SARS-CoV-2 Infection in Children and Adolescents Living With HIV in Madrid

Abstract

Multicenter study designed to describe epidemiologic and clinical characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive cases registered among children and adolescents living with HIV (CALWH). SARS-CoV-2 infection was confirmed in 13.3% of CALWH, with all patients presenting mild symptoms, and the outcome was good in all patients. None of the HIV- and antiretroviral treatment-related variables studied were associated with greater infection risk or could be considered protective.

Since March 2020, when the new coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) was declared a global pandemic, the virus has infected more than 250 million people all over the world, affecting vulnerable populations including children and adolescents living with HIV (CALWH). Coronavirus disease 2019 (COVID-19) in the general population is fairly well described, but the interaction between HIV infection in the severity and outcomes of COVID-19 remains little understood,^1,2 and data are sometimes contradictory.

Some evidence suggests that patients with advanced HIV disease (low CD4+ lymphocyte cell count), high viral load or those who are not on antiretroviral treatment (ART) are at higher risk of SARS-CoV-2 infection and associated complications.¹ However, other groups reported comparable rates of infection and complications in people living with HIV on ART, in good clinical and immunological conditions.² In a recent meta-analysis, Wang et al³ found an increased risk of COVID-19 mortality in patients with HIV, but probably modulated by age, region and study design. Whether ART might play an antiviral role against SARS-CoV-2 is also a question to be answered.

Data are lacking regarding COVID-19 in CALWH. The incidence of SARS-CoV-2, risk of complication and rate of seroconversion among CALWH have not been reported. The aims of the study were to describe the epidemiological and clinical characteristics of the first SARS-CoV-2 positive cases registered among CALWH and to assess possible HIV- and ART-related risk or protective factors.

METHODS

A prospective multicenter study including CALWH followed up in the pediatric outpatient clinics of 5 hospitals in Madrid (Spain) between June 2020 and March 2021.

SARS-CoV-2 infection was considered confirmed when either a polymerase chain reaction (PCR) or rapid SARS-CoV-2 antigen test (RAT) in nasopharyngeal swab returned positive. PCR or RAT was performed throughout the study period on patients with symptoms and in those who reported contact with someone infected with SARS-CoV-2, following the indications of the Spanish Ministry for Health.

Blood samples for serological testing were collected after confirmed infection when patients attended routine outpatient appointments. Depending on the availability, various chemiluminescence serologic assays were used to determine SARS-CoV-2 IgG: COVID-19 VIRCLIA IgG-monotest, Vircell; ADVIA Centaur SARS-CoV-2 Total, Siemens; Alinity SARS-CoV-2 IgG II Quant, Abbott. All assays were performed according to the manufacturer’s package insert.

Epidemiologic, immunovirological and ART data were collected from medical reports. Symptoms related to SARS-CoV-2 were actively collected during routine medical visits, by means of a specific questionnaire. Clinical and epidemiological characteristics, immunovirological data (undetectable plasma viral load: <50 copies/mL) and ART treatment (specifically, tenofovir alafenamide or tenofovir disoproxil fumarate exposure) were compared in patients with SARS-CoV-2 confirmed infection and those uninfected.

The study was approved by the ethical committees of the participating hospitals. For children under 18, a parent/guardian signed an informed consent. Informed assent forms were collected when applicable. Patients over 18 consented to participate themselves. Clinical symptom data were collected retrospectively for some patients to complete the gap between the beginning of the pandemic and the approval of the prospective study. Each patient received an anonymous number code to maintain confidentiality.

Median and interquartile ranges were used to describe continuous variables, and numbers and percentages to express categorical variables. To compare the characteristics of patients with confirmed SARS-CoV-2 infection and those without, Fisher’s exact tests were used for categorical variables, and the Mann-Whitney test was used for continuous variables. A P value < 0.05 was considered statistically significant. Windows SPSS.20 (Madrid, Spain) was used for statistical analysis.

RESULTS

A total of 60 CALWH were studied during the study period. Among them, SARS-CoV-2 infection was confirmed in 8 (13.3%) patients: 7 diagnosed by PCR and 1 by RAT.

Median age of CALWH with SARS-CoV-2 infection was 19 years old (17–19.5 years), 62.5% were female. Three were Spanish (Caucasian) and 5 were born abroad (3 from Sub-Saharan area and 2 from Latin America). All were vertically infected, 5 patients were classified as CDC clinical stage A, 1 as stage B and 2 as stage C. By the time of SARS-CoV-2 infection, all were receiving ART. Plasma viral load was undetectable in 87.5% of patients, median CD4+ T-cell count was 671.5 cells/μL (582.5–817.5), and none had CD4+ T-cell count less than 500 cells/μL.

SARS-CoV-2 symptoms were reported by 7 (87.5%) of the 8 patients (Table 1). The most common clinical manifestation was upper respiratory tract infection (62.5%). None presented with multisystem inflammatory syndrome in children or required hospital admission or SARS-CoV-2 specific treatment.

TABLE 1.

