Abstract Background and Aims Initial WHO guidance advised cautious fluid administration for patients with COVID-19 due to concern about the development of acute respiratory distress syndrome (ARDS). However, as the pandemic unfolded it became apparent that patients who were admitted to hospital had high rates of AKI and this initiated a change in local clinical guidelines during early April 2020. We aimed to ascertain the impact of judicious intravenous fluid use on mortality, length of hospitalisation and AKI. Method An observational cohort study of 158 adults admitted with confirmed SARS-Cov-2 between 18th March and 9th May 2020 was conducted in a teaching hospital and designated centre for infectious diseases, London, UK. Key clinical and demographic data collected included clinical severity markers on admission, biochemical and haematological parameters as well as radiological findings. Primary outcomes were inpatient mortality, mortality at 6-weeks post discharge, length of hospitalisation and intensive care (ICU) admission. We also measured requirement for kidney replacement therapy (KRT) and AKI recovery rate at discharge. Using tests of difference, we compared key outcomes between patients treated with varying fluid regimens and then identified risk factors for AKI and mortality using multivariate logistic regression with results expressed as odds ratios (OR) with corresponding 95% confidence interval (CI). Results The median age was 74.4 (IQR 59.90 - 84.35) years, 66% were male, 53% white with hypertension and diabetes being the commonest co-morbidities. The median duration of illness prior to admission was 7 days (IQR 2 – 10) with respiratory symptoms and fever most prevalent. The people who presented with AKI on admission were more likely to receive fluids (34% vs 15%, p=0.02). 118 patients (75%) received fluids within 24-hours of admission with no difference in volume administered after local guidance change (p=0.78). Comparing patients receiving fluids with those who did not, we observed no difference in mortality (p=0.97), duration of hospital stays (p=0.26) or requirement for ICU admission (p=0.70). 18% died as an inpatient, and 52 patients were either admitted with or developed AKI. Of these 52 patients, 43 received fluids and 9 did not with no difference in KRT requirement (p=0.34), mortality (p=0.50) or AKI recovery (p=0.63). Peak AKI stage was greater among participants who received fluids though stage of AKI at presentation was also greater (p=0.04). Mortality rate in patients with an AKI is higher compared to overall inpatient mortality (31% vs 18%). Of the 36 patients with AKI who were discharged home, 25 patients (69.4%) had renal recovery by the time of discharge. Increasing age and clinical severity on admission were associated with higher mortality (see Figure 1). Older age was associated with 34 - 53 times higher risk of death compared with those aged ≤ 65 years (age 76 - 85 years: OR 34.26, 95% CI: 3.94 - 297.48, p=0.001; age > 85 years: OR 53.07, 95% CI: 5.23 - 539.03, p=0.001). Patients with NEWS2 >4 on admission has 5-fold increased risk of death than those with a score ≤4 (OR 5.26, 95% CI: 1.32 - 20.92). Black ethnicity was associated with a 16-fold increased risk of developing AKI (OR 15.86, 95% CI: 1.67 - 150.99). Conclusion To our knowledge, this is the first study to examine the impact of fluid management on inpatient mortality as well as on renal-associated outcomes of COVID-19 admission. Fluid administration regimen did not have an impact on mortality, length of hospitalisation or ICU admission, nor did it affect renal outcomes. Given the high rates of AKI and KRT in COVID-19 disease, early fluid administration is likely to be an important cornerstone of future management. Further adequately powered prospective studies are required to identify whether early fluid administration can reduce renal injury.
Juvenile systemic lupus erythematosus (JSLE) is characterised by onset before 18 years of age and more severe disease phenotype, increased morbidity and mortality compared to adult-onset SLE. Management strategies in JSLE rely heavily on evidence derived from adult-onset SLE studies; therefore, identifying biomarkers associated with the disease pathogenesis and reflecting particularities of JSLE clinical phenotype holds promise for better patient management and improved outcomes. This narrative review summarises the evidence related to various traditional and novel biomarkers that have shown a promising role in identifying and predicting specific organ involvement in JSLE and appraises the evidence regarding their clinical utility, focusing in particular on renal biomarkers, while also emphasising the research into cardiovascular, haematological, neurological, skin and joint disease-related JSLE biomarkers, as well as genetic biomarkers with potential clinical applications.
Recently, there has been a paradigm shift from a paternalistic doctor-patient relationship towards more holistic, patient-centred care aimed at promoting patient autonomy. However, the effect of patient-centred care on important clinical outcomes, like patient satisfaction and disability, is unknown.
