COVID-19-related ARDS in a young infant with uncontrolled HIV after delay in EID

Abstract

Background

COVID-19 has shown to cause generally mild disease in healthy children and adolescents. However, pediatric patients with primary immunodeficiency may develop severe and even fatal disease due to COVID-19.

Case presentation

We report the case of COVID-19-related acute respiratory failure in a 3.5-month-old infant with the diagnosis of vertical HIV transmission at disease presentation during the COVID-19 pandemic. The mother had received antiretroviral therapy from the third trimester of pregnancy and the infant had received dual neonatal prophylaxis. The first two postnatal HIV-RNA screenings immediately after birth and at the age of seven weeks were negative in this infant and follow-up screening had been planned at the age of 4 months.

Conclusions

With the description of the disease presentation and clinical course, we intend to underscore awareness regarding the possibility of delayed diagnosis of vertical HIV transmission after previous antiretroviral drug exposure. We also demonstrate the delay in prevention of vertical transmission due to COVID-19 related pandemic barriers, which underscores the need for continuation of preventive services under all circumstances. Furthermore, this is the first pediatric report describing severe COVID-19 associated morbidity during immunocompromise caused by HIV.

Background

COVID-19 in immunocompromised children

Although COVID-19 has proven to be a generally mild disease in healthy children and adolescents during the recent pandemic, a proportion of pediatric patients with primary - (PID) or secondary immunodeficiency (SID), developed severe disease with sometimes even fatal outcome [1–3]. In a recent meta-analysis, data of 793 immunosuppressed children and young people was compared to data of 102,222 children and young people in the general population and showed higher estimated prevalence for hospitalization (46% vs. 16%), ICU admission (12% vs. 2%), mechanical ventilation (8% vs. 1%), and increased mortality due to severe COVID-19 infection (6.5% vs. 0.2%) in the immunocompromised age group [3]. Nevertheless, our knowledge of clinical outcomes and treatment in immunocompromised children with SARS-CoV2 infection is still limited, particularly in pediatric HIV. Therefore, one of the aims of the current report is to share our clinical experience with HIV/COVID-19 co-infection in a young infant.

Vertical transmission of HIV and prevention of vertical transmission

Another aim of the current report is to share the clinical course of delayed early infant diagnosis (EID), to underscore the vulnerability of this patient group. It is already known that children under 1 year of age are among those most vulnerable to rapid progression of HIV and early initiation of antiretroviral treatment (ART) in infants with HIV can save lives [4]. Vertical transmission is the most important mode of HIV-1 acquisition among infants and young children and is defined as transmission of HIV from an infected mother to her child during gestation, labour, or postpartum through breastfeeding [4, 5]. Vertical transmission is believed to be multifactorial and associated with viral, immunological, maternal, obstetrical, fetal and infant factors [4, 5]. The estimated risk of vertical transmission in the absence of maternal ART is 15 to 42% depending on the continent, with the highest risk in Africa [4]. Due to the impact of preventive programs, transmission rates have been reduced to below 1% in the most advanced settings [4–7]. ART during pregnancy, preferably starting pre-conception or in the first trimester and neonatal prophylaxis are the key factors in prevention of vertical transmission [4–7]. Suppression of the maternal viral load to undetectable levels (below 50 copies/mL) offers the greatest risk reduction [4]. The ANRS French perinatal cohort study showed that time at initiation of ART or duration of last ART were correlated with transmission risk [6, 7]. Assessment of HIV-infected women receiving ART showed transmission rates of 0%, 1%, 0,9% and 3,6% when ART was started pre-conception, in the first trimester, second trimester and third trimester, respectively [6, 7].

EID

EID programs guided by WHO aim at early HIV diagnosis and subsequent initiation of ART. Consequently, scheduled postnatal HIV testing of exposed infants must be performed according to international protocols. Virologic assays (HIV-RNA or HIV-DNA nucleic acid tests (NATs)) that directly detect HIV must be used to diagnose HIV in infants and children aged < 18 months with perinatal and postnatal HIV exposure. HIV antigen/antibody tests are unreliable in this age group due to the possibility of presence of maternal antibodies [8]. In this regard, plasma HIV-RNA or cell-associated HIV-DNA NATs are equally recommended, although, it is mentioned that the results of both can be affected by maternal ART and infant prophylaxis [8]. In the single pediatric department on the island of Curaçao, neonatal prophylaxis and assessment of vertical transmission after HIV exposure, are guided by Dutch protocols, based on the USA/NIH and British guidelines [9, 10]. By following these protocols for more than a decade already, the incidence of pediatric HIV on Curaçao is very low, almost zero.

