.2000.6010 11. Qureshi FG, Ergun O, Sandulache VC, et al. Laparoscopic splenectomy in children. JSLS 2005;(9)4:389-392.

12. Eraklis AJ and Filler RM. Splenectomy in childhood: A review of 1413 cases. J Pediatr Surg 1972;7(4):382-388. https://doi.org/10.1016/0022-3468(72)90006-1 13. Bisharat N, Omari H, Lavi I, Raz R. Risk of infection and death among postsplenectomy patients. J Infect 2001;43(3):182-186. https://doi.org/10.1053/ jinf.2001.0904 14. Seims AD, Breckler FD, Hardacker KD, Rescorla FJ. Partial versus total splenectomy in children with hereditary spherocytosis. Surgery 2013;154(4):853-855. https://doi.org/10.1016/j.surg.2013.07.019 15. Rice HE, Oldham KT, Hillery CA, Skinner MA, Oâ&#x20AC;&#x2122;Hara SM, Ware RE. Clinical and haematological benefits of partial splenectomy for congenital hemolytic anemias in children. Ann Surg 2003;237(2):281-288. https://doi.org/10.1097/01. sla.0000048453.61168.8f

Accepted 2 November 2017.

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RESEARCH

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

Neonatal mortality at Leratong Hospital J C Moundzika-Kibamba,1,2 MD, DCH, MSc (Med); F L Nakwa,2,3 MB BCh, MMed, FCPaed, Cert Neonatol Department of Paediatrics and Child Health, Leratong Hospital, Johannesburg South Africa Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 3 Division of Neonatology, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa 1 2

Corresponding author: J C Moundzika-Kibamba (jmoundzika@hotmail.com) Background. There has been a high demand for delivery services at Leratong Hospital; however, no study on the causes of neonatal mortality has been conducted. It was therefore essential to identify the causes of newborn deaths so as to implement policies that would advance neonatal care.

Objectives. To determine the neonatal mortality rate (NMR), the primary causes of neonatal death and the occurrence of avoidable health factors.

Methods. This prospective descriptive study was conducted at the neonatal unit of Leratong Hospital, Johannesburg, South Africa. Clinical records of all neonates who were admitted between April 2013 and July 2013 were reviewed.

Results. A total of 380 neonates were admitted to Leratong Hospital over the 4-month period and 46 newborns died. The mean age (standard deviation (SD)) of all neonates admitted was 5 (5.8) days. Their mean (SD) weight was 1824.5 (29) g. Almost 37% of neonates died within 24 hours of admission. The 3 most common causes of death were: prematurity (39%), perinatal asphyxia (26%) and infection (20%). More than 60% of deaths occurred in the admission room. Three-quarters of neonates who died (74%) were low-birth-weight neonates. Staff shortage was found to be a contributor in 63% of deaths. Thirty-seven per cent of neonates could not be ventilated due to a shortage of ICU beds. The significant predictors relating to neonatal death were: preterm birth (OR 3.1, 95% CI 1.7 - 6.0), extremely low birth weight (OR 27.5; 95% CI 8.2 - 92.6), very low birth weight (OR 5.0; 95% CI 2.1 - 12.3) and birth by caesarean section (OR 3.2; 95% CI 1.6 - 6.2).

Conclusion. The neonatal mortality rate at Leratong Hospital was lower than the rates found in other studies. Preterm birth, low birth weight and birth by caesarean section were the strongest predictors of death. These deaths could have been avoided through provision of high-care services and an adequate number of nurses who were trained in both newborn care and early detection of perinatal asphyxia.

S Afr J Child Health 2018;12(1):XX-XX. DOI:10.7196/SAJCH.2018.v12i1.1436

Each year there are an estimated 3.6 million neonatal deaths globally.[1] These deaths occur mostly in low-income countries. However, neonatal mortality and morbidity is also a problem in high-income countries.[2] Almost 41% of the 9.7 million deaths in children under the age of 5 occur in sub-Saharan Africa.[3] South Africa has an unacceptably high infant mortality rate, with neonatal deaths accounting for 35-40% of all deaths of children younger than the age of 5 years.[4,5] South Africa is also one of the countries which have not reached the Millennium Development Goalâ&#x20AC;&#x2122;s 2015 deadline to reduce child mortality by two-thirds.[4] Furthermore, deaths during the first 7 days of life account for 88% of South African neonatal deaths.[6] Poor survival rates in neonates admitted to Chris Hani Baragwanath Academic Hospital, Johannesburg, were linked to premature birth in association with very low birth weight, but was also related to limited resources, especially the lack of mechanical ventilation.[7] The present study was conducted at Leratong Hospital, a publicsector regional hospital in the West Rand region of Gauteng that renders secondary-level healthcare services. The institution is a site for the Perinatal Problem Identification Programme (PPIP), which is an audit tool for evaluating perinatal care that was designed and developed in South Africa. It is compulsory for all public health facilities to collect and report data to the National Department of Health using PPIP. In a meta-analysis of 7 before-after studies in lowand middle-income countries, perinatal mortality audit was shown to be associated with up to a 30% reduction in perinatal deaths.[8] Neonatal care rendered at Leratong Hospital includes: basic newborn care of healthy infants; special care to infants with moderate risk of serious complications related to immaturity, illness, requiring nasal cannulae and antibiotics; Kangaroo Mother Care (KMC) provided to stable premature infants waiting for weight gain; high care (HC) and intensive care unit (ICU) which provide continuous positive airway pressure (CPAP) or mechanical ventilator support to 24

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infants with severe illness. A neonatal intensive care unit (NICU) is run by a paediatrician and it has four beds and two ventilators. The unit lacked sufficient NICU equipment.

The aims of the present study were to describe the causes of neonatal deaths and to identify health services factors associated with neonatal deaths at Leratong Hospital between 15 April 2013 and 15 July 2013.

Methods

This was a prospective review of the clinical records of all neonates admitted to the hospital during the study period (15 April 2013 - 15 July 2013). Variables were age, birth weight, gender, race, place of origin, reason for admission and cause of death. The primary causes of neonatal death were categorised using the Perinatal Problem Identification Programme (PPIP). Health factors examined were: access to high-care services, access to the NICU and the number of staff on duty, admission room care for all neonates from the Leratong labour ward and theatre as well as those transferred in from other hospitals. Inborn mortality rate was calculated from the deaths and births at Leratong only and did not include the other hospitals.

Questionnaires were used to collect information, and consent to use clinical records was obtained from the mothers of the neonates.

Descriptive statistics were used to describe the frequencies and percentages of variables. Logistic regression of variables was applied to predict mortality.

Sampling

All neonates who died at Leratong Hospital during the study period and neonates born before arrival and outside Leratong Hospital were included in the study. However, neonates whose mothers did not give consent and patients whose records could not be traced were excluded.

Data collection and statistical analysis

All the information was captured on a data capture sheet with details

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RESEARCH of the mother, neonate and staffing. For each cause of death, the health services factors examined were: the presence or absence and availability of CPAP, ventilators; as well as the number and experience of doctors and nurses on duty.

Data were entered into an MS Excel spreadsheet and statistical analysis was done using the Epi Info software programme (Centers for Disease Control and Prevention, USA). Continuous variables were expressed as the mean (standard deviation (SD)) while categorical variables were summarised using frequencies and percentages. Logistic regression was conducted on a univariate level to identify the predictors of neonatal death. Variables with significant levels (p=0.05) of prediction of death were then entered into a multiple logistic regression analysis. Results were expressed as odds ratios (OR) with corresponding p-values and 95% confidence intervals (CIs).

Ethics

The study was approved by the Human Research Ethics Committee (Medical) of the University of the Witwatersrand (ref. no. M120867), the Gauteng Department of Health (Director, West Rand District Council), and the hospital management.

Results

Characteristics of admitted neonates

There were 380 admissions to the neonatal unit of which 256 (67%) were inborn patients. A third of the total admissions came from home (29%) or from another facility (4%). There were 196 (51.6%) term neonates. Eighty percent of all neonates were delivered by normal vaginal delivery. Fifty percent of the patients were lowbirth-weight neonates. Approximately half of the neonates were admitted to the unit for less than 7 days (Table 1).

Neonatal mortality

A total of 46 neonates died (12.1% of total admissions); 41.3% died within 24 hours of admission. Their mean (SD) age was 5 (5.8) days.

Of the total deaths, 28% of patients were between 1 500 g - 2 499 g, followed by 26% in the 2 500 g weight category, and 22% were in the category of neonates weighing <999 g. The mean (SD) weight of those who died was 1 824.5 (29) g. Seventy-four percent of deaths were early neonatal deaths, with the higher proportion occurring in the group of neonates with weight >1 500 g. Their mean stay in hospital was 5 (19) days. Sixty-three percent died in the admission room, followed by the NICU (15.2%) and the labour ward (10.9%).

Mortality rates

The inborn neonatal mortality rate was 17.8/1 000 live births, with the early neonatal mortality rate (ENMR) at 14.8/1 000 live births, and the late neonatal mortality rate (LNMR) was 3.0/1 000 live births. The inpatient mortality rate was 12.1%.

Causes of deaths

Prematurity-related (39%), perinatal asphyxia (26%), infection (20%), congenital abnormalities (9%) and other (6%) were the most common causes of death.

Health services factors associated with death

In two-thirds of deaths (63%) the nurse-to-neonate ratio was more than 1:10. Additionally, during day and night shifts there was an average of one neonatal-trained professional nurse in the admission room. The most common identifiable administrative factor related to death was the lack of NICU beds with ventilators (37%) in the category of neonates >1 000 g.

Table 1. Characteristics of the patients who were admitted Description Admissions (N=380), n (%) Place of origin Leratong (inborn) Home Dr Yusuf Dadoo Carletonville Private CH Baragwanath Gender Male Female Gestational age Term Preterm <28 weeks 28 - 32 weeks 32 - 36 weeks Mode of delivery Normal vaginal Caesarean section Birth weight (grams) 500 - 999 1 000 - 1 499 1Â 500 - 2 499 >2 500 Duration of stay (days) <1 1-3 4-7 8 - 28

25

Deaths (N=46), n (%)

Deaths per category (%)

256 (67.4) 110 (28.9) 8 (2.1) 3 (0.8) 2 (0.5) 1 (0.3)

35 (76.1) 5 (10.9) 3 (6.5) 2 (4.3 0 1 (2.2)

13.7 4.5 37.5 66.7 0 100

202 (53.2) 178 (46.8)

22 (47.8) 24 (52.2)

10.9 13.5

196 (51.6) 184 (48.4) 15 (8.1) 41 (22.3) 128 (69.6)

13 (28.3) 33 (71.7) 10 (30.3) 11 (33.3) 12 (36.4)

6.6 17.9 66.7 26.8 9.4

306 (80.5) 74 (19.5)

27 (58.7) 19 (41.3)

8.8 25.7

15 (4) 41 (10.8) 132 (34.7) 192 (50.5)

10 (21.7) 11 (23.9) 13 (28.3) 12 (26.1)

66.7 26.8 9.8 6.2

37 (9.7) 71 (18.7) 101 (26.6) 171 (45)

19 (41.3) 8 (17.4) 11 (23.9) 8 (17.4)

51.3 11.3 10.9 4.7

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RESEARCH Logistic regression analysis of predictors of mortality

Preterm delivery (OR 3.1; 95% CI 1.7 - 6.0), extremely low birthweight (OR 27.5; 95% CI 8.2 - 92.6), very low birth-weight (OR 5.0; 95% CI 2.1 - 12.3), and caesarean section (OR 3.2; 95% CI 1.6 - 6.2) were the four factors associated with neonatal death in the univariate analysis. In the multivariate model, the most important predictors of mortality were birth weight (OR 27.3; 95% CI 7.9 - 94.3) and caesarean section (OR 3.3; 95% CI 1.6 - 6.8) (Table 3).

