From actinic keratosis to squamous cell carcinoma.

Omicron (B1.1.529), the fifth variant of concern (VoC) of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), was first reported to the WHO by South African researchers on 24 November 2021. 1 , 2 Omicron caused a sharp rise in infections, leading to the fourth peak during the COVID-19 pandemic in South Africa with, for the first time, a decoupling of the number of infections from the numbers of hospitalisations and deaths, especially in adults, likely due to high seroprevalence in the population, either due to natural infection or COVID-19 vaccination resulting in some immunity against the virus.3

Regardless of VoC, the SARS-CoV-2 disease spectrum in children has been described as mild, with mostly out-of-hospital management. 3 , 4 However, a differential impact of SARS-CoV-2 was noted in sub-Saharan Africa compared to high-income countries (HICs), with hospitalised children presenting with higher morbidity and mortality. 5 – 7 Underlying comorbidities and young age are considered risk factors for more severe disease. Thus, far limited data are available on the role of TB and HIV in severity of COVID-19 disease in children and how this impacted the clinical presentation during the Omicron wave.

The aim of the present study was to describe the clinical presentation and risk factors associated with disease severity in children admitted in a tertiary hospital with SARS-CoV-2 infection during the Omicron wave in Cape Town, South Africa.

METHODS

This study describes routine care data from children aged 0–13 years with a laboratory-confirmed diagnosis of SARS-CoV-2 presenting to Tygerberg Hospital (TBH) in the period from 1 November 2021 until 1 March 2022. According to the National Institute of Communicable Diseases (NICD) Surveillance report, the Omicron wave in South Africa lasted from 28 November 2021 to 30 January 2022. 8 We defined laboratory confirmation as a positive real-time reverse-transcription polymerase chain reaction (rRT-PCR) or antigen test for SARS-CoV-2, performed on respiratory samples.

Setting

The study was conducted in TBH, Cape Town, South Africa, which is an academic teaching hospital that provides secondary-level care to the surrounding geographical areas, as well as tertiary care to the children of the Western Cape Province. 9 In this resource-limited setting, people experience a high burden of infectious diseases, including TB-HIV and live in poor socio-economic circumstances. 9 None of the children in this study received a vaccine.

SARS-CoV-2 molecular testing

Respiratory samples were eluted in phosphate-buffered saline. Total nucleic acid content was isolated using the Nuclisens EasyMag system (bioMerieux, Marcy l’Etoile, France), the NIMBUS automated extraction system (Seegene, Seoul, Republic of Korea), and the MICROLAB ® STARlet instrument (Hamilton, Reno, NV, USA) and NucleoMag Pathogen (Macherey–Nagel, Duren, Germany) extraction kit. Positive cases were identified using molecular assays in routine use, including Alinity m SARS-CoV-2 AMP Kit (Abbott Laboratories, Abbott Park, IL, USA), Xpert ® Xpress SARS-CoV-2 assay (Cepheid, Sunnyvale, CA, USA), TaqPath COVID-19 CE-IDV RT-PCR assay (Thermo Fisher Scientific, Waltham, MA, USA), Allplex TM 2019-nCoV Assay (Seegene), QA_CFX (Qiagen, Venlo, The Netherlands), and Artus SARS-CoV-2 Prep&Amp UM kit (Qiagen) at the Division of Medical Virology, Stellenbosch University, and the National Health Laboratory Service (NHLS) Tygerberg. Five samples obtained from nasopharyngeal swabs were tested using Abbott Panbio COVID-19 Ag Rapid Test Device (Abbott Diagnostic, Jena, Germany).

Viral co-infections

Total nucleic acid content was isolated using the Nuclisens EasyMag system, and tested using the Allplex TM Respiratory Panel 1, 2 and 3 Assays (Seegene), which is a multiplex PCR system that detects 16 different viruses in three PCR reactions. These viruses include adenovirus, influenza (A/B) virus, parainfluenza (1-4), human rhinovirus (A/B/C), respiratory syncytial virus (A and B), human bocavirus (1/2/3/4), human metapneumovirus, human coronavirus (229E, NL63, OC43) and human enterovirus.