Objectives
To investigate how the various aspects of patients' experiences of the care they received for their inflammatory arthritis was correlated with disease activity and health satisfaction, and use this to guide our clinical practice.
Methods
115 questionnaires (including 51 questions, in addition to HAQ) were randomly given to patients with inflammatory arthritis who attended rheumatology outpatient clinics at University College Hospital, London between November 2014 and January 2015 (104 were returned −90% response rate). Questions were semi-structured using a Likert scale and focused on diagnosis, symptomatology, treatment history, health status and experiences of clinic attendance. The strength of association between health satisfaction and experience of care was correlated using Spearman's correlation test (p<0.05 was considered statistically significant).
Results
We calculated correlations between various aspects of patients' experiences of their care with other components of the questionnaire (table 1).
Conclusions
Patients who felt that they experienced a more patient-centred approach (through greater involvement in clinical decisions, emotional support and ease of contact with specialists) reported greater satisfaction and regarded their treatment as more efficacious. This suggests that clinicians who go beyond their role of medically managing inflammatory arthritis to provide more holistic care may improve patient-orientated health outcomes. Patients in older age groups find it easier to contact the department, perhaps because they have more free time to make and receive calls. As ease of contact is a strong predictor of overall patient satisfaction, employing ideas to increase accessibility for younger age groups, such as improved access beyond working hours may improve satisfaction. The positive correlation of HAQ with employment status and age is expected, as HAQ is the current gold standard measure of functional status. This reaffirms its accuracy in clinical practice as a measure of a functional ability. Further research into comparing patients' experience of their care with objective measures of disease activity is needed.
Concerted efforts aim to reduce the burden of 6 months of anti-tuberculous treatment for tuberculosis (TB). Treatment cessation at 8 weeks is effective for most but incurs increased risk of disease relapse. We tested the hypothesis that blood RNA signatures or C-reactive protein (CRP) measurements discriminate 8-week sputum culture status, as a prerequisite for a biomarker to stratify risk of relapse following treatment cessation at this time-point.
Objective To explore Young Persons (YP) and healthcare professionals (HCP) experiences of virtual consultations (VC) and establish whether developmentally appropriate healthcare can be delivered virtually. Method YP and HCP questionnaire surveys were designed and piloted. Electronic questionnaire links were sent by post, email or text message January–April 2021 to YP aged 13–25 years old, with predefined chronic gastrointestinal conditions, attending a gastroenterology/hepatology VC. HCP undertaking VC were invited to complete staff questionnaire. Results were anonymous and collated using Excel version 2302. Results Five UK hospital trusts participated, with 35 HCP responses. Of the 100 YP completing the survey 66% were female and 34% male aged between 13 years and 25 years (median: 18 years). 13% were new appointments and 87% follow ups, 29% were by video, 69% by phone and 2% gave no response. 80% of HCP spoke to YP directly but not privately (69%). 87% of YP and 88% HCP found VC useful. 83% of YP want VC again, although 20% preferred face to face. 43% of HCP required improved phone/internet connection. 77% of YP required hospital appointments for tests following VC. Conclusions Overall respondents were satisfied with VC, finding them useful, convenient and time saving. Successful VC rely on appropriate patient selection and availability of reliable technology. Patient preference is key which may alter with time.