Discussion

This prospective study provided the causes and health factors relating to neonatal deaths. The overall in-hospital neonatal mortality rate at Leratong Hospital was lower than the rates found in other studies in sub-Saharan Africa.[9,10] However, the study was only over a 3-month period and it did not include deliveries and deaths from surrounding areas. The neonatal mortality rate (NMR) for the year 2013 (13.7/1 000 live births) was lower than the rate in South Africa (15/1 000 live births).[11] The NMR was similar to the NMR at Central and Eastern Tshwane district (13.6/1Â 000 live births) in 2011,[12] but it was higher than the rate in the West Rand region (8/1 000 live births).

There was a slight majority of male neonates in admissions and female in deaths, as opposed to male predominance for both

admissions (58%) and deaths (63%) at Empangeni Hospital in KwaZulu-Natal.[13] There was no explanation for our finding.

Hoque et al.[13] reported a male predominance and noted the issue of vulnerability of male neonates as it is found universally in other studies. In addition, low-birth-weight neonates (<2 500 g) accounted for higher rates of admissions and deaths in both studies. Our results revealed that the most common causes of neonatal mortality were related to prematurity, perinatal asphyxia, infection and congenital abnormalities, and were in keeping with the literature.[13,14] Prematurity and asphyxia represent more than 65% of all admissions and deaths, as reported in the seventh and ninth Saving Babiesâ&#x20AC;&#x2122; Reports.[14,15] Most neonates died within their first week of life (17.3/1 000 live births), and in 37% of cases death occurred within 24 hours of admission. The deaths were the result of multiple factors, including the following: severity of the disease (prematurity and extremely low birth-weight); insufficient number of trained nurses on duty; inadequate equipment to monitor the sick neonate; as well as limited access to ICU beds and ventilators.

Deaths occurring in the first 24 hours of admission to a hospital may reflect a range of quality-of-care issues such as late presentation and/ or inadequate first-line assessment and management on admission to hospital.[14] Zupan et al.[16] stated that globally, three-quarters of neonatal deaths happen in the first week after birth.

Table 2. Details of the causes of deaths (N=46) Description

Deaths, n (%)

Prematurity-related Extreme multi-organ immaturity Respiratory distress syndrome Pulmonary haemorrhage Intraventricular haemorrhage (grade III/IV) Perinatal asphyxia Hypoxic ischaemic encephalopathy (stage II/III) Persistent pulmonary hypertension of the newborn (PPHN) Infection Sepsis (2 contaminants with coagulase-negative Staphylococcus - laboratory or clinical suspicion)

18 (39.1) 9 (50) 6 (33.3) 2 (11.1) 1 (5.6) 12 (26.1) 10 (83.3) 2 (16.7) 9 (19.6) 7 (77.8)

Nosocomial infection (Klebsiella pneumoniae) Meningitis (Escherichia coli) Congenital abnormalities Gross congenital abnormalities Down syndrome Other Aspiration pneumonia Other

1 (11.1) 1 (11.1) 4 (8.7) 3 (75) 1 (25) 3 (6.5) 1 (33.3) 2 (66.7)

Table 3. Logistic regression analysis of predictors of mortality Univariate Variable Unadjusted OR 95% CI Gestational age Term Preterm Delivery Normal vaginal Caesarean Birth weight (g) 500 - 999 1 000 - 1 499 1 500 - 2 499 >2 500

p-value

Adjusted OR

Multivariate 95% CI

p-value

1 3.1

1.7 - 6.0

0.001

3.2

1.6 - 6.1

0.000

1 3.2

1.6 - 6.2

0.001

3.3

1.6 - 6.8

0.000

8.2 - 92.6 2.1 - 12.3 0.6 - 3.1

0.000 0.000 0.443

27.3 4.6 1.2

7.9 - 94.3 1.9 - 11.5 0.5 - 2.7

0.000 0.001 0.709

27.5 5.0 1.4 1

CI = confidence interval; OR = odds ratio.

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RESEARCH Preterm birth and low birth-weight had a high mortality rate in this analysis. In Hoque’s report,[13] preterm birth resulted in higher rates of admission (44%) and death (68%), and almost half of all deaths occurred among the very low birth weight patients (<1 500 g). Katz et al.[17] used a pooled analysis of 20 cohorts from Asia, Africa and Latin America and found that neonatal mortality and relative risks increased with decreasing gestational age across studies and regions.

Low birth-weight neonates represented nearly 74% of our deaths, identical to what was seen in many developing countries with limited resources, where they account for 60 - 80% of neonatal deaths.[18] On univariate logistic regression analysis, gestational age and birth-weight were the significant predictors of death. Preterm birth was associated with increased mortality risk compared with term birth. Similar results were documented in a rural hospital in KwaZulu-Natal,[13] and in both reports at Charlotte Maxeke Johannesburg Academic Hospital,[19,20] where the main determinants of survival were birth-weight and gestational age. Neonates with a birth-weight <1 000 g exhibited higher mortality (66.7%) in the first week of life. The survival rate was poorer (near zero) than that reported at Chris Hani Baragwanath Academic Hospital (34%)[7] and at Charlotte Maxeke Johannesburg Academic (34.9%),[19] which are both tertiary hospitals in Johannesburg. However, the survival rate was comparable to the 5% recorded in KwaZulu-Natal.[13] Due to limited resources in our hospital, extremely-low-birth-weight neonates were given insufficient high care support, hence they did not qualify for ICU, neither were they given surfactant nor put on nasal continuous positive airway pressure (NCPAP). The cut-off birth-weight used was 1 000 g for these life-sustaining measures.

Perinatal asphyxia was the second most prominent cause of neonatal admissions and mortality at 26.8% and 26%, respectively. In 58%, labour-related asphyxia was the cause of death in >2 500 g neonates.

There were challenges associated with monitoring fetal distress as the partogram was not utilised correctly and there was a shortage of cardiotocogram machines. Equipment to detect fetal distress was not readily available, and if detected the time to deliver the newborns might have been insufficient due to a staff shortage (midwife to prepare the patient, porter and anaesthetist). Out of 16 caesarean sections performed on neonates who weighed >1 000 g, 12 neonates (75%) had a low Apgar score (<5/10) at 1 minute. On the multivariate model, the study found that caesarean section was an important predictor of death. Surprisingly, the finding was contrary to other data,[19,20] which reported that delivery by caesarean section improved the chance of survival compared with neonates born by normal vaginal delivery. A possible reason for the differences was the lack of information on the decision-to-delivery interval (DDI) for emergency caesarean sections at Leratong Hospital, and was not analysed in this study. Neonatal infection, although the fourth cause of admission (10%), represented the third cause of death (20%) at Leratong Hospital. This was comparable to the mortality rate due to sepsis (20.8%) in the Johannesburg Hospital neonatal unit in 2003.[21] Among the deaths related to infection, sepsis accounted for almost 78% of deaths. Bryce et al.[22] and Rhoda[23] noted that preventing neonatal infection is complex, especially where access to health facilities is limited. In our neonatal ward, neonates shared the same overhead heated bed (radiant warmer) or neonates with sepsis were not cohorted. Thus, there was no space for isolation. Inadequate hand hygiene was an important factor that contributed to sepsis.

The adherence to infection prevention control measures was not consistent.

The high neonatal mortality observed in our results was also related to some local factors in the health system and were seen in other reports.[24-26] The study identified an insufficient number of personnel and inadequate neonatal facilities as the main administrative problems associated with deaths (37%). More deaths (63%) occurred in the admission room than in the NICU (15%). The 27

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skilled and trained nurse-to-neonate ratio in the admission room was ≥1:10. The work load, coupled with shortage of trained nurses during the day and night shifts, was a major challenge to newborn survival.

However, the logistic regression analysis did not find the lack of supervision of medical doctors to be a predictor of death. In order to reduce neonatal deaths, Velaphi and Rhoda[25] recommended that the emphasis must be placed on providing adequate nursing and medical staff in our labour, delivery and neonatal wards, with appropriate training and equipment.

Study strengths and limitations

As the data employed in our study were prospective, it was possible to assess data accurately. The study identified problems in the management of sick newborns in our unit and provided evidence to facilitate change. The limitations of this study were: (i) the short period of data collection for analysis; (ii) the small sample size; and (iii) the study did not include deliveries and deaths from surrounding areas.

Conclusion

The study found the neonatal mortality rate at Leratong Hospital to be lower than rates recorded elsewhere in South Africa. Our results revealed that the most common causes of neonatal admissions and mortality were similar to those in other hospitals. Most neonates died within the first week of life as reported in the literature.

Preterm delivery, low birth-weight and caesarean section were major predictors of death. A high number of neonatal deaths were avoidable by providing high-care services (including NCPAP and surfactant), as well as an adequate number of nurses trained in newborn care in the admission room. These factors improve access to the neonatal ICU, aid the early detection of perinatal asphyxia and improve neonatal resuscitation rates.

Acknowledgements. We wish to acknowledge and thank Prof. Peter Cooper for reviewing the questionnaire and Mr Cornelius Nattey for initial assistance with the statistical analysis.

Author contributions. Writing of the questionnaire, data collection and manuscript preparation were done by JCMK and FLN was involved in drafting the manuscript. Both authors contributed to the final manuscript.

Conflicts of interest. None.

Funding. None.

1. Lawn JE, Kerber K, Enweronu-Laryea C, Cousens S. 3.6 million neonatal deaths – what is progressing and what is not? Semin Perinatol 2010;34:371-386. https://doi.org/10.1053/j.semperi.2010.09.011 2. Lawn JE, Osrin D, Adler A, Cousens S. Four million neonatal deaths: Counting and attribution of cause of death. Paediatr Perinat Epidemiol 2008;22:410-416. https://doi.org/10.1111/j.1365-3016.2008.00960.x 3. Rutherford ME, Mulholland K, Hill PC. How access to health care relates to under-five mortality in sub-Saharan Africa: Systematic review. Trop Med Int Health 2010;15:508-519. https://doi.org/10. 1111/j.1365-3156.2010.02497.x 4. Baleta A. World report. South Africa takes steps to reduce perinatal mortality.

Lancet 2011;377:1303-1304. http://doi.org/10.1016/S0140-6736(11)60523-0 5. Child mortality in South Africa: Minister of Health Briefing, 2013: https://pmg. org.za/committee-meeting/15489 (accessed 14 September 2017).

6. Saloojee H, Velaphi SC. Neonatal disorders. In: Kibel M, Haroon S, Westwood T eds. Child Health for All. Cape Town: Oxford University Press, 2008:317-328.

7. Velaphi SC, Mokhachane M, Mphahlele RM, Beckh-Arnold E, Kuwanda ML, Cooper PA. Survival of very-low-birth-weight infants according to birth weight and gestational age in a public hospital. S Afr Med J 2005;95:504-509.