Data collection and definitions

Routine care clinicians prospectively completed a case report form for each child with SARS-COV-2 on admission. The hospital laboratory system was used to ensure no children with a positive SARS-COV-2 PCR or antigen test were missed, and we retrospectively completed data of these children from hospital records. Radiological data were collected through the digital site, Picture Archiving and Communication System (PACS). Anterior-posterior (AP) and/or lateral view chest X-ray (CXR) was routinely done in children requiring oxygen or at the discretion of the treating clinician. Single CXR reading was done retrospectively according to the WHO guidelines for pneumonia 10 by a paediatric pulmonologist (PG).

SARS-CoV-2 testing strategies changed during the pandemic. During the study period, children were only tested if they required admission. Incidental infections were defined as surveillance cases, usually done routinely before planned medical procedures or surgery.

Severity of disease

We adapted the WHO severity grading for SARS-COV-2 infection in our setting as follows: 1) critical: requiring mechanical ventilation, shock or multi-organ dysfunction/multisystem inflammatory syndrome in children (MIS-C); 2) severe: all children requiring continuous positive airway pressure (CPAP)/high-flow nasal canula (HFNC); 3) moderate: children needing low-flow nasal prong oxygen (NPO 2 ) or without oxygen need but with any CXR changes; 4) mild: if symptomatic but without a need for oxygen.

Data analysis

De-identified data were entered into a RedCap database (Vanderbilt University, Nashville, TN, USA) and analysed using SPSS v27 (IBM SPSS, Armonk, NY, USA). 11 , 12 The clinical characteristics of the children with laboratory-confirmed COVID-19 were summarised with descriptive statistics. Pearson χ 2 test was used to compare the differences between the different age groups. The Yates continuity correction was used if the expected cell size was <5. Non-parametric tests were used to compare differences between the age groups and continuous/dichotomous variables (Kruskal–Wallis test/Mann-Whitney U -test). For risk factor analysis, severity of disease was divided into severe disease (critical and severe) and non-severe disease (mild, moderate). Logistic regression was used to analyse risk factors for disease severity using univariate analysis. Variables with P < 0.20 were included in the multivariate model.

The Health Research Ethics Committee of Stellenbosch University, South Africa, approved this study (HREC N20/04/013_COVID). The data were entered without patient identifiers using only routinely collected data, a waiver of consent for this process was obtained.

RESULTS

During the Omicron wave, a total of 95 children tested positive for SARS-CoV-2. In total, there were 87 (91.6%) children with symptoms compatible with COVID-19 and 8 (8.4%) incidental (asymptomatic) detections ( Figure 1 ). Clinical data were lacking in 1 child who was excluded from the analysis, and clinical description was done for the 86 symptomatic cases only. The median age was 11.0 months (interquartile range [IQR] 3.0–60.0); 37/86 (43.0%) were females and 45/86 (52.3%) had one or more underlying comorbidities ( Table 1 ). Prematurity was the most common comorbidity in children under the age of 1 year. Older children more often had a recent diagnosis or history of TB or malignancy. In total, 21/86 (24.7%) children were HIV-exposed, with 7/86 (8.1%) living with HIV (CLHIV).

The clinical findings varied among the different age groups. Most children presented with fever (31/82, 37.8%), dyspnoea (29/85, 34.1%) or dry cough (23/80, 28.8%). Respiratory symptoms were more frequently seen in younger children. The children aged >5 years presented more often with vomiting (3/20, 15.0%), abnormal neurology (9/20, 45.0%) and seizures (3/20, 15.0%). One 16-month-old child presented with typical febrile seizures. The other eight children with seizures were either very young or older children with a fever and seizure (atypical febrile seizure) or in the typical age group, but without associated fever. None of these children had a previous history of febrile seizures. Two children, both 3 months old, presented with a croup-like illness. One child was ventilated with oxygen requirements for 14 days and the other required CPAP for 3 days.

Laboratory findings of the different age groups were similar. The median C-reactive protein (CRP) of all children was 10 (IQR 3.0–41.8), with the lowest values noted in in the group of children between 1 and 5 years old, and the highest values noted in the oldest age group (≥5 years).

Baseline CXRs were done in 49/86 (57.0%) children, with abnormal findings in 28/49 (57.1%). CXRs were consistent with pneumonia in 22/49 (44.9%) cases and pneumonia with effusion in 2/49 (4.1%) cases. Most children with radiological evidence of pneumonia were less than 1 year old, with 8 (50.0%) who were less than 3 months old.

