We aimed to estimate the respiratory syncytial virus positivity rate among ambulatory children with bronchiolitis according to the bronchiolitis epidemic period as defined by the French Public Health Institute. The positivity rate was 28.9% during the nonepidemic period and 50.6% during the epidemic period, which suggests continuous virus circulation between bronchiolitis annual peaks.

*Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia †Infectious Diseases Unit, Royal Children’s Hospital Melbourne, Parkville, Victoria, Australia ‡Infectious Diseases Group, Murdoch Children’s Research Institute, Parkville, Victoria, Australia §OpenAI L.L.C, San Francisco, California, USA. Accepted for publication January 18, 2023 The authors have no funding or conflicts of interest to disclose. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com). Address for correspondence: Nigel Curtis, PhD, FRCPCH, Department of Paediatrics, The University of Melbourne, Royal Children’s Hospital Melbourne, 50 Flemington Road, Parkville, VIC 3052, Australia. E-mail: [email protected]; Twitter: @nigeltwitt.

CASE An 8-year-old boy was admitted with a fever of 4 weeks duration. Twelve days after fever onset, a blood test revealed elevated C-reactive protein (CRP) of 68.6 mg/L and procalcitonin (PCT) of 1.38 (ng/mL), with unremarkable white blood count and normal renal and liver function. He was treated with amoxicillin-clavulanate for 10 days, for presumed sinusitis, with no improvement. He then developed scarce petechiae on his legs and was admitted for further testing. The boy was born to Bulgarian parents and lived in rural Spain. His grandfather was a farmer and owned lambs, turkeys, dogs, and cats, but the family denied consumption of unpasteurized milk. He had a history of congenital heart disease consisting of double outlet right ventricle (DORV) with ventricular septal defect (VSD) and pulmonary artery stenosis and underwent a Rastelli procedure when he was 2 years old. His latest surgery, 20 months prior to admission, consisted of closing the VSD with a bovine pericardial patch and placement of a prosthetic pulmonary valved conduit (Contegra®). On admission, his weight was 18.8 kg, temperature was 38.7°C, heart rate was 102 beats per minute, respiratory rate was 25 breaths per minute, blood pressure was 92/57 mm Hg and oxygen saturation was 98%. On physical examination cardiac auscultation showed grade II-III/VI systolic murmur in pulmonary artery focus, and normal lungs auscultation. He had an enlarged liver and spleen (4 and 5 cm below costal margin respectively) and scarce petechiae on his legs. His CBC, including blood smear, and renal and liver function tests were normal. His erythrocyte sedimentation rate was 48 mm/h, CRP 26.8 mg/L and PCT 0.6 ng/mL. Urine culture and throat swab culture as well as tuberculin skin test were negative. His chest radiograph was unremarkable aside from postsurgical changes. An abdominal ultrasound revealed homogeneous hepatosplenomegaly. A transthoracic echocardiography (TTE) did not show any evidence of endocarditis. Four blood culture sets taken separately in two consecutive days were negative. He was empirically started on cefotaxime and vancomycin but continued to spike fever 3–4 times daily. Serologic tests for Brucella, Coxiella, Leishmania, Rickettsia, Cytomegalovirus and Epstein Barr virus were sent, and one of these results revealed the diagnosis. DENOUEMENT Five days after admission, a serum sample was positive for IgG antibodies against Coxiella burnetii phase II antigen, by indirect chemiluminescent immunoassay (CLIA, Vircell, Spain), and this positive result, was confirmed and quantified by a commercial indirect immunofluorescence assay (IFA, Vircell), showing phase I IgG of ≥1:16384 and phase II IgG of 1:8192. Q-fever (QF) blood polymerase chain reaction (PCR) assay that amplifies the multicopy IS1111 insertion sequence was also positive. Considering these results, a repeat TTE revealed a 7x10 mm vegetation at the prosthetic valve without significant valvular dysfunction, mild pulmonary regurgitation, and mild pulmonary stenosis (Fig. 1). He was diagnosed with Q Fever (QF) endocarditis and was started on treatment with doxycycline at 4.4 mg/kg/d twice daily, becoming afebrile within the next 72 h. After a literature review and normal ophthalmological examination, hydroxychloroquine was added 4 days later at 200 mg/d but was stopped after 14 days due to nausea and vomiting and was replaced with cotrimoxazole at 8 mg/kg/d twice daily.FIGURE 1.: Maximal intensity projection FDG-PET (A) and transaxial PET/CT (B and D), before treatment, show increased 18F-FDG uptake in the proximal valved conduit anastomosis in right ventricle (red arrows), as well as pulmonary infiltrate (D, yellow arrow), diffuse increased activity in the spleen (blue arrow) and reactive bone marrow (green arrow). Transaxial PET/CT (C) show normalization of metabolic activity after homograft replacement. 