Unknown Origin In Children Research Articles

Fever of Unknown Origin in Children

Fever is a common symptom in children and fever of unknown origin (FUO) is not uncommon in paediatric age group. The FUO remains a challenging clinical problem and is an important cause of morbidity and mortality in children. These undifferentiated prolonged fevers need step-wise approach for diagnosis. Details and proper history taking, thorough serial physical examination, critical analysis of sign-symptoms diary and investigation reports are crucial to get a clue that led to the diagnosis. Though in some aspect more concerned with developing countries data, this article is based on reviewing of published papers from both developed and developing countries. Worldwide infection remains the most common cause of FUO in children, followed by collagen vascular diseases, neoplasm, miscellaneous diseases and undiagnosed illnesses. Indiscriminate use of antimicrobials and other medications may mask the real diagnosis. Awareness of primary-level healthcare providers about the cause and logical management approach of pediatric FUO is important for better outcome. Journal of Monno Medical College December, 2023; 9 (2):78-84

Fever of Unknown Origin in Children: A Single Center Experience from Southern Türkiye

Fever of Unknown Origin in Children: A Single Center Experience from Southern Türkiye

Severe acute hepatitis of unknown origin in children: Is it still amystery? What role does adenovirus play?

On March 31, 2022, severe acute hepatitis of unknown origin was first reported from the Royal Glasgow Children's Hospital in Scotland. According to the criteria by WHO-ECDC, a probable case of unknown acute hepatitis in children is defined as a subject under 16 years of age, who tested negative for viral hepatitis and transaminases >500 U/L, starting from the 1st of October 2021. WHO invites Member States to participate in the global effort to collect anonymized clinical data on probable cases of severe acute hepatitis of unknown aetiology. As of May 26, 2021, 650 cases were already registered on the platform worldwide, of whom at least 38 cases have required liver transplants. Several hypotheses such as previous SARS-CoV-2 infection or coinfection or infection with another virus were examined and a strong association was found between adenovirus (41F) and acute hepatitis of unknown aetiology cases. This review article summarizes the global epidemiological evidences on acute hepatitis of unknown origin in children, analysing their incidence and characteristics.

Clinical and metagenomic characteristics of lymphadenopathy related to fever of unknown origin in children.

Diagnosis of fever of unknown origin remains challenge for pediatricians. Lymphadenopathy is a separate entity that mainly originates from infection or malignancy. 168 patients with FUO accompanied by lymphadenectasis were reviewed. 33 lymph node tissue samples were examined by mNGS. Differences in clinical characteristics were compared among different disease groups. The value of mNGS in diagnosing and improving the clinical situation was assessed. Multivariate analysis revealed that hepatosplenomegaly and LDH levels were associated with infectious diseases. Arthralgia was correlated with non-infectious inflammatory diseases. Weight loss and a node located in supraclavicular region may indicate neoplastic diseases. mNGS-positive rate was 60.60%, higher than that obtained with traditional methods. Treatment for 3/4 patients was adjusted according to the pathogen detected by mNGS, and antibiotics uses was discontinued or degraded in over 1/2 of the patients according to mNGS results. Clinical characteristics of children with lymphadenopathy related to FUO have limited diagnostic value for distinguishing different kinds of diseases, while mNGS of lymph node tissue serves as a useful tool for identifying infectious diseases, especially those caused by rare pathogens. mNGS results can lead to not only adjustments in targeted treatment but also further confirmation of underlying diseases. 1. The clinical features of children with FUO and lymphadenopathy differ according to disease group,although multivariate analysis indicated little diagnostic value for these features. 2. mNGS on lymph node tissue from children with FUO may serve as a efficient tool for distinguishing infectious diseases from other diseases. This is especially useful when a diagnosis cannot be determined with traditional methods. 3. mNGS targeted treatment can be administered in a timely manner and some underlying diseases can be indicated.

Acute Hepatitis of Unknown Origin in Children: Analysis of 17 Cases Admitted to the Bambino Gesù Children's Hospital in Rome.