Nasopharyngeal aspirates (NPAs) were tested for other respiratory viruses in 69/86 (80.2%) children. Of these, 20/69 (29.0%) were positive for one or more additional viruses. Human rhinovirus (11/20, 55.0%), adenovirus (6/20, 30.0%) and human bocavirus (5/20, 25.0%) were

the most frequently detected viral co-infections ( Figure 2 ).

In total, 13 (15.1%) children were admitted to PICU, nine of whom were younger than 1 year of age ( P = 0.40). Two children were diagnosed with MIS-C, but both were managed outside of the PICU setting. Respiratory support was required in 38 (44.2%) children, with the highest proportion (78.9%) in children younger than 1 year ( P < 0.01). The overall median oxygen duration need was 5 days (IQR 1.8–9.0), without no observed differences between groups. Eight children, of whom six had at least one comorbidity, required oxygen for ≥10 days.

Using the adapted WHO severity grading system for SARS-COV-2 infection, overall, 14/86 (16.3%) children were assessed as having critical, 12/86 (14.0%) severe and 60/86 (69.8%) non-severe disease ( Table 1 ). Most children (19/26, 73.1%) with critical or severe disease were younger than 1 year. Univariate analysis showed that age, prematurity and features of pneumonia on CXR were associated with more severe disease. In multivariate analysis, this association disappeared ( Table 2 ). HIV exposure, infection or TB disease was not associated with more severe disease.

Table 3 shows the clinical presentation and underlying comorbidities seen in children with TB. TB co-infection was seen in 11 children: 6 children were diagnosed with TB during admission and 5 children were recently started on TB treatment. In total, 5 (45.5%) were CLHIV and 4 (36.4%) were confirmed TB, while 7 (63.6%) were clinically diagnosed. Typical features for TB were seen on the CXR of 3/5 (60.0%) children, with hilar lymphadenopathy being the most common. Of the 5 children who were recently diagnosed with TB, 2 had possible TB-immune reconstitution syndrome (IRIS) with clinical and or radiological worsening of disease.

The median hospital admission duration was 6 days (IQR 1.0–11.0), without no observed differences between the different age groups. Three (3.5%) children died: one death (1.2%) was considered related to COVID-19. This child was less than 3 months old, and, as previously described, lung tissue was SARS-COV-2-positive at autopsy. 13 The other two children had comorbidities, one 3-month-old with a cardiac defect and the other almost 9 years old with a pelvic rhabdomyosarcoma complicated by anasarca.

DISCUSSION

This study describes the clinical presentation and outcomes of children in Cape Town during the Omicron wave. In general, outcomes were good, but more severe disease continued to be seen in infants and young children with underlying comorbidities.

The first Omicron study from Tshwane, South Africa, found that 20.0% of children in their setting required oxygen therapy; however, this was not analysed according to age groups. 14 Our study found that a third of children aged 0–3 months required some form of respiratory support, which was lower than we previously found during the first SARS-CoV-2 wave in our hospital. 7 This confirms a trend of less severe SARS-CoV-2 disease seen in our population, with the youngest children remaining at highest risk for severe disease.

Several instances of atypical croup during the Omicron wave have been documented in the literature. 15 – 18 These include very young or older children, children with persisting symptoms and those requiring repeated doses of dexamethasone and other steroids. 15 , 18 , 19 In our study, one 3-month-old child required intubation and ventilation for 4 days, and subsequently needed oxygen for 8 more days. The child received a prolonged course of steroids.

Furthermore, a third of children in our study presented with atypical febrile seizures. 20 A possible explanation for this finding could be that cells within the central nervous system express ACE2, which is a binding site for SARS-CoV-2. 21 , 22 A quarter of the children in this cohort were HIV-exposed, with 8% of CLHIV. Previous studies have shown that HIV-exposed, non-infected infants generally have a higher risk of hospitalisation due to a lower respiratory tract infection when compared to non-HIV-exposed infants. 23 Our data do not show more severe disease in children living with HIV or with TB disease but there was a relative high proportion of children who were identified with a new diagnosis of TB and two children with possible TB-IRIS. Both SARS-CoV-2 and Mycobacterium tuberculosis ( M. tb) can elicit a hyperinflammatory state in the lung and the hyperinflammatory environment, induced by either M. tb or SARS-CoV-2 infection, could potentially accelerate TB disease progression or cause more severe COVID-19 disease. 24 The exact role of viral co-infections in the inception, progression and severity of TB disease is unknown, and whether SARS-CoV-2 plays a role requires further investigations.