18F-FDGPET/CT = 18F-fluorodeoxyglucose positron emission tomography/computerized tomography. Transthoracic echocardiography (TTE): (E) Parasternal short axis (pulmonary valve at systolic phase) showing a 10 mm length vegetation attached to pulmonary valve; (F) Suprasternal view showing an axial view of pulmonary valve with the vegetation; (G) Parasternal short axis (pulmonary valve at diastolic phase) the arrow denotes the vegetation. Within a week of the diagnosis a full body positron emission tomography/computed tomography (PET/CT) scan, performed to search for other infectious foci and establish baseline metabolic activity, revealed enhancement at prosthetic valve and spleen with lower lobe infiltrates in the left lung with no bone involvement (Fig 1). Two weeks into treatment, blood PCR for QF persisted positive and intermittent fevers continued. The case was presented in a multidisciplinary meeting, and the decision was to replace the pulmonary-valve conduit after 3 weeks of treatment. During the surgery, multiple vegetations were observed on the conduit mainly adhering to the leaflets, and an aortic homograft was placed. PCR for QF of the lesions on the removed conduit was also positive. During follow-up, blood QF PCRs, tested on months 1, 4, 8, 20, 24, 28, and 36 after surgery were negative in all the visits and serology titers decreased and increased in subsequent follow-ups (phase I IgG of 1/16,384, 1/8192, 1/2048 and 1/8192 respectively on months 8, 20, 28, and 36 after surgery). The increase in phase I titers, tested routinely to monitor for relapse, happened while the child was asymptomatic with normal inflammatory markers, echocardiograms without evidence of vegetation, and negative blood QF PCRs and therefore serology titers were not helpful in making clinical decisions. Eighteen months into treatment, a repeat PET/CT showed clear improvement with no significant uptake around the valvular prosthesis, so it was decided to stop treatment after 19 months. At the latest follow-up, 23 months from treatment discontinuation and 3 years from the diagnosis, he is asymptomatic and growing well. Q fever (QF) is a worldwide zoonotic disease caused by Coxiella burnetii. According to the 2019 report from the European Center for Disease Prevention and Control (ECDC), the highest QF notification rate in Europe was observed in Spain (0.7 cases per 100,000 population).1 QF is usually transmitted from farm animals, mainly cattle, sheep, and goats, via inhalation of contaminated aerosols. Acute QF is usually asymptomatic in children. Endocarditis is the predominant form of chronic infection and has been observed in 1-16% of reported cases of QF, but few pediatric cases have been reported and even fewer have been associated with prosthetic material.2,3 The diagnosis of QF normally relies on serological methods. In acute infection, the immune response induces the production of anti-phase II and anti-phase I antibodies. Anti-phase II antibodies are predominant during primary infection and are detectable 7 to 15 days after clinical onset. The diagnosis of QF can be confirmed by a 4-fold increase in phase II IgG or IgM antibodies between two serum samples taken 3 to 6 weeks apart. Generally, titers of phase II IgG of ≥200 and/or IgM of ≥50 are considered significant for the diagnosis of primary QF. Anti-phase I IgG titers are associated with persistent infection and higher titers correlate with a higher positive predictive value for the diagnosis of Q fever endocarditis (QFE). It is recommended to investigate further when anti-phase I IgG titers are above 1:800 6 months after completion of treatment for acute QF. Residual IgG antibody titers may be detectable for years and even for life.4 Diagnosis of QFE typically requires demonstration of abnormalities on an echocardiogram; however, emerging data suggest that PET/CT could be a useful diagnostic tool. Unlike an echocardiogram, the diagnosis of endocarditis is essentially ruled out when PET/CT is negative. Conversely, an abnormal PET/CT can point to endocarditis in settings when there is a high index of suspicion of QFE and echocardiograms are negative for vegetations. PET/CT may also be also useful for clinical monitoring and guiding antibiotic therapy, especially when serology is misleading.5 However, there are concerns that FDG uptake around the prosthetic/periprosthetic area after heart surgery is common of PET/CT, and the uptake intensity and distribution pattern may remain stable during the first year after surgery. The recommended treatment regimen for QFE is doxycycline and hydroxychloroquine or doxycycline with a quinolone. The combination of doxycycline and hydroxychloroquine requires a shorter duration of treatment and has demonstrated a lower risk of relapse, without evidence of lower mortality or the need for surgery.6 Limited data are available on treatment of chronic QF in children, and the safety of long-term hydroxychloroquine in children has not been determined. Alternative long-term treatment options in children include the use of a fluoroquinolone with rifampin or trimethoprim/sulfamethoxazole with doxycycline. According to treatment recommendations, chronic QFE should be continued for at least 18–24 months and should be further prolonged until phase I IgG decrease by a fourfold. However, given that most patients treated appropriately for 18 months will clinically recover, they might not benefit from continued treatment despite high phase I IgG, as there is data suggesting a poor correlation between clinical and serological response.7 In our experience serologic monitoring created confusion as titers were erratic and increased and decreased without correlation to clinical events or evidence of relapse. In conclusion, the diagnosis of QFE should be considered in any patient with blood culture-negative endocarditis and compatible exposure history. The patients should be closely monitored, basing medical decisions on clinical and inflammatory marker responses rather than on serological titers. Although promising, the role of PET-CT for decision making in follow-up needs to be further evaluated. ACKNOWLEDGMENTS Thank you to Dr. Arístides for clinical advice in this case.

