M Malone

Infection and sudden unexpected death in infancy: a systematic retrospective case review

BACKGROUND The cause and mechanism of most cases of sudden unexpected death in infancy (SUDI) remain unknown, despite specialist autopsy examination. We reviewed autopsy results to determine whether infection was a cause of SUDI. METHODS We did a systematic retrospective case review of autopsies, done at one specialist centre between 1996 and 2005, of 546 infants (aged 7-365 days) who died suddenly and unexpectedly. Cases of SUDI were categorised as unexplained, explained with histological evidence of bacterial infection, or explained by non-infective causes. Microbial isolates gathered at autopsy were classified as non-pathogens, group 1 pathogens (organisms usually associated with an identifiable focus of infection), or group 2 pathogens (organisms known to cause septicaemia without an obvious focus of infection). FINDINGS Of 546 SUDI cases, 39 autopsies were excluded because of viral or pneumocystis infection or secondary bacterial infection after initial collapse and resuscitation. Bacteriological sampling was done in 470 (93%) of the remaining 507 autopsies. 2079 bacteriological samples were taken, of which 571 (27%) were sterile. Positive cultures yielded 2871 separate isolates, 484 (32%) of which showed pure growth and 1024 (68%) mixed growth. Significantly more isolates from infants whose deaths were explained by bacterial infection (78/322, 24%) and from those whose death was unexplained (440/2306, 19%) contained group 2 pathogens than did those from infants whose death was explained by a non-infective cause (27/243, 11%; difference 13.1%, 95% CI 6.9-19.2, p<0.0001 vs bacterial infection; and 8.0%, 3.2-11.8, p=0.001 vs unexplained). Significantly more cultures from infants whose deaths were unexplained contained Staphylococcus aureus (262/1628, 16%) or Escherichia coli (93/1628; 6%) than did those from infants whose deaths were of non-infective cause (S aureus: 19/211, 9%; difference 7.1%, 95% CI 2.2-10.8, p=0.005; E coli: 3/211, 1%, difference 4.3%, 1.5-5.9, p=0.003). INTERPRETATION Although many post-mortem bacteriological cultures in SUDI yield organisms, most seem to be unrelated to the cause of death. The high rate of detection of group 2 pathogens, particularly S aureus and E coli, in otherwise unexplained cases of SUDI suggests that these bacteria could be associated with this condition.

Myogenin and MyoD1 expression in paediatric rhabdomyosarcomas

The diagnosis of paediatric solid tumours is often based on small tissue needle biopsies in which many different entities demonstrate a “small round cell tumour” phenotype and in which there may be insufficient tissue to allow the interpretation of diagnostic architectural features, which may be present in larger specimens. Therefore, the extensive use of a panel of immunohistochemical markers is part of the routine handling and investigation of such biopsies to reach a definite diagnosis. However, in some cases the morphological and routine immunohistochemical findings may be insufficient for a precise diagnosis or they may be difficult to interpret in the given clinical context. Although many paediatric tumours exhibit characteristic chromosomal translocations with resultant specific fusion transcripts, these require molecular methods for their detection, usually on fresh tissue samples, which may not always be available. As more immunohistochemical markers become available, more precise diagnosis on such small biopsies may be possible. This review examines the use of the immunohistochemical markers, MyoD1 and myogenin, in the diagnosis of paediatric rhabdomyosarcoma, including its subtypes.

Histopathological features of chronic granulomatous disease (CGD) in childhood.

Aims : To describe the spectrum of histopathological features encountered in children with chronic granulomatous disease (CGD) at a specialist centre.

Isolated EBV lymphoproliferative disease in a child with Wiskott-Aldrich syndrome manifesting as cutaneous lymphomatoid granulomatosis and responsive to anti-CD20 immunotherapy

Patients with primary immunodeficiencies such as the Wiskott-Aldrich syndrome (WAS) are prone to develop Epstein-Barr virus (EBV) related lymphoproliferative disorders (LPDs). EBV LPD is most frequently seen in patients receiving immunosuppressive treatment after organ transplantation (post-transplant lymphoproliferative disorder), but can also arise in the primary immunodeficiencies. Typically, EBV LPD presents as a diffuse systemic disease with lymphadenopathy and organ involvement. A rare angiocentric and angiodestructive form of EBV associated B cell LPD, lymphomatoid granulomatosis (LyG), has also been reported in association with WAS. LyG most commonly involves the lung, but can also be seen in brain, kidney, liver, and skin. This report describes the case of a 16 year old boy with WAS who presented with an isolated non-healing ulcerating skin lesion. Biopsy revealed an EBV related LPD with the histological features of LyG. This cutaneous lesion responded dramatically to treatment with specific anti-CD20 immunotherapy and the patient remains clinically free of LPD at 18 months.

Clinicopathological features of paediatric deaths due to myocarditis: an autopsy series

Introduction: Myocarditis is a recognised cause of cardiac failure in childhood but the frequency of myocarditis as a cause of sudden unexpected death across the paediatric age range is uncertain. Methods: A structured review of the results of all autopsies carried out in a single paediatric centre over a 10-year period, including the results of all investigations performed as part of the centre’s policy for the post-mortem investigation of paediatric deaths. Results: During the study period there were 1516 autopsies of children aged 0–18 years. Histologically proven myocarditis was present in 28 cases (1.8%, age range 10 days to 16 years, median age 10 months), of which 16 (57%) presented as sudden death. More than half of all cases (54%) occurred in infants less than 1 year of age, accounting for 2% of infant deaths referred for autopsy, compared with around 5% of childhood deaths over the age of 5 years. In almost 40% of cases there were no macroscopic cardiac abnormalities, the diagnosis being entirely dependent on routine histological examination of the heart, and post-mortem heart weight was normal in the majority of cases. Virus was detected in nine (36%) of the 25 cases in whom virological analyses were performed. The histological features were similar in all cases, with an interstitial inflammatory cell infiltrate, predominantly lymphocytic, with focal myocyte necrosis and interstitial oedema. Conclusions: Myocarditis is a rare cause of death in infancy and childhood, and the majority of cases present as sudden unexpected deaths, which require routine histological sampling of the heart for its detection.

