Neonatal COVID-19 treatment: Are there new chances?

Abstract

Coronavirus disease 2019 (COVID-19) is considered an infectious disease which is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Neonatal COVID-19 had been occurred in many countries which would indicate the need of effective and safe treatment for these vulnerable group. In this study, we showed symptoms of corona virus in neonates, investigation of coronavirus in neonates and radiological features of neonatal COVID-19. In addition, we discussed management of neonates with COVI-19, antiviral treatment, monoclonal antibodies administration, immunomodulatory therapy, antibiotics, vitamins, and minerals in the treatment of neonatal COVID-19, and also telemedicine in neonatal COVID-19 and feeding the newborn of COVID-19 mother. We also discussed multisystem inflammatory syndrome in neonates (MIS-N), management of affected COVID-19 neonates and discussion of the complication of the neonatal COVID-19. We further discussed the methods of dealing with COVID-19 neonates and the research done on the neonatal COVID-19 treatment.

Keywords

COVID-19 neonate remdesivir treatment

1 Introduction

COVID-19 is considered an infectious disease which is caused by SARS-CoV-2, which was 1st appeared in China. It affects adult as well as pediatrics even the neonates had been affected by this newly discovered virus [1].

2 Transmission & pathogenesis [2 –6]

Suspected cases of COVID-19 neonate are defined as neonates of COVID-19 affected mothers in the period between 2 weeks before birth & 4 weeks after birth. Confirmed COVID-19 neonate is diagnosed when RT-PCR specimen is positive for COVID-19. The transmission route is mainly via droplet infection, air borne infection especially through nebulization, stool or vertical transmission. The neonates could be infected from their parents or through their community. SARS-CoV-2 transmission from their maternal blood, placental route, fetal amniotic fluid or neonatal cord blood and this highly supports the maternal transmission of SARS-CoV-2 to their fetuses (vertical) transmission. vaginal delivery was shown to increase the risk of SARS-CoV-2 infection in neonates as SARS-CoV-2 was detected in the vaginal discharge. In NICUs, SARS-CoV-2 −ve results from the respiratory or anal region should be confirmed before discharge (48 hours at least). Strict isolation and regular follow-up of the neonates who discharged with +ve results should be done for their possible transmission of infection. The replication of the SARS-CoV-2 virus inside the respiratory epithelium of the neonates causes a proinflammatory reactions through the release of chemokines and cytokines, including Interleukin-1(IL-1), IL-6, and tumor necrosis factor. The changes in the maternal immune, respiratory and coagulation system response in pregnancy may affect the response to SARS-CoV-2.

3 Diagnosis of neonatal COVID-19 [7 –18]

Symptoms of coronavirus in neonates include fever, runny nose, cough, early breathing problems (because neonates have tinier airways & new immune systems), shortness of breath, nausea, vomiting, poor feeding, feeding intolerance, diarrhea, fatigue, milk rejection, lethargy. Neonates were more prone to present with GIT symptoms compared with other age group. Neonates showed a mild clinical manifestation of COVID-19 compared to other age group or don’t get any symptoms at all and the infection seems to go away faster and this may be explained that the immune system of neonates deal with the coronavirus with no exaggerated reaction to it while in adults, the exaggerated reaction to COVID-19 infection, with autoimmune destruction of own cells (in a cytokine storm), also the diabetes is less common in neonates which is a susceptible cause in COVID-19 infection, in addition to decreased of ACE2 receptor which help the penetration of SARS-CoV-2, however, there are may be neonatal deaths, but fortunately the infant mortality rates are low. Neonates cannot express their problems but they feel the symptoms.

Investigation of coronavirus in neonates include swabs could be obtained from pharynx, throat, blood, anal and stool. These swabs were done in the first day after delivery and if −ve, the sample should be repeated. Anal swabs might be more useful in neonates to increase the accuracy of detection of neonatal COVID-19 as neonates seem to manifest GIT symptoms more commonly. Active infection could be detected by elevation of IgG titer. IgM antibodies are more specific for neonatal affection due to inability of crossing the placenta. RT-PCR test is the most sensitive technique for SARS-CoV-2, this test was done in cases of any suspicion for SARS-CoV-2 infection either in the mother or the neonate (However, there are still some atypical cases with typical manifestation, and +ve chest CT picture that have −ve RT-PCR results for the virus). CRP > = 5 mg/dL, lymphopenia with absolute lymphocyte count <1000/mm³ and thrombocytopenia. Markers of inflammation were elevated in neonatal COVID-19 like elevated ferritin, LDH, IL-6 and procalcitonin, in addition there were elevated coagulation profile (PT, PTT, D-dimer, fibrinogen).