The current report describes the case of a 3.5-month-old infant with delayed EID, presenting with COVID-19-related acute respiratory distress syndrome (ARDS) during the recent pandemic. His course of disease will be described in detail, followed by discussions regarding the influence of ARV drug exposure on EID, the impact of the COVID-19 pandemic barriers on prevention of vertical transmission and possible consequences of pediatric HIV/COVID-19 co-infection.

Case presentation

A 36 year-old previously healthy pregnant woman from Curaçao, gravida 5 para 4, was tested positive for HIV by standard prenatal laboratory screening during the first trimester outside of hospital maternity clinic during the COVID-19 pandemic in 2020. Conformation testing was significantly delayed due to pandemic related logistic barriers and patient factors. At 26 weeks of pregnancy, a prenatal ultrasound at the maternity clinic showed a gemelli pregnancy of which one twin had died around the gestational age of 15 weeks. She was referred to the gynaecology outpatient department again with delay, whereafter diagnosis of HIV was confirmed at 29 weeks and 5 days. Two days later ARV combination therapy was started, consisting of bictegravir/emtricitabine/tenofoviralafenamide. Her initial HIV-RNA copy number was 33800.00 copies/mL with a CD4 cell count of 504 cells/uL. She was in good clinical condition without co-infections (Chlamydia, Gonorrhea and Syphillis PCR’s and serology were negative). Her compliance to the prescribed ART was good and she experienced no side effects. Four weeks after start of ART (gestational age 34 weeks), her HIV viral load had decreased to < 40 copies/mL and thereafter viral load remained undetectable with confirmed negative viral loads at 2 days prepartum and 3 months postpartum. HIV-RNA assays in our center are performed by a CE-IVD PCR system which necessitates a minimum of 1.5 ml EDTA plasma and reports both qualitative and quantitative results, with a detection limit of 40 copies/mL. She was counselled to have a normal vaginal delivery and it was decided to treat the infant with dual neonatal prophylaxis according to the increased risk scenario of the Dutch protocol at that time.

At gestational age 38 weeks and 3 days (May 2021), a healthy looking male neonate was born via an uncomplicated vaginal delivery with a birth weight of 3010 g (25th percentile Fenton). The first neonatal HIV-RNA viral load testing at day 0 was negative. The infant started with neonatal dual prophylaxis consisting of zidovudine 8 mg/kg/day and lamivudine 4 mg/kg/day for 4 weeks. Breast milk feeding was prohibited which was well communicated with the mother and accepted by her. During 2 days of clinical observation, the neonate tolerated the medication well and adequate administration by the mother was observed. After discharge, he was followed at the pediatric outpatient department where he showed good growth and development with exclusively bottle feeding. Neonatal prophylaxis was stopped after 4 weeks and at the age of 7 weeks the second HIV-RNA screening also resulted negative. The next and presumably last follow-up testing for assessment of vertical transmission was planned at the age of 4 months.

Unfortunately, at the age of 3.5 months, the infant was referred by the general practitioner with persistent fever and rapidly increasing dyspnea, about nine days after receiving his first vaccination according to the local vaccination protocol. At that time the family stayed in quarantine because of a COVID-19 positive family member. At presentation, a severely dyspneic, inconsolably crying infant was seen, with an initial oxygen saturation of 55% in room air for which immediate supplemental oxygen via nasal cannula was started with a flowrate of 2–5 L/min. Saturations increased to > 90%, but he remained severely dyspneic and tachypneic, without stridor. The rest of his initial vitals showed a temperature of 38,6 °C, respiratory rate 60–80/min, heart rate 160–180/min, blood pressure 112/77 mmHg, weight 5,4 kg (20th percentile Fenton). Detailed physical examination revealed normal heart sounds, bilateral crackles and rhonchi over both lung fields, oral and genital candidiasis and symmetrical limb movements. The severe respiratory distress was suspected to be due to lung tissue disease, possible multilobar pneumonia. He was subsequently transferred to our neonatal intensive care unit (NICU) for further management. On the NICU high flow 14 L/min, 100% O2 and broad-spectrum intravenous antibiotics (cefuroxime + gentamicin, later clarithromycin was added) were started after obtaining blood cultures, superficial cultures and a COVID-19 test. Extensive labs including blood gas and an X-ray were performed. The result of the X-ray was consistent with bilateral pneumonia/ARDS (Fig. 1), and his blood gas showed associated respiratory acidosis (Table 1). Additional laboratory results showed a normal bloodcount, apart from mildly elevated neutrophils, CRP was low and the COVID-19 test was positive (Table 1). The initial working diagnosis was COVID-19 related bilateral pneumonia/ARDS with the suspicion of a bacterial superinfection. Because of his HIV exposure, follow-up viral load testing was requested. Despite the high flow support, his respiratory situation did not improve and a couple of hours after NICU admission he was intubated and needed high ventilator settings. During the first admission week his respiratory situation did not improve (tidal volume maximum 8 ml/kg, PEEP 8 cm H2O, 100% O2). His CRP rose to a maximum of 28 mg/L at day 2 after admission while initial blood and sputum cultures remained negative. Therefore, antibiotics were stopped after 7 days. Already at presentation, his history of HIV exposure together with the severity of his clinical condition raised concerns regarding missed diagnosis of vertical transmission. Due to repeated insufficient amount of bloodsamples and delays in reporting this back, the HIV-RNA result was delayed until day 7 after admission and this time the result was highly positive with a viral load of 9.3 million copies/mL.

