Bacterial infections in a pediatric cohort of primary and acquired complement deficiencies

Abstract Background Acquired complement deficiency can occur in the setting of autoimmune syndromes, such as systemic lupus erythematosus (SLE), with very low or, occasionally, undetectable C3 levels. Based on inherited complement defects, patients with transiently low complement may be at similar risk for serious bacterial infection, but the degree of risk related to C3 level and temporal association is unknown. Methods We performed a retrospective study including pediatric patients with undetectable total complement activity or absent individual complement components measured at our institution from 2002 to 2018. We assessed annual rate of serious bacterial infection (SBI) defined as requiring hospitalization and/or parenteral antibiotics by manual chart review. Among included SLE patients, we assessed the 30-day probability of SBI for given C3 measurements using a logistic regression model to determine risk. Primary complement deficiency was analyzed for SBI rate as comparison. Covariates included age, level of immune suppression and history of lupus nephritis. Results Acquired complement deficiency secondary to SLE-related disease [n = 44] was the most common underlying diagnosis associated with depressed complement levels and were compared to a cohort of primary complement deficient patients [n = 18]. SBI per 100 person-years and cohort demographics were described in parallel. Our logistic regression analysis of pediatric patients with SLE showed low C3 level was temporally associated with having an SBI event. Given equivalent immunosuppression, patients with an SBI had lower C3 levels at the beginning of the observation period relative to patients without SBI. Conclusion Pediatric patients with the diagnosis of SLE can develop very low C3 levels that associate with risk of serious bacterial infection comparable to that of patients with primary complement deficiency. Patients prone to severe complement consumption may particularly be at risk.

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Bacterial infections in a pediatric cohort of primary and acquired complement deficiencies.

10.21203/rs.2.23978/v2 ◽

2020 ◽

Author(s):

Taha Al-Shaikhly ◽

Kristen Hayward ◽

Matthew L Basiaga ◽

Eric J Allenspach

Keyword(s):

Logistic Regression ◽

Bacterial Infection ◽

Lupus Erythematosus ◽

Bacterial Infections ◽

Pediatric Patients ◽

Complement Deficiency ◽

Temporal Association ◽

Complement Components ◽

History Of ◽

Total Complement

Abstract Background: Acquired complement deficiency can occur in the setting of autoimmune syndromes, such as systemic lupus erythematosus (SLE), with very low or, occasionally, undetectable C3 levels. Based on inherited complement defects, patients with transiently low complement may be at similar risk for serious bacterial infection, but the degree of risk related to C3 level and temporal association is unknown. Methods: We performed a retrospective study including pediatric patients with undetectable total complement activity or absent individual complement components measured at our institution from 2002 to 2018. We assessed annual rate of serious bacterial infection (SBI) defined as requiring hospitalization and/or parenteral antibiotics by manual chart review. Among included SLE patients, we assessed the 30-day probability of SBI for given C3 measurements using a logistic regression model to determine risk. Primary complement deficiency was analyzed for SBI rate as comparison. Covariates included age, level of immune suppression and history of lupus nephritis.Results: Acquired complement deficiency secondary to SLE-related disease [n=44] was the most common underlying diagnosis associated with depressed complement levels and were compared to a cohort of primary complement deficient patients [n=18]. SBI per 100 person-years and cohort demographics were described in parallel. Our logistic regression analysis of pediatric patients with SLE showed low C3 level was temporally associated with having an SBI event. Given equivalent immunosuppression, patients with an SBI had lower C3 levels at the beginning of the observation period relative to patients without SBI. Conclusion: Pediatric patients with the diagnosis of SLE can develop very low C3 levels that associate with risk of serious bacterial infection comparable to that of patients with primary complement deficiency. Patients prone to severe complement consumption may particularly be at risk.