The COVID-19 mitigation strategies during the early phase of the pandemic initially led to temporary reduction in the occurrence of some other respiratory viruses. 25 , 26 With the easing of non-pharmaceutical interventions such as lockdown measures and mask-wearing, respiratory virus infections increased. 27 A relatively low proportion of children had viral co-infections compared to previous studies. 28 This is partially because the Omicron wave occurred during summer in South Africa, with a general lower circulation of respiratory viruses. There was no evidence that viral co-infections were associated with more severe disease.

The interpretation of our data needs to be cognizant of some limitations. This study was conducted in a tertiary referral hospital and could therefore represent more severe disease. We did not include all cases of MIS-C seen during the Omicron wave; however, the role of Omicron in MIS-C cases in Cape Town have been previously described and clinical presentation and outcomes of MIS-C during the Omicron wave were similar to the previous three waves. 29 Furthermore, we did not record COVID-19 vaccination coverage in the mothers of the children, which could potentially mitigate severe outcomes in infants. However, widespread SARS-CoV-2 seroprevalence was seen before the Omicron wave due to a combination of natural infection and vaccination immunity. 30 Finally, due to changes in testing strategy, it is difficult to know how many people were infected during the Omicron wave and the estimated proportion of children and adults requiring hospitalisation.

In conclusion, the clinical presentation and outcomes of children during the Omicron wave in Cape Town were generally favourable, but severe respiratory disease was seen especially in infants and young children with underlying comorbidities. There was no evidence for more severe disease in children living with HIV or TB. Vaccination strategies for vulnerable young children need to be reviewed, especially in some African countries where there is not yet a policy for this age group. Children born premature might benefit from maternal vaccination during pregnancy.

Acknowledgements

This work is part of the VERDI Project (101045989), which is funded by the European Union. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Health and Digital Executive Agency. Neither the European Union nor the granting authority can be held responsible for these.

MVDZ was supported by a career development grant from the EDCTP2 programme supported by the European Union (grant number TMA2019SFP-2836 TB-Lung FACT2), by the Fogarty International Center of the National Institutes of Health under Award Number K43TW011028 and funding from the South African Medical Research Council researcher-initiated grant.

References

1. Singhal T. The emergence of Omicron: challenging times are here again! Indian J Pediatr Published online 2022; doi: 10.1007/s12098-022-04077-4.

2. World Health Organization . Classification of Omicron (B.1.1.529): SARS-CoV-2 variant of concern. Geneva, Switzerland: WHO, 2021.

3. Abdullah F, et al. Decreased severity of disease during the first global omicron variant covid-19 outbreak in a large hospital in tshwane, South Africa. Int J Infect Dis 2022;116:38–42.

4. Mohapatra RK, et al. Twin combination of Omicron and Delta variants triggering a tsunami wave of ever high surges in COVID-19 cases: A challenging global threat with a special focus on the Indian subcontinent. J Med Virol 2022;94(5):1761–1765.

5. Kitano T, et al. The differential impact of pediatric COVID-19 between high-income countries and low- And middle-income countries: A systematic review of fatality and ICU admission in children worldwide. PLoS One 2021;16(1 January):1–12.

6. Nachega JB, et al. Clinical characteristics and outcomes of patients hospitalized for COVID-19 in Africa: Early insights from the Democratic Republic of the Congo. Am J Trop Med Hyg 2020;103(6):2419–2428.

7. Van Der Zalm MM, et al. Clinical experience with severe acute respiratory syndrome coronavirus 2-related illness in children: hospital experience in Cape Town, South Africa. Clin Infect Dis 2021;72(12):E938–E944.

8. Hui KPY, et al. SARS-CoV-2 Omicron variant replication in human bronchus and lung ex vivo. Nature 2022;603(7902):715–720.