Fig. 1.

Thorax X-ray postintubation after admission on NICU

Table 1.

Laboratory results at admission on NICU department

Laboratory test	Result	Reference
Bloodgas (ven)
pH	7.28	7.35–7.45 kPa
pCO2	8.1	4–6 kPa
Bicarbonate	27.8	22–25 mmol/L
Base excess	-0.1	-1 to + 1 mmol/L
sO2	47%
Lactate	1.4	< 1 mmol/L
Chemistry
Sodium	141	135–145 mmol/L
Potassium	4.3	3.9–5.7 mmol/L
Calcium ionized	1.2	1.12–1.23 mmol/L
Chloride	105	97–107 mmol/L
Glucose	4.6	(mmol/L)
CRP	5	< 10 mg/L
Hematology
Hemoglobin	6.7	5.9–8.4 mmol/L
MCV	82	70–86 fl.
Thrombocytes	350	140–400 × 10^9/L
Leukocytes	14.7	6.0–18 × 10^9/L
Neutrophils	8.8	2.5–7.5 × 10^9/L
Lymphocytes	4.3	4.0–10.0 × 10^9/L
Virology
Covid	Pos CT-value 28

X-ray after intubation several of hours after admission with deep position of the endotracheal tube, patchy consolidations in both lungs, with diminished cardiac contour on the right side. No arguments for pneumothorax. No significant amount of pleural fluid. Significant aerogastria, indication for placing a gastric tube.

Immunocytology measurements showed CD4 count: 221 cells/uL [ref 560–1490], CD8: 310 cells/uL [ref 260–990], CD4/CD8 ratio: 0.7 [ref 1.0–4.0] and CD3: 550 cells/ul [ref 860–2490]. These results together with his clinical situation were consistent with active HIV clinical stage 3. Triple ART (lamivudine/zidovudine/lopinavir/ritonavir) and cotrimoxazole prophylaxis were immediately started, where it should be noted that dolutegravir for more rapid achievement of viral load decline was considered, but due to lack of availabity of pediatric formulations and doubts regarding absorption and effectivity of dissolving the available 25 mg dolutegravir tablets, the choice was made for the above regimen.

On day 9 after admission he showed further deterioration and again fever, for which new blood- and sputum cultures were obtained and rescue antibiotics (meropenem) were started. Because of the active HIV infection, a coinfection with Pneumocystis Jiroveci (PJP) could not be ruled out. Therefore, PCR and pathology examination were performed on material obtained by broncho-alveolar lavage (BAL) on the same day. Microscopy and stainings did not show presence of this pathogen and the PJP PCR showed a CT-value of 31. Nonetheless, due to the clinical severity of disease, it was decided to switch to cotrimoxazole in therapeutic dose immediately after material for the BAL was obtained. This treatment was continued for a total of 4 weeks, whereafter prophylaxis dose was given according to protocol. COVID-19 CT-value was repeated on day 9 after admission and showed a lower value than at presentation (CT value 14), indicating ongoing active COVID-19 infection. CRP rose to maximum 65 mg/L, and the new sputum culture this time showed Klebsiella Pneumoniae with normal sensitivity, consistent with a ventilator acquired pneumonia. Starting from 10 days after admission, his respiratory situation gradually improved and he could be detubated 19 days after admission, whereafter respiratory support with high flow was continued for 4 more days. Thereafter, he was transferred to our general pediatric ward for further recovery. He showed a decrease of his viral load to 2930 copies/mL after 4 weeks of ART (Fig. 2). COVID-19 CT-value that had decreased to 14 on day 9 after admission, increased back to 24 at day 18 after admission. Six weeks after admission he was discharged with tube feeding, antihypertensive medication, a low dose of abstinence medication, ART and cotrimoxazole prophylaxis. Diagnosis at discharge was respiratory failure due to COVID-19/active HIV co-infection, due to delayed EID, further complicated by ventilator associated pneumonia with Klebsiella Pneumonia. Associated PJP was not confirmed, but could not be completely excluded, hence it was treated. Currently, at the age of 3 years, he shows normal psychomotor development, absent chronic lung problems and negative viral loads with good compliance of ART.