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Risk of Bacterial Infection in Acquired Complement Deficiencies

10.21203/rs.2.23978/v1 ◽

2020 ◽

Author(s):

Taha Al-Shaikhly ◽

Kristen Hayward ◽

Matthew L Basiaga ◽

Eric J Allenspach

Keyword(s):

Logistic Regression ◽

Bacterial Infection ◽

Lupus Erythematosus ◽

Perceived Risk ◽

Logistic Regression Model ◽

Pediatric Patients ◽

Complement Deficiency ◽

Complement Components ◽

Related Disease ◽

Total Complement

Abstract Background: Acquired complement deficiency can occur in the setting of autoimmune syndromes, such as systemic lupus erythematosus (SLE), with very low or, occasionally, undetectable C3 levels. Based on data from patients with inherited complement defects, a perceived risk for serious bacterial infection exists amongst patients with transiently low complement, but the degree of risk related to C3 level is unknown. Methods: We performed a retrospective study of all pediatric patients with an undetectable total complement activity or absent individual complement components measured at our institution from 2002 to 2018. We assessed annual rate of serious bacterial infection (SBI) defined as requiring hospitalization and/or parenteral antibiotics. Among included SLE patients, we assessed the 30-day probability of SBI for given C3 measurements using a logistic regression model to determine risk. Results: Acquired complement deficiency secondary to SLE-related disease [n=44] was the most common underlying diagnosis associated with depressed complement levels. While controlling for immunosuppression level and lupus nephritis diagnosis, our logistic regression analysis of pediatric patients with SLE showed low C3 level was temporally associated with having an SBI event. Even in patients with equivalent immunosuppression, patients with an SBI were found to have lower C3 levels preceding the infection relative to patients without SBI. Conclusion: Pediatric patients with the diagnosis of SLE can develop very low C3 levels that are independently associated with risk of serious bacterial infection. Patients prone to complement consumption may particularly be at risk.

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Blood leukocyte microarrays to diagnose systemic onset juvenile idiopathic arthritis and follow the response to IL-1 blockade

Journal of Experimental Medicine ◽

10.1084/jem.20070070 ◽

2007 ◽

Vol 204 (9) ◽

pp. 2131-2144 ◽

Cited By ~ 159

Author(s):

Florence Allantaz ◽

Damien Chaussabel ◽

Dorothee Stichweh ◽

Lynda Bennett ◽

Windy Allman ◽

...

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Lupus Erythematosus ◽

Bacterial Infections ◽

Pediatric Patients ◽

Expression Profiles ◽

Systemic Disease ◽

Response To Therapy ◽

Healthy Children ◽

Initiation Of Therapy ◽

Systemic Onset

Systemic onset juvenile idiopathic arthritis (SoJIA) represents up to 20% of juvenile idiopathic arthritis. We recently reported that interleukin (IL) 1 is an important mediator of this disease and that IL-1 blockade induces clinical remission. However, lack of specificity of the initial systemic manifestations leads to delays in diagnosis and initiation of therapy. To develop a specific diagnostic test, we analyzed leukocyte gene expression profiles of 44 pediatric SoJIA patients, 94 pediatric patients with acute viral and bacterial infections, 38 pediatric patients with systemic lupus erythematosus (SLE), 6 patients with PAPA syndrome, and 39 healthy children. Statistical group comparison and class prediction identified genes differentially expressed in SoJIA patients compared with healthy children. These genes, however, were also changed in patients with acute infections and SLE. An analysis of significance across all diagnostic groups identified 88 SoJIA-specific genes, 12 of which accurately classified an independent set of SoJIA patients with systemic disease. Transcripts that changed significantly in patients undergoing IL-1 blockade were also identified. Thus, leukocyte transcriptional signatures can be used to distinguish SoJIA from other febrile illnesses and to assess response to therapy. Availability of early diagnostic markers may allow prompt initiation of therapy and prevention of disabilities.