This study described 17 cases of children admitted to the Bambino Gesù Children's Hospital with acute hepatitis of unknown origin between mid-April and November 2022. Following the World Health Organization's working case definition of probable cases, 17 children, with a median age of 2.1 years (interquartile range: 1.0-7.1), presenting with acute hepatitis non-AE, with serum transaminase >500 IU/L, were included in the study. A pre-specified set of microbiological tests was performed on different biological specimens for all pediatric patients. All patients resulted negative for the common hepatotropic viruses. The most common pathogen detected in blood specimens was human-herpes-virus-7 (52.9%). Adenovirus was detected more frequently in stool specimens (62.5%) than in respiratory (20.0%) or blood samples (17.6%). Regarding Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, one child tested positive two days after admission, while antibodies against spike and nucleoprotein were present in 82.3% of patients. A co-pathogen detection was observed in 94.1% of children. Overall, 16 children recovered without clinical complications, while one patient required liver transplantation. In these cases of acute hepatitis of unknown origin, adenovirus was mainly detected in stool samples. A co-pathogen detection was also frequently observed, suggesting that the etiology of this acute hepatitis is most probably multifactorial.

“Masks” of fever of unknown origin in children

The article presents an analysis of cases of hospitalized children with fever of unknown origin. Purpose: to study the nosological structure of the causes of fever of unknown genesis in hospitalized children. Material and methods: a retrospective analysis of the medical histories of children hospitalized in the pediatric department was carried out for 2022–2023. All children underwent a comprehensive laboratory and instrumental examination. Results: the largest proportion (43,9 %) were school-age children who, in addition to fever, had complaints of weakness (87,8 %) and decreased appetite (85,4 %). Anemia (51,2 %), acceleration of ESR (47,6 %) and an increase in C-reactive protein (45,1 %) were most often recorded in the analyses. The causes of fever of unknown origin in 65,9 % of children were infectious diseases, in 19,5 % — autonomic dysfunction syndrome with a violation of thermoregulation, in 6,1 % — systemic connective tissue diseases, in 4,9 % — oncological pathology, in 2,4 % — inflammatory diseases of the gastrointestinal tract. The results of the study can be applied in pediatric practice, monitoring of children with infectious pathology.

Update on Fever of Unknown Origin in Children: Focus on Etiologies and Clinical Approach.

Fever of unknown origin (FUO) can be caused by four etiological categories of diseases. The most common cause of FUO in children is represented by infections, followed by inflammatory conditions and neoplastic causes; a decreasing quote remains still without diagnosis. Despite the fact that several diagnostic and therapeutic approaches have been proposed since the first definition of FUO, none of them has been fully validated in pediatric populations. A focused review of the patient's history and a thorough physical examination may offer helpful hints in suggesting a likely diagnosis. The diagnostic algorithm should proceed sequentially, and invasive testing should be performed only in select cases, possibly targeted by a diagnostic suspect. Pioneering serum biomarkers have been developed and validated; however, they are still far from becoming part of routine clinical practice. Novel noninvasive imaging techniques have shown promising diagnostic accuracy; however, their positioning in the diagnostic algorithm of pediatric FUO is still not clear. This narrative review aims to provide a synopsis of the existent literature on FUO in children, with its major causes and possible diagnostic workup, to help the clinician tackle the complex spectrum of pediatric FUO in everyday clinical practice.