9. Mahase E. Omicron sub-lineage BA.2 may have “substantial growth advantage,” UKHSA reports. BMJ 2022;376:o263.

10. World Health Organization Pneumonia Vaccine Trial Investigators’ Group . Standardization of interpretation of chest radiographs for the diagnosis of pneumonia in children. Geneva, Switzerland: WHO, 2001.

11. Harris PA, et al. Research electronic data capture (REDCap)―a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42(2):377–381.

12. Harris PA, et al. The REDCap consortium: Building an international community of software platform partners. J Biomed Inform 2019:95:103208.

13. Goussard P, et al. Fatal SARS-CoV-2 Omicron variant in a young infant: Autopsy findings. Pediatr Pulmonol 2022;57(5):1363–1365.

14. Cloete J, Kruger A, Masha M, et al. Paediatric hospitalisations due to COVID-19 during the first SARS-CoV-2 omicron (B.1.1.529) variant wave in South Africa: a multicentre observational study. Lancet Child Adolesc Heal February 2022; doi: 10.1016/S2352-4642(22)00027-X

15. Murata Y, Tomari K, Matsuoka T. Children with croup and SARS-CoV-2 infection during the large outbreak of Omicron. Pediatr Infect Dis J 2022;41(5):E249.

16. Martin B, et al. Acute upper airway disease in children with the Omicron (B.1.1.529) variant of SARS-CoV-2-A report from the US National COVID Cohort Collaborative. JAMA Pediatr 2022;176(8):819–821.

17. Brewster RCL, Parsons C, Laird-Gion J, et al. COVID-19-associated croup in children. Pediatrics. Published online March 8, 2022; doi: 10.1542/peds.2022-056492

18. Tsoi K, et al. A child with SARS-CoV2-induced croup. Pediatr Pulmonol 2021;56(7):2377–2378.

19. Venn AMR, Schmidt JM, Mullan PC. Pediatric croup with COVID-19. Am J Emerg Med 2021;43:287.e1-287.e3.

20. Ludvigsson JF. Convulsions in children with COVID‐19 during the Omicron wave. Acta Paediatr. Published online February 10, 2022; doi: 10.1111/apa.16276

21. Zhou Z, et al. Understanding the neurotropic characteristics of SARS-CoV-2: from neurological manifestations of COVID-19 to potential neurotropic mechanisms. J Neurol 2020;267(8):2179–2184.

22. Essajee F, et al. Child with tuberculous meningitis and COVID-19 coinfection complicated by extensive cerebral sinus venous thrombosis. BMJ Case Rep 2020;13(9):1–3.

23. Le Roux DM, et al. Lower respiratory tract infections in children in a well-vaccinated South African birth cohort: spectrum of disease and risk factors. Clin Infect Dis 2019;69(9):1588–1596.

24. Visca D, et al. Tuberculosis and COVID-19 interaction: A review of biological, clinical and public health effects. Pulmonology 2021;27(2):151–165.

25. Sinha P, et al. Coronavirus disease 2019 mitigation strategies were associated with decreases in other respiratory virus infections. Open Forum Infect Dis 2021;8(6):2019–2021.

26. Marriott D, et al. Concomitant Marked Decline in Prevalence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Other Respiratory Viruses among Symptomatic Patients Following Public Health Interventions in Australia: Data from St Vincent’s Hospital and Associated Screening Clinics, Sydney, NSW. Clin Infect Dis. 2021;72(10):E649-E651. doi: 10.1093/cid/ciaa1256

27. Hodjat P, et al. The reemergence of seasonal respiratory viruses in Houston, Texas, after relaxing COVID-19 restrictions. Microbiol Spectr 2021;9(2):2020–2022.

28. O’Brien KL, et al. Causes of severe pneumonia requiring hospital admission in children without HIV infection from Africa and Asia: the PERCH multi-country case-control study. Lancet 2019;394(10200):757–779.

29. Abraham DR, et al. The impact of SARS-CoV-2 variants on the clinical phenotype and severity of multisystem inflammatory syndrome in children in South Africa. Pediatr Infect Dis J 2022;41(12):e510–e512.

30. Madhi SA, et al. Population immunity and Covid-19 severity with Omicron variant in South Africa. N Engl J Med 2022;386(14):1314–1326.