8. Pattinson R, Kerber K, Waiswa P, et al. Perinatal mortality audit: Counting, accountability, and overcoming challenges in scaling up in low- and middleincome countries. Int J Gynaecol Obstet 2009;107:S113-S121. https://doi. org/10.1016/j.ijgo.2009.07.011 9. Kinney MV, Kerber KJ, Black RE, et al. Sub-Saharan Africa’s mothers, newborns, and children: Where and why do they die? PLoS Med 2010;7(6):e1000294. https://doi.org/10.1371/journal.pmed.1000294 10. Greenfield D, Rhoda N, Pattinson RC. Ten years of the National Perinatal Care Surveys. In: Saving Babies 2008 - 2009: Seventh Report on Perinatal Care in South Africa. Pattinson RC, ed. Pretoria: Tshepesa Press, 2011:46.

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RESEARCH 11. You D, Hug l, Ejdemyr S, Beise J. Level & Trends in Child Mortality. Report 2015. Estimates Developed by the UN Inter-agency Group for Child Mortality Estimation. United Nation's Children's Fund, New York, 2015.

12. Lloyd LG, de Witt TW. Neonatal mortality in South Africa: How are we doing and can we do better? S Afr Med J 2013;103:518-519. https://doi.org/10.7196/ SAMJ.7200 13. Hoque M, Haaq S, Islam R. Causes of neonatal admissions and deaths at a rural hospital in KwaZulu-Natal, South Africa. S Afr J Epidemiol Infect 2011;26:2629.

14. Pattinson RC. Saving Babies 2008 - 2009: Seventh report on perinatal care in South Africa. Preoria: Tshepesa Press, 2011.

15. Pattinson RC, Rhoda NR. Saving Babies 2012 - 2013: Ninth report on perinatal care in South Africa. Pretoria: Tshepesa Press, 2014.

16. Zupan J, Aahman E. Perinatal Mortality for the year 2000: Estimates Developed

by WHO. Geneva: World Health Organization, 2005.

17. Katz J, Lee ACC, Kozuki N, Lawn JE, Cousens S, Blencowe H, et al. Mortality risk in preterm and small-for-gestational-age infants in low-income and middle-income countries: A pooled country analysis. Lancet 2013;382:417-425. https://doi.org/doi.org/10.1016/S0140-6736(13)60993-9 18. Lawn JE, Cousens S, Zupan J. 4 million neonatal deaths: When? Where?

Why? Lancet 2005;365:891-900. https://doi.org/doi.org/10.1016/S01406736(05)71048-5 19. Ballot DE, Chirwa TF, Cooper PA. Determinants of survival in very low birth weight neonates in a public sector hospital in Johannesburg. BMC Pediatrics 2010,10:30. https://doi.org/doi.org/10.1186/1471-2431-10-30

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20. Kalimba EM, Ballot DE. Survival of extremely low-birth-weight infants. S Afr J Child Health 2013;7:13-16. https://doi.org/doi.org/10.7196/SAJCH.488 21. Motara F, Ballot DE, Perovic O. Epidemiology of neonatal sepsis at Johannesburg Hospital. S Afr J Epidemiol Infect 2005;20:90-93. https://doi.org/10.1080/1015 8782.2005.11441243 22. Bryce J, Black RE, Victoria CG. Millennium Development Goals 4 and 5: Progress and challenges. BMC Medicine 2013;11:225. https://doi.org/doi. org/10.1186/1741-7015-11-225 23. Rhoda NR. National newborn care: Key findings and recommendations. The 5th South African Child Health Priorities Conference. Bloemfontein, 3 - 5 December 2014.

24. Wall SN, Lee ACC, Carlo W, et al. Reducing intrapartum-related neonatal deaths in low- and middle-income countries­– what works? Semin Perinatol 2010;34:395-407. https://doi.org/doi.org/10.1053/j.semperi.2010.09.009 25. Velaphi S, Rhoda N. Reducing ne onatal deaths in South Africa – are we there yet, and what can be done? S Afr J Child Health 2012;6:67-71. https://doi. org/10.7196/SAJCH.493 26. Friberg IK, Kinney MV, Lawn JE, et al. Sub-Saharan Africa’s mothers, newborns, and children: How many lives could be saved with targeted health interventions? PLoS Med 2010;7(6):e1000295. https://doi.org/10.1371/journal. pmed.1000295

Accepted 21 September 2017.

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RESEARCH

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

Retrospective review of neonates with persistent pulmonary hypertension of the newborn at Charlotte Maxeke Johannesburg Academic Hospital I Harerimana, MB ChB, MMed, FCPaed (SA); D E Ballot, MB ChB, FCPaed (SA), PhD; P A Cooper, MB ChB, FCPaed (SA), PhD Department of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Corresponding author: I Harerimana (harinosa@gmail.com) Background. Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome characterised by high pulmonary pressures, low systemic pressures and severe hypoxaemia due to circulation transition failure after birth.

Objective. To determine the incidence of and describe the risk factors, infant characteristics and treatment strategies for PPHN at Charlotte Maxeke Johannesburg Academic Hospital over the last 8 years.

Methods. This was a retrospective descriptive study. Patient records of neonates who had a discharge diagnosis of PPHN were reviewed for the period from January 2006 to December 2013. Neonatesâ&#x20AC;&#x2122; PPHN diagnosis was based on clinical criteria and, where possible, echocardiography. Neonates with a congenital cyanotic heart defect were excluded.

Results. A total of 81 neonates had a discharge diagnosis of PPHN, of whom 72 were included in the study. Of the 72 neonates, 37 (51.4%) were female, 38 (52.8%) were born by vaginal delivery and 44 (61.1%) were inborn. The mean (standard deviation (SD)) birth weight was 2.94 (0.69) kg while the mean (SD) gestational age was 38.2 (3.3) weeks. Meconium aspiration syndrome (MAS) was seen in 43 neonates (59.7%) and was the most common disease underlying PPHN. Of the 72 neonates, 67 (93.1%) required mechanical ventilation, but only18.1% required high-frequency oscillatory ventilation. Magnesium sulphate and sildenafil were used in 12 (16.7%) and 9 neonates (12.5%), respectively. Inhaled nitric oxide (iNO) and extracorporeal membrane oxygenation treatments were not available. Of the 72 neonates, 25 (34.7%) died. The need for inotropic support was associated with a poor outcome (p=0.01).

Conclusion. PPHN was uncommon in our unit, but its management proved challenging owing to the high mortality risk. The leading cause of PPHN was MAS. Consideration should be given to introducing iNO, given that ECMO treatment is expensive and labour intensive and probably not justified at this time.

S Afr J Child Health 2018;12(1):29-33. DOI:10.7196/SAJCH.2018.v12i1.1245

Persistent pulmonary hypertension of the newborn (PPHN) is a clinical condition characterised by severe respiratory failure and hypoxaemia.[1] Its incidence is estimated at around 2 per 1 000 live births worldwide and it is associated with a high morbidity and mortality.[2,3] Despite the progress in treating PPHN it remains a potentially fatal disease, especially in resource-limited settings.[4] The reported overall mortality ranges from 4% to 33% in developed countries[2] and from 25% to 48% in developing countries.[5,6] In SA, previous studies reported the incidence of PPHN to be 1.1%, with a mortality rate of 31% at Tygerberg Childrenâ&#x20AC;&#x2122;s Hospital[7] and 48% at Chris Hani Baragwanath Academic Hospital.[8] PPHN develops due to the failure of circulatory transition at birth, causing the pulmonary artery pressure to remain higher than systemic pressures.[9] A patent ductus arteriosus (PDA) or the right-to-left shunting of blood through a patent foramen ovale (PFO) results in severe hypoxaemia.[1,10,11] PPHN usually affects term or near-term newborns, although preterm neonatess can also be affected.[1] PPHN was initially known as persistent fetal circulation, but was later renamed to the current form to better describe its pathophysiology.[11] PPHN is usually secondary to an underlying pulmonary pathology, although primary or idiopathic PPHN also occurs.[1,10,11] Konduri et al.[11] reported that meconium aspiration syndrome (MAS) was the leading cause of PPHN (42%) in a multicentre trial of inhaled nitric oxide (iNO), followed by idiopathic PPHN (27%), respiratory distress syndrome (RDS) (17%), pneumonia or sepsis (13%) and, less frequently, lung hypoplasia. Other potential

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risk factors for PPHN include perinatal asphyxia, polycythaemia, acidosis and hypothermia.[3] PPHN is suspected when there is a considerable difference between preductal and postductal oxygen saturation, in combination with severe hypoxaemia that does not improve when the infant is subjected to 100% supplemental oxygen. As it is difficult to differentiate PPHN from cyanotic congenital heart disease on clinical grounds alone, echocardiography is usually required to confirm a diagnosis of PPHN.[1,3] The survival rate of neonates suffering from PPHN has been improved by the use of high-frequency oscillatory ventilation (HFOV), selective pulmonary vasodilators such as iNO and phosphodiesterase inhibitors (sildenafil and milrinone), surfactant and extracorporeal membrane oxygenation (ECMO).[1,10-15] In resource-limited facilities, sildenafil and magnesium sulfate have been shown to be safe, effective pulmonary vasodilators for improving oxygenation when iNO is not available.[16-19] Adjuvant treatments such as inotropic support, correction of metabolic disturbances and minimal handling also have invaluable roles in the management of these Neonatesneonates.[11,15] Alkalinisation by hyperventilation has been abandoned because of consequent neurological complications and the increased risk of chronic lung disease.[11,15] The current mainstay of PPHN treatment when conventional ventilatory support alone fails, consists of a combination of HFOV and administering iNO. This combination treatment has been shown to reduce the need for ECMO more effectively than when either of them is used

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RESEARCH separately.[10,13] However, the treatment does not reduce the duration of hospitalisation or the mortality risk[13] and there are still unresolved debates and controversies regarding the appropriate time of initiation and the optimal dose of iNO.[10] ECMO is used as a rescue therapy for neonatesNeonates in respiratory failure and who are unresponsive to other therapies.[20,21] Although it is an expensive and labour-intensive treatment, its introduction has markedly improved the outcome of Neonates suffering from PPHN in well-resourced centres.[22,23] The use of iNO and ECMO is not currently offered routinely to neonates at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH) owing to resource constraints and a lack of equipment, although the cardiothoracic unit does offer ECMO to selected Neonates following open-heart surgery.

PPHN can be fatal and MAS, a leading cause of PPHN, is frequent in our setting. As there were no outcome data from our centre, we conducted a retrospective review of the neonatal database at CMJAH to describe the neonates’ characteristics, risk factors and treatment modalities associated with PPHN over an 8-year period.

Methods

This was a retrospective, descriptive study of neonates with a discharge diagnosis of PPHN. The sample included both inborn and outborn neonates admitted to the neonatal unit at CMJAH from January 2006 to December 2013.

Neonates with a discharge diagnosis of PPHN were identified from a computerised database at the neonatal unit of CMJAH, where data were initially collected for the purpose of clinical audit using REDCap (Research Electronic Data Capture) software hosted by the University of the Witwatersrand. Retrieved data of both mothers and neonates were supplemented by a review of their medical records if available. Maternal data included age, parity, gravidity, disease during pregnancy, use of nonsteroidal anti-inflammatory drugs and mode of delivery. Infant data included gestation age, birth weight, gender, place of birth, Apgar score, ventilation mode and duration, drug therapy in the intensive care unit (ICU), echocardiographic findings, hospital stay and outcome on discharge. ICU charts were not available and we therefore were unable to determine the severity of respiratory failure based on the oxygenation index.

The diagnosis of PPHN was made on clinical grounds by the attending neonatologist. Factors considered in the diagnosis included differential oxygen saturation ≥10% (difference between preductal and postductal) or difference in arterial PO2 ≥20 mmHg, hypoxaemia disproportionate to the chest X-ray changes and unresponsiveness to a hyperoxia test. Owing to limited capacity of paediatric cardiologists at CMJAH, echocardiography to confirm PPHN was performed only in selected cases.