Fig. 2

Discussion

The current report describes the clinical course of a 3.5-month-old male infant with HIV/COVID-19 co-infection. The reported case illustrates the possible clinical consequences of delay in EID after ARV drug exposure. This report also demonstrates the effect of disruption of (preventive) care by the pandemic and underscores the morbidity of immunocompromise during Sars-CoV-2 infection.

In the current case maternal ART was started at 30 weeks of gestation and resulted in undetectable viral load from gestational age 34 weeks onwards. The term born infant was treated with dual neonatal prophylaxis consisting of zidovudine and lamivudine according to the increased risk scenario of the local protocol at that time. Notably, according to the criteria at birth (term birth, maternal viral load 2x < 50 cp/mL after 36 weeks of gestation, no acute HIV during pregnancy and good compliance), a low risk neonatal prophylaxis treatment would have been applicable [10].The decision to choose for dual prophylaxis was based on concerns of the care providers regarding the late start of ART. In the infant, both the postpartum - and post-prophylaxis HIV-RNA screening at 7 weeks after birth were negative and it was decided to perform the third screening at 4 months of age as indicated by the local protocol at that time. Unfortunately, the infant presented with HIV stage 3 and COVID-19 related ARDS at the age of 3.5 months, which indicates that viral rebound must have occurred very rapidly after the second negative HIV-RNA test. Based on the clinical course, we suspect that vertical transmission in this infant most probably occurred intra-uterine during the first two trimesters or halfway through the third trimester, because at gestational age 34 weeks, intrapartum and at 3 months postpartum, the maternal viral loads were undetectable and the infant was immediately bottle fed after well prepared education of the mother guided by a personal HIV nurse. Even when we consider the possibility of secret breastfeeding, the risk of postpartum transmission would have been very small, given the mother’s good compliance and confirmed undetectable viral loads. Presuming intra-uterine transmission, the severity of the viral rebound within 2.5 months after cessation of neonatal prophylaxis, illustrates the importance of accurate timing of EID. It was already mentioned that although HIV-DNA/RNA assays have a very good accuracy in detection of EID and are the recommended tests in international guidelines for assessment of infant HIV status, there are concerns when the infant is on ART because of the reduced amount of detectable RNA [11–16]. Because of the observation that infant prophylactic regimens can result in loss of detectability by PCR assays in HIV-infected infants, current international guidelines recommend that infants at high risk of HIV transmission undergo repeat nucleic acid testing 2 to 4 weeks after cessation of ARV prophylaxis [12–16]. Out of similar concern, South Africa’s testing guidelines recommend routine HIV PCR testing at 10 weeks post-delivery, instead of the previous 6 weeks, for detection of intrapartum infections [13]. In the presented case it seems reasonable to presume that after intra-uterine transmission had already occurred, the effective maternal ART starting from the third trimester of pregnancy, resulted in undetectable viral load at birth. With the second negative HIV-RNA test 3 weeks after cessation of neonatal prophylaxis, there still must have been complete viral suppression as a result of the dual prophylaxis. When we consider the very quick viral rebound resulting in clinical HIV stage 3 within 2.5 months after stopping prophylaxis, this could fit with observations that intra-uterine infected infants without ARV medication have a more rapid disease onset and higher risk of mortality than those infected through other transmission routes and show significant morbidity within 6 weeks postpartum [17, 18]. By following the current updated USA and British prevention of vertical transmission guidelines, the last and most often third postnatal test should be performed 8 weeks after cessation of prophylaxis in all HIV-exposed neonates, thus at the age of 3–4 months. The current case underscores the necessity to follow these updated recommendations strictly and to individualise with extra screenings where necessary, considering all factors regarding vertical transmission.