Fever of Unknown Origin in Children: The Challenge of History Taking

A fever of unknown origin (FUO) in children is usually described as a fever of at least 8 days duration with no apparent diagnosis after initial investigations, including taking medical history and preliminary laboratory assessment. Infectious diseases are the most common cause of FUO, followed by rheumatologic and neoplastic conditions. In this report, we present a case of a 15-year-old Caucasian boy with a silent past medical history, who presented at our Pediatric ER department with a three-day history of fever, fatigue, and abdominal pain with diarrhoea. Initial laboratory testing and microbiological work-up were non-significant. At hospital admission, a broad infectious diagnostic work-up was pursued, including serologies and polymerase-chain-reaction (PCR) for CMV, EBV, HAV, Parvovirus, Toxoplasma gondii and Adenovirus, all negative. Given mild splenomegaly and linfadenopathy, systemic Juvenile Idiopathic Arthritis (s-JIA) was suspected, as well as Multi-inflammatory Syndrome in Children (MIS-C), but the patient did not meet their main diagnostic criteria. Malignancy was ruled out by a negative bone marrow fine-needle aspiration cytology and whole-body PET-CT scan. On hospital day 8, Brucella was identified on a new set of blood cultures and a combined antibiotic therapy was started with IV Gentamicin plus per os Doxycycline. The patient’s general conditions rapidly improved, and both fever and diarrhoea resolved. A reassessment of the patient’s medical history before discharge revealed exposure to unpasteurized soft cheese in the weeks prior to the onset of symptoms. This case underlines the importance of taking a complete medical history, as well as a full diagnostic work-up to unveil unusual infectious etiologies behind FUO. After the preliminary negative microbiological tests, a connective tissue disease was ruled out (i.e. lack of cutaneous or articular involvement), as well as malignancy, which led to a closer evaluation for infection and the diagnosis of Brucellosis.

Investigating acute hepatitis of unknown origin in children.

In late 2021, the CDC was alerted to a cluster of children with hepatitis of unknown etiology at a US hospital. Similar reports began to emerge out of Europe. This article discusses the systematic investigation into these cases.

Hepatitis of unknown origin in children and adolescents

Hepatitis of unknown origin in children and adolescents

Acute hepatitis of unknown origin in children: analysis of probable etiologies

Background. An outbreak of hepatitis of unknown origin in children aged 1 month — 16 years was first reported by the WHO in April 2022. It was accompanied by a high frequency of acute liver failure, and up to 5 % of children required liver transplantation. The purpose of the review was to determine probable etiological factors and mechanisms of acute hepatitis of unknown origin based on a systematic analysis of literary sources. Materials and methods. We conducted a search for studies on cases or case series of acute hepatitis of unknown origin in the PubMed between January 2022 and February 2023. A combination of the following terms was used for the search: “unknown hepatitis”, “hepatitis of unknown origin”, “non-A-E hepatitis”, “hepatitis of unknown etiology” and “children”. Results. According to the search results, 312 publications were found. After the selection, 14 publications were included in the review. A systematic analysis of 1,188 cases of acute hepatitis of unknown origin, which corresponded to the identified case, showed a high variability of causative agents. However, most children were tested positive for adenovirus (almost 57 %), and 14 % of children had a positive PCR for SARS-CoV-2. Among other viruses detected in children, viruses of the herpes family should be noted, especially human herpesvirus 7 (34.2 %), human herpesvirus 6 (20 %), Epstein-Barr virus (18.2 %), cytomegalovirus (9.2 %). Rhinovirus (40.7 %), enterovirus/rhinovirus (28.7 %), parainfluenza virus (15.4 %), streptococcal infection, and other pathogens were also found. Conclusions. Viruses, genetic predisposition and other factors that change the body’s immune response play an important role in the development of an outbreak of severe hepatitis. Systematic analysis has shown that human adenovirus most often acts as a helper for adeno-associated virus 2, which plays a major role in initiating an immune response in genetically predisposed individuals, causing acute hepatitis and acute liver failure. SARS-CoV-2 infection probably also plays a certain role in immune activation and in the development of hyperinflammation, as do other viruses that act as helpers for adeno-associated virus 2. Continued collection of detailed clinical, microbiological, and epidemiological data on probable cases, as well as well-planned and coordinated follow-up studies are necessary to identify risk factors and other etiological factors associated with this disease.

Acute severe hepatitis of unknown origin in children in Canada.