Radiological signs of neonatal COVID-19 include opacity in a picture of ground glass (GGO). CT scan of advanced cases of COVID-19 include opacities as GGO and consolidation in the lung. The accuracy of diagnosis of chest CT scan are higher than that of RT-PCR. The +ve chest CT appear first, and the recovery appear early in the chest CT, indicating its higher accuracy in detection of COVID-19. Presence of +ve CT chest & RT-PCR are the best way for diagnosis & follow up of neonates with COVID-19. imaging was done with high caution in neonates to avoid the risk of radiation. pulmonary U/S in neonates is safe in comparison with X-rays & CTs, which could be used in continuous follow up of the cases.

Manifestation of MIS-N include maternal SARS-CoV-2 may potentially cause MIS-N due to transplacental transfer of antibodies. MIS-N occur in the 1st week after delivery due to maternal affection, or neonates may have COVID-19 and then, manifest with MIS-C after that. Decrease or unstable temperature, are common than fever in cases of suspected neonatal MIS-C. CVS manifestations include mostly arrhythmias like prolonged QTc interval with or without AV block (which is possibly treated with immunomodulatory drugs e.g., methylprednisolone (mPRED) & IVIG), SVT (which treated by beta blockers) & bradycardia. Other CVS manifestations include cardiac dysfunction & shock (which treated by inotropic with or without fluids), coronary dilatation with thrombus formation in the blood vessels or intracardiac thrombus (which treated by LMWH), cardiomegaly, TR, MR & pericardial effusion. Respiratory manifestation includes RDS, respiratory depression (treated by surfactant & MV), pneumonia (treated by Remdesivir & antibiotics if bacterial superinfection) & pleural effusion. GIT manifestation includes feeding intolerance, diarrhea, vomiting, brownish gastric aspirates (treated like NEC), GIT bleeding & ascites. Neurological manifestation including convulsions in addition to cutaneous manifestation including skin rash & peeling. Renal manifestation might occur including renal failure & multiorgan failure.

4 Dealing with COVID-19 neonates [19, 20]

Neonates with COVID-19 harbor the virus in their oral cavity, nose & discharge and so the spread of the virus infection occur via coughing, sneezing or may be through bowel discharge, so a mask and gloves should be used during dealing with the infected neonates or their diapers. SARS-CoV-2 may be supposed to be in the breast milk of the affected mothers, but probably this do not cause infection in their neonates. It’s likely safe to breastfeed their neonate but the COVID-19 infected mother is still could pass the coronavirus to her neonate from mouth and nose droplets, so the infected mothers should wash their hands, wear masks & avoid touching their nose or any part of their face while they are breastfed their neonates. If the neonate of affected mother needs NICU, the neonate is incubated in a separate room with –ve pressure. These neonates are examined at 24 & 48 hours, then every 2–3 days until two –ve results are reached. If the neonate is cannot be examined, they should be managed as +ve for 2 weeks. Videoconferencing facilities could be used to enable the parents to see their admitted or isolated neonate. Disinfection Policy include cleaning the equipment with a soap & water solution, then 70% ethyl alcohol is used to disinfect surfaces. H2O2 is used in case of incubators, pumps, scales, MV, all surfaces. H2O2 is used only when equipment is not used.

