Population-Based Surveillance of Pneumococcal Infections in Children with Sickle Cell Disease before and after Prevnar 7® and Prevnar 13® Licensure: Implications for Expanded Vaccination

Before prophylactic antibiotic use, approximately 1/10 children <5 years old with sickle cell disease (SCD) developed invasive pneumococcal disease (IPD) with a high risk of meningitis and death. Although the emergence of penicillin-resistance in IPD threatened benefits of penicillin prophylaxis, after licensure of the 7-valent pneumococcal polysaccharide vaccine (PCV7) in 2000, IPD rates in children with SCD decreased by over 2/3. In 2010, PCV13 (serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F, 18C, 23F) was licensed in children, and in 2021, two additional conjugated vaccines were approved for use in adults: PCV15 (VAXNEUVANCE®, PCV13+: 22F, 33F) and PCV20 (PREVNAR20®, PCV13+: 8, 10A, 11A, 12F, 15B, 22F, 33F). IPD rates in children with SCD over 24 years in Atlanta were evaluated to describe trends in age of infection, frequency of antibiotic resistance, non-vaccine IPD serotype distribution after vaccine licensures, and estimates for serotype coverage by newer vaccines. IPD among children with SCD, ages 0 to 4 years and 5 to 9 years, residing in the Metropolitan area of Atlanta, Georgia, USA, from 1/1/1994 through 7/31/2018, were compared to the general population. The Centers for Disease Control and Prevention (CDC)-funded Georgia Emerging Infections Program (GA EIP) Active Bacterial Core Surveillance network included initially 8 counties in 1994 and from 1997 onward, 20 counties (total populations of approximately 3.8 and 5.1 million, respectively). Two registries of patients with SCD seen at least once at one of 3 pediatric hospitals serving the region were merged and matched with GA EIP data. The serotyping and antibiotic susceptibility testing were conducted at the CDC. The study was approved by the Emory University Institutional Review Board. Data from 3 periods: pre PCV period (94-99), PCV7 period (00-09) and PCV13 period (10-18) were analyzed. Compared to the pre PCV period, overall, IPD rates decreased in children with SCD vs 91% in the RP for 0-4 years; and 80% in children with SCD vs 78% in the RP for 5-9 years (table1). The difference in IPD rates between patients with SCD and the general population increased over time: pre PCV period, relative risk (RR)=24.22 (95 % Confidence Interval [CI] 17.43,32.88), P<.001; PCV 7 period, RR=32.17 (95 %CI 22.17,45.37), P<.001; PCV 13 period, RR=39.18 (95 %CI 22.35,64.69) P<.001. Meningitis and deaths from IPD decreased significantly in all populations examined but remained significantly higher in patients with SCD compared to RP (table 2). The mean age at IPD diagnosis for the 3 periods examined increased both in SCD and in the RP. For those with SCD (n=50), pre-PCV7 period mean age was :2.7 standard deviation (+/-) 2.3 years; for the PCV 13 period: n=19; 3.7 years +/-2.2 years p= 0.0877; for the RP: Pre-PCV period: n=1025; 1.3 +/-1.6 years; PCV 13 period: n=213; 2.2 +/-2.3 years. Overall absolute IPD rates declined for all age groups examined (table 1). Prior to PCV7 licensure, IPD in patients with SCD were significantly less likely to be penicillin susceptible (MIC <0.06 µg/mL) compared to the RP: 41.9% (18/43) vs 60.0% (476/793) RR=0.70 (95% CI 0.49,1.00), p=0.025. This difference was no longer present after PCV licensure (PCV 13 period , SCD 52.9% [9/17], vs RP 48.6% [70/144]). Non PCV serotypes IPD rates increased after PCV7 licensure but remained stable after PCV13 licensure; 16% of non PCV13 serotypes during all time periods are included in PCV15, whereas PCV20 may cover between 29% and 50% depending on related serotypes cross protection (table3). Although significantly less frequent compared with pre-PCV-era, IPD can be severe in patients with SCD. Increase in IPD age was seen in both SCD and RP. Lower rates of penicillin non-susceptibility may may reflect lower exposure to penicillin prophylaxis. Newer vaccines may offer expanded coverage for children with SCD. Ongoing surveillance will help determine their effect. Vaccines that cover all serotypes are needed. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Rheumatic heart disease in The Gambia: clinical and valvular aspects at presentation and evolution under penicillin prophylaxis

Background Rheumatic heart disease (RHD) remains the leading cause of cardiac-related deaths and disability in children and young adults worldwide. In The Gambia, the RHD burden is thought to be high although no data are available and no control programme is yet implemented. We conducted a pilot study to generate baseline data on the clinical and valvular characteristics of RHD patients at first presentation, adherence to penicillin prophylaxis and the evolution of lesions over time. Methods All patients registered with acute rheumatic fever (ARF) or RHD at two Gambian referral hospitals were invited for a clinical review that included echocardiography. In addition, patients were interviewed about potential risk factors, disease history, and treatment adherence. All clinical and echocardiography information at first presentation and during follow-up was retrieved from medical records. Results Among 255 registered RHD patients, 35 had died, 127 were examined, and 111 confirmed RHD patients were enrolled, 64% of them females. The case fatality rate in 2017 was estimated at 19.6%. At first presentation, median age was 13 years (IQR [9; 18]), 57% patients had late stage heart failure, and 84.1% a pathological heart murmur. Although 53.2% of them reported history of recurrent sore throat, only 32.2% of them had sought medical treatment. A history suggestive of ARF was reported by 48.7% patients out of whom only 15.8% were adequately treated. Two third of the patients (65.5%) to whom it was prescribed were fully adherent to penicillin prophylaxis. Progressive worsening and repeated hospitalisation was experienced by 46.8% of the patients. 17 patients had cardiac surgery, but they represented only 18.1% of the 94 patients estimated eligible for cardiac surgery. Conclusion This study highlights for the first time in The Gambia the devastating consequences of RHD on the health of adolescents and young adults. Our findings suggest a high burden of disease that remains largely undetected and without appropriate secondary prophylaxis. There is a need for the urgent implementation of an effective national RHD control programto decrease the unacceptably high mortality rate, improve case detection and management, and increase community awareness of this disease.