In spring 2022, a series of reports from the United Kingdom and the United States identified an increase in the incidence of acute severe hepatitis in children. The Public Health Agency of Canada (PHAC) collaborated with provincial/territorial health partners to investigate in Canada. Clinical hepatitis, or inflammation of the liver, is not reportable in Canada, so to determine if an increase was occurring above historical levels, the baseline incidence in Canada was estimated. This article estimates the pre-existing baseline incidence of acute severe hepatitis of unknown origin in children in Canada using administrative databases. It further summarizes the outbreak investigation using information from the national case report forms. A committee with representatives from PHAC and provincial/territorial health partners was established to investigate current cases in Canada. A national probable case definition and case report form were developed, and intentionally created to be highly sensitive to capture all potential cases for etiological investigations. To estimate a nationally representative baseline incidence, hospitalization data were extracted from the Discharge Abstract Database and was combined with data from Québec from the Ministère de la Santé et des Services sociaux. Twenty-eight probable cases of acute severe hepatitis of unknown origin in children were reported between October 1, 2021, to September 23, 2022, by six provinces: British Columbia=1; Alberta=5; Saskatchewan=1; Manitoba=3; Ontario=14; and Québec=4. The estimated national baseline incidence was an average of 70 cases annually, or 5.8 cases per month. There was no apparent increase above the estimated historical baseline levels.

Orchestrated regulation of immune inflammation with cell therapy in pediatric acute liver injury.

Acute liver injury (ALI) in children, which commonly leads to acute liver failure (ALF) with the need for liver transplantation, is a devastating life-threatening condition. As the orchestrated regulation of immune hemostasis in the liver is essential for resolving excess inflammation and promoting liver repair in a timely manner, in this study we focused on the immune inflammation and regulation with the functional involvement of both innate and adaptive immune cells in acute liver injury progression. In the context of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, it was also important to incorporate insights from the immunological perspective for the hepatic involvement with SARS-CoV-2 infection, as well as the acute severe hepatitis of unknown origin in children since it was first reported in March 2022. Furthermore, molecular crosstalk between immune cells concerning the roles of damage-associated molecular patterns (DAMPs) in triggering immune responses through different signaling pathways plays an essential role in the process of liver injury. In addition, we also focused on DAMPs such as high mobility group box 1 (HMGB1) and cold-inducible RNA-binding protein (CIRP), as well as on macrophage mitochondrial DNA-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway in liver injury. Our review also highlighted novel therapeutic approaches targeting molecular and cellular crosstalk and cell-based therapy, providing a future outlook for the treatment of acute liver injury.

Clinicoetiological profile of pyrexia of unknown origin in children 1-12 years of age in a tertiary care centre

Background: A primary concern of the paediatricians in evaluating a child with PUO is the limited use of investigations that are case-specific especially in developing countries such as India where availability and affordability are the limiting factors. Hence, this study was conducted to evaluate the various etiological factors and the clinical profile of children presenting with PUO in this region. Methods: A hospital based cross sectional study was conducted among 200 children presenting with fever i.e., temperature >100.9⁰F/38.3 ⁰C of more than one week duration, with no clear diagnosis after initial investigations Results: A total of 193 children were included in the study with a mean age of 6.2±1.8 years. Most (62.5%) of the participants had infectious etiology, followed by collagen vascular disorders (10 %) and malignancies (9.5%). Among the participants, 10% remain undiagnosed. Among infectious causes, the most common was respiratory tract infections (17.5%), followed by scrub typhus (13.5%) and urinary tract infections (10%). Conclusions: Our study was conducted to outline the clinic-etiological profile of pediatric patients with PUO in our region. After proper investigations, a diagnosis could be reached in most patients. The commonest aetiology was infectious, followed by collagen vascular disorders and malignancies. Further studies with a larger sample size are suggested.

Severe acute hepatitis of unknown origin in children: Clinical issues of concern.

Severe acute hepatitis of unknown origin in children: Clinical issues of concern.