Both preterm and term neonates who fulfilled the criteria were included in this study, whether inborn or outborn. Neonates with congenital diaphragmatic hernia were included in the study whereas those with a cyanotic congenital heart defect on echocardiography were excluded. Neonates for whom adequate data were not available or whose medical records could not be retrieved were excluded.

Neonates had been managed by the attending neonatologist according to unit protocols. All neonates who were clinically diagnosed with PPHN and required ventilation were initially ventilated with conventional mechanical ventilation (CMV); those who did not respond to CMV were changed to HFOV treatment. All neonates on assisted ventilation were sedated with venous boluses of morphine orfentanyl, with or without a benzodiazepine (midazolam). Neonates were generally not paralysed. Only sildenafil and magnesium sulphate were used as pulmonary vasodilators; the unit did not offer iNO or ECMO treatment during the study period.

Adjuvant therapy for PPHN included exogenous surfactant for RDS or severe MAS and haemodynamic support with inotropes (dopamine, dobutamine and adrenaline) when indicated. In the case of severe 30

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metabolic acidosis, sodium bicarbonate infusion was used to keep pH ≥7.25 if ventilation and improved perfusion did not correct the pH balance. Hyperventilation was not used in our unit. General measures included correction of metabolic disturbances when indicated and ‘minimal’ handling.

Statistics

Data were analysed using STATA version 2, overseen by a statistician.

Categorical variables were described according to frequencies and percentages, whereas continuous variables were described using mean and standard deviation or median and range, depending on the data distribution. The Pearson chi-square test and Fisher’s exact test were used for univariate analysis of categorical variables, while Student’s t-test or the Mann-Whitney test was used for continuous variables to compare maternal or infant characteristics between neonates who died and those who survived. Statistical significance was accepted at p<0.05.

Ethics

Permission to conduct the study was obtained from the University of the Witwatersrand’s Human Research Ethics Committee (ref. no.

M130650) and from the Chief Executive Officer of CMJAH.

Results

During the 8-year period, 81 neonates with a discharge diagnosis of PPHN were identified. Of these, 72 were included in the study. Of the remaining nine neonates, six were excluded because they had major congenital heart defects other than a PDA or PFO on echocardiography, two were excluded because the relevant data could not be retrieved and one was excluded because the discharge diagnosis of PPHN had been allocated erroneously. Demographic characteristics of the neonates are summarised in Table 1.

The mean (standard deviation (SD)) birth weight was 2.94 (0.69) kg and the mean (SD) gestational age was 38.2 (3.3) weeks. The mean (SD) maternal age at delivery was 26.2 (5.8) years. The majority of mothers (81.9%) did not have a chronic or pregnancy-related disease predisposing their neonates to PPHN and only 5 (6.9%) had pregnancy-induced hypertension. None of the mothers reported using nonsteroidal anti-inflammatory drugs during pregnancy. A total of 54 neonates (75%) were born at term, with 44 (61.1%) being inborn. Just over half of the neonates were female (51.4%). A similar proportion (52.8%) were born by vaginal delivery. A 5-minute Apgar score <7 was reported for 16 neonates (22%).

Echocardiography to confirm the diagnosis of PPHN by demonstration of right-to-left shunt was performed in only 27 neonates (37.5%). Of these, 10 neonates had either a PDA and PFO or a PDA only with a right-to-left shunt.

Table 1. Demographic characteristics of neonates (N=72)* Characteristic Frequency, n (%)* Female Delivery mode Vaginal Caesarean section Inborn Apgar at 5 min <7 Birth weight/gestational age Appropriate for gestational age Small for gestational age Large for gestational age Gestational age groups (weeks) Premature (≤34) Late premature (35 - 36) Term (≥37)

37 (51.4) 38 (52.8) 31 (43.1) 44 (61.1) 16 (22.2) 58 (80.6) 9 (12.5) 4 (5.6) 10 (13.9) 7 (9.7) 54 (75.0)

*Totals not adding up to 72 are due to missing data.

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RESEARCH MAS was the most common underlying pathology (59.7%), followed by congenital pneumonia and RDS, accounting for nine (12.5%) and six (8.3%) cases, respectively (Table 2).

Although CMJAH is a surgical referral centre, only seven neonates were admitted with congenital diaphragmatic hernia during the study period, two of whom had had PPHN, neither survived.

Mechanical ventilation was given to 67 neonates (93.1%) (Table 3).

Of these, 13 were unresponsive to CMV and required HFOV. Table 2. Underlying pathologies seen in study sample (N=72) Underlying pathology Frequency, n (%) MAS 43 (59.7) Congenital pneumonia 9 (12.5) Respiratory distress syndrome 6 (8.3) Asphyxia* 2 (2.8) MAS/Asphyxia 3 (4.2) Idiopathic PPHN 2 (2.8) Sepsis 1 (1.4) Transient tachypnoea of the newborn 1 (1.4) Hypoplastic lung 1 (1.4) Congenital diaphragmatic hernia 2 (2.8) Pulmonary haemorrhage 1 (1.4) Vein of Galen malformation 1 (1.4) MAS = meconium aspiration syndrome; PPHN = persistent pulmonary hypertension of the newborn. *Asphyxia was defined as an Apgar score ≤5 at 10 min, pH ≤7.0 and base excess ≤–16, neonatal encephalopathy and evidence of multi-organ dysfunction.

Table 3. Therapeutic intervention and outcome (N=72) Therapy Frequency, n (%) Mechanical ventilation Yes No Mode of ventilation (n=67) Conventional mechanical ventilation High-frequency oscillatory ventilation Surfactant use Yes No Sodium bicarbonate infusion Yes No Inotropic support Yes No Vasodilators used Magnesium sulphate Sildenafil Inhaled nitric oxide No vasodilator given Number of deaths

67 (93.1) 5 (6.9) 67 (100) 13 (18.1) 14 (19.4) 57 (79.1) 16 (22.2) 56 (77.8) 38 (52.8) 34 (47.2) 12 (16.7) 9 (12.5) 0 (0.0) 50 (69.4) 25 (34.7)

The median duration of mechanical ventilation was 4 (range 0 - 31) days. Of the 43 neonates who presented with MAS, only seven (16.3%) were treated with exogenous surfactant. Magnesium sulphate and sildenafil were used in 12 (16.7%) and 9 (12.5%) neonates, respectively.

The mortality rate was 34.7% and the majority (62.5%) died within 24 hours of admission. The median duration of hospital stay was 8 (range 0 - 42) days.

The comparison between survivors and nonsurvivors is shown in tables 4 and 5. The variables analysed were similar between survivors and nonsurvivors, except for the use of inotropes associated with non-survival.

There was no difference between survivors and nonsurvivors with regard to birth weight, 5-minute Apgar scores or gestational age (p>0.05). The duration of both ventilation and hospital stay was longer for the survivors than nonsurvivors (p=0.000), likely because of early death in nonsurvivors (Table 5).

MAS was the most common associated disease in this study. The characteristics of Neonates with MAS are shown in Table 6.

Discussion

MAS accounted for 43 cases (59.7%) of PPHN in this study. Meconiumstained amniotic fluid (MSAF) has been reported to complicate 7 - 22% of term deliveries and up to 52% of postdate deliveries (>41 weeks of gestation).[24] The incidence of MAS has recently declined owing to improved obstetric practices, including reduced postdate deliveries, good intrapartum monitoring of the fetal heart rate and resuscitation of depressed neonates born through MSAF.[25] Despite remarkable progress in understanding the pathophysiology and treatment of PPHN,[10,11-14] the condition remains a treatment challenge for neonatologists, especially in developing countries, and the associated mortality rate remains high in resource-limited settings.[5-9,26,27] Of the 72 neonates included in our study, 51.4% were female and 52.8% were born by vaginal delivery. Birth weight was appropriate for gestation age in 80.6% of cases in this study. These results differ from those of previous studies, which reported PPHN to be associated more with males, being large for gestation age and delivery through caesarean section.[5,6,9,26-29] The majority of the neonates included in this study (75%) were born after 37 weeks, the mean gestational age being 38.2 weeks and the mean birth weight 2.94 kg. These results are consistent with evidence that PPHN affects mainly term and post-term neonates.[9,11,29] Only 5 neonates (6.9%) were born to mothers who presented with pregnancy-induced hypertension, a known risk factor for PPHN, although this number may be an underestimation owing to maternal history not always being well documented in the infant’s medical records. In our study, the most common underlying diseases in PPHN were MAS, pneumonia and RDS. MAS has repeatedly been reported as the most common lung parenchymal disease resulting in PPHN, followed by idiopathic PPHN and pneumonia or RDS.[1,10,11,13,30] Our results were similar to those reported in previous studies[2,6,7] except that idiopathic PPHN accounted for only 2.8% in our study.

The majority (93.1%) of neonates included in our study were mechanically ventilated (18.1% did not respond to CMV and were

Table 4. Comparison of parameters at birth and during therapeutic intervention for survivors and (N=72) Characteristic Non survivors (n=25)† Survivors (n=47)†

p-value

Birth weight (kg) Apgar score at 5 min Gestational age (weeks) Duration of ventilation (days) Duration of hospital stay (days)

0.30 0.95 0.39 0.000* 0.000*

2.82 (0.77) 7.2 (1.37) 37.7 (3.88) 1 (0 - 26) 1 (0 - 36)

*Mann-Whitney test. †Data reported as mean (standard deviation) or median (range).

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2.99 (0.64) 7.23 (1.46) 38.4 (2.98) 6 (0 - 31) 7 (1 - 32)

RESEARCH Table 5. Comparison of delivery variables and treatment modalities between survivors and non-survivors Characteristic Non-survivors, % Survivors, % Mode of delivery (n=68) Vaginal Male (n=35) Apgar 5 min <7 (n=63) Inborn Gestational age (weeks) (n=71) Preterm (<37) Full-term (≥37) Birth weight/gestational age (n=70) Appropriate for gestation age Large or small for gestation age Mechanical ventilation CMV/HFOV HFOV Inotropic support Vasodilators used (n=71) Type of vasodilator (n=20) Magnesium sulphate Sildenafil Sodium bicarbonate infusion Surfactant use

p-value 0.23

15 (65.2) 15 (60) 8 (38.1) 12 (48)

23 (50) 27 (57.4) 8 (19) 32 (68.1)

6 (25) 18 (75)

11 (23.4) 36 (76.6)

19 (79.2) 5 (20.8) 25 (100) 18 (72) 7 (28) 18 (72) 10 (41.7)

39 (83) 8 (17) 42 (89.4) 36 (85.7) 6 (12.8) 20 (42.6) 11 (23.4)

7 (66.7) 3 (30) 8 (32) 6 (25)

5 (45.5) 6 (54.5) 9 (19.1) 8 (17)

0.15 0.10 0.09 0.88

0.75

0.15 0.20 0.12 0.01 0.11 0.38

0.22 0.53

CMV = conventional mechanical ventilation; HFOV = high frequency oscillatory ventilation.