5 Management of neonates with COVI-19 & MIS-N [21, 22]

Neonates with COVID-19 (either suspected or confirmed) is incubated in NICUs. Asymptomatic cases need follow up, mild & moderate cases need antipyretic only while severe cases need remdesivir, these drugs are used in clinical trial, so its efficiency and safety are not established completely yet. The treatment of mild cases is mainly supportive as antipyretic (paracetamol (10 mg/kg/6 h). Respiratory support by O2 to maintain proper O2 saturations which might be delivered through O2 hood, nasal canula, CPAP or even MV & this will decrease pulmonary vasoconstriction & minimize the risk of PPHN. In some cases; fluid resuscitation, inotropes & vasopressors are needed. Antibiotics may be used in indicated cases. MIS-C may need anti-inflammatory and immunomodulatory therapies like IVIG 1 g/kg/day, IV steroids (IV dexamethasone of 0.15 mg/kg/day, hydrocortisone 0.5 mg/kg/12 hours or methyl prednisolone 0.8 mg/kg once daily), COVID-19 convalescent plasma and anticoagulants like Enoxaparin, which is a common LMWH, for prophylaxis (0.75 mg/kg SC q12 h) & for therapeutic (1.5 mg/kg SC q12 h). MIS-N may be treated by systemic steroids (either methylprednisolone or the prednisolone). Antiarrhythmic therapy was used in cases of arrythmias in CVS involvement of COVID-19 infection of some neonates, IVIG is used in serious MIS-N with CVS affection or presence of aneurysms (coronary or peripheral) however, caution during IVIG use in neonates for the development of NEC in some cases. Anticoagulants were given when the neonates with MIS-N with thrombosis formation, however, LMWH is used under strict follow up to avoid IVH, especially in preterm neonates. The prophylaxis for thrombotic complications is important as their incidence is high in neonates. The preferred treatment is with SC enoxaparin which is LMWH 150–300 U/kg/day. Antibiotic could be used in bacterial superinfection, elevated procalcitonin & CRP are suggestive of bacterial infection.

6 Antiviral treatment [23 –26]

Remdesivir (RDV) is antiviral drug which cause decrease in viral replication of corona viruses including SARS-CoV-2. Remdesivir could be used in acute RD due to COVID-19. Neonates weighing <3.5 kg could be treated by RDV Lyophilized powder IV, the starting dose is 5 mg/kg on first day & then decreased after that. Neonates weighing ≥3.5 kg could be treated by Lyophilized powder IV; the starting dose is 5 mg/kg; then decrease the dose after that. The duration of treatment is 5–10 days. RDV accumulates in patients with kidney & liver dysfunction, when SCr ≥1 mg/dL or hepatic toxicity, the use is discontinued. In preterm neonate, IV RDV (2.5 mg/kg/dose then 1.25 mg/kg day in addition to IV dexamethasone up to 0.5 mg/kg/day could be used.

RDV is active against the occurrence of viral resistance, so RDV IV could be given for the management of COVID-19 in neonates hospitalized with severe disease. RDV is the best antiviral drug in COVID-19 treatment protocols & RDV is FDA used drug for the management of COVID-19 as an only antiviral therapy. RDV had probable adverse effects which may include bradycardia, hypotension, aminotransferase elevation, hypersensitivity reactions, renal affection, skin rash with decreased Hb & lymphocyte.

RDV administration led to marked decrease in the needed respiratory requirement in neonates (either term or preterm) with early extubation with eradication of SARS-CoV-2 in affected neonates. RDV side effects are very uncommon, but the evidence is still needing more studies to recommend or avoid the use of RDV in neonates. Use of RDV in neonates (either full term or preterm) with COVID19 was shown in some case reports. Certain studies had used the RDV on newborn with +ve SARS-Cov-2, where RDV was used. No adverse effects were noted except for transient elevation of AST with good prognosis.

Lopinavir/ritonavir [27, 28] is used in clinical trials from 2 weeks of life as it could not be used in preterm & the 1st 14 days of full term. Their use is generally safe; it is used as suspension or tablets.

Favipiravir [27, 28] is an antiviral drug, it inhibits RNAP. Some studies demonstrated its role in management of COVID-19.

Some clinical studies revealed that molnupiravir have a role against the Omicron variant.

Immunomodulatory therapy [29]: mPRED or dexamethasone, IVIG, Tocilizumab and Anakinra. These therapies are indicated in case of ARDS, respiratory dysfunction, MIS or increasing levels of inflammatory parameters.

Steroids: mPRED use is used in case of decreasing of respiratory function or increasing levels of inflammatory parameters after at least 1 week from the starting of manifestation. mPRED 2 mg/kg /day for 5 days. Dexamethasone (0.3 mg/kg), indicated in case of patients needing O2 & reduce deaths in ventilated patients.

Anakinra: it decreases the proinflammatory cytokines IL-1 with an advantage of decreased half-life that could be stopped immediately in case of any problems with good safety profile. Anakinra reduced the MV requirement in the ICU & death in serious COVID-19. Anakinra can be administered IV or SC. Anakinra is used in cytokine storm. However, its use in neonate is controversial & no obvious recommendation for its use in neonatal COVID-19.

Emapalumab: anti-interferon γ and act as monoclonal antibody which could be used in pediatric group i.e., infants and children However, its use in neonate is controversial & no obvious recommendation for its use in neonatal COVID-19.