At the onset of the coronavirus disease 2019 (COVID-19) pandemic, children were thought to be at low risk for infection, severe disease and death, while the impact of immunocompromise on disease manifestations was unknown. As the prevalence of the disease increased, studies have reported severe disease phenotypes, such as Multisystem Inflammatory Syndrome in Children (MIS-C) or Pediatric Inflammatory Multisystem Syndrome, respiratory failure and death, and have reported outcomes in immunocompromised cohorts. While it is impossible to know the true rates of infection, due to asymptomatic carriage and variable testing policies, European surveillance data from August 2020 to October 2021 reported 2692 pediatric cases per 100,000 with rates of hospitalization, intensive care unit (ICU) admission and death of 1.17%, 0.08% and 0.01%, respectively.1 The very low rates of severe outcomes in children compared to adults are thought to be partly due to higher levels of cross-reactive humoral immunity to other coronaviruses, lower rates of comorbidities (eg, obesity, diabetes and respiratory disease) and lower expression of angiotensin-converting enzyme 2, the receptor used by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to enter cells. PRESENTATION OF COVID-19 IN IMMUNOCOMPROMISED CHILDREN In 6 large studies, including a total of 393 immunocompromised children with COVID-19, 19%–32% of patients were asymptomatic and were detected through screening (Table 1). The most common presenting symptoms in immunocompromised children are fever (35%–65%), cough (38%–52%), rhinorrhea (12%–32%), anosmia (8%–22%), gastrointestinal symptoms (8%–25%) and dyspnea (4%–19%). This does not appear to differ from the symptomatology in nonimmunocompromised children, although a meta-analysis demonstrated a lower prevalence of fever, fatigue, myalgia, cough, dyspnea and neurological symptoms in pediatric cancer patients compared to the general population and other immunocompromised cohorts.2 Complications of COVID-19 infection were reported in immunocompromised children, including acute respiratory distress syndrome (0%–12%), bacterial superadded infection (0%–13%) and venous thromboembolism. Of particular concern in children are the hyperinflammatory complications such as haemophagocytic lymphohistiocytosis (HLH) and the newly emerged MIS-C, which is a poorly understood and under-recognized disease process that can lead to critical illness characterized by persistent fever, marked inflammation and evidence of single or multi-organ failure. Among the 393 immunocompromised children, there were 2 cases of MIS-C (an incidence of 51 per 10,000 cases) and 7 cases of HLH. In comparison, the incidence of MIS-C in nonimmunocompromised children has been reported as 3.16 per 10,000 cases.3 The difficulties in identifying COVID-associated complications arise from the nonspecific presentation and delayed temporal association—usually 4–6 weeks—between the acute viral infection and the onset of the illness, resulting in low sensitivity of PCR and reliance on serological assays, with variability in seroconversion and preexisting seropositivity. In addition, some COVID-associated complications may overlap with the clinical and laboratory manifestations seen in the underlying immunosuppressive condition. TABLE 1. - Comparison of Symptoms, Outcomes and Therapy in 6 Large Studies of Immunocompromised Children with COVID-19 Infection, with a Nonselective Cohort (Götzinger Et Al) Author Type of study, subject age Comorbidity N Symptoms n (%) Asymptomatic n (%) Hospitalized n (%) ICU n (%) Respiratory support n (%) Death n (%) Complication n (%) COVID therapy n (%) Marlais et al Multicentre worldwide prospective study on patients ≤19 years Renal patients on immunosuppressant: steroids 86 (76%), TAC 58 (51%), MMF 66 (54%), RIX 11 (10%), AZA 9 (8%), CSA 8 (7%), CYC 8 (7%), SRL 5 (4%), BAS 3 (3%), everolimus 3 (3%), ATG 2 (2%), eculizumab 2 (2%), ofatumumab 1 (1%), alemtuzumab 1 (1%), adalimumab 1 (1%), levamisole1(1%)Diagnosis: kidney Tx 53 (47%), nephrotic syndrome 30 (27%), SLE 11 (10%), GN 7 (6%),other 12 (11%) 113 Fever 73 (65%), cough 59 (52%), rhinorrhoea 35 (31%), GI 17 (15%), dyspnea 20 (18%) 21 (19%) 68 (60%) 6 (5%) Total: 25 (22%)O2: 14 (12%)HFNO: 5 (4%)NIV: 1 (1%)IV: 5 (4%) 4 (4%) Not reported HCQ 10 (9%), oseltamivir 2 (2%), RDV 1 (1%), favipiravir 1 (1%), LPV/r 1 (1%) Madhusoodan et al Multicentre US retrospective study on patients ≤21 years CA on