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Complement-mediated granulocyte dysfunction in paroxysmal nocturnal hemoglobinuria

Blood ◽

10.1182/blood.v47.6.931.bloodjournal476931 ◽

1976 ◽

Vol 47 (6) ◽

pp. 931-939

Author(s):

PR Craddock ◽

J Fehr ◽

HS Jacob

Keyword(s):

Alkaline Phosphatase ◽

Bacterial Infection ◽

Trypan Blue ◽

Bacterial Infections ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Serum Complement ◽

Significant Morbidity ◽

Complement Components ◽

Leukocyte Alkaline Phosphatase ◽

Bacterial Products

In paroxysmal nocturnal hemoglobinuria (PNH), infection, both viral and bacterial, disproportionate to the mild neutropenia seen in many such patients is responsible for significant morbidity. We report impaired granulocyte chemotaxis efficiency which may contribute to the problems induced by bacterial infections. PNH (but not normal) granulocytes, after exposure to very small concentrations of activated serum complement components, migrate poorly, as documented by their inhibited chemotaxis toward bacterial products or activated complement components in Boyden chambers. The granulocytes remain intact, excluding trypan blue, phagocytosing, and killing bacteria, despite this activated complement exposure. It is also suggested that this chemotactic defect may involve only a clone of cells, analogous to the clonal lysis of PNH erythrocytes; those few granulocytes capable of migration after exposure to activated complement contain normal quantities of leukocyte alkaline phosphatase (LAP), in contrast to the LAP deficiency of the overall PNH granulocyte population. Since bacterial infection may initiate or potentiate hemolysis, one of the major symptoms of the disease, these results could explain much of the morbidity of PNH.

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Chikungunya and dengue virus infection among febrile children in North-Eastern Tanzania: prospective study

10.21203/rs.3.rs-22979/v1 ◽

2020 ◽

Author(s):

Adonira Saro ◽

Debora Kajeguka ◽

Kaunara Azizi ◽

Steven Mwakalinga ◽

Franklin Mosha ◽

...

Keyword(s):

Logistic Regression ◽

Dengue Virus ◽

Bacterial Infections ◽

Chikungunya Virus ◽

Clinical Symptoms ◽

Dengue Viruses ◽

North Eastern ◽

Kilimanjaro Christian Medical Centre ◽

History Of ◽

Arusha Region

Abstract Background There are several unknown illnesses including chikungunya and dengue viruses that present with fever in children. Therefore there are many cases that are misdiagnosed. Consequently we performed a study to determine the clinical characteristics of dengue and chikungunya in order to assist clinicians in management. Methods A total of 196 children with history of fever for ≤ 10 days were enrolled prospectively at Kilimanjaro Christian Medical Centre from September 2015 to May 2016. All cases were screened for chikungunya and dengue viruses by PCR as well as other febrile illnesses such as malaria, bacteria and HIV through other diagnostic method. We performed logistic regression to find association between clinical symptoms and chikungunya infection. Results In our study, 21.9% (43/196) of the cases received laboratory investigations and the diagnoses were as follows; malaria only (n = 1, 0.5%), bacterial infections only (n = 4, 2.0%), HIV/AIDS only (n = 37, 18.9%), as well as malaria, meningitis and urinary tract co-infection (n = 1, 0.5%). Further investigation of all cases revealed that 11.7%( 23) had chikungunya virus while none had dengue virus. For the cases of chikungunya, 78.3% (18) were below 5 years of age, 65.2%( 15) were females, majority were from Kilimanjaro 95.7%( 22) and Arusha region 4.3% (1). The clinical features were as follows; nausea/vomit 50.0% (98), cough 48.5% (95), convulsion/comma 34.7%( 68), diarrhea 26.0% (51), joint pain 13.3% (26), sore throat 7.1%( 14), rashes 4.1%(8)chills 2.6%༈5༉. Nevertheless, there was no statistical significant relationship between chikungunya virus and aforementioned symptoms/signs according to logistic regression. Conclusion This study reveals that chikungunya infection is common cause of febrile illnesses; however it does not have treatment. Therefore, we encourage chikungunya infection to be included in routine investigation as these children are receiving inappropriate treatments such as antibiotics and ant malarial which should be avoided in order to minimize over use of drugs and resource wastage.

