Preamble
COVID-19, the disease caused by SARS-CoV-2, has rapidly become a global pandemic. This review aims to complement the other NephJC pages with a focus on how children with kidney disease are impacted by this pandemic. Our aim is to review what we know about COVID19 as it pertains to kidney disease in kids. As with all the other NephJC pages on COVID19, the summary provided is not meant to provide treatment recommendations. This page includes opinions from the workgroup, and we will attempt to update as more data become available.
A few words about the state of SARS-CoV2 science
Before we start reviewing the literature it is important to recognize the current landscape of peer review (or lack thereof). Especially in the fast moving world of COVID19 research. Brian Byrd provides a nice overview for our readers here. The differences between preprints, letters to editor, rapid response and other publication types are discussed in detail.
Last Update: Oct 3, 2020, 10:23 AM EST
What was updated: Review and updating of entire page; changed advice about commencing rituximab; updated data on transplant outcomes and added the AAP guidance on MIS-C.
Contributors
Cathy Quinlan, MD, Royal Children’s Hospital, Australia Michelle N Rheault, MD, University of Minnesota, Minneapolis, MN
Caoimhe Costigan, MD, Pediatric Specialist Registrar, Dublin, Ireland
Joseph T Flynn, MD, MS, University of Washington/Seattle Children’s Hospital, Seattle WA
Michelle Starr, MD, MPH, Indiana University School of Medicine, Indianapolis, IN
Curated and Edited by
Swapnil Hiremath, MD, MPH, University of Ottawa, Canada
Joel Topf, MD, FACP Oakland University William Beaumont School of Medicine, Rochester, MI
Official and FOAMed Sources
American Society of Pediatric Nephrology
British Association for Paediatric Nephrology
Dontforgetthebubbles.com
Patient FAQs
We provide detailed FAQs below, but for a video overview from Apr 3rd, please check out this video of Dr Cathy Quinlan, produced by the Kidney Health Australia:
Is my child at higher risk than other children?
The majority of children who develop COVID-19 are mildly affected, although rare, serious cases have been reported. Although adults with kidney disease have worse outcomes than adults without kidney disease, we have no evidence to date that children with kidney disease are at higher risk of serious outcomes than children without kidney disease.
What special precautions should I take?
Children with kidney disease and their families should follow the official advice from their own country. As a general rule this should include thorough, frequent hand washing and social distancing.
Will this affect my child’s treatment regime?
Your child’s nephrologist will take the local impact of COVID-19 into account when making the medical plan. This may include converting face-to-face clinic visits to telehealth or telephone appointments, spacing out appointments or reviewing patients in isolated areas of the office/hospital.
My child has nephrotic syndrome - what should I do?
At this point in time there is no evidence that children with nephrotic syndrome are affected differently by SARS-CoV2. Your doctor may make some changes to your child’s immunosuppressive regimen on a case-by-case basis.
Should I be seeing my doctor more often?
Many centres across the world have changed to fewer face-to-face appointments and more phone or telehealth reviews during the pandemic. So, if your child is well you may be seeing your doctor less often.
Should I avoid hospitals?
If your child is unwell with respiratory symptoms then call your health team before bringing her to the hospital. If your treating team thinks your child needs to come to the hospital then you should come. Unless otherwise advised you should limit visitors and wash your hands.
How will this affect transplant programs?
Transplant programs around the world are monitoring increased COVID-19 activity. In some countries this has resulted in temporary suspensions of transplant. In some places deceased donor transplant programs are continueing. Your local team will keep you informed if you will be impacted by these changes.
How long will this last?
This will differ across the globe depending on how many of the population is affected. Most doctors expect that it will be at least another year before life can return to normal.
FAQs for Professionals
What is the risk of COVID-19 in the general pediatric population?