chemotherapy: mildly immunosuppressed 45 (46%), moderately immunosuppressed 21 (21%), severely immunosuppressed 32 (33%). Immumotherapy 10 (10%) (blinatumomab, RIX, BAS).Diagnosis: ALL 52 (53%), AML 9 (9.2%), lymphoma 3 (3%), CNS tumor 9 (9%), neuroblastoma 5 (5%), solid tumor 16 (16%), other 4 (4%) 98 Fever 60 (61%), cough 45 (46%), respiratory distress 19 (19%), fatigue 18 (18%), myalgia 11 (11%), GI 8 (8%), sore throat 5 (5%), anosmia 4 (4%), ageusia 3 (3%), other 17 (17%) 32 (33%) 28 (29%)* 17 (17%) Total: 32 (33%)O2: 25 (26%)IV: 7 (7%) 4 (4%) ARDS 12 (12%), bacterial superinfection 7 (7%), AKI 4 (4%), HLH 1 (1%) other 8 (8%) HCQ 15 (15%), TOZ 5 (5%),RDV 4 (4%) Meyts et al Multicentre worldwide retrospective study on patients ≤21 years Inborn errors of immunity: CID 12 (38%), immune dysregulation 5 (16%), Aicardi-Goutières syndrome 3 (9%), CVID 2 (6%), phagocyte defect 3 (9%), hypogammaglobulianemia 2 (6%), x-linked agammaglobulinaemia 1 (3%), other 5 (16%) 32 Fever 23 (72%), cough 12 (38%), URTI 9 (28%), GI 8 (25%), myalgia 1 (3%), other 9 (28%) 9 (28%) 21 (66%) 6 (19%) Total: 9 (28%)O2/NIV: 3 (9%) IV: 6 (19%) 2 (6%) HLH 5 (16%), bacterial superinfection 4 (13%), sepsis 2 (6%), MIS-C 1 (3%) Steroids 6 (19%), IVIG 5 (16%), RDV 3 (9%), LPV/r 2 (6%), convalescent plasma 2 (6%), aspirin 1 (3%), TOZ 1 (3%), chloroquine 1 (3%) Goss et al Multicentre US prospective study on patients ≤18 years Solid organ Tx on immunosuppression: TAC (± SRL, prednisolone, MMF, CSA, AZA) 25 (96%), SRL+ prednisolone + CYC1 (4%)Diagnosis: kidney Tx 8 (31%), liver Tx 10 (38%), heart Tx 6 (23%), lung Tx2(8%) 26 Cough 12 (46%), fever 9 (35%), sore throat 3 (12%), rhinorrhoea 3 (12%), anosmia 2 (8%), chest pain 2 (8%), GI 2 (8%), dyspnea 1 (4%), headache1(4%) 6 (23%) 5 (19%)* 0 (0%) Total: 0 (0%) 0 (0%) None HCQ 1 (4%) Kamdar et al Single center US retrospective study on patients <18 years Mixed: SCD 30 (34%), CA on chemotherapy/ immunotherapy 51 (59%), HSCT6 (7%)Diagnosis: Leukaemia 22 (43%), solid tumor 19 (37%), brain tumor 5 (10%), lymphoma 3 (6%), histiocytic disorders 2 (4%) 87 Not reported 26 (30%) 21 (24%) 7 (8%) Total: 10 (12%)O2: 3 (3%)IV: 7 (8%) 2 (2%) MIS-C 1 (1%), thromboembolism1(1%) RDV 6 (7%), convalescent plasma 2 (2%) Rouger-Gaudichon et al Multicentre French retro- & prospective study on patients <25 years Mixed: CA on chemotherapy 33 (89%), HSCT on immunosuppressant4 (11%)Diagnosis: solid tumor 17 (46%), haematological CA 16 (43%), nonmalignant 4 (11%) 37 Fever 20 (54%), cough 14 (38%), rhinorrhoea 12 (32%), fatigue 12 (32%), anosmia 8 (22%), GI 7 (19%), chest pain 6 (16%), myalgia 5 (14%), respiratory distress 5 (14%), tachycardia 4 (11%), headache 3 (8%), skin rash 2 (5%), neurological signs 2 (5%) 9 (32%) 20 (54%) 5 (14%) Total: 6 (16%)O2: 1 (3%)NIV: 3 (8%)IV: 2 (5%) 1 (3%) HLH 1 (3%), polyneuropathy1(3%) HCQ 2 (5%), TOZ 2 (5%), RDV 1 (3%) Götzinger et al Multicentre European prospective study on patients <18 years No comorbidities 437 (75%).Comorbidities 145 (25%): chromosomal abnormalities 10 (2%), chronic pulmonary disease 29 (5%), congenital heart disease 25 (4%), CA 27 (5%), neurological disorder 26 (4%), CKD 9 (2%), immunodeficiency 3 (1%), on immunosuppressive therapy 29 (5%), chemotherapy in previous 6 months 25 (4%) 582 Fever 379 (65%), URTI 313 (54%), LRTI 143 (25%), GI 128 (22%), headache 28% 93 (16%) 363 (62%) 48 (8%) Total: 75 (13%)O2: 19 (3%)NIV 31 (5%)IV: 25 (4%) 4 (0.7%) Co-infection with another virus29(5%) HCQ 40 (7%), RDV 17 (3%), LPV/r 6 (1%), oseltamivir 3 (1%), steroids 22 (4%), IVIg 7 (1%), TOZ 4 (1%), anakinra 3 (1%), siltuximab 1(<1%) *Reported additional patients admitted but for reasons not related to COVID-19 infection.AKI, acute kidney injury; ALL, acute lymphoblastic leukaemia; AML, acute myeloid leukaemia; ARDS, acute respiratory distress syndrome; ATG, anti-thymocyte globulin; AZA, azathioprine; BAS, basilixumab; CA, cancer, CID, combined immunodeficiency; CKD, chronic kidney disease; CSA, ciclosporin; CVID, common variable immunodeficiency; CYC, cyclophosphamide; GI, gastrointestinal; GN, glomerulonephritis; HCQ, hydroxychloroquine; HFNO, high flow nasal oxygen; HLH, haemophagocytic lymphohistiocytosis; HSCT, hemopoietic stem cell transplant; ICU, intensive care unit; IQR, interquartile range; IV, invasive ventilation; IVIg, intravenous immunoglobulin; LPV/r, lopinavir/ritonavir; MIS-C, multisystem inflammatory syndrome in children; MMF, mycophenolate mofetil; NIV, noninvasive