Bartonella henselae-mediated disease in solid organ transplant recipients: two pediatric cases and a literature review.

Bartonella henselae, the etiologic agent of cat-scratch disease, causes a well-defined, self-limited syndrome of fever and regional lymphadenopathy in immunocompetent hosts. In immunocompromised hosts, however, B. henselae can cause severe disseminated disease and pathologic vasoproliferation known as bacillary angiomatosis (BA) or bacillary peliosis. BA was first recognized in patients infected with human immunodeficiency virus. It has become more frequently recognized in solid organ transplant (SOT) recipients, but reports of pediatric cases remain rare. Our review of the literature revealed only one previously reported case of BA in a pediatric SOT recipient. We herein present 2 pediatric cases, one of which is the first reported case of BA in a pediatric cardiac transplant recipient, to our knowledge. In addition, we review and summarize the literature pertaining to all cases of B. henselae-mediated disease in SOT recipients.

Proteus syndrome: three case reports with a review of the literature.

Proteus syndrome (PS) is a rare, progressive disorder that manifests as asymmetric, disproportionate overgrowth affecting tissues derived from any germline layer. Cases of PS from 2005-2010 were retrieved from the pathology files at our institution. Two confirmed cases and one possible case of PS were identified. All patients came from different ethnic backgrounds. Patient 1 displayed classic skin and overgrowth lesions. Patient 2 displayed various features, particularly vascular malformations. Patient 3 demonstrated a cerebriform connective tissue nevus alone. These patients demonstrate the spectrum of presentations of PS. Much is left to learn about this disfiguring disease.

Splenic cysts in the pediatric population: a report of 21 cases with review of the literature.

Splenic cysts are rare lesions that can occur in parasitic and non-parasitic forms. Because they are uncommon, the classification, pathogenesis, and management techniques are still debated. The continual review of splenic cyst cases in the pediatric population is essential for establishing a clear diagnosis and course of treatment. This report presents 21 cases of pediatric splenic cysts observed at Children's Healthcare of Atlanta over an 18 year period (1993-2011). The cases include both parasitic and and nonparasitic cysts. The current splenic cyst classification and treatment methods are analyzed through a review of the current theories and based on our experiences.

Ganglioside GD2 specific monoclonal antibody 3F8: a phase I study in patients with neuroblastoma and malignant melanoma.

The murine IgG3 monoclonal antibody (MoAb) 3F8, specific for the ganglioside GD2, activates human complement, is active in antibody-dependent cell-mediated cytotoxicity (ADCC), and can target specifically to human neuroblastoma in patients with metastatic disease. In a phase I study, 3F8 was administered intravenously (IV) to 17 patients with metastatic GD2 positive neuroblastoma or malignant melanoma at doses of 5, 20, 50, and 100 mg/m2. Serum 3F8 levels achieved were proportional to the dose of 3F8 infused. However, serum antimouse antibody levels did not increase with the amount of 3F8 administered. Toxicities included pain, hypertension, urticaria, and complement depletion. All acute side effects were controllable with symptomatic therapy. No long-term side effects were detected in patients observed for more than 14 months. None of the 17 patients received any antitumor therapy postantibody treatment. Antitumor responses occurred in seven of 17 patients. These ranged from complete clinical remissions to mixed responses. The murine monoclonal antibody (MoAb) 3F8 has clinical utility for the diagnosis and therapy of neuroblastoma and melanoma.

Ten-year course of early-onset Weber-Christian syndrome with recurrent pneumonia: a suggestion for pathogenesis.

A surviving 10-year-old boy with infant-onset systemic Weber-Christian syndrome is reported. He has had recurrent episodes of fever, aseptic panniculitis, and pneumonia. Although corticosteroid therapy has succeeded, colchicine and non-steroidal anti-inflammatory drugs have failed to abort or prevent acute episodes. The persistent leukocytosis (even during remission), the recurrent episodes of fever with associated increase in the acute phase reactants, and the failure of the nonsteroidal anti-inflammatory drugs leads us to propose that this form of Weber-Christian syndrome reflects an inborn error in the regulation of the inflammatory response. Systematic investigation of this hypothesis could yield important information on the normal regulation of inflammation and could lead to a rational therapeutic approach to this puzzling and usually devastating illness.

Long-term dual perfusion of isolated human placental lobules with improved oxygenation for infectious diseases research.