Table 6. Characteristics of Neonates with MAS (N=43) Characteristics Frequency, n (%) Sex Female Gestational age (weeks) Preterm (<37) Term (≥37) Mode of delivery Vaginal Caesarean section Place of birth Inborn Outborn Surfactant therapy Yes No Mechanical ventilation Yes No Outcome Died Discharged

26 (60.5) 8 (18.6) 35 (81.4) 21 (51.2) 20 (48.8) 26 (60.5) 17 (39.5) 7 (16.7) 35 (83.3) 40 (93) 3 (7) 12 (27.9) 31 (72.1)

MAS = meconium aspiration syndrome.

switched to HFOV). In a study by Rocha et al.,[9] 30.7% of neonates were treated with exogenous surfactant whereas only 19.4% of neonates in our study were treated similarly. It is possible that artificial surfactant was used too sparingly in our unit, which may have contributed to the mortality rate.

Our findings are consistent with reports that assisted ventilation constitutes the mainstay of PPHN treatment.[1,13-15,30] The high proportion of neonates treated with mechanical ventilation in our study may reflect the severity of their disease, although we were unable to calculate the neonates’ oxygenation indices as a measure of the severity of respiratory failure.[1,31] None of the neonates were 32

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treated with iNO or ECMO, as our unit did not offer these treatment modalities at the time.

Data showed that magnesium sulfate and sildenafil were used for pulmonary vasodilatation in 16.7% and 12.5% of neonates, respectively. This is similar to findings of other studies[6,32,33] and it has been shown that magnesium sulfate and sildenafil are safe and cost-effective vasodilators for the treatment of PPHN when iNO is not available.[34,35] Hyperventilation is no longer practised in the treatment of PPHN owing to associated neurological complications and the development of chronic lung disease.[1,2] Sodium bicarbonate infusion is also being used less frequently than before and in our study only 22.2% of neonates were treated accordingly. Similar findings (25%) were reported by Abdel et al.[6] In a multicentre study in the USA, WalshSukys et al.[2] reported an overall alkali infusion rate of 75% prior to the use of iNO becoming the preferred treatment option.

Adequate cardiac output and improved perfusion or oxygenation can be achieved by volume expansion, inotropic support, or both.

[10,11,14,36] However, inotropes should be used cautiously as they can also increase the pulmonary artery pressure and worsen the right-to-left shunt.[10] Just over half of the neonates included in our study (52.8%) required inotropic support. This was lower than the 84% of cases in which inotropic support was used in a multicentre study in the USA.[2] PPHN is associated with a high mortality rate, especially in resource-limited settings.[4] Of the 72 neonates included in this study, 25 (34.7%) did not survive. Similar mortality rates, either directly or indirectly related to PPHN, were reported in previous studies across the world, e.g.: 48% at Chris Hani Baragwanath Academic Hospital[8] and 31% at Tygerberg Children’s Hospital[7] in SA; 25% at Al-Minya University Hospital in Egypt;[6] 26.6% at the Children’s Hospital Multan in Pakistan;[5] 32% at Hospital de São João EPE in Portugal,[9] and 27.6% at the Chang Gung Children’s Hospital in Taiwan.[29] High PPHN mortality in resource-limited settings may be attributed to new therapies such as HFOV, iNO and ECMO not being readily available. ECMO specifically is considered a rescue therapy for neonates with severe PPHN and who are unresponsive to other

MARCH 2018 Vol. 12 No. 1

RESEARCH treatment modalities; 40% of neonates with PPHN do not respond to the combination of HFOV and iNO and require ECMO as a last resort.[3,10,13] Of the 25 nonsurvivors in this study, 62.5% died within 24 hours of admission. Univariate analysis showed that the characteristics of survivors and non-survivors were similar, except for the need for inotropic support. As the use of inotropes is associated with a poor outcome, the availability of iNO as a treatment option may have reduced the mortality among this sample.

Study limitations

Owing to its retrospective design, this study had some limitations.

There were some missing data regarding infant characteristics. It was not possible to calculate the oxygenation indices as there were no ventilation parameters available. The severity of respiratory failure could therefore not be determined.

Echocardiography was performed on only a few neonates. The incidence of PPHN may therefore have been underestimated, as diagnosis was based mainly on clinical observation.

Conclusion

In this study MAS was found to be the most common underlying cause of PPHN. Infant characteristics were similar between survivors and non-survivors. Magnesium sulphate and sildenafil were the only pulmonary vasodilators used. There was a considerable mortality rate (34.7%) and the need for inotropic support was the only factor associated with poor outcome.

Reducing MAS incidence may be a cost-effective measure in mitigating PPHN. MAS incidence could be reduced by improving antenatal and intrapartum obstetric care, reducing postdate deliveries, proper monitoring of at-risk pregnancies, offering adequate neonatal resuscitation, using surfactant replacement therapy and initiating assisted ventilation for depressed neonates with MAS early on.

As ECMO therapy is expensive and labour intensive and thus currently inaccessible in our setting, serious consideration should be given to introducing iNO to reduce the PPHN-associated mortality rate.

Acknowledgements. None.

Author contributions. IH was the primary researcher and conducted this project for his MMed degree. DB supervised the project, assisting with formulation of research question, data analysis, review of manuscript drafts and submission of final manuscript Funding. None.

Conflicts of interest. None.

1. Lakshminrushimha S, Kumar VH. Diseases of pulmonary circulation. In: Fuhrman BP, Zimmerman JJ, eds. Pediatric Critical Care. 4th ed. Philadelphia: Elsevier, 2011:638-645.

2. Walsh-Sukys MC, Tyson JE, Wright LL, et al. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: Practice variation and outcomes.

Pediatrics 2000;105(1 Pt 1):14-20. https://doi.org/10.1542/peds.105.1.14 3. D’cunha C, Sankaran K. Persistent fetal circulation. Paediatr Child Health 2001;6(10):744-750. https://doi.org/10.1093/pch/6.10.744 4. Agrawal A, Agrawal R. Persistent pulmonary hypertension of the newborn: Recent advances in the management. Int J Clin Pediatr 2013;2(1):1-11. https:// doi.org/10.4021/ijcp79w 5. Razzaq A, Quddusi AI, Nizami N. Risk factors and mortality among newborns with persistent pulmonary hypertension. Pak J Med Sci 2013;29(5):1099-1104. https://doi.org/10.12669/pjms.295.3728 6. Abdel Mohsen AH, Amin AS. Risk factors and outcomes of persistent pulmonary hypertension of the newborn in neonatal intensive care unit of Al-Minya University Hospital in Egypt. J Clin Neonatol 2013;2(2):78-82. https://doi. org/10.4103/2249-4847.116406 7. Smith J, Kirsten GF. Persistent pulmonary hypertension of the neonate in a developing country – does extracorporeal membrane oxygenation have a role to play? S Afr Med J 1993;83:742-745.

8. Velaphi S, van Kwawegen AV. Meconium aspiration syndrome requiring assisted ventilation: Perspective in a setting with limited resources. J Perinato 2008;28(Suppl 3):S36-S42. https://doi.org/10.1038/jp.2008.155

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9. Rocha G, Baptista MJ, Guimaraes H. Persistent pulmonary hypertension of non cardiac cause in a neonatal intensive care unit. Pulm Med 2012;10:818971. https://doi.org/10.1155/2012/818971 10. Nair J, Lakshminrusimha S. Update on PPHN: Mechanisms and treatment.

Semin Perinatol 2014;38(2):78-91. https://doi.org/10.1053/j.semperi.2013.11.004 11. Konduri GG, Kim UO. Advances in the diagnosis and management of persistent pulmonary hypertension of the newborn. Pediatr Clin N Am 2009;56:579-600. https://doi.org/10.1016/j.pcl.2009.04.004 12. Oishi P, Datar SA, Fineman JR. Advances in the management of pediatric pulmonary hypertension. Respir Care 2011;56(9):1314-1339. https://doi. org/10.4187/respcare.01297 13. Teixeira-Mendonc C, Henriques-Coelhob T. Pathophysiology of pulmonary hypertension in newborns: Therapeutic indications. Rev Port Cardiol 2013;32(12):1005-1012. https://doi.org/10.1016/j.repce.2013.06.026 14. Abman SH. Recent advances in the pathogenesis and treatment of persistent pulmonary hypertension of the newborn. Neonatology 2007;91:283-290. https:// doi.org/10.1159/000101343 15. Bendapudi P, Barr S. Diagnosis and management of pulmonary hypertension of the newborn. Paediatr Child Healt 2013;24(1):12-16. https://doi.org/10.1016/j. paed.2013.05.021 16. Abu-Osba YK, Galal O, Manasra K, Rejjal A. Treatment of severe persistent pulmonary hypertension of the newborn with magnesium sulphate. Arch Dis Child 1992;67(1 Spec No):31-35. https://doi.org/10.1136/adc.67.1_spec_no.31 17. Daffa SH, Milaat WA. Role of magnesium sulphate in treatment of severe persistent pulmonary hypertension of the neoborn. Saudi Med J. 2002;23(10):1266-1269.

18. Porta NFM, Steinhorn RH. Pulmonary vasodilator therapy in the NICU: Inhaled nitric oxide, sildenafil, and other pulmonary vasodilating agents. Clin Perinatol 2012;39(1):149-164. https://doi.org/10.1016/j.clp.2011.12.006 19. Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oral sildenafil in Neonates with persistent pulmonary hypertension of the newborn: A pilot randomized blinded study. Pediatrics 2006;117(4):1077-1083. https://doi.org/10.1542/peds.2005-0523 20. Ichiba S, Bartlett RH. Current status of extracorporeal membrane oxygenation for severe respiratory failure. Artif Organs 1996;20(2):120-123. https://doi. org/10.1111/j.1525-1594.1996.tb00712.x 21. Maslach-Hubbard A, Bratton SL. Extracorporeal membrane oxygenation for pediatric respiratory failure: History, development and current status. World J Crit Care Med 2013;2(4):29-39. https://doi.org/10.5492/wjccm.v2.i4.29 22. Lazar DA, Cass DL, Olutoye OO, et al. The use of ECMO for persistent pulmonary hypertension of the newborn: A decade of experience. J Surg Res 2012;177(2):263-267. https://doi.org/10.1016/j.jss.2011.11.487 23. Lewandowski K. Extracorporeal membrane oxygenation for severe acute respiratory failure. Crit Care 2000;4(3):156-168. https://doi.org/10.1186/cc689 24. Xu H, Wei S, Fraser WD. Obstetric approaches to the prevention of meconium aspiration syndrome. J Perinatol 2008;28(Suppl 3):S14–S18. https://doi. org/10.1038/jp.2008.145 25. Whitfield JM, Charsha DS, Chiruvolu A. Prevention of meconium aspiration syndrome: An update and the Baylor experience. Proc (Bayl Univ Med Cent) 2009;22(2):128-131. https://doi.org/10.1080/08998280.2009.11928491 26. Alano MA, Ngougmna E, Ostrea EM Jr, Konduri GG. Analysis of nonsteroidal antiinflammatory drugs in meconium and its relation to persistent pulmonary hypertension of the newborn. Pediatrics 2001;107(3):519-523. https://doi. org/10.1542/peds.107.3.519 27. Hernandez-Diaz S, van Marter LJ, Werler MM, Louik C, Mitchell AA. Risk factors for persistent pulmonary hypertension of the newborn. Pediatrics 2007;120(2):e272-282. https://doi.org/10.1542/peds.2006-3037 28. Roofthooft MTR, Elema A, Bergman KA, Berger RMF. Patient characteristics in persistent pulmonary hypertension of the newborn. Pulm Med 2011;2011:85815. https://doi.org/10.1155/2011/858154 29. Hsieh WS, Yang PH, Fu RH. Persistent pulmonary hypertension of the newborn: Experience in a single institution. Acta Paediatr Taiwan. 2001;42(2):94-100.