ventilation; O2, oxygen; RDV, remdesivir; RIX, rituximab; SCD, sickle-cell disease; SLE, systemic lupus erythematosus; SRL, sirolimus; TAC, tacrolimus; TOZ, tocilizumab; Tx, transplant; URTI, upper respiratory tract infection. Similar to immunocompetent children with COVID-19, laboratory findings in immunocompromised children are nonspecific and variable; lymphopenia, elevated C-reactive protein and elevated transaminases are the most commonly reported abnormalities (23%–42%, 17%–63% and 0%–53%, respectively). COVID-19 causes characteristic radiological changes in bilateral, multifocal pulmonary infiltrates; however, chest imaging is variably performed and radiological changes are variably reported. Chest imaging was performed in 31% of solid-organ transplant (SOT) patients, 41% of cancer patients and 34% of nonimmunocompromised patients and was abnormal in 25%, 93% and 52%, respectively.4–6 This variability means that, like for nonimmunocompromised children, chest imaging should not be relied on for diagnostic purposes. SEVERITY OF COVID-19 IN IMMUNOCOMPROMISED CHILDREN Early in the pandemic, it was presumed that immunocompromise would increase the risk of severe COVID-19 infection, due to uncontrolled viral replication and poor viral clearance, and the impact of immunocompromise on the later, severe and hyperinflammatory phase of the disease was unknown. A prospective, cross-specialty cohort study that followed 1527 children on immunosuppressants reported only 38 infections, 4 hospitalizations and no severe cases, suggesting that immunocompromised children were not at increased risk of severe disease, although study outcomes were self-reported.7 However, a meta-analysis demonstrated a significantly higher need for ICU care (36% vs. 23%) and higher mortality (23% vs. 13%) in adult and pediatric SOT patients hospitalized with COVID-19 compared to the general population.2 Outcomes for pediatric cancer patients were no different from the general population, although mortality was lower than in adult cancer patients (11% vs. 28%).2 Table 1 shows the outcomes of COVID-19 infection in 6 varied cohorts of immunocompromised patients and a nonimmunocompromised cohort for comparison, which was selected for its similarity in study design and recruitment of patients from tertiary and quaternary institutions. There was a large range in hospitalization rate (19%–66%) in the immunocompromised cohorts, which likely reflects variation in clinical practices between centers/countries. The best outcomes were observed in a cohort of SOT recipients; no patients required respiratory support (including supplemental oxygen or ventilation) or died. In the other studies, the rate of respiratory support was 12%–22%, ICU admission was 5%–19%, invasive ventilation was 4%–19% and death was 2%–6%, compared to 13%, 8%, 4% and 1%, respectively in the nonimmunocompromised cohort. There was no correlation between disease severity and underlying diagnosis, form of drug immunosuppression and degree of chemotherapy-induced immunosuppression, with the exception of patients with sickle-cell disease who were more likely to require hospitalization, possibly due to the need to exclude or treat vaso-occlusive crises.8–11 No studies reported differences in disease severity/outcomes based on sex, ethnicity, age, comorbidities, obesity or laboratory findings, although 2 studies reported a greater frequency of severe disease in older children that did not reach statistical significance, and all 5 patients with trisomy 21 required respiratory support or intensive care.8–10 Although overall, the presentation of COVID-19 infection in immunocompromised children is similar to that in immunocompetent children, the difference in the prevalence of various complications is difficult to attribute to immunosuppression alone. There is a great variability in practices related to COVID-19 testing strategies in immunocompromised children, potentially leading to underreporting of asymptomatic/minimally symptomatic COVID-19 infection. Different thresholds for hospitalization in immunocompromised children may reflect a tendency for physicians to have a lower threshold for admitting children with significant underlying comorbidities. The most likely causative factors leading to poorer outcomes of COVID-19 infection in immunosuppressed children are related to impaired viral control and viral clearance, dysregulated immune response reflecting both COVID-infection and underlying disease that