The Don’t Forget the Bubbles team have a fantastic review of the COVID-19 literature as it pertains to general paediatrics. In brief, while children can certainly be infected by SARS-CoV2, they appear to be less susceptible to severe disease. In the first large pediatric report out of China, 731 lab confirmed cases, only 3 children had critical illness (defined as respiratory failure) and 2.5% had hypoxia. 41% of children had moderate disease defined as fever or pneumonia without hypoxia. Importantly, 12.9% of children had asymptomatic disease. This finding has been repeated elsewhere. The largest multinational European study to date described patients <18 years of age who had confirmed infection in April 2020 across 21 countries. 145 children had pre-existing medical conditions, 363 were admitted to hospital, 48 to ICU, 4 died and 25 remained on respiratory support or symptomatic at the end of the study. In the US a large single centre study in Washington reported the outcomes of 177 children and young adults with confirmed infection, of whom 69 had pre-existing medical conditions. Forty four patients were hospitalised and 9 were critically ill, 4 of whom were >18 years of age. Just 2 patients <18 years of age required intubation and all recovered.
A manuscript from Lu et al (NEJM 2020) reported outcomes from 171 children with COVID-19. In this report 15.8% were asymptomatic. Three children required ICU care for respiratory failure and there was one death reported in a 10 month old with multisystem organ failure. Comorbidities were not reported in either of these manuscripts and will be important to tease out as the pandemic rages on.
Out of 22,512 cases reported from Italy by Livingston and Bucher (JAMA 2020), only 1.2% of infections were in children <18 and no deaths were reported in this age group. Data from Spain is similar, with only 41/4695 (0.8%) of confirmed cases in the Madrid region in children younger than 18 years. In this cohort of 41 patients, 60% required hospitalization. (Tagarro et al, JAMA Pediatrics).
While pediatric data in the US are limited due to the ongoing nature of the pandemic, growing epidemiologic data appears to be similar to findings in other countries. Children appear to have more asymptomatic disease, and less viral symptoms upon presentation (only 73% of fever, cough or shortness of breath). While severe disease does exist in children, relatively few children were hospitalized or admitted to the ICU. Early reports from the US outbreak (MMWR 2020) show pediatric patients hospitalized at a rate of 1.6-2.5% compared to a hospitalization rate of 20.7-31.4% for the general population. (MMWR, 2020)
What do we know about a SARS-CoV-2 related inflammatory syndrome in children?
At present, we know very little about the pathophysiology of this condition Publications to date have been limited to case series and alerts from various professional organizations. There continues to be coverage of this topic in both mainstream and medical social media, prompting us to provide some clarification.
In general, this has been described as “children presenting with a multisystem inflammatory state requiring intensive care”. “Overlapping features with Kawasaki Disease and Toxic Shock Syndrome” are described, with abdominal pain, gastrointestinal symptoms and cardiac inflammation also being prominent. This presentation has been reportedly seen both in children who are Sars-CoV-2 PCR positive and PCR negative. The uncertainty of the role of COVID-19 in affected children is a key distinction to highlight at this point. To add to the confusion, different terms have been used to describe this condition - “Pediatric Inflammatory Multisystem Syndrome-temporally associated with SARS-CoV-2 (PIMS-TS)” in Europe (Frontiers, 2020), and “Multisystem Inflammatory Syndrome in Children (MIS-C)” in the United States (CDC, 2020).
Alerts and other guidance have been issued by a variety of organizations. The Paediatric Intensive Care Society (statement link) in the UK cite the first case report of this condition and allude to a small number of other children who fit the clinical picture described in their statement. As we do not yet fully understand the association between this novel presentation and SARS-CoV-2, the purpose of these alerts has been to increase awareness amongst healthcare professionals caring for children and to advise early consultation with paediatric infectious disease specialists. The Paediatric Intensive Care Society in the UK updated their earlier communication more recently to clarify this point and to reassure parents that serious illness related to COVID19 in children remains rare.
In early May 2020 the RCPCH in the UK released a guidance document on a Paediatric Multisystem Inflammatory Syndrome, which they describe as “temporally” related to COVID-19. This document was developed following expert review of cases identified over recent months and provides a case definition and management advice for clinicians. It was created by experts from multiple disciplines including paediatric intensive care, infectious diseases, immunology, rheumatology and cardiology.