An improved method for long-term perfusion of the isolated human term placental lobule has been developed to investigate the maternofetal transfer of infectious agents, in particular the human immunodeficiency virus (HIV). The purpose of this paper is to describe those modifications that allow for substantially prolonged perfusions in in a biohazard environment. The method described has been adapted from previous models. The perfusion apparatus has been modified for use within a biohazard hood, and, intravenous bags contain the medium for circulation of perfusates in closed circuits. A Mera Silox-S 0.3 membrane oxygenator delivers more oxygen to the tissue, and, Electromedic Cardioplegia heat exchangers warm the perfusate prior to oxygenation. Viability criteria (glucose consumption, lactate production, de novo production of human placental lactogen (hPL), volume loss, flow, temperature, pressure, oxygen transfer, carbon dioxide production, absence of IgM transfer and light and electron microscopy) demonstrate that the placental tissue remains in a functional state throughout the perfusion. Oxygen and glucose consumption are both stable over time; lactate levels remain constant; and hPL continues to be produced. These significant modifications of the perfusion system have permitted the investigators to increase the duration of perfusion to 48 h while preserving normal metabolic function of ultrastructurally intact tissue as demonstrated by ultra structural observations. This perfusion model device provides biohazard precautions and may be applied to other studies of placental physiology.

Clinical and pathologic aspects of recurrent placental villitis.

In a retrospective survey, recurrent villitis was identified in ten of 59 patients in whom placental villitis had been diagnosed. The ten patients had a total of 41 pregnancies, with a reproductive loss of 60 per cent. In addition to enhanced fetal losses in all trimesters of gestation and postnatally, the incidences of fetal growth retardation and premature delivery were increased. There was no evidence of recent TORCH (toxoplasma, rubella, cytomegalovirus, herpes) infection, but all patients tested had rubella immunity. In six patients genital cultures were positive for gonorrhea and assorted microorganisms. Uterine abnormalities, including two septate uteri, one incompetent cervix, one submucosal leiomyoma, and one retroflexion, were common, and vaginal bleeding had occurred in five patients. Other factors included obesity (five patients) and clinical and laboratory evidence of autoimmunity (four of the five patients tested). In a control group of 20 patients with nonrecurrent villitis, the perinatal loss rate (37 per cent) was lower, and the incidences of positive cultures, uterine structural anomalies, obesity, and autoimmunity were also lower. Placental histologic findings included decidual plasma cell and intervillous fibrin and histiocytic infiltration, in addition to villous inflammation. These lesions, although consistent for a given patient, defined two clinically relevant groups of patients. The results of this study suggest that recurrent villitis is more frequent than previously reported, that it is associated with high perinatal mortality, and that immunologic and structural abnormalities in the host may play a role in its pathogenesis.

The nephropathy of cystic fibrosis: a human model of chronic nephrotoxicity.

Patients with cystic fibrosis are chronically exposed to several potentially nephrotoxic factors. These include bacterial infections with their associated immune complexes and the antibiotics (aminoglycosides) used in their treatment. In addition, diabetes mellitus, liver disease, and cor pulmonale, commonly seen in these patients, may produce renal injury. To assess the extent of this injury, we performed morphologic and immunopathologic studies of the kidneys of 34 patients at autopsy. The group included 23 female and 11 male patients; their ages ranged from 4 months to 35 years and their disease was diagnosed one month to 22 years prior to death. The histological changes included glomerulomegaly, a mesangiopathic lesion, and tubulointerstitial disease frequently associated with acute and chronic tubular injury. The last was characterized by abundant tubular lysosomal proliferation and tubular atrophy suggestive of chronic amino-glycoside injury. Diagnostic diabetic lesions were not seen. Immunofluorescence studies predominantly revealed deposits of IgM or C3, or both, in glomeruli and arterioles in 18 patients. Although an anti-Pseudomonas antiserum did not show bacterial antigens in the tissues, elution studies in two specimens demonstrated antibacterial antibodies. These observations, coupled with the finding of ultrastructural glomerular deposits, suggest immune complex-mediated injury. No correlation was found between the severity or type of renal histologic lesion and patient age or duration of cystic fibrosis. Despite the occurrence of renal failure in six patients, renal involvement is currently of limited clinical concern in cystic fibrosis. Nevertheless, continued exposure to bacterial immune complexes and aminoglycosides, among other factors, can result in potentially serious renal disease.

Regional enteritis-like enteropathy in a patient with agammaglobulinemia: histologic and immunocytologic studies.