The importance of prevention of vertical transmission regardless of pandemics

Since the start of preventive vertical transmission programs on Curaçao, more than a decade ago, with standard maternal HIV testing in first trimester of pregnancy and availability of ART via the hospital pharmacy regardless of insurance, the incidence of HIV-positive infants as a result of intra-uterine transmission is almost 0% on the island. Unfortunately, the presented case illustrates the severe consequences of disruption of care caused by the COVID-19 pandemic. Maternal positive HIV screening during the first trimester was treated with significant delay, due to a combination of pandemic related logistic barriers and personal situation regarding transportation and pandemic-related anxiety. Consequently, ART was started with delay, until the third trimester. It was previously mentioned that women and children were unable to adequately access essential HIV services during the COVID-19 pandemic and it was stated that COVID-19-related service disruptions threaten to reverse the decade-long progress made for children and pregnant women in the fight against HIV [19, 20]. The current case underscores these findings and emphasizes that global measures should focus on strengthening the health care system at all levels during pandemics.

Morbidity of COVID-19 during pediatric immune-compromise by HIV

Data of COVID-19 outcomes in pediatric HIV/AIDS patients are very scarce. A systematic review and multicenter USA adult study describing people living with HIV (PLHIV) and were infected with SARS-CoV-2 identified 3 themes: (1) controlled HIV infection does not appear to result in poorer COVID-19 outcomes, (2) more data are needed to determine COVID-19 outcomes in patients with AIDS due to conflicting reports and (3) HIV-infected patients presenting with COVID-19 symptoms should be investigated for superinfections [21, 22]. The only pediatric report regarding clinical outcome of COVID-19 in children with HIV describes a prospective multicenter study including children and adolescents living with HIV (CALWH) in Madrid between June 2019 and March 2020 [23]. A total of 60 vertically infected CALWH were included and among them, SARS-CoV-2 infection was confirmed in 8 (13.3%). Median age of CALWH with SARS-CoV-2 infection was 19 years old (17–19.5 years), 62.5% were female. Five 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 and none had CD4 + T-cell count less than 500 cells/µL. Symptoms in these children were comparable to COVID-19 symptoms in the general adolescent population and outcome was good in all 8 patients. Despite the small numbers, it was concluded, that HIV infection since birth in children with good immunovirological control does not seem to lead to a greater risk of SARS-CoV-2 morbidity [23]. Our case is the first reported pediatric case of severe COVID-19 related ARDS in a young infant with uncontrolled HIV after delay in EID. After ventilatory support for 19 days, start of ART, cotrimoxazole and treatment of ventilator-associated pneumonia, his clinical situation gradually improved and discharge followed 6 weeks after admission in good clinical situation. An initial decrease of his COVID-19 CT value during admittance, together with his complicated respiratory course suggests difficulties with SARS-CoV-2 clearance due to his immunocompromise by HIV. It should be noted that during the pandemic, zero other infants necessitated admissionv due to COVID-19 on our pediatric department. The current case underscores the vulnerability of immunocompromised pediatric patient groups with SARS-CoV-2 infection and underscores that careful risk assessment regarding pediatric HIV and SARS-CoV-2 must be performed at all times.

Conclusions and recommendations

With the presented case, assuming that vertical transmission had occurred in utero, we illustrate that assessment of infant HIV status after ARV exposure can cause delay in EID, most likely due to effective maternal and infant viral suppression, lasting up to at least 3 weeks after cessation of infant dual prophylaxis. We also showed that viral rebound can be very rapid in young infants, underscoring the need for timely assessment of infant HIV status both according to protocol and individualized considering all risk factors for vertical transmission, to prevent morbidity and mortality. We also showed that COVID-19 in the HIV immunocompromised infant can cause severe lung disease/ARDS, underscoring the need for careful risk assessment and decision making in SARS-CoV-2 infection/prevention during pediatric immunocompromise. With our current knowledge based on the recent meta-analysis of Greenan-Barrett et al. [3], together with our current report, we believe that preventive decisions can be made regarding immunocompromised children during outbreaks/pandemics of a circulating respiratory virus. Among the preventive measures, vaccination of this patient group and creating awareness for the increased occurence of bacterial superinfections can be mentioned.

Abbreviations

EID

Early infant diagnosis

COVID-19

Coronavirus disease

SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2

ARDS

Acute respiratory distress syndrome

ARV

Antiretroviral

ART

Antiretroviral therapy

NATs

DNA nucleic acid tests

PLHIV

People living with HIV

CALWH

Children and adolescents living with HIV

Author contributions

F. Falix and S. Nikkels wrote the main manuscript text and S. Nikkels prepared Figs. 1 and 2; Table 1. All authors reviewed the manuscript.

Funding

None.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.