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Covid-19 Associated Hepatitis in children (CACH) during the second wave of SARS-CoV-2 infections in Central India: Is it a complication or transient phenomenon.

10.1101/2021.07.23.21260716 ◽

2021 ◽

Author(s):

Sumit K Rawat ◽

Ajit anand Asati ◽

Ashish Jain ◽

Radha Kant Ratho

Keyword(s):

Acute Hepatitis ◽

Inflammatory Markers ◽

Pediatric Patients ◽

High Titer ◽

Central India ◽

Clinical Work ◽

Sudden Onset ◽

Temporal Association ◽

History Of ◽

Second Wave

Background: Besides Covid-19, SARS-CoV-2 infection has been associated with Multiple Inflammatory Syndrome in children (MIS-C). However, a unique presentation of a transient form of hepatitis in pediatric age group occurring subsequent to the asymptomatic SARS-CoV-2 infection is yet to be reported in children. Presently the clinical work, temporal association and characteristics different than MIS-C of the cases of CAHC is being dealt with. Methods: As a retrospective and follow up observational study we reviewed all pediatric patients presenting with acute hepatitis during the study period from April 2021 to mid- June 2021. We observed a sudden rise of features of hepatitis in a group of pediatric patients during the second wave of SARS CoV-2 infections, where children or adolescents developing sudden onset acute hepatitis with no history of pre-existing liver disease in the absence of familiar etiology of acute hepatitis and with a recent 3-6 week history of RT-PCR positivity or a retrospectively proven Covid-19 infection with high titer SARS CoV-2 antibodies. Such patients had asymptomatic Covid-19 infection, while another very small group (n=8) patients having findings similar to MIS-C was identified with protracted and grave presentation, having multiple organ involvement along with Covid-19 diagnosis. Routine lab workup along with viral serology of acute hepatitis was performed in all such patients. These patients were negative for Hepatitis A, B, C and E but had high titer of SARS CoV-2 antibodies. Results: Among 33 patients who presented with hepatitis, 25 patients showed unique features of CAHC, they had hepatitis only. These patients did not have any typical Covid-19 symptoms, had normal to borderline inflammatory markers, with admission to general care wards, all recovered on supportive treatment without any complications or mortality. Whereas patients with MIS-C (n=8) required admission to critical care, they had high level of inflammatory markers and 3 (37.5%) had an adverse outcome. Conclusion: With emergence of newer variants of concern such as the Delta variant which caused the massive wave of Covid-19 in India, with varied presentations, CAHC is one of them. Such new entities need to be timely identified and differentiated from other types of emerging syndromes in children for appropriate management.

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Development of Meningitis During Therapy with Cefamandole

PEDIATRICS ◽

10.1542/peds.67.5.727 ◽

1981 ◽

Vol 67 (5) ◽

pp. 727-728

Author(s):

S. C. Aronoff ◽

W. Thomford ◽

J. S. Bertino ◽

W. T. Speck

Keyword(s):

Bacterial Infections ◽

Antimicrobial Agents ◽

Pediatric Patients ◽

Potential Hazard ◽

Procaine Penicillin ◽

Source Of Infection ◽

Local Physician ◽

Life Threatening ◽

History Of

Cefamandole nafate is a relatively new cephalosporin approved for use in pediatric patients. This compound offers certain advantages over previously approved cephalosporins including its in vitro antimicrobial activity against β-lactamase-producing Haemophilus influenzae. The purpose of this report is to describe a potential hazard associated with the use of this and closely related antimicrobial agents in life-threatening bacterial infections. CASE REPORT This was the first Rainbow Babies and Childrens Hospital admission for this 7-month-old boy with a ten-day history of fever and irritability. Seven days prior to admission he was seen by a local physician for fever. No source of infection was noted and the infant was treated with 300,000 units of intramuscular procaine penicillin.