A 24-year-old man with agammaglobulinemia developed a form of chronic inflammatory bowel disease over the past 18 years characterized by recurrent diarrhea, malabsorption, and protein-losing enteropathy. In the most recent admission he presented with abdominal cramps and active intestinal bleeding. Radiologic studies showed distal ileal irregularities and strictures that led to two distal intestinal and ileocecal resections. The gross pathologic appearance of these specimens was consistent with regional enteritis. Microscopically, healing ulcers, mucosal irregularities, and a prominent lymphocytic infiltrate without plasma cells or granulomas were observed. Immunocytochemical studies revealed a prominent T-helper cell and a modest T-suppressor/cytotoxic lymphocyte population in the lamina propria. Early and late B-cell differentiation markers were not detected in any of the cells. The immunocytologic findings suggest that T-helper lymphocytes proliferated without inhibition to stimulate non-existent B cells. The study confirms the occurrence of a regional enteropathy-like lesion in the total absence of B-cell function.

Secretory immunoglobulin deposits in renal glomeruli of children with extrahepatic biliary atresia: studies in a human counterpart of experimental ligation of the bile ducts.

Experimental ligation of the biliary tract often results in glomerular deposits of polymeric IgA commonly associated with secretory component. These studies offer evidence that, in animals, hepatobiliary transport of polymeric IgA, which is of mucosal origin, is crucial for its clearance from the serum. We studied a human counterpart of bile duct ligation--extrahepatic biliary atresia--for the presence of secretory or polymeric immunoglobulins in renal glomeruli. Kidney was available at autopsy as paraffin or frozen blocks from 24 patients with biliary atresia and age-matched controls (5 weeks to 5 years old). Several of the patients had undergone portoenterostomy (Kasai procedure) or liver transplantation. Immunohistologic studies showed glomerular (often mesangial) deposits of IgA in 10 of 24 and IgM in 16 of 24 specimens. The differences with controls were highly significant for IgA but not for IgM. In frozen sections, secretory component was positive in glomeruli in seven of 12 specimens. In vitro glomerular binding of purified secretory component to glomeruli was shown in four of 12 samples, including three with IgM only. This last observation suggests that IgM in some of these patients was polymeric and thus derived from a mucosal source. Our study shows that in humans with biliary atresia, secretory IgA, polymeric IgA, and possibly polymeric IgM are deposited in glomeruli. The study confirms the occurrence of renal immunopathologic findings in liver disease and supports the existence of an active hepatobiliary immunosecretory transport mechanism even at the early age of these patients.

Cryptococcosis of the placenta in a woman with acquired immunodeficiency syndrome.

Multiple microscopic colonies of encapsulated budding yeasts morphologically consistent with Cryptococcus sp were found in the maternal (intervillous) space of the placenta from a woman with AIDS. The patient contracted acquired immunodeficiency syndrome from her affected husband, who had died of the disease 3 years previously. The woman, who was in her sixth pregnancy at term, became symptomatic 1 month before delivery with malaise, oral thrush, and cervical lymphadenopathy. Tests for human immunodeficiency virus and serum hepatitis were negative. Cryptococcus neoformans was cultured in the blood and herpes simplex virus type II was isolated from the cervix. On the second postpartum day, the patient had difficulty breathing and died suddenly. Post-mortem examination disclosed a massive pulmonary embolus and disseminated infection with Cryptococcus organisms.

Circulating immune complexes and the nephropathy of cystic fibrosis.

To explore the putative nephropathic role of Pseudomonas-associated immune complexes, the authors measured the quantity of immune complexes in sera obtained, before death, from 20 patients with cystic fibrosis, and compared these findings with the histologic features of the lesions and with immunofluorescence patterns of kidney tissue obtained at autopsy. The immune complexes were measured by solid-phase C1q (C1q immune complex) and conglutinin to detect complexes containing IgM, IgA, and IgG. Elevated levels of C1q immune complex (13 patients) suggested the possibility of renal deposition of C3 (P less than 0.005) and IgM (P less than 0.05). The only three patients with IgA tissue deposits had elevated levels of C1q immune complex with normal IgA immune complexes. No other assay findings correlated with the immunofluorescence findings. Despite the prominent C3 in tissue deposits, the histologic features were not significantly associated with the results of the immune complex assays. This study indicates that complement-activating IgM-containing complexes can be deposited in renal tissues of patients with cystic fibrosis, but their nephropathogenicity is doubtful. These observations of kidney lesions, which diminish the injurious role of immune complexes in cystic fibrosis, may be relevant to an understanding of the pathogenesis of the lung lesions, which recent studies have linked to the presence of immune complexes.

The pathology of fungal infection and colonization in patients with cystic fibrosis.