The case definition covers three key elements: specific clinical features which must be identified in a child who does not have an alternative microbial aetiology and who can be either SARS-CoV-2 PCR positive or negative. The clinical picture is broadly described as persistent fever, with laboratory evidence of inflammation and single or multi-organ dysfunction. Possible similarities to Kawasaki disease are again highlighted. A useful appendix document is provided which gives more details on specific clinical and laboratory features, sub-divided by the frequency with which they have been seen to date; namely - “all” “most” and “some” of cases. The appendix also includes information on features of cardiac inflammation which may be identified on echocardiography or ECG, and inflammatory gastrointestinal changes which may be present on abdominal ultrasound. Chest X - Ray and CT features are also described.
Detailed guidance is given on suggested investigations based on patterns seen in cases to date. The importance of identifying multi-organ involvement early, in particular cardiac involvement, with appropriate investigation and referral is highlighted. In addition to SARS-CoV-2 PCR testing on NPA, stool and serology samples are also recommended and consideration of inclusion of children into ongoing research studies is suggested.
With regards to management, it is recommended that in addition to standard resuscitation and sepsis management, all children meeting the case definition should be managed as suspected COVID-19 based on local guidelines. Early involvement of paediatric intensive care and infectious disease specialists is strongly emphasised. If children meet the clinical criteria for Kawasaki disease or Toxic Shock Syndrome they should be managed accordingly with IVIG with or without aspirin as appropriate. Candidate antiviral therapies are recommended in the context of a clinical trial only, and immunomodulatory therapy on a case by case basis following discussion with appropriate specialist services and again in the context of a trial if available.
In the United States, the American Academy of Pediatrics has published interim guidance on MIS-C, including a case definition based on that from the CDC, and recommendations on diagnosis and management. (AAP, 2020). There is also a comprehensive list of the growing number of case series of children with this syndrome. Like the statement from the RCPCH, the AAP guidance provides a useful framework for clinicians to help navigate this complex condition whilst awaiting the emergence of further evidence. As mentioned previously, it is important to emphasize that the majority of COVID-19 infection in children is mild, and that the link between COVID-19 and this rare inflammatory condition is not understood at this point.
Is there vertical transmission of COVID-19?
We are starting to learn more about neonates born to mothers with COVID-19. In a small cohort (7 women) with clinical diagnosis of COVID-19, there was no vertical transmission and only one infant was infected with SARS-CoV-2 36 hours after birth. (Yu, Lancet Infectious Diseases, 2020). A larger study from New York of 43 pregnant women with COVID-19 also found no transmission to neonates upon initial testing on the first day of life. (Breslin, AJOG, 2020). A German study looked at the outcomes of 66 families exposed to a staff member infected with SARS-CoV-2 where just 5 infants developed symptoms and were admitted to NICU. (Preßler, PAI, 2020)
Why do children get less severe disease?
The short answer is, we don’t know, but a similar pattern was seen in the SARS outbreak from 2003. Stockman Et al (Ped Infectious Dis J 2007) There is speculation as to the pathogenetic mechanisms ranging from immaturity of the immune system, the impact of comorbidities, or immuno-naivety to coronavirus species. At this point it is all merely speculation.
Should I be concerned about ACE inhibitors?
Adults with hypertension, a history of smoking, or diabetes appear to have increased mortality rates and children in general are less likely to have these morbidities. There has been some speculation as to whether ACEi increase the risk of severe disease but as noted in this NephJC review the evidence is incomplete and conflicting. The current advice is not to change anti-hypertensive management.
What do we know about COVID-19 outcomes in children with kidney disease?
Chronic kidney disease and end-stage kidney disease appear to be risk factors for severe disease in adults. It should be remembered that many adults with end-stage kidney disease will also have accrued independent risk factors for severe disease such as diabetes and they are more likely to be impacted by rationing of critical care as healthcare systems become overwhelmed. These factors are less likely to impact on the outcome of paediatric patients. An international registry of children with kidney disease requiring immunosuppression (kidney transplant, nephrotic syndrome, ANCA vasculitis, aHUS) reported outcomes of 18 children with COVID-19. Symptoms were generally mild with fever and cough most common. Only 3 children required supplemental oxygen and no child required ICU admissions.