30. Konduri GG. New approaches for persistent pulmonary hypertension of newborn.

Clin Perinatol 2004;31:591–611. https://doi.org/10.1016/j.clp.2004.04.001 31. Steinhorn RH. Neonatal pulmonary hypertension. Pediatr Crit Care Med 2010;11:(2 Suppl):S79–S84. https://doi.org/10.1097/PCC.0b013e3181c76cdc 32. Mohamed S, Matthews T, Corcoran D, Clarke T. Magnesium sulfate improves the outcome in persistent pulmonary hypertension of the newborn. Sudanese Journal of Paediatrics 2007;8:102-113.

33. Engelbrecht AL. Sildenafil in the management of neonates with PPHN: A rural regional hospital experience. S Afr J Child Health 2008;2:166-169.

34. Tolsa JF, Cotting J, Sekarski N, Payot M, Micheli JL, Calame A. Magnesium sulphate as an alternative and safe treatment for severe persistent pulmonary hypertension of the newborn. Arch Dis Child Fetal Neonatal Ed 1995;72(3):F184-F187. https:// doi.org/10.1136/fn.72.3.f184 35. Dehdashtian M, Tebatebae K. Magnesium sulphate as a safe treatment for persistent pulmonary hypertension of newborn resistant to mechanical hyperventilation. Pak J Med Sci 2007;23(5):693-697.

36. Sharma M, Mohan KR, Narayan S, Chauhan L. Persistent pulmonary hypertension of the newborn: A review. Med J Armed Forces India 2011;67:348353. https://doi.org/10.1016%2FS0377-1237(11)60082-8

Accepted 21 December 2017.

MARCH 2018 Vol. 12 No. 1

ARTICLE

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

Ultrasonographic assessment of renal length in 310 Turkish children in the Eastern Anatolia region M Özdikici, MD, PhD Department of Radiology, Bakirköy Training and Research Hospital, Istanbul, Turkey Corresponding author: M Özdikici (meteozdikici@hotmail.com) Background. Kidney size varies with age in children. It is therefore clear that a standardisation of measurements by age group is required.

Objectives. To determine the normal renal length of healthy children in the Eastern Anatolia region of Turkey using ultrasonography and to study the relationship between renal length and sex, age, body height and weight, repsectively.

Methods. A retrospective study of 310 children aged 0 - 16 years (150 girls and 160 boys) was performed. The children were divided into 11 age groups. Scanning was performed with a 3.5 MHz ultrasound probe in the supine position. The ultrasonographic appearance of the kidneys we measured was normal. The maximum length of each kidney was measured. The renal length was correlated with somatic parameters including age, body height and weight. Regression equations were derived for each pair of dependent and independent variables.

Results. No difference was found between the renal lengths of the boys and girls (p>0.05). The mean left renal length was greater than the right renal length, and this difference was statistically significant (p<0.001). Renal length showed the strongest correlation with body height (r=0.966 and r=0.958 for the right and left kidneys, respectively; p<0.001).

Conclusion. It is important to know the limits of kidney size on ultrasound examination. We found that renal length showed the strongest correlation with body height. The renal length can be calculated easily by deriving a linear regression equation. We hope that our study will be useful in daily routine ultrasonography.

S Afr J Child Health 2018 ;12(1):XX-XX. DOI:10.7196/SAJCH.2018.v12i1.1405

The kidneys are paired organs, placed symmetrically retroperitoneal in the abdominal region. The size of the kidney varies with age and there may also be racial differences in renal length (RL). It is important to have a reliable reference to kidney size in children[1-6] as many diseases lead to an increase or decrease in renal size.

Ultrasonography is a non-invasive modality that can be used to measure RL.[2] The purpose of the study was to determine the relationship between RL and age, body height and weight, respectively, in healthy Turkish children (0 - 16 years old) in the Eastern Anatolia region using ultrasonography.

Methods

This retrospective study was approved by the Erzurum State Hospital Ethics Committee (ref. no. Erzurum BEAH KAEK 2016/12-114) and included children who were referred to the Radiology Department at Erzurum State Hospital in Istanbul, Turkey, for ultrasonography for any reason unrelated to the kidneys. Over the course of ~2 years, all normal cases were selected for inclusion in the study.

Ultrasonography was performed using an ultrasound unit with a 3.5 MHz convex transducer. RL measurements were performed in the sagittal plane, with children in the supine position. The distance between the top and bottom poles of both kidneys was measured (Fig. 1).

Body parameters such as gender, age, body height, and weight were determined and the data were divided into 11 age groups.

Measurements were analysed separately for the right and left kidneys, within each age group. Data were analysed using SPSS version 15.0 (SPSS Inc., USA). Pearson’s correlation coefficients and simple regression analysis were used.

Results

A total of 310 children (150 girls and 160 boys) aged 0 - 16 years were included in the study. There was no significant difference in RL between the sexes (p>0.05) and therefore all data were rearranged in 11 different age groups regardless of gender. The descriptive analysis of the right and left RL (mean, median, minimum and maximum 34

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Fig. 1. Measurement of the left renal length from the upper pole to the lower pole.

values; standard deviations; 10th and 90th percentile values; and 95% confidence interval (CI) values) are shown in Tables 1 and 2.

The left RL was significantly larger than the right RL (p<0.001).

Correlations of the right and left RL with body height are shown in Figs 2 and 3. Percentile curves of the right and left RL v. age group are shown in Fig. 4.

The RL has been correlated with the children’s age (right, r=0.930; left, r=0.913), and weight (right, r=0.934; left, r=0.917). The length of both the right (r=0.966) and the left (r=0.958) kidneys showed the strongest correlation with body height.

Linear regression equations for predicting a variable (renal length) from independent variables (height and weight) were obtained as follows: Right renal length (mm) = 25.473 + 0.438 × height (cm); and 50.240 + 0.944 × weight (kg) Left renal length (mm) = 29.196 + 0.435 × height (cm); and 53.984 + 0.929 × weight (kg)

MARCH 2018 Vol. 12 No. 1

ARTICLE Table 1. Right renal length correlation with age by ultrasonography in healthy children (N=310) Right renal length (mm) n (%) Mean (SD) Median (IQR) 10th percentile 90th percentile 95% CI for the mean 1 2 3 4 5 6 7 8 9 10 11

0 - <3 mo 3 - <6 mo 6 - <12 mo 1 - <2 y 2 - <4 y 4 - <6 y 6 - <8 y 8 - <10 y 10 - <12 y 12 - <14 y 14 - <16 y

21 (6.77) 24 (7.74) 24 (7.74) 30 (9.67) 27 (8.70) 27 (8.70) 31 (10.0) 26 (8.38) 27 (8.70) 38 (12.25) 35 (11.29)

49 (8) 52 (8) 57 (5) 61 (4) 67 (6) 73 (6) 79 (6) 83 (7) 88 (6) 94 (6) 97 (8)

47 (38 - 65) 53 (40 - 65) 57 (50 - 68) 61 (54 - 69) 66 (55 - 77) 75 (61 - 83) 79 (67 - 93) 83 (71 - 97) 87 (80 - 102) 94 (82 - 104) 100 (82 - 108) 120

38 42 52 55 58 63 72 73 81 85 87

64 64 65 67 73 81 91 94 99 101 106

45 - 52 49 - 56 56 - 61 59 - 62 64 - 69 71 - 76 77 - 82 77 - 83 86 - 91 91 - 96 94 - 100

Right renal length (mm)

mm = millimetres; SD = standard deviation; IQR = interquartile range; CI = confidence interval; mo = months; y = years.

Observed Linear

100

Table 2. Left renal length correlation with age by ultrasonography in healthy children (N=310) Left renal length (mm) 80 n (%) Mean (SD) Median (IQR) 10th percentile 90th percentile 95% CI for the mean 1 2

0 - <3 mo 3 - <6 mo

21 (6.77) 24 (7.74)

52 (8) 56 (7)

51 (38 - 65) 56 (40 - 65)

3 4 5 6 7 8 9 10 11

6 - <12 mo 1 - <2 y 2 - <4 y 4 - <6 y 6 - <8 y 8 - <10 y 10 - <12 y 12 - <14 y 14 - <16 y

24 (7.74) 30 (9.67) 27 (8.70) 27 (8.70) 31 (10.00) 26 (8.38) 27 (8.70) 38 (12.25) 35 (11.29)

61 (4) 65 (5) 71 (5) 77 (7) 83 (7) 86 (7) 92 (6) 97 (8) 99 (9)

60 (50 - 68) 64 (54 - 69) 71 (55 - 77) 76 (61 - 83) 84 (67 - 93) 87 (71 - 97) 93 (80 - 102) 97 (82 - 104) 98 (82 - 108)

60

40

20

40 46 55 58 63 67 50 73 75 82 84 86

65 65

75

48 - 55 53 - 59

67 73 76 10086 125 93 Height (cm) 97 100 107 113

150

59 - 62 62 - 67 69 - 72 75 - 80 175 81 - 86 81 - 87 89 - 94 94 - 99 96 - 102

mm = millimetres; SD = standard deviation; IQR = interquartile range; CI = confidence interval; mo = months; y = years.

Observed Linear

100

80

60

40

Observed Linear

120

Left renal length (mm)

Right renal length (mm)

120

100 80 60 40

20

20 50

75

100

125

150

175

50

75

Height (cm)

100

125

150

175

Height (cm)

Fig. 2. Correlation curve of right renal length with body height. (mm = millimetres; cm = centimetres.)

Fig. 3. Correlation curve of left renal length with body height. (mm = millimetres; cm = centimetres.)

DiscussÄąon

children in the Eastern Anatolia region of Turkey. Our aim was to determine the normal standards of kidney sizes of Turkish children living in the Eastern Anatolia region.

Ultrasonography is the most widely used imaging method in routine practice and does not expose patients to ionising radiation.

Ultrasonographic examination can be performed in the lateral decubitus, supine and prone positions.[4-6] Our subjects were placed

Left renal length (mm)

Renal diseases can lead to changes in kidney size and therefore knowing the normal limits of the kidney size of healthy children would be useful to distinguish abnormal conditions.Observed It is also 120 important to note that body height and weight mayLinear vary with ethnicity.[1,7] Although there are numerous studies in the literature 100to the kidney size of children, there are no data related to related 80 60 40

35

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MARCH 2018 Vol. 12 No. 1

ARTICLE in the supine position for measurement of the distance between the upper and lower poles of both kidneys.

There is no consensus on which measurement parameter to use when evaluating kidney size. The assessment of kidney volume is time-consuming and impractical and as a number of previous studies have shown that RL correlates better with body parameters, we chose to compare RL with age, body height and weight, which

was the easiest and most practical approach for us. [1,7-10] Some studies found a linear relationship between RL and body height. They observed that the increase in the RL is much more rapid during the first years of life.[7-9,11,12] The results of our study were in accordance with the findings of those studies.

There were discrepancies in sizes between the right and the left kidney.[10-13] In our study, the left kidney was significantly larger Age group

Renal length (mm)

100

1 2 3 4

7 8 9 10

5 6

11

80

Conclusion

Dependent variables RRL LRL

60

40 5

10

25

50

75

90

than the right kidney (p<0.001). For this reason, the size of both kidneys should be measured separately.

Some studies suggest that girls have smaller kidneys, while other studies indicate no differences in renal size between the genders.[7,9-13] In our study, there were no significant differences in RL with respect to gender (p>0.05), which was not a determining factor of organ size within this age group.