Monoclonal antibodies (mAbs) [30]: these are proteins that were made in the laboratory which resemble the immune system, it has the ability to attack the pathogens, like viruses.

Bamlanivimab & etesevimab are mAbs that are focused against the virus spike protein, which interfere with the virus invasion of the cells. Bamlanivimab & etesevimab attach to various sites on the virus spike protein and given for the management of COVID-19 in pediatric cases, including neonates, however the data about their use in neonates are scarce and not available. The expected side effects of combined bamlanivimab & etesevimab included hypersensitivity, anaphylaxis, and infusion-related reactions, nausea, itchiness, and rash.

Tocilizumab is mAb and IL-6 receptors antagonist & IL-6 is pro-inflammatory cytokine which elevated in COVID-19 cases. This drug is indicated in severe COVID-19 as cytokine storm & also in MIS-C. However, its use in neonate is controversial & no obvious recommendation for its use in neonatal COVID-19 and safety data of tocilizumab in neonates are scarce. Tocilizumab should be avoided in individuals with hypersensitivity to tocilizumab, serious infections other than COVID-19, ANC <1000 cells/microL.

COVID-19 Convalescent Plasma (CCP): It is a kind of passive form of antibodies (Abs) treatment that include the use of anti-SARS-CoV-2 Abs to the affected individual in order to prevent or treat the disease. hyperimmune plasma infusion from recovered patients, lead to good results [31].

Treatment of neonatal COVID-19 according to severity: mild cases: mild cases: antipyretics (paracetamol) & isolation with follow up, mild to moderate cases: lopinavir /Ritonavir (not used in preterm or full-term neonates before 2 weeks of age), antibiotics if bacterial coinfection or superinfection, anticoagulant (e.g.: Enoxaparin in case guided by the clinical conditions and the levels of D-dimer, Preterm neonates: 2 mg/kg/dose SC every 12 hours. Term neonates: 1.5 mg/kg/dose SC every 12 hours), sever cases: Lopinavir/Ritonavir (not used in preterm or full-term neonates before 2 weeks of age and there are many recommendations against their use), antibiotics if bacterial coinfection or superinfection, Tocilizumab, mPRED. newborns with SARS-CoV-2 may need surfactant, nitric oxide, MV or even HFOV. Treatment of MIS-C which may be used in neonates include in severe cases an IVIG 2 gm/kg over 24–48 hours, methyl prednisolone 10–30 mg/kg/d, empirical antibiotics, enoxaparin (LNWH) 1 mg, BD, SC. In moderate cases of MIS-C, the treatment includes IVIG 2 gm/kg over 24–48 hours, methyl prednisolone 1–2 mg/kg/d, empirical antibiotics, enoxaparin (LNWH) 1 mg, BD, SC. Outlining various neonatal COVID-19 therapies were showed in Table 1.

Table 1
Outlining various neonatal COVID-19 therapies (21–26)

Therapy Administration &Dosage

Antipyretic: paracetamol 10 mg/kg/6 h

Respiratory support by O2 Delivered through O2 hood, nasal canula, CPAP or even MV

IVIG 1 g/kg/day, IV

Steroids

IV dexamethasone 0.15 mg/kg/day

Hydrocortisone 0.5 mg/kg/12 hours

Methyl prednisolone 0.8 mg/kg once daily

COVID-19 convalescent plasma plasma infusion from recovered patient (passive form of antibodies)

Anticoagulants

Enoxaparin (LMWH) Prophylaxis (0.75 mg/kg SC q12 h) Therapeutic (1.5 mg/kg SC q12 h)

Antiviral drugs

Remdesivir (RDV) Starting dose is 5 mg/kg on first day &then decreased after that. Duration of treatment is 5–10 days. In preterm neonate, IV RDV (2.5 mg/kg/dose then 1.25 mg/kg day)

Therapy	Administration &Dosage
Antipyretic: paracetamol	10 mg/kg/6 h
Respiratory support by O2	Delivered through O2 hood, nasal canula, CPAP or even MV
IVIG	1 g/kg/day, IV
Steroids
IV dexamethasone	0.15 mg/kg/day
Hydrocortisone	0.5 mg/kg/12 hours
Methyl prednisolone	0.8 mg/kg once daily
COVID-19 convalescent plasma	plasma infusion from recovered patient (passive form of antibodies)
Anticoagulants
Enoxaparin (LMWH)	Prophylaxis (0.75 mg/kg SC q12 h) Therapeutic (1.5 mg/kg SC q12 h)
Antiviral drugs
Remdesivir (RDV)	Starting dose is 5 mg/kg on first day &then decreased after that. Duration of treatment is 5–10 days. In preterm neonate, IV RDV (2.5 mg/kg/dose then 1.25 mg/kg day)

CPAP, continuous positive airway pressure; MV, mechanical ventilation; IVIG, intravenous immunoglobulin; LMWH, low molecular weight heparin.