Following an increase in notifiable invasive group A streptococcal (iGAS) infections in the Netherlands, we conducted a survey among 7 hospitals. Pediatric iGAS case numbers were 2-fold higher between July 2021 and June 2022 versus pre-COVID-19. A sharp increase occurred early 2022, most pronounced in <5 years old and for diagnoses empyema and necrotizing fasciitis. This recent pediatric iGAS surge warrants investigation and vigilance.

In patients with SarS-CoV2 and chronic Hepatitis B (HBV) co-infection liver injury is associated with a worse prognosis. We report a case of acute chronic liver failure (ACLF) with encephalopathy due to HBV reactivation during COVID-19 with undetectable INR. Thromboelastography showed a profile consistent with a prothrombotic state so INR was not a reliable marker of liver function until plasma infusion. After plasma infusion, indeed, an imbalance of hepatic function was shown by an underlying INR prolongation that was consistent with an ACLF.

To understand the regional epidemiology and clinical characteristics of adenovirus pneumonia in hospitalized children during the 2019 outbreak of respiratory adenoviruses in China. We analyzed the epidemiologic trend of adenovirus in children hospitalized for acute lower respiratory tract infections in Xiamen in 2019. Adenovirus was identified using direct fluorescent antibody detection. During the peak seasons of adenovirus epidemic, 170 adenovirus-positive specimens were obtained for molecular typing, and the clinical data were collected. Among the 9890 children hospitalized for acute lower respiratory tract infection, 609 (6.2%) were tested positive for adenovirus. The detection rate of adenovirus was significantly higher in boys than in grils (9.5% vs. 4.6%, P < 0.05). Adenovirus activity increased markedly between April and August with the prevalence of 7.3%-12.4%. During the outbreak season, type 7 accounted for 70.6%, followed by type 3 (28.8%) and type 4 (0.6%). Of the 155 cases of adenovirus pneumonia, the median age was 3.0 years (range: 4 month to 9 years), 153 (98.7%) had fever with a mean fever duration of 9.04 ± 5.52 days, 28 (16.5%) had wheezing, 93 (60%) showed segmental or lobar consolidation with atelectasis and 13 (8.4%) showed pleural effusion. Forty-six (29.6%) cases developed severe pneumonia, 7 (4.1%) required mechanical ventilation and 2 (1.2%) died. Younger age, longer duration of fever and higher fever spike were more frequently seen in severe cases (P < 0.05). Twenty-five (16.2%) had C-reactive protein ≥ 40 mg/L, and 91 (58.7%) had procalcitonin ≥ 0.25 mg/L. Adenovirus types 7 and 3 caused the outbreak of adenovirus pneumonia in community children during late spring to summer in 2019 in Xiamen. The majority of adenovirus pneumonia resembles bacterial pneumonia. The incidence of severe pneumonia was high when type 7 predominantly prevailed. Adenovirus type 7 was more common in severe cases than in nonsevere cases.

