key: cord-0840677-z52pwy17 authors: L’Huillier, Arnaud G.; Danziger‐Isakov, Lara; Chaudhuri, Abanti; Green, Michael; Michaels, Marian G.; M Posfay‐Barbe, Klara; van der Linden, Dimitri; Verma, Anita; McCulloch, Mignon; Ardura, Monica I. title: SARS‐CoV‐2 and pediatric solid organ transplantation: Current knowns and unknowns date: 2021-03-10 journal: Pediatr Transplant DOI: 10.1111/petr.13986 sha: 3e43e68f7f5c115dc1b9e63b9a2aba990520b327 doc_id: 840677 cord_uid: z52pwy17 The COVID‐19 pandemic has proven to be a challenge in regard to the clinical presentation, prevention, diagnosis, and management of SARS‐CoV‐2 infection among children who are candidates for and recipients of SOT. By providing scenarios and frequently asked questions encountered in routine clinical practice, this document provides expert opinion and summarizes the available data regarding the prevention, diagnosis, and management of SARS‐CoV‐2 infection among pediatric SOT candidates and recipients and highlights ongoing knowledge gaps requiring further study. Currently available data are still lacking in the pediatric SOT population, but data have emerged in both the adult SOT and general pediatric population regarding the approach to COVID‐19. The document provides expert opinion regarding prevention, diagnosis, and management of SARS‐CoV‐2 infection among pediatric SOT candidates and recipients. • Fever, respiratory distress, diarrhea • PTD 2 + SARS-CoV-2 RT-PCR in donor (mother) and child (nasal); RT-PCR not performed on blood or liver tissue Based on emerging data, 2-8 the CDC has included SOT as a risk factor for severe This is in line with the increased disease severity seen with other viral respiratory infections in this population, 10 particularly influenza. 11, 12 In adult SOT recipients, the clinical presentation of COVID-19 does not seem to differ from that of the general population, with fever and cough being most frequently reported. [3] [4] [5] 13 It is unclear whether it is the transplant and ongoing immunosuppression, the associated comorbidities such as diabetes and hypertension, or a combination of factors that place adult SOT recipients at increased risk for severe SARS-CoV-2 infection. [3] [4] [5] 13 Clinicians should be aware of the risk for clinical decompensation around day 7-9 of illness. Among adult SOT cohorts, the reported risk of progression to severe disease varies, with need for intensive care and mechanical ventilation occurring in 15%-39% of patients, 4, 14, 15 leading to a 20% mortality (range 7%-28%), [3] [4] [5] [6] 13 the higher rates seen among SOT recipients with respiratory failure 3, 13, [16] [17] [18] [19] [20] Disease severity may also depend on graft type, with adult lung transplant recipients presenting with more severe disease whereas KTx recipients had similar disease severity and survival to matched, non-SOT patients with similar comorbidities. 21, 22 Overall, children are underrepresented among SARS-CoV-2infected patients, accounting for 2%-10% of diagnosed cases. [23] [24] [25] [26] The cause of this remains unclear; it is debated whether this is related to a lower attack rate among children 27, 28 or to children presenting more frequently with asymptomatic or mild clinical man- ifestations, and accordingly being tested less often. Like adults, cough and fever are the most frequently reported symptoms 23 ; however, 20% of children may also present with gastrointestinal symptoms. 23 Overall, up to 95% of pediatric cases have mild, or moderate symptoms, 29 or are asymptomatic, with rates of asymptomatic infection of 20%-30%. 30 and 99%-100%, respectively, from a NP source, 93%-100% and 99%-100% from mid-turbinate, and 59%-94% and 99%-100% from a nasal swab (assuming a pre-test-probability of 10%). 47, 67 Importantly, the true clinical test performance characteristics have yet to be determined and compared across assays. 68 Lack of a reference standard and suboptimal systematic analysis contribute to reported sensitivities as low as 55%-70%. 69 who may not mount a robust antibody response. 77, 78 It is unknown whether pediatric SOT recipients will mount a robust serologic response to SARS-CoV-2. 72, 79 If protective, the duration of protection is also unknown. 80 Lastly, concerns for possible false-positive antibody results secondary to cross-reactivity with other coronavirus have also been reported in some, but not all studies. 81 As 43%-75% of children as young as 6 months to 3.5 years of age have antibodies against one of the four endemic human coronaviruses, this has important implications for possible false-positive results. 82 109 Similarly, the FDA issued and EUA for the use of baricitinib in combination with remdesivir, for the treatment of COVID-19 in hospitalized patients ≥2 years of age. 110, 111 The safety and effectiveness of these biologics for the treatment and prevention of COVID-19 require ongoing study, particularly in children. The optimal approach regarding the management of transplant- The father of a 9-year-old boy recipient of a liver transplant has been If possible, the father should limit his use of shared living spaces, ideally by staying in a separate room with a designated bathroom. Other family members should not share that bathroom when possible, nor towels, cloths, toothbrushes, razors, utensils, food, or beverages. Selfmonitoring for symptoms during the incubation period with periodic temperature checks is suggested. 117 Masking in the home should be There is a COVID-19 outbreak in the city, with many cases in the commu- Definitive data-driven safe-living strategies in children after SOT are lacking, but the information presented herein provides some The institution of strict isolation orders in response to the COVID-19 pandemic to slow the spread of infection to a manageable rate is crucial. 