Vaccines [33]: The vaccines include mRNA vaccines, inactive whole-virus (IWV) vaccine, and vaccines with alive but weaken virus. Messenger RNA (mRNA) is a piece of genetic material that had instructions to direct the cells in anybody to synthesize a specific protein. In COVID-19 vaccines, the mRNA in the vaccine help in the production of spike protein. The protein is then transported to the cell surface, where it acts as an antigen. This means that the immune system will detect the foreign protein and synthesize protective antibodies against it. Following the vaccine, the body will be ready with the necessary antibodies to fight off infection. COVID-19 vaccination could be given for all infants & children, 6 months of age and older who do not have contraindications. However, its use in neonate is controversial & no obvious recommendation for its use in neonatal COVID-19. maternal mRNA COVID-19 vaccination during gestation was accompanied by lower risks of neonatal infection with subsequent morbidity and even mortality, and also NICU admission. Also, neonatal admissions for COVID-19 infection were DECREASED in neonates of mothers vaccinated during pregnancy if compared with those of mothers who are not vaccinated during pregnancy.

Vitamins & minerals in neonatal COVID-19 [34, 35]: Vitamin A, C, D, zinc & folic acid could be used in the treatment of infection especially viral infection. Vitamin A, C, D & folic acid deficiency are accompanied by impairment of immune mechanism, and there is evidence of antiviral activity of folic acid. Selenium (Se) has antiviral & anti-inflammatory action, Manganese (Mn) has antiviral & immunomodulatory action, Copper (Cu) is enlisted as the essential micronutrient against viral infections. Zn shows antiviral property and plays an essential role in immunity. There may be a decrease in the activity of ACE2(which allow virus entry into host cells) in lungs after Zn treatment. Zn inhibit replication of COVID-19, so, Zn may be used in COVID-19 treatment, however, there are no strong evidence of the use of vitamin A, C, D, E, B9 (folic acid) & k in the management of COVID-19.

Telemedicine in neonatal COVID-19: Telemedicine means that supplying the health support via high technology connection, in spite of personal communication. These recent technologies decrease the incidence of the infection with COVID-19 [36].

Postnatal dealing with COVID-19 Neonates [37, 38]: the ideal transport the neonate to the hospital is done through specific incubators with using monitors to follow up all the vital signs. The team of the transport must wear PPE. High risk infants should be treated in isolation places with isolated equipment. Suitable spaces (2 m at least) between every incubator and ventilator. Respiratory lines of treatment of COVID-19 in neonates including the presence of noninvasive ventilation, however, the Nebulizer & the use of nasal cannula are better to be avoided due to the risk of infection transmission to the remaining neonates & the working doctors & nurses with presence of headbox that prevent the transmission of infection through the air. Use oa protective measures especially in procedures that lead to close contact between the treating staff and the infected neonates. Waste products from infected neonates should be safely discarded.

Complication of neonatal COVID-19 [39, 40]: In severe cases, DIC may complicate neonatal COVID-19 infection. The prognosis of the infected neonates include death in severe cases (65, 66). In some cases, newborn appeared lethargic, refractory fever, progressing to viral encephalitis with poor prognosis.

7 Conclusion

There are many drugs & treatment protocols that have been approved in the treatment protocols of neonatal COVID-19 and there are also another drugs & regimens in the phase of clinical trials that may be approved later on in the future treatment protocols and there may be also drugs that there will be a recommendation against it in the treatment protocols of neonatal COVID-19, so further studies and clinical trials are needed to approve or disapprove new drugs and recent treatment regimens for the recommended future treatment protocols of neonatal COVID-19.

Author contributions

ME collected the scientific data and references and did the scientific writing. TA, DE & AR did the scientific revision of the content.

Conflict of interest

There are no conflicts of interest by all authors.

Ethical approval

This is a review article with no research protocol to be approved by the ethics committee.

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