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Natural Course of Cerebral Cavernous Malformations in Children: A Five-Year Follow-Up Study

Stroke ◽

10.1161/strokeaha.121.035338 ◽

2021 ◽

Author(s):

Alejandro N. Santos ◽

Laurèl Rauschenbach ◽

Dino Saban ◽

Bixia Chen ◽

Annika Herten ◽

...

Keyword(s):

Logistic Regression ◽

Brain Stem ◽

Odds Ratio ◽

Pediatric Patients ◽

Cox Regression ◽

Cerebral Cavernous Malformations ◽

Multivariate Logistic Regression ◽

Cavernous Malformations ◽

History Of

Background and Purpose: The purpose of this study was to investigate the natural course of cerebral cavernous malformations (CCM) in the pediatric population, with special emphasis on the risk of first and recurrent bleeding over a 5-year period. Methods: Our institutional database was screened for patients with CCM treated between 2003 and 2020. Patients ≤18 years of age with complete magnetic resonance imaging data set, clinical baseline characteristics, and ≥1 follow-up examination were included. Surgically treated individuals were censored after CCM removal. We assessed the impact of various parameters on first or recurrent intracerebral hemorrhage (ICH) at diagnosis using univariate and multivariate logistic regression adjusted for age and sex. Kaplan-Meier and Cox regression analyses were performed to determine the cumulative 5-year risk for (re)hemorrhage. Results: One hundred twenty-nine pediatric patients with CCM were analyzed. Univariate logistic regression identified brain stem CCM (odds ratio, 3.15 [95% CI, 1.15−8.63], P =0.026) and familial history of CCM (odds ratio, 2.47 [95% CI, 1.04−5.86], P= 0.041) as statistically significant predictors of ICH at diagnosis. Multivariate logistic regression confirmed this correlation (odds ratio, 3.62 [95% CI, 1.18−8.99], P= 0.022 and odds ratio, 2.53 [95% CI, 1.07−5.98], P =0.035, respectively). Cox regression analysis identified ICH as mode of presentation (hazard ratio, 14.01 [95% CI, 1.80−110.39], P= 0.012) as an independent predictor for rehemorrhage during the 5-year follow-up. The cumulative 5-year risk of (re)bleeding was 15.9% (95% CI, 10.2%−23.6%) for the entire cohort, 30.2% (20.2%−42.3%) for pediatric patients with ICH at diagnosis, and 29.5% (95% CI, 13.9%−51.1%) for children with brain stem CCM. Conclusions: Pediatric patients with brain stem CCM and familial history of CCM have a higher risk of ICH as mode of presentation. During untreated 5-year follow-up, they revealed a similar risk of (re)hemorrhage compared to adult patients. The probability of (re)bleeding increases over time, especially in cases with ICH at presentation or brain stem localization.

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Association of procalcitonin values and bacterial infections in pediatric patients receiving extracorporeal membrane oxygenation

Perfusion ◽

10.1177/0267659117743806 ◽

2017 ◽

Vol 33 (4) ◽

pp. 278-282 ◽

Cited By ~ 3

Author(s):

Vi Ean Tan ◽

Wayne S. Moore ◽

Arun Chopra ◽

Jeffrey J. Cies

Keyword(s):