To the Editor: Some years ago, childhood spondylodiscitis was used to describe a continuum of primary pyogenic spinal infections (PPSIs), from discitis to vertebral osteomyelitis, including spondylodiscitis with its occasional associated soft-tissue abscesses. The pathophysiology of PPSIs has, nevertheless, become clearer and less controversial. The theory suggesting that spondylodiscitis was a self-limiting inflammatory condition is now considered completely obsolete. A better understanding of pathophysiological processes has made it possible to differentiate forms of childhood PPSI according to patients’ ages, their immune system development, better knowledge of their bacterial etiology, and the vascularization of their vertebrae and disks. The different clinical forms of PPSI have now been categorized in various ways that physicians and pediatricians should know. The first classification is based on the child’s age and the development of their immune system, and it distinguishes three main clinical forms of childhood PPSI. The neonate form of spondylodiscitis generally affects infants under 6 months old and is recognized as the most severe manifestation of the disease: patients often present with septicemia and multiple infectious foci. Fortunately, this is the rarest form of the disease. The infantile form concerns children from 6 to 48 months old (a period during which maternally derived immunity decreases and stops), the age group representing 60%–80% of cases of childhood spondylodiscitis. Finally, in the third form, affecting children above 4 years old, patients are more prone to being febrile and appearing very ill. The second classification can be superimposed on the first and assigns each age group a bacterial probability of spondylodiscitis. Approximately 80% of spondylodiscitis cases in children younger than 6 months are due to S. aureus. For children from 6 to 48 months old, there are now robust arguments supporting the hypothesis that K. kingae should be considered the primary etiological pathogen for spondylodiscitis. The third form affects children older than 4 years of age, and S. aureus is the predominant pathogen. Finally, a third classification is based on the anatomical characteristics of the patient’s vertebral endplate and disk vascularization. Many studies have demonstrated that the vertebral endplates and the superficial portion of the disks share a common blood supply at birth that gradually regresses during infancy. In children, the metaphysis of the vertebral body has a rich blood flow, with an incomplete vascular ring ending at the pedicle’s base. Otherwise, it has been shown that several fine anastomotic branches exist between the upper and lower metaphyseal rings of two adjacent vertebrae, mostly present around the disk’s posterolateral region, providing its blood flow. It is also commonly accepted that infection starts under the vertebral endplates, that it subsequently and successively crosses both the vertebral endplate and the disk’s surface via those fine anastomotic branches, reaching the adjacent vertebral body and, lastly, the disk space between the two affected vertebral bodies. Interestingly, the blood vessels which cross the vertebral endplates evolve at around 7 or 8 years old. These anatomical observations lead to two conclusions. First, it becomes reasonable to think that pure discitis, as some authors have suggested, cannot occur. Secondly, it seems highly likely that children will tend to have spondylodiscitis before the age of 7 to 8 years old and, afterwards, that older children and adolescents are more likely to develop vertebral osteomyelitis, providing that the infection is not neglected. Unfortunately, these concepts do not yet appear in textbooks or university curricula, thus perpetuating enormous confusion about these infections.