Recent data from London have been reassuring; Great Ormond Street Hospital has managed most hospitalised paediatric patients with COVID-19 in North London since the 25th of March. They reported on a cohort of 52 children, of whom 37 warranted PICU admission and 15 developed AKI. None were biopsied, none required dialysis and all but one recovered to baseline creatinine. The patient who did not fully recover had a history of AKI and an underlying metabolic disorder. Of the 15 children with AKI, 2 had PIMS-TS, and the majority had diarrhoea and vomiting at presentation with recovery of renal function following fluid resuscitation and inotropic support. None of the children with AKI were on immunosuppression. Considering the catchment area was one of the largest paediatric renal transplantation centres in the world this is a reassuring report for children with a kidney transplant.
Similarly encouraging results have been reported from Spain, where a national questionnaire sent to all paediatric nephrologists across 43 hospitals found just 16 children who had both PCR+ COVID-19 and pre-existing renal pathology. Three were on dialysis, three were post-transplant and five had nephrotic syndrome. Nine were on immunosuppression, three post-transplant, one on dialysis with vasculitis and four had steroid dependent nephrotic syndrome. All showed only mild disease and none died or required admission to PICU. Three children had AKI, two of whom were post-transplant and one had CKD stage 2. All three had reduced oral intake and one also had tacrolimus toxicity. All recovered their baseline GFR with fluids. Two patients had a relapse of their nephrotic syndrome.
There is a plethora of case reports and small case series all of which are reassuring as to the outcomes for immunosuppressed children infected with SARS-CoV-2. For example, an Italian study described 3 children infected post liver transplant who did not develop respiratory symptoms. In the UK between 26 March and 15 July just 5 children with CKD tested positive for SARS-CoV-2 and none died. In general, children with CKD and COVID-19 chould be expected to behave like other children their age rather than adults with CKD.
A recent multi-center, multi-organ (kidney, heart, liver, lung) case series of 26 pediatric transplant recipients reported that in general, manifestations of COVID-19 in this population were similar to non-immunosuppressed children. There were no deaths, and all patients fully recovered. (Pediatric Transplantation, 2020).
How does COVID-19 affect children with nephrotic syndrome?
At time of writing there is no evidence that children with nephrotic syndrome are affected differently by COVID-19.
We had previously suggested the deferral of commencement of rituximab however a recent Italian study where 159 patients maintained on rituximab or ofatumumab were interviewed weekly during a period of high incidence of SARS-CoV-2. None developed symptoms at any point despite 6 patients having co-habitants who were symptomatic with COVID-19.
There is no evidence to suggest that children who are stable on their immunosuppressive regimen should have changes made to their management.
What precautions should be taken for children requiring dialysis to prevent COVID-19 infection?
Children requiring in-center dialysis may be at increased risk of contracting COVID19 due to their frequent contact with the medical system. The US CDC has developed guidelines for infection prevention in the dialysis unit to minimize the risk of spread. The Chinese Society of Pediatric Nephrology and Chinese Medical Doctor Association of Pediatric Nephrology recently published consensus recommendations (Shen et al, Pediatric Nephrology 2020) specific to the care of children receiving chronic dialysis based on their early experience in the pandemic. These recommendations largely mirror the CDC recommendations with a few exceptions. They additionally recommend disinfection of the air in the dialysis unit (or home if PD patient) by ultraviolet light (≥ 1.5 W/m3 ) for more than 30 min. In addition, they recommend that home PD patients disinfect their drainage solution with chlorine bleach prior to pouring down the toilet. Evidence supporting these recommendations were not provided.
List of Updates:
March 25: Initial post
April 6: Video from KHA added
April 8: Data from Spain, MMWR added; paragraph on risk of vertical transmission added
April 28: Section on rare presentation with inflammatory syndrome in children added
May 1: Recommendations from CDC and Chinese Societies for dialysis patients added
May 21: Added: Link and details of the ERKNet registry; Lancet report on good outcomes in 18 children on immunosuppression; more guidance on the Kawasaki-like inflammatory syndrome
June 30: Outcome data from London (GOSH) and Spain added
Oct 3: Review and updating of entire page; changed advice about commencing rituximab; updated data on transplant outcomes and added the AAP guidance on MIS-C.