Table 3 compares the data of our study with those of Konuş et al.[9] and Otiv et al.[11] As the age groups were different in those studies, we attempted to align the groups as closely as possible. Data from our study and that of Konuş et al.[9] differed owing to the fact that data were collected from different regions in Turkey.

95

Percentiles Fig. 4. Percentile curves of the right and left renal length v. age group. (RRL = right renal length; mm = millimetres; LRL = left renal length.)

The present study showed that the best correlation was between RL and body height.

Both should be measured separately, as there may be a size difference between the right and left kidneys. It was also found that there was no difference between the genders in terms of kidney size. We have tabulated the correlation of age with kidney length in this report and believe that these tables can be used in radiology clinics to assess conditions that lead to changes in renal size. We have also built the prediction models of RL (mm)

Table 3. Mean renal length (mm) according to age group in different studies Age*

Mean RL*

Age (mo)†

R-Mean RL†

L-Mean RL†

Age‡

R-Mean RL‡

L-Mean RL‡

1 mo

43

1-3

50

50

0-<3 mo

49

52

3 mo

47

4-6

53

56

6 mo

55

7-9

59

61

3 - <6 mo

52

56

9 mo

56

6 - <12 mo

57

61

1y

57

1 - <2 y

61

65

2y

61

2 - <4 y

67

71

3y

67

4y

68

4 - <6 y

73

77

5y

67

6y

67

6 - <8 y

79

83

7y

72

8y

76

8 - <10 y

83

86

9y

80

10 y

80

10 - <12 y

88

92

11 y

85

12 y

86

12 - <14 y

94

97

14 - <16 y

97

99

12 - 30

61

36 - 59

67

60 - 83

74

84 - 107

80

108 - 131

80

132 - 155

89

66 71 79 84 84 91

156 - 179

94

96

180 - 200

92

99

mo = months; RL = renal length; R = right; L = left y = years. *Otiv et al. † Konus et al. ‡ This study.

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MARCH 2018 Vol. 12 No. 1

ARTICLE according to body height (cm) and weight (kg) as an alternative method for radiologists and paediatricians to assess changes in renal size.

Acknowledgements. None.

Author contributions. Sole author.

Funding. None.

Conflicts of interest. None.

1. Rosenbaum DM, Korngold E, Teele RL. Sonographic assessment of renal length in normal children. Am J Roentgenol 1983;142:467-469. https://doi. org/10.2214/ajr.142.3.467 2. Abdulla AA. Ultrasonographic measurements of kidney dimensions of 109 Filipinos in South Luzon – a descriptive study. Acta Medica Philippina 2010;44(3):35-38.

3. Kadioglu A. Renal measurements, including length, parenchymal thickness, and medullary pyramid thickness, in healthy children: What are the normative ultrasound values? Am J Roentgenol 2010;194:509-515. https://doi. org/10.2214/AJR.09.2986 4. Larson DB, Meyers ML, O’Hara SM. Reliability of renal length measurements made with ultrasound compared with measurements from helical CT multiplanar reformat images. Am J Roentgenol 2011;196(5):592-597. https:// doi.org/10.2214/AJR.10.5486 5. Achim OF, Veştemean IL. Ultrasound relation between the dimensions of the spleen and left kidney in children. Acta Medica Transilvanica 2010;2(4):251-252.

6. Eze CU, Agwu KK, Ezeasor DN, Agwuna KK, Aronu AE. Sonographic determination of spleen to left kidney ratio among Igbo school age children of south east Nigeria. African Health Sci 2014;14(1):246-254. https://doi. org/10.4314/ahs.v14i1.38

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7. Gavela T, Bayle MS, Mardones GG, Gallego S, Martínez-Pérez J, Pintado MT. Ultrasonographic study of kidney size in children. Nefrologia 2006;26:325-329.

8. Kim JH, Kim MJ, Lim SH, Kim J, Lee MJ. Length and volume of morphologically normal kidneys in Korean children: Ultrasound measurement and estimation using body size. Korean J Radiol 2013;14(4):677-682. https://doi.org/10.3348/ kjr.2013.14.4.677 9. Konus OL, Ozdemir A, Akkaya A, Erbas G, Celik H, Isik S. Normal liver, spleen, and kidney dimensions in neonates, infants, and children: Evaluation with sonography. Am J Roentgenol 1998;171(6):1693-1698. https://doi.org/10.2214/ ajr.171.6.9843315 10. Safak AA, Simsek E, Bahcebasi T. Sonographic assessment of the normal limits and percentile curves of liver, spleen, and kidney dimensions in healthy school-aged children. J Ultrasound Med 2005;24(10):1359-1364. https://doi. org/10.7863/jum.2005.24.10.1359 11. Otiv A, Mehta K, Ali U, Nadkarni M. Sonographic measurement of renal size in normal Indian children. Indian Pediatrics 2012;49:533-536. https://doi. org/10.1007/s13312-012-0120-7 12. Park CW, Yu N, Yun SW, et al. Measurement and estimation of renal size by computed tomography in Korean children. J Korean Med Sci 2017;32(3):448456. https://doi.org/10.3346/jkms.2017.32.3.448 13. Sultana S, Rahman S, Basak BK, Afza NS, Hossain N, Ferdaus S. Determination of kidney length and volume by ultrasound in 100 term Bangladeshi newborns.

Bangladesh J Child Health 2012;36(1):26-29. https://doi.org/10.3329/bjch. v36i1.13032

Accepted 7 August 2017.

MARCH 2018 Vol. 12 No. 1

CASE REPORT

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

Neonatal HIV-associated nephropathy R Bhimma,1 MB ChB, DCH, FCP (Paeds), MMed, MD, Cert Nephrol (Paeds); E Naicker,1 MB ChB, DCH, FCP (Paeds), Cert Nephrol (Paeds); B W Mzimela,2 MB ChB Department of Paediatrics and Child Health, School of Clinical Medicine, College of Health Science, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa 2 Department of Paediatrics and Child Health, Inkosi Albert Luthuli Central Hospital, Durban, KwaZulu-Natal, South Africa 1

Corresponding author: R Bhimma (bhimma@ukzn.ac.za) Human immunodeficiency virus (HIV)-related nephropathy is a significant cause of morbidity and mortality in HIV-1 seropositive children in Africa that presents at any age. To date the youngest patient reported in the literature was from our centre, presenting at 4 months of age.

We present here a neonate born to an HIV-1 infected mother on combined anti-retroviral therapy (cART), who had vertical transmission of the virus and presented with congenital nephrotic syndrome at three weeks of life. The child was confirmed to have HIV-1 infection at 6 weeks. Kidney biopsy showed features consistent with HIV-associated nephropathy. On commencement of cART and angiotensin converting enzyme antagonist treatment, there was a substantial decrease in proteinuria. To the best of our knowledge, this is the first report of HIV-associated nephropathy presenting as congenital nephrotic syndrome.

S Afr J Child Health 2018;12(1):XX-XX. DOI:10.7196/SAJCH.2018.v12i1.1437

The earliest reports of childhood HIV-1-associated nephropathy (HIVAN) were in African-American children from Miami and New York in 1984.[1] Subsequently, several forms of kidney disease in HIV-1-endemic regions have been described in both children and adults,[2] resulting from the direct effects of HIV-1 on the kidney or indirect effects of intercurrent illness or medications. HIV-related nephropathy is now recognised as a significant cause of morbidity and mortality in HIV-1-seropositive children in Africa.[3] It is among the ten most common non-infectious conditions occurring in perinatal HIV-infected children and adolescents in the highly active anti-retroviral therapy era.[4] Based on currently available literature, the youngest age of presentation of a child with HIVAN was 4 months in a series published from our centre in Durban, KwaZulu-Natal, South Africa (SA).[3] HIVAN is almost exclusively found in black patients, with African-Americans having a fourfold increased risk of progression to end-stage kidney disease.[5] HIVAN was initially reported as being a late presentation of HIV infection.[6] Subsequently, following the recognition of the disease in children, HIVAN was identified in younger children around 2 to 3 years of age.[1] In one of the largest reported series of children with HIV-related kidney disease in Africa, 19 children (37.3%) were younger than 5 years; the youngest patient was 4 months old with features of HIVAN on histopathology.[3] In another series of 10 Nigerian patients, the youngest was aged 5 months.[7] To date, there have been no reports in the literature of HIVAN presenting with congenital nephrotic syndrome (CNS). We report here what we believe is the first case of a child with CNS, who was diagnosed with perinatally acquired HIV-1 infection due to vertical transmission.

Case report

A 7-week-old female child born to non-consanguinous Mozambican parents presented at 3 weeks of age with poor appetite, skin lesions, anarsaca, severe hypoalbuminaemia (8.0 g/L), and anaemia (haemoglobin 9.2 g/dL). The child was born at term by normal vaginal delivery with a birth weight of 3.2 kg and Apgar scores of 8/10 and 9/10 at 5 and 10 minutes, respectively. The placental weight was not available. The mother had been booked at 24 weeks gestation and tested HIV-positive with a CD4+ cell count of 98 cells/µL. Unfortunately, her HIV viral load was not available. She was initiated on fixed-dose 38

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combined antiretroviral therapy (cART) using ATRIPLA (efavirenz, emtricitabine (FTC) and tenofovir disoproxil fumerate) and the child was initiated on the elimination of mother-to-child transmission (EMTCT) programme using nevirapine (2 mg/kg for 6 weeks). The child was diagnosed with severe acute malnutrition and managed in accordance with World Health Organization guidelines. After a week, the oedema failed to resolve and she was initiated on daily albumin infusions for 6 days. Urinary dipstick analysis that was initially negative showed proteinuria of 3+ following albumin infusions and the urinary protein (mg/dL):creatinine (mg/dL) ratio was 3.0 (normal ratio <0.5), which was consistent with massive proteinuria. The child was subsequently referred to Inkosi Albert Luthuli Central Hospital (IALCH) in Durban for further management.

At IALCH the child was oedematous, haemodynamically stable, with a normal blood pressure of 90/46 mmHg). Her urinary protein:creatinine ratio on admission was 4.2. A 24-hour urine sample confirmed massive proteinuria of 5.04 g/24 hours (normal value ≤29 mg/24 hours). The serum albumin was 23 g/L and serum cholesterol was 4.5 mmol/L. The child was hyponatraemic with a serum sodium of 125 mmol/L and mildly acidotic (serum bicarbonate 18 mmol/L) with a disproportionately raised blood urea and low serum creatinine, which was suggestive of pre-renal failure. Serological tests were conducted for toxoplasmosis, EpsteinBarr virus, hepatitis B and C, syphilis (rapid plasma reaction) and CMV (including a qualitative polymerase chain reaction (PCR) test). In addition, staining for Mycobacterium tuberculosis was conducted on a renal biopsy. Serum complement, lipid levels and cardiac echocardiography were normal. Unfortunately, genetic testing for the various candidate genes implicated in CNS was not undertaken as this was unavailable for routine clinical care. The mother tested negative for hepatitis B and C, syphilis, tuberculosis and lupus, with evidence of past exposure to cytomegalovirus.

Ultrasound of the child’s kidneys showed both kidneys to be normal in position and size but echogenic with poor cortico-medullary differentiation with the right and left kidney measuring 5.6 cm and 5.5 cm, respectively. There was no evidence of hydronephrosis, hydroureter or perinephric collections. The child was commenced on an angiotensin converting enzyme antagonist (enalapril), thiazide diuretic (hydrochlorothiazide) and an aldosterone antagonist (spironolactone), with ongoing cART. There was no evidence of extra-

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CASE REPORT renal manifestations of CNS such as neurological, ophthalmological, haematological, cutaneous and pulmonary manifestations.