can predispose to hyperinflammation, as well as potential flares of underlying conditions and increased risk of secondary, often healthcare-related, infections. THERAPEUTICS AND VACCINATION IN IMMUNOCOMPROMISED CHILDREN The most important intervention in severe COVID-19 infection is the treatment of hypoxemic respiratory failure with respiratory support, usually with oxygen or invasive ventilation. The use of noninvasive ventilation and high-flow nasal oxygen was reported in 3 of the 6 studies. Refractory hypoxemia can be managed with proning, inhaled nitric oxide and extracorporeal membrane oxygenation, which was used on only a single patient across the 6 cohorts. Pharmacological therapy varies largely between centers and countries (Table 1). Decreased ability to mount antibody responses post COVID-19 infection could be associated with risk for prolonged illness or complications in immunosuppressed children. The current National Institute of Health treatment guidelines for children with COVID-19 infection recommend remdesivir (for hospitalized children older than 12 years), and remdesivir and dexamethasone (for hospitalized children of all ages if they require high flow oxygen or ventilation), as well as anti-SARS-CoV-2 monoclonal antibodies (bamlanivimab, bamlanivimab plus etesevimab and casirivimab plus imdevimab), specifically for the treatment of immunocompromised children older than 12 years and at risk for disease progression or hospitalization on a case-by-case basis. It is recognized, however, that the efficacy of monoclonals depends on the type of COVID-19 virus strain and that new therapeutic agents are likely to emerge as the pandemic evolves. Other therapeutic options, such as baricitinib, tocilizumab and other IL-6 targeted therapies can be considered on a case-by-case basis as well, especially in hospitalized children with hyperinflammatory syndromes. Convalescent plasma is currently investigated in clinical trials in children. Chemotherapy was delayed in 13%–67% of patients infected with SARS-CoV-2 in an attempt to reduce immunosuppression, although no trials on the impact of this on COVID-19 severity and cancer prognosis are available.6,9,11 Long-term immunosuppression was reduced in 39% of renal patients and in 8% of SOL patients; the impact on the underlying disease and COVID-19 severity is unknown.4,8 Reducing background immunosuppression during the initial stages of viral replication may improve viral clearance, while increasing it back to a maintenance dose after seroconversion (12–14 days) may prevent a possible hyperinflammatory immune response to COVID-19 infection as well as minimize the risk of relapse from the underlying disease. In the UK, the Joint Committee of Vaccination and Immunisation recommends vaccination for children over 12 years and for children 5–11 years who are immunocompromised. Very recently, reflecting a resurgence of COVID-19 infections worldwide, Moderna is seeking emergency-use authorization from regulators for its vaccine in babies, toddlers and preschoolers, based on encouraging clinical trial data. Immunocompromised patients, however, have reduced seroconversion rates after vaccination, which could translate in reduced protection from both infection and severe disease. A meta-analysis demonstrated seroconversion rates after 2 doses of a COVID-19 vaccine of 89% in patients with solid-organ malignancy, 62% in hematological malignancy, 77% in immune-mediated inflammatory conditions and 35% in SOT, compared to 97% in immunocompetent recipients.12 For maximal protection, vaccination should occur before immunosuppression is commenced and additional doses may be offered, while other preventative measures, such as household vaccination and infection control measures may also be required. To date, immunocompromise has not been demonstrated to predispose to post-vaccination myopericarditis, which is reported with higher rates in adolescent males after mRNA vaccines, although further research is needed to address the role of different classes of immunomodulating drugs on this complication potentially resulting from the aberrant T-cell response. RESEARCH CHALLENGES There are several challenges that make the interpretation of studies on COVID-19 in immunocompromised children difficult for researchers and clinicians. There are low numbers of patients in studies due to low rates of pediatric immunocompromise and low case rates within these cohorts, likely as a result of the