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.
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].
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.
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.
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.
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.
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.
Some clinical studies revealed that molnupiravir have a role against the Omicron variant.
Outlining various neonatal COVID-19 therapies (21–26)
Outlining various neonatal COVID-19 therapies (21–26)
CPAP, continuous positive airway pressure; MV, mechanical ventilation; IVIG, intravenous immunoglobulin; LMWH, low molecular weight heparin.
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.