EBV as the cause of fever of unknown origin in children

EBV is a human herpesvirus which is ubiquitous in nature and infects most of the world population. Children mostly acquire primary EBV infection from close contact that involves exchange of oral secretions. Primary EBV infection in children may go undetected as it is often asymptomatic or is presented with atypical or partial Infectious Mononucleosis syndrome. This study aimed to highlight the role of primary EBV as a cause of Fever of Unknown Origin in childhood. Fever resulted the most common symptom of IM in 97% of children, it was of long duration and correlated with the massive lymphocytosis of primary EBV infection in children. Primary EBV infection is a potential cause of Fever of Unknown Origin in Children.

Clinical Guideline and Diagnostic Algorithm of Acute Hepatitis with Unknown Origin in Children: Tehran Children’s Medical Center Protocol

: Reports of acute hepatitis with unknown origin in children have been published worldwide since April 2022. Due to the unfamiliar nature of the disease and the alarming trend of increasing reports worldwide, health workers must become aware of its diagnosis and treatment. Accordingly, the committee for developing guidelines for the Department of Pediatrics, Tehran University of Medical Sciences, prepared a clinical guideline for more efficient management of these patients. Due to the limited information about this disease, it has been tried to categorize and specify the required diagnostic and treatment measures based on the latest published data. Herein we express this algorithmic approach and diagnostic and therapeutic guidelines for acute hepatitis with unknown origin in children.

May 2022 acute hepatitis outbreak, is there a role for COVID-19 and other viruses?

There has been an increasing number of reported cases of acute hepatitis of unknown origin in previously healthy children since first reported on March 31, 2022. This clinical syndrome is identified by jaundice and markedly elevated liver enzymes with increased aspartate transaminase and/or alanine aminotransaminase (greater than 500 IU/L). We conducted an inclusive literature review with respect to acute hepatitis outbreaks in children using the search terms acute hepatitis, outbreak, children, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease 2019 (COVID-19), and adenovirus. According to the cumulative data presented in four main studies, the median age is 4 years, with a male predominance (1.3:1). Jaundice was the most common clinical manifestation (69%), followed by vomiting (63%), anorexia (52.9%), diarrhea (47.2%), abdominal pain (39%), pyrexia (33.3%), pale stool (30%), and dark urine (30%). Coryza and lethargy were reported in 16.6%, while pruritus was reported in 2% of cases. Acute liver failure was observed in 25% of cases. The exact mechanism of this acute hepatitis outbreak is still not entirely clear. Adenoviruses and SARS-CoV-2 were detected in a significant number of patients. Coinfection with adenovirus and SARS-CoV-2 could be a possible underlying mechanism. However, other possible infections and mechanisms must be considered in the pathogenesis of this condition. Acute hepatitis of unknown origin in children has been a serious problem since the start of the COVID-19 pandemic but has not yet been sufficiently addressed. Many questions remain regarding the underlying mechanisms leading to acute liver failure in children, and it is likely that extensive future research is needed.

Severe Acute Hepatitis: An Emerging Grave Illness in Children

Acute hepatitis of unknown origin in children has been recently described in the literature, and a case definition has also been proposed for this condition. The exact etiology is unknown and exclusion of infectious, metabolic, autoimmune and toxin mediated injuries is essential. Management for this condition is supportive, but some may require liver transplantation. Infection prevention and control practices are important as the etiology remains unidentified.

Updated information regarding acute severe hepatitis of unknown origin in children: Viewpoints of and insights from pediatricians.

Recently, the morbidity of acute severe hepatitis of unknown origin in children (SHIC) has tended to decrease, but this condition should not be ignored because of its uncertain but severe nature. The current study briefly summarizes updated information regarding the epidemiological, clinical, and etiological aspects of SHIC based on the newest information available. Opinions from pediatricians are also presented. In light of the status quo of SHIC and COVID-19 globally, several suggestions are proposed to improve future studies, which could help to further explore the underlying mechanisms of SHIC in the context of COVID-19.