We used methenamine silver stains to retrospectively evaluate the prevalence of fungi and their associated inflammatory reactions in 63 patients with cystic fibrosis (CF) autopsied between 1982 and 1987. Fungi were detected in 13 patients (21%) who fell into three groups: respiratory tract colonization (five patients); localized infection (five patients); and disseminated infection (three patients). Hyphae consistent with Aspergillus sp were present in five patients; yeast-like cells and/or pseudohyphae consistent with Candida sp occurred in eight patients; and Histoplasma capsulatum produced fibrocaseous lymph node and splenic granulomas in one patient. Acute inflammation typified most fungal lesions, while bronchocentric granulomatosis affected one patient. Compared with patients with no fungi, those with fungi were more frequently treated with indwelling central venous catheters (P less than .05). Autopsy reports on 156 CF patients from 1964 to 1982 disclosed only one with disseminated mycosis (P less than .05). We conclude that stainable fungi can be found in CF patients at autopsy more frequently than previously realized. Fungi usually represent respiratory tract colonization or minimal localized infection, but the prevalence of fatal disseminated infection (4.8%) has also increased. Fungal infection in CF appears to be most closely associated with aggressive therapeutic intervention.

Nontuberculous mycobacterial infections: comparison of the fluorescent auramine-O and Ziehl-Neelsen techniques in tissue diagnosis.

Nontuberculous (i.e., atypical) mycobacterial infections are increasing among pediatric and immunosuppressed patients, who commonly present with subcutaneous inflammatory masses or adenitis, which is often surgically excised. Since the most frequently isolated species also grow slowly in culture, early diagnosis may depend on histologic detection of a mycobacterial organism in the biopsy specimen. However, the histologic methods used for this purpose are of uncertain value in the diagnosis of these infections. Biopsy specimens from 22 patients with clinical histories highly consistent with nontuberculous mycobacteriosis in which part of the tissue was cultured were selected for study. Coded tissue blocks and control specimens were stained by the Ziehl-Neelsen (ZN) or auramine-O (A0) fluorescent technique and examined blindly for the presence of characteristic organisms. Results of these studies were compared with the culture results, and predictive values were calculated. This experience showed that the AO technique is technically simpler, allowing faster screening at lower power and showing greater sensitivity and predictive value of a negative result although less specificity than the ZN technique. The lower specificity of AO may be factitious and due to the detection in the tissue of organisms that did not grow in culture. Previous observations that nontuberculous mycobacterial infections may elicit tissue reactions that simulate cat-scratch disease, sarcoidosis, and nonspecific chronic inflammation were also confirmed.

Comparative demonstration of pulmonary fat emboli by "en bloc" osmium tetroxide and oil red O methods.

The presence and localization of fat in human lung tissue was evaluated by the "en bloc" staining procedure with osmium tetroxide performed with formalin fixed tissue with subsequent paraffin sectioning and with the oil red O technique performed with frozen sections. Fifty-one autopsy cases were divided into three clinical groups: group A, consisting of 17 patients with severe skeletal trauma; group B, consisting of 14 patients with minor skeletal trauma; and group C, consisting of 20 control patients without trauma. Adjacent sections of lung were selected from all cases, stained with the "en bloc" osmium tetroxide and oil red O methods, coded, and examined under the light microscope without knowledge of the clinical grouping, Stainable fat was graded on a 1 to 4+ scale, and attention was given to histologic localization in tissue sections. The "en bloc" osmium tetroxide technique revealed greater amounts of stainable lipid in clinical groups A and B and was most effective in demonstrating lipid when present in small quantities (group B). Since the method permits the employment of paraffin sections, evaluation of fine histologic detail is an advantage that is not always obtained in frozen sections. It is concluded that the "en bloc" osmium tetroxide technique is superior to the oil red O technique in terms of visualization and histologic localization of minute amounts of lipid in lung tissue.

Postmortem demonstration of esophageal varices by a simple method.

The usual methods available to demonstrate esophageal varices in postmortem material have met with little success because of their unreliability, difficulty to execute, or cost. A simple, inexpensive method, which consists in separating the esophageal mucosa and submucosa from the muscularis and stretching the former over a suitable absorbent paper, is described. In a few minutes, as the adherent membrane dries, the submucosal vascular pattern gradually develops, and after overnight drying, even the smallest venules are clearly visible. The specimen can be stored dry, photographed, or made into a more permanent preparation in a few days. The esophageal mucosal vascular patterns in groups of patients who died with a variety of hepatic diseases and other potential causes of esophageal varices were studied and compared with controls. A consistent pattern of prominent venous trunks located towards the distal third of the esophagus was seen in most specimens from cirrhotic patients, predominantly in micronodular forms with severe lobular distortion. Other potential causes of esophageal varices (hepatic tumors, congestion, etc.) resulted in less predictable vascular patterns.