Multisystem inflammatory syndrome in children (MIS-C) following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been infrequently described in Africa. To describe the clinical characteristics, outcomes and associations of severe disease in children hospitalized with MIS-C in KwaZulu-Natal. Retrospective multicenter study of children (0-13 years) who met the Centers for Disease Control and Prevention criteria for MIS-C. Children with shock were compared with children without shock to determine the characteristics of severe MIS-C. Twenty-nine children with MIS-C were identified, the mean age was 55 (SD ±45) months, 25 (86%) were Black-African, and 8 (28%) had pre-existing comorbidities. The predominant presenting symptoms included fever 29 (100%), gastrointestinal symptoms 25 (83%), skin rash 19 (65%), and shock 17 (59%). Children with shock had significantly increased CRP (P = 0.01), ferritin (P < 0.001), troponin-T (P = 0.02), B-type natriuretic peptide (BNP) (P = 0.01), and lower platelets (P = 0.01). Acute kidney injury (P = 0.01), cardiac involvement (P = 0.02), and altered levels of consciousness (P = 0.03) were more common in children with shock. The median length of hospital stay was 11 (IQR 7-19) days, with a mortality of 20.6%. Children who did not survive had significantly higher ferritin levels 1593 (IQR 1069-1650) ng/mL versus 540 (IQR 181-1156) ng/mL; P = 0.03) and significantly more required mechanical ventilation (OR 18; confidence interval 1.7-191.5; P = 0.005). Hospitalized children with MIS-C in KwaZulu-Natal had more aggressive disease and higher mortality than children in better-resourced settings. Markedly elevated biomarkers and critical organ involvement were associated with severe disease. Risk factors for poor outcomes include higher ferritin levels and the need for mechanical ventilation.

The clinical features of coronavirus disease 2019 (COVID-19) in children have been changing because of the emergence and rapid spread of variants of concern (VOC). The increase in cases infected with VOC has brought concern with persistent symptoms after COVID-19 in children. This survey aimed to analyze the clinical manifestations and persistent symptoms of pediatric COVID-19 cases in Japan. We analyzed the clinical manifestations of pediatric COVID-19 cases reported between February 2020 and April 2022 in Japan, using a dedicated database updated voluntarily by the members of the Japan Pediatric Society. Using the same database, we also analyzed persistent symptoms after COVID-19 in children who were diagnosed between February 2020 and November 2021. A total of 5411 and 1697 pediatric COVID-19 cases were included for analyzing clinical manifestations and persistent symptoms, respectively. During the Omicron variant predominant period, the percentage of patients with seizures increased to 13.4% and 7.4% in patient groups 1-4 and 5-11 years of age, respectively, compared with the pre-Delta (1.3%, 0.4%) or Delta period (3.1%, 0.0%). Persistent and present symptoms after 28 days of COVID-19 onset were reported in 55 (3.2%). Our survey showed that the rate of symptomatic pediatric COVID-19 cases increased gradually, especially during the Omicron variant predominant period, and a certain percentage of pediatric cases had persistent symptoms. Certain percentages of pediatric COVID-19 patients had severe complications or prolonged symptoms. Further studies are needed to follow such patients.

In 2019, South Africa, Nigeria, Tanzania, Democratic Republic of Congo, Uganda, Mozambique, Zambia, Angola, Cameroon, Zimbabwe, Ghana, Ethiopia, Malawi, Kenya, South Sudan and Côte d'Ivoire accounted for 80% of children living with HIV (CLHIV) not receiving HIV treatment. This manuscript describes pediatric HIV testing to inform case-finding strategies. We analyzed US President's Emergency Plan for AIDS Relief monitoring, evaluation, and reporting data (October 1, 2018 to September 30, 2019) for these 16 countries. Number of HIV tests and positive results were reported by age band, country, treatment coverage and testing modality. The number needed to test (NNT) to identify 1 new CLHIV 1-14 years was measured by testing modality and country. The pediatric testing gap was estimated by multiplying the estimated number of CLHIV unaware of their status by NNT per country. Among children, 6,961,225 HIV tests were conducted, and 101,762 CLHIV were identified (NNT 68), meeting 17.6% of the pediatric testing need. Index testing accounted for 13.0% of HIV tests (29.7% of positive results, NNT 30), provider-initiated testing and counseling 65.9% of tests (43.6% of positives, NNT 103), and universal testing at sick entry points 5.3% of tests (6.5% of positives, NNT 58). As countries near HIV epidemic control for adults, the need to increase pediatric testing continues. Each testing modality - PITC, universal testing at sick entry points, and index testing - offers unique benefits. These results illustrate the comparative advantages of including a strategic mix of testing modalities in national programs to increase pediatric HIV case finding.