125 However, school plays a critical role in a child's development and well-being. The confinement at home may have profound social, economic, and health consequences with negative effects on children's mental and physical well-being. 126 When outside, it is still important to maintain six feet/two meters distance from others, frequently wash or sanitize hands, and avoid touching the face or eyes. The CDC recommends wearing a mask at all times in public places except for children under 2 years of age or those who cannot remove the mask themselves 133 ; the European CDC (ECDC) and WHO recommend to consider wearing a mask, especially in crowded areas. 134, 135 It is important to perform hand hygiene before and after placing the mask and to avoid touching the outside of the mask. Single-use masks should be thrown away after each use and cloth masks should be washed between each use. N95 masks are not required and should be preserved for healthcare professionals. Available evidence suggests that face shields are not as efficient in preventing SARS-CoV-2 transmission when used on their own, without concurrent mask use. 133, 135 Gloves are recommended only to clean surfaces but otherwise are not necessary; instead, performing hand hygiene, either by washing with soap and water or using sanitizer with >60% alcohol, should be enforced. These measures are also particularly important within the same household. Donor type SARS-CoV-2 scenario The Transplantation Society [138] AST [49] European Centre for Disease Prevention and Control [137] Deceased No known SARS-CoV-2 infection Negative RT-PCR/NAT before organ procurement (timing not specified) • At least one negative respiratory tract specimen RT-PCR/ NAT performed ≤72 hours of procurement Both SOT candidates and LD should follow prevention strategies to reduce exposure to SARS-CoV-2 in the immediate pre-SOT period. This includes complying with self-quarantine in the 14 days prior to living donation and avoiding exposure to potentially infected individuals. LD organ transplants offer the opportunity to plan for the transplant in a way that can maximize the ability to mitigate risks for both the recipient and for the donor, as such additional preventive efforts should be considered. The AST has published comprehensive recommendations for LD's testing and screening. 136 If feasible, the donor is encouraged to respect self-quarantine during 14 days prior to donation. 136 Ideally, others in their household or perhaps friends could complete certain tasks (eg, shopping) for the 2 weeks prior to planned donation. If anyone in their household develops any symptoms of illness, they should either minimize their contact with the potential donor within the house, or if possible find an alternative place for either the donor or the symptomatic household member to reside. The risk-benefit of SOT during the pandemic should be discussed with the recipient, including the potential indirect effects of the COVID-19 pandemic such as decrease in total SOTs performed and potential for waitlist mortality. 19, 20 If it is decided to proceed with the SOT, screening and testing of both the candidate and the donor prior to surgery is warranted. In low prevalence settings, the risk of transmission through donation is very low when the donor has not had a COVID-19 exposure, is asymptomatic, and has a negative respiratory (most frequently NPS) RT-PCR performed within 3 days of organ donation. Most transplant societies strongly recommend universal screening of potential deceased donors before organ procurement. Guidance recommendations for donor SARS-CoV-2 testing are summarized in Table 3 Adenovirus-based vaccines have also been shown to be safe and immunogenic in phase II studies. 148, 149 In phase 3 studies, mRNA and adenovirus-based vaccines have demonstrated promising results regarding vaccine safety and immunogenicity. However, it is currently unknown if these different vaccines will be safe and immunogenic in immunosuppressed patients. Pediatric data are also lacking and vaccine trials that include children down to 12 years of age are only just starting. 150 It will be critical to evaluate the immunogenicity and efficacy of a SARS-CoV-2 vaccine in SOT recipients as immunity to other vaccines may be diminished and wane in immunosuppressed patients, requiring booster doses. 151 If indeed safe and immunogenic, additional studies will be needed to estimate duration of protection after vaccination in SOT recipients. As with other vaccines, a cocoon strategy is recommended so that close contacts and household members be appropriately vaccinated against SARS-CoV-2 as soon as possible in an effort to increase the potential protection of pediatric SOT candidates and recipients. CoV-2 infection, 39 and by reducing T cells over-activation seen in lung tissues of patients with COVID-19 acute respiratory distress syndrome. 152 The fact that pediatric SOT recipients may be more protected than their adult SOT counterparts against severe COVID-19 could also be related to the increased likelihood of known risk factors for severe COVID-19 in the adult SOT setting, such as diabetes, hypertension, cardiovascular, and chronic respiratory disease comorbidities. 153 Additional SOT-specific data, that include children, are needed to better understand the pathophysiology of infection in the immunocompromised host, the optimal management of SARS-CoV-2 infection in pediatric SOT recipients, and the impact of the current pandemic on transplant outcomes. The emergence of multiple SARS-CoV-2 variants have raised concern for possible enhanced viral transmission and susceptibility to infection; at this time however, it remains unclear how that may change the paradigm of the current COVID-19 pandemic. 154, 155 None. 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