Positive Predictive Value ◽

Extracorporeal Membrane Oxygenation ◽

Bacterial Infection ◽

Predictive Value ◽

Bacterial Infections ◽

Pediatric Patients ◽

Linear Regression Analysis ◽

Data Set ◽

Predictive Values ◽

Membrane Oxygenation

Objective: There is increasing data in pediatrics demonstrating procalcitonin (PCT) is more sensitive and specific than other biomarkers in the setting of bacterial infections. However, the use of PCT in neonatal and pediatric extracorporeal membrane oxygenation (ECMO) is not well described. Therefore, the purpose of this study was to describe the clinical utility of PCT in determining the absence or presence of bacterial infections in neonatal and pediatric patients on ECMO. Methods: This was a retrospective electronic medical record (EMR) review of data between January 1, 2010 to June 30, 2016 at a single, free-standing, children ’s hospital. All patients on ECMO with ≥1 PCT level obtained while receiving ECMO support were eligible for inclusion. The EMR was searched for chest radiographs (CXR) and bacterial culture results (urine, blood, cerebrospinal fluid (CSF), bronchoalveolar lavage (BAL) and respiratory cultures). All bacterial and viral cultures obtained within 5 days of PCT levels being obtained were analyzed. PCT levels of 0.5, 0.9, 1.0, 1.4 and 2.0 were used as the initial cut-off values for the analysis. The sensitivity, specificity, positive predictive value (PPV), negative predictive values (NPV) and likelihood ratios were calculated for each of the PCT levels. Results: Twenty-seven patients met the inclusion criteria and contributed 193 PCT values for the analysis. The median age was 8 months (range 0 days to 18 years). Linear regression analysis demonstrated that a PCT cut-off of 0.5, 0.9 and 1.4 predicted the presence of a bacterial infection. The PCT value with the most utility was 0.5, with a sensitivity of 92%, a specificity of 43%, a positive predictive value of 60% and a negative predictive value (NPV) of 86%. Conclusion: This is the largest data set evaluating PCT in neonatal and pediatric patients on ECMO. A PCT value of 0.5 ng/mL had the most utility for determining the absence or presence of a bacterial infection in the setting of ECMO with a high sensitivity and NPV.

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1213. A TRAIL/IP-10/CRP Signature Distinguishes between Viral and Bacterial Infection in Chronic Obstructive Pulmonary Disease Patients

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1398 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S628-S628

Author(s):

Meital Paz ◽

Salim Halabi ◽

Shachaf Shiber ◽

Ami Neuberger ◽

Neta Petersiel ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Bacterial Infection ◽

Bacterial Infections ◽

Viral Infections ◽

Expert Panel ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Antibiotic Overuse ◽

Copd Patients ◽

History Of

Abstract Background Challenges in determining the etiology of acute exacerbations of chronic obstructive pulmonary disease (COPD) lead to significant overuse of antibiotics. A new host-response assay that integrates the levels of three proteins (TRAIL, IP-10, and CRP) was shown to exhibit high performance in distinguishing between bacterial and viral disease in two double-blind pediatric validation studies. Here we sought to evaluate its ability to differentiate bacterial from viral infection in adult COPD patients with suspicion of lower respiratory tract infection (LRTI). Methods The study population included 492 febrile adult patients prospectively recruited in “Observer”, an EU Horizon 2020 funded study (grant #684589). Patient etiology was determined by majority expert panel based on clinical, laboratory, multiplex PCR, radiological and follow-up data. We compared the expert panel diagnosis with the assay that gives three possible outcomes: viral, bacterial (including viral with bacterial coinfection) or equivocal. Results 45 out 492 adult patients prospectively recruited with suspicion of LRTI had a medical history of COPD. Of these, 20 cases were assigned as suspected viral infections and 19 as suspected bacterial infections (Figure 1). Antibiotics were prescribed to 19/19 bacterial infections and 16/20 viral infections. The assay correctly classified 19/19 bacterial infections and 12/20 viral infections, with 2 viral cases classified by the assay as bacterial and 6 receiving an equivocal outcome. These data support the assay’s potential to reduce antibiotic overuse from 16/20=80% to 8/20=40% (P=0.01). FIgure 1: Flow through of COPD patients in prospective performance validation study “Observer” Conclusion A new TRAIL/IP-10/CRP signature has potential to significantly reduce antibiotic overuse for patients with suspected LRTI and a history of COPD without missing bacterial infection. Disclosures Meital Paz, MD, MeMed Ltd. (Employee) Noa Avni, PhD, MeMed (Employee) Michal Stein, MeMed Ltd. (Employee) Liran Shani, MD, MeMed Ltd. (Employee) Tanya Gottlieb, PhD, MeMed (Employee) Kfir Oved, MD, PhD, MeMed (Employee) Eran Eden, PhD, MeMed (Employee)

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