Candida-associated renal papillary necrosis.

An autopsy series of 42 patients who had visceral candidiasis was studied to determine the incidence and clinicopathologic features of Candida-associated renal papillary necrosis. Papillary necrosis was found in nine patients (21%), associated in all instances with fungal invasion of the kidney. The single most common associated condition was prematurity, present in three neonates, and antibiotic or immunosuppressive therapy was a contributing factor in most instances. The clinical significance of candidal papillary necrosis is unclear because most patients had other causes of renal failure. Antemortem diagnosis is exceptionally difficult and had not been made in any of these patients. Pyelograms have aided in the diagnosis in only one well-documented case in the literature. This study shows that the pathologic features of candidal renal papillary necrosis correlate well with the findings in experimentally induced disease, and that this lesion appears to be more common than previously suspected.

The pathologic characteristics of interstitial pneumonia cystic fibrosis. A retrospective autopsy study.

Interstitial pneumonia is a poorly understood variant of lung injury in patients with cystic fibrosis (CF). The authors identified prominent interstitial pneumonia (defined as an inflammatory reaction predominantly involving alveolar septa) in 9 of 43 autopsied patients with CF. Lungs from these nine were studied by light microscopy to determine the histopathologic features, clinicopathologic correlates, and potential causes of CF-associated interstitial pneumonia. Two histologic variants were identified, alveoloseptal (in which the inflammatory reaction was confined to the alveolar wall) and organizing (in which intraalveolar granulation tissue was present in addition to septal inflammation), which respectively affected four and five patients. Cholesterol deposits and capillary proliferation were prominent associated features in some patients. Interstitial pneumonia was not diagnosed antemortem and was identified on chest roentgenogram in only two patients. There were no distinctive clinical features associated with different histologic subtypes, nor did histologic or clinical data identify a specific cause(s) of interstitial pneumonia. The authors conclude that CF-associated interstitial pneumonia, although usually an incidental finding at autopsy, may potentially contribute to respiratory impairment and death. Although there are multiple possible causes of interstitial lung injury associated with CF, the authors were unable to identify, with certainty, the pathogenesis of interstitial pneumonia in any patient in this study.

The normal pediatric larynx on CT and MR.

PURPOSE: To determine the MR and CT appearance of the normal pediatric larynx. METHODS: Fifteen CT scans and 15 MR examinations of children with normal larynges and airways were reviewed retrospectively. Characteristics that were noted included the level of the hyoid bone, calcification and signal intensity within separate laryngeal components, amount of paraglottic fat, anteroposterior airway diameters, and airway contours. Two cadaveric larynges were imaged by CT and MR and were then sectioned at corresponding levels and section thicknesses. RESULTS: The larynx is higher in children than in adults, with the hyoid bone found at the C2-3 level in the youngest children (newborn to 2 years). The subglottic airway was narrowest in the youngest children. The hyoid bone was the only laryngeal structure ossified in any of the children. A thin line of high density was seen in the expected location of the thyroid cartilage in some children. The featureless circumferential soft tissue seen around the airway represented the uncalcified laryngeal cartilaginous structures. This was confirmed on gross sectioning of cadaveric larynges. The supraglottic airway contour was triangular or oval, the glottis was shaped like a teardrop, and the subglottic contour was oval. Contours were confirmed on histologic examination of necropsy specimens. CONCLUSIONS: This preliminary study suggests that the pediatric larynx differs from the adult larynx with respect to size, position, consistency, and shape, and these differences are reflected on CT and MR studies.

The causes of morbidity and mortality among infants born at term.

Previous studies have reported on the pathologic spectrum of perinatal mortality; however, in our opinion, the problems pertaining to the term newborn have not been emphasized sufficiently. We reviewed the autopsies of all term infants up to 2 months of age in a ten-year period (July 1975 to July 1985). These 342 patients comprised 20% of all pediatric autopsies. The patients were grouped according to cause of death in the following categories: congenital anomalies (59%); infection (10%); perinatal injury, including meconium aspiration (9%); maternal-placental problems (11%); and miscellaneous (5%). In 4% of the cases, mainly stillbirths, the cause of death was unclear. Of the congenital anomalies, the cardiovascular system was most affected (57%). Hyaline membrane disease and intraventricular hemorrhage, usually frequent in series involving many preterm patients, were seldom seen. This study emphasizes the different pathologic spectrum of mortality between premature and term newborns.