Characteristics of Children and Adolescents Coinfected: HIV and SARS-CoV-2

Total Patients Coinfected (HIV and SARS-CoV-2)	8
Epidemiologic characteristics
Female	5 (62.5%)
Median age (yr)	19 (IQR: 17–19.5)
Born in Spain	3 (37.5%)
Clinical presentation
Asymptomatic	1 (12.5%)
Symptomatic	7 (87.5%)
Upper respiratory tract infection symptoms	5 (62.5%)
Fever	4 (50%)
Anosmia and dysgeusia	3 (37.5%)
Asthenia	2 (25%)
Abdominal pain	1 (12.5%)
SARS-CoV-2 diagnosis (microbiologic test)
Rapid antigen test (nasopharyngeal swab)	1 (12.5%)
PCR positive (nasopharyngeal swab)	7 (87.5%)
Epidemiologic status
Contact with confirmed COVID-19 case  (microbiological confirmation)	3 (37.5%)
Contact with someone with COVID-19 symptoms  (no microbiological confirmation)	2 (25%)
No COVID-19 contact known	3 (27.3%)

IQR indicates interquartile range.

After confirmed infection, a SARS-CoV-2 IgG test was positive for 7 of 8 (87.5%) patients a median of 39 days (36.5–42.5 days) later. One asymptomatic patient with positive PCR, tested negative for SARS-CoV-2 IgG in 2 consecutive visits, at 1 and 6 months after the acute infection.

Patients with confirmed SARS-CoV-2 infection tended to be older than other CALWH, but the difference was not statistically significant [19 (17–19.5) vs. 13.5 (11–19) years old; P = 0.12). There were no differences in SARS-CoV-2 infection according to clinical stage (25% vs. 15% patients at CDC clinical stage C; P = 0.79), immunovirological status [CD4+ T-cell count: 671 (582–817) vs. 857 (666–982) cells/μL; P = 0.14], or tenofovir disoproxil fumarate/tenofovir alafenamide exposure (25% vs. 22%; P = 0.80).

DISCUSSION

In our study of 60 CALWH in Madrid, the clinical presentation and outcome of cases diagnosed with SARS-CoV-2 infection were comparable to that in the general pediatric population.⁴ We found 13.3% of confirmed infection, with all patients presenting mild symptoms or asymptomatic. None required admission or specific antiviral treatment. The seroconversion rate after acute infection was 87.5%, which does not appear to be different in healthy children,⁵ although the numbers are small. All positive PCR were performed before November 2021, so we assume that infections were probably caused by alpha and delta variants (no microbiological confirmation).

To our knowledge, this is one of the first series describing the incidence and clinical outcomes of SARS-CoV-2 infection in CALWH. Our results are reassuring, as data suggest an incidence that seems comparable to that of the pediatric Spanish population. All data were actively collected according to a structured questionnaire, reducing the potential for recall bias. Symptoms related to SARS-CoV-2 were predominately cough/rhinorrhea, followed by fever, similar to previously published data in healthy children^6,7 with a similar rate of complications. Despite the deleterious effects of HIV on the immune system of vertically infected patients, including chronic inflammation and immunoactivation,⁸ our results do not suggest that HIV infection since birth in patients with good immunovirological control leads to a greater risk of SARS-CoV-2 morbidity.

Some studies have found higher mortality among HIV-COVID-19 coinfected people³ and other groups described with low levels of CD4+ cell count as a risk factor of poor outcome.⁹ In contrast, other studies found no relationship between COVID-19 incidence and outcomes and with virological or immunological factors.^10,11 We found no differences regarding CDC clinical stage, CD4+ T-cell count or viral load among CALWH with and without confirmed COVID-19. Patients with lower CD4+ T-cell counts tended to present a higher risk of SARS-CoV-2 infection, but the differences did not reach statistical significance. However, the small sample size of our cohort may have limited our ability to detect any difference. In addition, all children were receiving ART and had good immunovirological control, limiting our ability to assess the possible influence of immunosuppression or ART on the outcome.

Patients with SARS-CoV-2 infection tended to be older in our series. This finding might be explained by the fact that adolescents probably have more social interaction and riskier behavior (meeting friends, breaking restrictive social rules, or being less aware of SARS-CoV-2 infection risks), whereas younger children would have been more consciously protected against virus exposure by their parents.

CONCLUSIONS

In our cohort of perinatally CALWH, SARS-CoV-2 infection was confirmed in 13.3%. Symptoms did not appear to be different from those reported in the general population, and the outcome was good in all patients. None of the HIV- and ART-related variables studied were associated with greater infection risk. Larger, longitudinal studies are needed to describe the clinical course of SARS-CoV-2 infection among CALWH and the potential effect of ART on COVID-19.

ACKNOWLEDGMENTS

The authors thank Rafael Sánchez del Hoyo, Research Methodological Support Unit, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), Madrid, Spain, and Santiago Jimenez de Ory, Health Research Institute of the Gregorio Marañón Hospital (IisGM), Gregorio Marañón Hospital, CoRISpe, Madrid; Spain.