practice of shielding. Furthermore, the low rates of severe illness and mortality may not lead to statistically significant results. Retrospective study design, inclusion only of patients presenting to or being admitted to hospital and underreporting of asymptomatic/minimally symptomatic infection may contribute to apparent higher rates of severe infection. In immunocompromised children, attributing causality of complications or severe disease to COVID-19 can be challenging due to co-existent pathology, such as neutropenic sepsis in chemotherapy recipients. Comparing studies throughout the pandemic is challenging because of evolving recommendations regarding testing, public health strategies and available therapeutics. Additionally, changes in SARS-CoV-2 strain predominance and variation in immunity due to the previous infection, and more recently vaccination, are several confounding variables that impact outcomes. Finally, studies on immunocompromised children have included highly heterogeneous cohorts with large variations in length, intensity and modality of immunocompromise and it is becoming increasingly clear that 'not all immunocompromise is equal'. DIRECTIONS OF FUTURE RESEARCH Future work must establish the role of different types of immunocompromise on disease severity and vaccination efficacy. The serological threshold required to prevent infection is unknown and a more accurate biomarker of immunity to monitor vaccination response that also acknowledges T-cell immunity is needed. There is a need for the investigation of the role of specific therapy, such as convalescent plasma, in immunocompromised children. Longer-term follow-up is needed for immunocompromised COVID-19 patients to establish rates and severity of reinfection, the impact of the infection and immunocompromising therapy discontinuation on the underlying disease, as well as to monitor the efficacy of vaccines in the context of ongoing SARS-CoV-2 mutations. Vaccination is likely to become available for children <5 years of age soon and the efficacy and side effect profile of this should be carefully monitored in both immunocompromised and immunocompetent children.
Abstract Background Translation of blood RNA signatures may be accelerated by identifying more parsimonious biomarkers. We tested the hypothesis that single-gene transcripts provide comparable accuracy for detection of subclinical TB to multi-gene signatures and benchmarked their clinical utility to interferon-y release assays (IGRAs). Methods We identified datasets where participants underwent RNA sampling and at least 12 months of follow-up for progression to TB. We performed a one-stage individual participant data meta-analysis to compare multi-gene signatures against single-gene transcripts to detect subclinical TB, defined as asymptomatic prevalent or incident TB (diagnosed ≥21 days from enrolment, irrespective of symptoms) over a 12-month interval. We performed decision curve analysis to evaluate the net benefit of using RNA biomarkers and IGRA, alone or in combination, compared to treating all or no individuals with preventative treatment. Results We evaluated 80 single-genes and eight multi-gene signatures in a pooled analysis of four RNAseq and three qPCR datasets, comprising 6544 total samples and including 283 samples from 214 individuals with subclinical TB. Five single-gene transcripts were equivalent to the best-performing multi-gene signature over 12 months, with areas under the receiver operating characteristic curves ranging from 0.75-0.77, but none met the WHO minimum target product profile (TPP) for a TB progression test. IGRA demonstrated much lower specificity in higher burden settings, while sensitivity and specificity of RNA biomarkers were consistent across settings. In higher burden settings, RNA biomarkers had greater net benefit than IGRA, which offered little clinical utility over treating all with preventative therapy. In low burden settings, IGRA approximated the TPP and offered greater clinical utility than RNA biomarkers, but combining both tests provided the highest net benefit for services aiming to treat <50 people to prevent a single case. Interpretation Single-gene transcripts are equivalent to multi-gene signatures for detection of subclinical TB, with consistent performance across settings. Single transcripts demonstrate potential clinical utility to stratify treatment, particularly when used in combination with IGRA in low burden settings.