Community-based prevalence of rheumatic heart disease in rural Ethiopia: Five-year follow-up

Background As little is known about the prevalence and clinical progression of subclinical (latent) rheumatic heart disease (RHD) in sub-Saharan Africa, we report the results of a 5 year follow-up of a community based, echocardiographic study of the disease, originally carried out in a rural area around Jimma, Ethiopia. Methods Individuals with evidence of RHD detected during the baseline study as well as controls and their family members were screened with a short questionnaire together with transthoracic echocardiography. Results Of 56 individuals with RHD (37 definite and 19 borderline) in the original study, 36 (26 definite and 10 borderline) were successfully located 57.3 (range 44.9–70.7) months later. At follow-up two thirds of the definite cases still had definite disease; while a third had regressed. Approximately equal numbers of the borderline cases had progressed and regressed. Features of RHD had appeared in 5 of the 60 controls. There was an increased risk of RHD in the family relatives of borderline and definite cases (3.8 and 4.0 times respectively), notably among siblings. Compliance with penicillin prophylaxis was very poor. Conclusions We show the persistence of echocardiographically demonstrable RHD in a rural sub-Saharan population. Both progression and regression of the disease were found; however, the majority of the individuals who had definite features of RHD had evidence of continuing RHD lesions five years later. There was an increased risk of RHD in the family relatives of borderline and definite cases, notably among siblings. The findings highlight the problems faced in addressing the problem of RHD in the rural areas of sub-Saharan Africa. They add to the evidence that community-based interventions for RHD will be required, together with appropriate ways of identifying active disease, achieving adequate penicillin prophylaxis and developing vaccines for primary prevention.

Epidemiology of Stroke in Sickle Cell Disease

Sickle cell disease is the most common cause of stroke in childhood, both ischaemic and haemorrhagic, and it also affects adults with the condition. Without any screening or preventative treatment, the incidence appears to fall within the range 0.5 to 0.9 per 100 patient years of observation. Newborn screening with Penicillin prophylaxis and vaccination leading to reduced bacterial infection may have reduced the incidence, alongside increasing hydroxyurea prescription. Transcranial Doppler screening and prophylactic chronic transfusion for at least an initial year has reduced the incidence of stroke by up to 10-fold in children with time averaged mean of the maximum velocity >200 cm/s. Hydroxyurea also appears to reduce the incidence of first stroke to a similar extent in the same group but the optimal dose remains controversial. The prevention of haemorrhagic stroke at all ages and ischaemic stroke in adults has not yet received the same degree of attention. Although there are fewer studies, silent cerebral infarction on magnetic resonance imaging (MRI), and other neurological conditions, including headache, epilepsy and cognitive dysfunction, are also more prevalent in sickle cell disease compared with age matched controls. Clinical, neuropsychological and quantitative MRI screening may prove useful for understanding epidemiology and aetiology.

2396. Clostridium difficile Infection is Children with Sickle Cell Disease: An Uncommon Entity

Background Children with sickle cell disease (SCD) have numerous risk factors for intestinal dysbiosis, including frequent hospitalization, iron overload, antibiotic exposure including penicillin prophylaxis, hypoxia, and altered gut permeability. Many of these conditions are also established risk factors for C. difficile infection (CDI); however, the incidence of CDI in children with SCD has not been characterized. Methods We performed a 10-year retrospective review from 1/2008–December 2017. Patients who qualified with CDI were either admitted or within 2 weeks of discharge from our site and had a positive test. A positive test was defined as a positive glutamate dehydrogenase 1 test in conjunction with either a positive ELISA or a positive PCR for toxin. Three investigators independently reviewed if patients had active diarrhea during the time of their positivity. Patients excluded were <2 years old and patients undergoing a stem cell transplant (SCT) or irritable bowel disease (IBD) at the time of a positive test. Chi-square test with Yates correction, descriptive statistics were used when comparing groups<./p> Results Over a 10-year period (2008–2017), there were 5666 admissions for children with SCD, corresponding to 25,915 hospitalization days and 957 unique patients. The average age of this cohort at the time of admission was 10.6 ± 6.7 years; 51.7% were male. One patient qualified; a 12-year-old who developed diarrhea and abdominal pain after recent hospitalization for pneumonia (Figure 1). This yielded a CDI incidence of 0.39/10,000 patient-days or 0.18 cases per 1000 admissions (Table 1). There were 208 cases of CDI in non-SCD children, with an incidence of 5.53/10,000 patient-days (P < 0.001) or 2.77 cases per 1000 admissions (P < 0.001) (Table 2) during the study period. In 2015–2017, there were no cases of CDI in 957 SCD patients, of which 218 were on penicillin prophylaxis. Conclusion There is a very low incidence of CDI in children with SCD despite significant antibiotic exposure and other risk factors for intestinal dysbiosis. These findings are consistent with recent studies in adults (N Engl J Med 2019; 380:887–888) and suggest that sickle cell patients are somehow protected against CDI. Additional studies are needed to define the host and biome factors that confer this protection. Disclosures All authors: No reported disclosures.