Blood film examination for vacuolated lymphocytes in the diagnosis of metabolic disorders; retrospective experience of more than 2500 cases from a single centre

Background: A range of metabolic diseases can result in abnormal accumulation of metabolic byproducts, resulting in abnormal lymphocyte cytoplasmic vacuolation, identifiable on routine blood film examination. Aims: This study retrospectively examines the usefulness of blood film examination for vacuolated lymphocytes in a specialist paediatric pathology department in relation to patient’s age and presentation. It also describes specific diagnostic features in relation to specific classes of metabolic disease. Methods: Retrospective review of a histopathology database to identify all blood films examined for the detection of vacuolated lymphocytes during a 15 year period (1989–2004). Results: In total, 2550 blood films were investigated. The median age at submission was 2 years (range, birth to 88), and > 90% of samples were from children < 18 years. The most common indications were developmental delay/regression, ataxia, seizures, and cardiomyopathy. Vacuolated lymphocytes were identified in 156 films (6.1%). The frequency of vacuolated lymphocytes varied with clinical presentation, with ophthalmic indications having the highest positive rate (40%). In cases with vacuolated lymphocytes, a wide range of underlying metabolic diagnoses was apparent, the most common being juvenile neuronal ceroid lipofuscinosis and acid maltase deficiency, which accounted for more than half of the diagnoses. Conclusions: The examination of blood films for lymphocyte vacuolation is clinically useful in patients with a history suggestive of metabolic disease. The test is cheap, rapid, minimally invasive, and provides first line screening, with some findings indicating clues to a specific underlying diagnosis.

Pathology of astrovirus associated diarrhoea in a paediatric bone marrow transplant recipient

Human astrovirus infection often causes outbreaks of self limiting diarrhoea, but may also infect patients who are immunodeficient or immunocompromised. Although there are previous publications relating to various aspects of astroviruses, there is a minimal amount of literature on the histopathological features of gastrointestinal astrovirus infection in humans. We report the histopathological findings, including immunohistochemical and electron microscopic features, of astrovirus infection in a bone marrow transplant recipient aged 4 years with diarrhoea. The appearance of a small intestinal biopsy did not suggest graft versus host disease, but demonstrated villous blunting, irregularity of surface epithelial cells, and an increase in lamina propria inflammatory cell density. Immunohistochemical staining with a murine astrovirus group specific monoclonal antibody demonstrated progressively more extensive staining in the duodenal and jejunal biopsies, predominantly restricted to the luminal surface and cytoplasm of surface epithelial cells, most marked at the villus tips. Electron microscopic examination demonstrated viral particles within the cytoplasm of enterocytes, focally forming paracrystalline arrays.

Congenital alveolar capillary dysplasia and associated gastrointestinal anomalies.

Congenital alveolar capillary dysplasia is a rare cause of irreversible pulmonary hypertension with 100% mortality. We present three cases of congenital alveolar capillary dysplasia with associated gastrointestinal abnormalities. Three full-term neonates presented with pulmonary hypertension needing ventilatory support by oscillation. Of the three, two neonates subsequently needed extracorporeal membrane oxygenation. Abdominal distension associated with bilious aspirates was the gastrointestinal manifestation. One child had duodenal atresia and anorectal anomaly, one with intestinal malrotation and the other with a rare combination of intestinal malrotaion and total colonic Hirschsprungs disease. All three infants succumbed to pulmonary hypertension at mean age 34 days. The etiopathogenesis and pathology of this condition are discussed with a comprehensive review of the literature.

Light microscopic examination of scalp hair samples as an aid in the diagnosis of paediatric disorders: retrospective review of more than 300 cases from a single centre

Background: Microscopic examination of scalp hair can provide important diagnostic information in a range of paediatric conditions. It is a non-invasive and cost effective investigation, which is not widely performed. Aims: To examine retrospectively the value of hair examination by light microscopy, including polarising microscopy, in a specialist paediatric pathology department during a 15 year period (1989–2004) and to describe the morphological abnormalities indicative of specific paediatric conditions. Methods: Three hundred and twenty two hair samples were submitted. Microscopic changes were analysed in the light of clinical information categorised as: (1) erythroderma, (2) neurological impairment, (3) immunological/haematological defect, (4) ectodermal dysplasia, (5) abnormal hair only, and (6) non-specific/absent clinical details. Results: Abnormalities were evident in 49% of the samples. In 25%, the changes were compatible with specific diagnoses including Menkes disease, Netherton’s syndrome, trichothiodystrophy, Griscelli and Chediak-Higashi syndromes, monilethrix, uncombable hair, and loose anagen syndromes. In respect of the clinical presentation groups noted above, diagnostic changes were seen in 41%, 32%, 33%, 0%, 29%, and 0%, respectively. Conclusions: Morphological light microscopic examination of scalp hair is an inexpensive, rapid, and non-invasive investigation, which can provide valuable diagnostic information in a range of paediatric conditions.

Capillary apposition and density in the diagnosis of alveolar capillary dysplasia

Aim:  Alveolar capillary dysplasia (ACD) is a rare disorder, typically presenting with persistent pulmonary hypertension of the newborn. The aim was to characterise further the histological features of patients suspected of having ACD and to correlate histopathological features with outcome.