At 6 weeks, the child’s HIV test using reverse transcriptase anti-DNA PCR (HIV Viral Load Kit, Roche Diagnostics, SA) was positive and she was initiated on cART. An open kidney biopsy by the surgical team showed 38 glomeruli on light microscopy, with no global sclerosis.

Several glomeruli showed focal and segmental increase in mesangial cellularity and sclerosis. There was no evidence of periglomerular fibrosis, crescent formation or karyorrhexis. Spike formation and double contours were not seen on special stains. The adjacent tubulointerstitium showed minimal fibrosis but no interstitial inflammation. Tubules did not show microsystic tubular dilatation and there were no established alternations of benign hypertension or accelerated nephroangiosclerosis. Infective pathogens were not seen.

The kidney biopsy specimen for immunofluorescence unfortunately showed only one glomerulus that stained negative for C1. Staining for C3, C4, IgA, IgG and IgM was negative. Electron microscopy showed subepithelial deposits and variable thickening of the glomerular basement membrane. There was podocyte foot process effacement and minimal mesangial sclerosis. Viral inclusions were not seen.

Despite the poor representation of glomeruli on the specimen used for immunofluorescence, the overall features on histopathology favoured a histopathological diagnosis of HIV-immune complex kidney disease. Unfortunately, immunohistochemistry was not done.

After two doses of albumin infusions, the child’s oedema resolved completely and no further albumin infusions were necessary. Her urinary protein:creatinine ratio decreased from 4.2 to 2.6 and her discharge albumin was 23 g/dL, despite not having had albumin infusions for a fortnight (Table 1). The child was discharged and unfortunately lost to follow-up.

Discussion

CNS is a rare but severe form of nephrotic syndrome presenting in the first three months of life. The disease is characterised by heavy proteinuria, hypoproteinaemia and oedema, which most often progresses to anasarca. The degree of proteinuria immediately after birth is variable and hence clinical signs of nephrotic syndrome may only present after a few weeks of life, with the true magnitude of proteinuria sometimes only becoming apparent after partial correction of hypoalbuminaemia following albumin infusions.[8] The disease is either primary or secondary to systemic diseases, typically perinatal infections, including congenital syphilis, rubella, toxoplasmosis, cytomegalovirus and hepatitis B.[9] Non-infectious cases of CNS have been reported in association with maternal systemic lupus erythematosus and neonatal alloimmunisation against neonatal endopeptidase present on podocytes.[10] The primary or genetically inherited forms are most commonly associated with mutations encoding structural proteins of the slit diaphragm, i.e. nephrin (NPHS1) and podocin (NPHS2), as well as a transcription factor (WT1).

HIV-1 has been implicated as a secondary cause of CNS;[9] however, an extensive literature search failed to reveal any report of CNS secondary to HIV infection. The youngest child reported to date has been a 4-month-old from our centre.[3] To the best of our knowledge, this is the first case of CNS reported from and HIV-1 endemic area. The spectrum of kidney disease described to date that occurs with perinatal HIV-1 infection in children encompasses chronic glomerular disorders, such as HIVAN and HIV immune complex kidney disease, the thrombotic microangiopathies (including atypical forms of haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura), disorders of proximal tubular function and acute kidney injury.[4] All of these disorders have been reported in older patients, of which the youngest was 4 months old. This is older than the patient we presented in this report who was only 7 weeks old. Also, HIVAN or HIV-immune complex kidney disease has not been reported as part of the spectrum of CNS. Although the mother had been commenced on cART early in her pregnancy, she had a low CD4 count with a high viral load, making a strong case for perinatal transmission of the virus. The child tested positive at 6 weeks of age using HIV-1 polymerase chain reaction thus confirming infection. The classical presentation of CNS in the setting of HIV-1 infection with a biopsy finding consistent with HIV immune complex disorder will strongly support HIV-1 as a secondary cause of CNS in this case, although tissue for immunofluorescence was suboptimal and lights microscopy did not show microcytic tubular dilatation (a typical finding of nephropathy in the setting of HIV). Electron microscopy however strongly supported a diagnosis of HIV-1 immune complex kidney disease showing subepithelial deposits and variable thickening of the glomerular basement membrane. Failure to demonstrate other common known pathogens causing CNS further supports a diagnosis of HIV-1 associated immune complex disease. HIVAN is a distinct entity from immune complex glomerulopathy and membranous glomerulopathy. It can be difficult to differentiate immune complex glomerulpathy (HIVICK) from membranous glomerulopathy in a patient with HIV because HIVICK has varying morphologies, including a membranous pattern. Thus, a secondary membranous glomerulopathy and HIVICK will have the same histomorphology.[11] It is possible that the findings of HIV-1 infection in the case of a child with CNS in a highly endemic region may be purely coincidental. However, to date, primary CNS (genetic form) has not been reported with histopathological findings of immune complex kidney disease. Genetic forms of CNS may cause histopathological lesions, including mesangial expansion, minimal change disease, focal segmental glomerulosclerosis, and diffuse mesangial sclerosis (with or without tubular dilatation, interstitial fibrosis and inflammation).

[12] However, to date, primary CNS (genetic form) has not been reported with histopathological findings of immune complex kidney disease.

Table 1. Laboratory findings during admission to Inkosi Albert Luthuli Central Hospital

Sodium (mmol/L) Potassium (mmol/L) Chloride (mmol/L) Bicarbonate (mmol/L) Urea (mmol/L) Creatinine (µmol/L) Albumin (g/L) Urine protein (mg/dL):Creatinine (mg/dL)

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04/01/17

125 5.5 97 18 11.2 15 23

132 5.4 101 13 9.9 <9 17

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Date 06/01/2017 16/01/2017 19/01/2017 23/01/2017 131 4.9 107 12 7.6 <9 19 4.2

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124 5.8 97 22 5.7 <9 13

129 5.9 104 20 3.8 <9 15

138 4.9 108 27 2.5 <9 23 2.6

CASE REPORT The response to cART and angiotensin converting enzyme therapy, with partial remission of the disease without the need for constant albumin infusions, favours a secondary form of CNS, as the primary (genetic) forms are usually recalcitrant to therapy. The control of oedema in these children requires multiple therapeutic interventions.

Unfortunately, the child was lost to follow-up and her response to cART and angiotensin inhibitor therapy could not be assessed.

Conclusion

We believe this is the first case of neonatal HIVAN reported in the literature that has been confirmed on histology. The long-term response to cART and angiotensin inhibitor therapy could not be assessed due to loss to follow-up.

Acknowledgements. We would like to thank the medical manager of Inkosi Albert Luthuli Hospital for permission to publish and Miss Louansha Nandlal for her assistance in drafting the manuscript.

Author contributions. All authors were involved in the clinical care of the patient. E Naicker and BW Mzimela were involved with the writing of the clinical case and review of the final draft of the paper.

Funding. None.

Conflicts of interest. None.

1. Pardo V, Meneses R, Ossa L, et al. AIDS-related glomerulopathy: Occurrence in specific risk groups. Kidney Int 1987;31(5):1167-1173.

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2. Nochy D, Glotz D, Dosquet P, et al. Renal disease associated with HIV infection: A multicentric study of 60 patients from Paris hospitals. Nephrol Dial Transplant 1993;8(1):11-19.

3. Ramsuran D. The Spectrum of HIV Related Nephropathy in KwaZuluNatal: A Pathogenetic Appraisal and Impact of HAARTT. Durban: University of Kwazulu-Natal, 2012. https://researchspace.ukzn.ac.za/xmlui/ handle/10413/10447 (accessed 12 November 2017).

4. Bhimma R, Udharam M, Kala U. Kidney disease in children and adolescents with perinatal HIV-1 infection. J Int AIDS Soc 2013;16(1). https://doi. org/10.7448/IAS.16.1.18596 5. Kopp JB, Nelson GW, Sampath K, et al. APOL1 Genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol 2011;22(11):2129-2137. https://doi.org/10.1681/ASN.2011040388 6. Brasile L, Green E, Haisch C. Ex vivo resuscitation of kidneys after postmortem warm ischemia. ASAIO J 1997;43(5):427-430.

7. Anochie IC, Eke FU, Okpere AN. Human immunodeficiency virus-associated nephropathy (HIVAN) in Nigerian children. Pediatric Nephrol 2008;23(1):117122. https://doi.org/10.1007/s00467-007-0621-0 8. Jalanko H. Congenital nephrotic syndrome. Pediatric Nephrol 2009;24(11):2121-2128.

9. Barratt TM, Avner ED, Harmon WE. Pediatric Nephrology, 4th ed. Baltimore: Lippincott, Williams and Wilkins, 1999:933-945.

10. Kerjaschki D. Pathomechanisms and molecular basis of membranous glomerulopathy. Lancet 2004;364(9441):1194-1196. https://doi.org/10.1016/ S0140-6736(04)17154-7 11. Motala AI, Mogotlane L, Goetsch S. Renal pathology in the HIV-positive child: From nephrosis to nephritis and everything in between. Diagnostic Histopathol 2009;15(5):232-240. https://doi.org/10.1016/j.mpdhp.2009.02.012 12. Jalanko H, Holmberg C. Congenital nephrotic syndrome. Pediatr Nephrol 2009; 24(11): 2121â&#x20AC;&#x201C;2128. https://doi.org/10.1007%2Fs00467-007-0633-9

Accepted 28 September 2017.

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True (T) or false (F): Regarding overweight and obesity in children and adolescents in Nigeria 1. Overweight was diagnosed if the body mass index was between the 80th and 94th centiles of the Centers for Disease Control reference values.

2. Depression was more common than anxiety in the overweight and obese children.

3. Males were more likely to suffer from anxiety disorders.

Regarding hypernatraemic dehydration in children 4. Approximately 12% of admitted infants with acute gastroenteritis had hypernatraemia.

5. Hypernatraemia is diagnosed when the serum sodium is >148 mmol/L. 6. Among those who were hypernatraemic, the majority were <6 months of age.

Regarding meningitis in children in a tertiary hospital in South Africa (SA) 7. To diagnose viral meningitis, the cerebrospinal fluid biochemistry and cell count must be within the normal reference range.

8. Streptococcus pneumoniae was the most common cause of definite bacterial meningitis in children.

9. Tuberculous meningitis (definite or probable) was almost as common as proven bacterial meningitis.

Regarding the neonatal mortality at a regional hospital in Gauteng 12. One-third of neonates admitted to the hospital were born at home.

13. One-quarter of neonatal deaths occurred in babies weighing more than 2 500 g.

14. Only 10% of deaths were associated with a neonate-to-nurse ratio of less than 1:10.

Regarding persistent pulmonary hypertension of the newborn (PPHN) 15. In SA, the mortality rate from persistent pulmonary hypertension of the neonate is low at about 12%.

16. PPHN occurs most commonly in severely premature neonates.

Regarding renal size in children 17. Male children have larger kidneys than female children.

18. Renal length correlated closely with body height.

Regarding neonatal HIV-associated nephropathy 19. HIV infection is associated with congenital nephrotic syndrome.

20. Cytomegalovirus and rubella infections may be associated with congenital nephrotic syndrome.

Regarding splenectomy in children 10. Over 90% of splenectomies in children <16 years of age were performed for malignant haematological disorders.

11. Postoperative complications were more common in those splenectomies performed by laparoscopy.

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