Background Despite children and young people (CYP) having a low risk for severe coronavirus disease 2019 (COVID-19) outcomes, there is still a degree of uncertainty related to their risk in the context of immunodeficiency or immunosuppression, primarily due to significant reporting bias in most studies, as CYP characteristically experience milder or asymptomatic COVID-19 infection and the severe outcomes tend to be overestimated. Methods A comprehensive systematic review to identify globally relevant studies in immunosuppressed CYP and CYP in general population (defined as younger than 25 years of age) up to 31 October 2021 (to exclude vaccinated populations) was performed. Studies were included if they reported the two primary outcomes of our study, admission to intensive therapy unit (ITU) and mortality, while data on other outcomes, such as hospitalization and need for mechanical ventilation were also collected. A meta-analysis estimated the pooled proportion for each severe COVID-19 outcome, using the inverse variance method. Random effects models were used to account for interstudy heterogeneity. Findings The systematic review identified 30 eligible studies for each of the two populations investigated: immunosuppressed CYP ( n = 793) and CYP in general population ( n = 102,022). Our meta-analysis found higher estimated prevalence for hospitalization (46% vs. 16%), ITU admission (12% vs. 2%), mechanical ventilation (8% vs. 1%), and increased mortality due to severe COVID-19 infection (6.5% vs. 0.2%) in immunocompromised CYP compared with CYP in general population. This shows an overall trend for more severe outcomes of COVID-19 infection in immunocompromised CYP, similar to adult studies. Interpretation This is the only up-to-date meta-analysis in immunocompromised CYP with high global relevance, which excluded reports from hospitalized cohorts alone and included 35% studies from low- and middle-income countries. Future research is required to characterize individual subgroups of immunocompromised patients, as well as impact of vaccination on severe COVID-19 outcomes. Systematic Review Registration PROSPERO identifier, CRD42021278598.
Background: Despite children and young people (CYP) having a low risk for severe Coronavirus disease 2019 (COVID-19) outcomes, there is still a degree of uncertainty related to their risk in the context of immunodeficiency or immunosuppression, primarily due to significant reporting bias in most studies, as CYP characteristically experience milder or asymptomatic COVID-19 infection and the severe outcomes tend to be overestimated. Methods: A comprehensive systematic review to identify globally relevant studies in immunosuppressed CYP and CYP in general population (defined as younger than 25 years of age) up to 31st October 2021 (to exclude vaccinated populations), was performed. Studies were included if they reported the two primary outcomes of our study, admission to intensive therapy unit (ITU) and mortality, while data on other outcomes, such as hospitalisation and need for mechanical ventilation were also collected. A meta-analysis estimated the pooled proportion for each severe COVID-19 outcome, using the inverse variance method. Random effects models were used to account for interstudy heterogeneity. Findings: The systematic review identified 30 eligible studies for each of the two populations investigated: immunosuppressed CYP (n=793) and CYP in general population (n=102,022). Our meta-analysis found higher estimated prevalence for hospitalization (46% vs. 16%), ITU admission (12% vs. 2%), mechanical ventilation (8% vs. 1%) and increased mortality due to severe COVID-19 infection (6.5% vs. 0.2%) in immunocompromised CYP compared to CYP in general population. This shows an overall trend for more severe outcomes of COVID-19 infection in immunocompromised CYP, similar to adult studies.Interpretation: This is the only up to date meta-analysis in immunocompromised CYP with high global relevance, which excluded reports from hospitalised cohorts alone and included 35% studies from low- and medium-income countries. Future research is required to characterise individual subgroups of immunocompromised patients, as well as impact of vaccination on severe COVID-19 outcomes.Funding: There was no funding source specifically dedicated for this study. CC is supported by a National Institute of Health Research (NIHR) Biomedical Research Centre (BRC) at University College London Hospital (UCLH). The study was performed within the Centre for Adolescent Rheumatology Versus Arthritis at University College London (UCL), UCL Hospital and Great Ormond Street Hospital (GOSH) supported by grants from Versus Arthritis (21593 and 20164), Great Ormond Street Children’s Charity, and the NIHR-BRC at both GOSH and UCLH.Declaration of Interests: None.
Abstract Blood transcriptional biomarkers of acute viral infections typically reflect type 1 interferon (IFN) signalling, but it is not known whether there are biological differences in their regulation that can be leveraged for distinct translational applications. We use high frequency sampling in the SARS-CoV-2 human challenge model to show induction of IFN-stimulated gene (ISG) expression with different temporal and cellular profiles. MX1 gene expression correlates with a rapid and transient wave of ISG expression across all cell types, which may precede PCR detection of replicative infection. Another ISG, IFI27 , shows a delayed but sustained response restricted to myeloid cells, attributable to gene and cell-specific epigenetic regulation. These findings are reproducible in experimental and naturally acquired infections with influenza, respiratory syncytial virus and rhinovirus. Blood MX1 expression is superior to IFI27 expression for diagnosis of early infection, as a correlate of viral load and for discrimination of virus culture positivity. Therefore, MX1 expression offers potential to stratify patients for antiviral therapy or infection control interventions. Blood IFI27 expression is superior to MX1 expression for diagnostic accuracy across the time course of symptomatic infection and thereby, offers higher diagnostic yield for respiratory virus infections that incur a delay between transmission and testing.
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