Biomarkers in solid organ transplantation.

This workshop was organized by the US Food and Drug Administration (FDA) Office of Clinical Pharmacology Review Team supporting the Division of Special Pathogen and Transplant Products in the Center for Drug Evaluation and Research. The main goal of the workshop was to enhance the knowledge base regarding biomarkers in solid-organ transplantation via presentation and discussion of scientific findings.

Development of serum IgM antibodies against superantigens of Staphylococcus aureus and Streptococcus pyogenes in Kawasaki disease.

To serologically determine the association of microbial superantigens and the pathogenesis of Kawasaki disease (KD), we conducted a case-control study. Serum IgG and IgM antibodies against staphylococcal enterotoxin A (SEA), SEB, SEC, toxic shock syndrome toxin-1 (TSST-1), and streptococcal pyrogenic exotoxin A (SPEA) were measured by an enzyme-linked immunosorbent assay in 293 serum samples from 65 KD patients on clinical days 1-28 and 120 control samples. The administration of immunoglobulin products, which contain high concentrations of IgG antibodies against all the superantigens, directly elevated antitoxin IgG antibodies in KD patients. In contrast, antitoxin IgM antibodies were not detected in immunoglobulin products. Actually, we found a significant elevation of IgM antibodies against SEA in KD patients in the first (median titre: 0.020, P < 0.01 versus control), second (0.024, P < 0.001), third (0.030, P < 0.001) and fourth (0.038, P < 0.001) weeks, compared to the controls (0.015). Significant differences of IgM antibodies were also true for SEB, TSST-1, and SPEA throughout the first to fourth weeks, and for SEC throughout the second to fourth weeks. The prevalence of KD patients having high IgM titres (> mean + 2SD of control values) to the 5 superantigens was increased with the clinical weeks, and reached 29-43% of KD subjects at the fourth week. This is the first study that describes kinetics of IgM antibodies against superantigens and clarifies the serological significance throughout the clinical course of KD. Our results suggest that multiple superantigens involve in the pathogenesis of KD.

Spontaneous rupture of mediastinal cystic teratoma into the pleural cavity: report of two cases and review of the literature.

The authors report on two female patients aged 12 and 14 years, who spontaneously developed a rupture of benign mediastinal cystic teratoma into the right pleural cavity. They presented with acute onset of severe chest pain and respiratory distress. The tumors were completely resected by thoracotomy. The serum and pleural fluid levels of carcinoembryonic antigens, CA-125 and CA19-9 were invariably elevated, then decreased to normal range after the surgical resection. Rapid diagnosis of this extremely rare complication is important because it may progress to a life-threatening condition.

Early elevation of serum thrombopoietin levels and subsequent thrombocytosis in healthy preterm infants.

To verify pathophysiological mechanisms underlying thrombocytosis in low-birth-weight (LBW) preterm babies, we evaluated kinetic changes in platelet counts and thrombopoietic cytokines including thrombopoietin (TPO), interleukin 6 (IL-6) and IL-11 in 24 uncomplicated preterm infants. Platelet counts in cord blood (CB) (265 +/- 64 x 10(9)/l) were similar to adult levels, increased by d 14 (473 +/- 140 x 10(9)/l), and then remained fairly constant. Thrombocytosis (> 500 x 10(9)/l) was observed in 9/24 (38%) subjects. Mean TPO level in CB was 5.11 +/- 1.51 fmol/ml, peaked at d 2 (7.64 +/- 3.28 fmol/ml), decreased at d 5 (3.93 +/- 1.67 fmol/ml), and thereafter kept fairly constant during the remaining neonatal period. Compared with term infants, mean TPO levels of preterm infants in CB and at d 2 were significantly higher (P < 0.01). There was an inverse correlation between platelet counts and TPO levels (r = 0.45, P < 0.001, n = 88). Preterm neonates with thrombocytosis had significantly higher TPO values in CB than those without thrombocytosis (P < 0.05). There was no significant relationship between platelet counts and IL-6. IL-11 was not detectable. These results suggest that an early elevation of serum TPO levels is related to the subsequent thrombocytosis in LBW preterm infants.

Peroneal mononeuropathy in pediatric Hodgkin's disease.

A 12-year-old boy with Hodgkin's disease developed left peroneal nerve palsy during combination therapy with chemotherapy and low-dose irradiation. The palsy occurred twice; around 1-2 weeks after the second administration of vincristine in the second and third COPP (cyclophosphamide, vincristine, prednisolone, and procarbazine) regimens. Without any treatment, the peroneal neuropathy completely resolved clinically three months and electromyographically six months after the onset. He used to play television games for more than 6 hours a day with the legs crossed while sitting on the bedside. Compared to adult patients, little is known about the relationship between peroneal neuropathy and systemic malignant diseases in pediatric patients. This case shows for the first time that habitual leg crossing during potentially neurotoxic chemotherapy could induce peroneal mononeuropathy in a pediatric cancer patient.

Severe aplastic anemia associated with human parvovirus B19 infection in a patient without underlying disease.

Human parvovirus B19 (B19 virus) infection is known to induce aplastic crisis in patients with hemolytic anemia. In healthy subjects, B19 infection may sometimes cause mild pancytopenia, but these changes are transient and recovery is spontaneous. We report the first case of aplastic anemia in a previously healthy boy without any underlying diseases, following asymptomatic infection with the B19 virus. Laboratory examination initially showed thrombocytopenia, mild leukopenia in the peripheral blood, and severe hypoplastic bone marrow. Since pancytopenia developed and worsened progressively, immunosuppressive therapy was given, resulting in a complete remission. Despite the lack of an infectious prodrome, serological and histological analysis revealed an underlying infection with the B19 virus. Thus, B19 virus infection must be considered one of the causes of aplastic anemia in patients without underlying hemolytic anemia and an apparent episode of the viral infection.

Ocular involvement and visual sequelae in hemophagocytic lymphohistiocytosis in association with congenital dyfsfibrinogenemia.

We report a 7-year-old girl with hemophagocytic lymphohistiocytosis and an uncommon complication of vascular retinopathy and visual sequelae. She was also verified to be complicated with dysfibrinogenemia. The patient was treated with etoposide, dexamethasone, and cyclosporin A. During the fifth hospital week, a generalized tonic-clonic convulsion developed followed by deep coma. When she regained full consciousness, she complained of a visual disturbance. The ophthalmologic examination showed bilateral extensive retinal edema with numerous cotton-wool spots, indicative of vaso-occlusive retinopathy. This is inconsistent with the main finding of previous cases with ocular involvement, namely papilledema. Severely reduced visual acuity and visual field defects remained in both eyes even after systemic therapy. An awareness of this rare but serious complication is important because it may be preventable by early institution of chemotherapy. The pathogenesis of the retinopathy is also discussed.

Chromosome abnormality in solid and cystic tumor of the pancreas.

We report a case of a solid and cystic tumor of the pancreas with chromosomal abnormalities. The patient, a 13-yr-old girl, successfully underwent surgical excision and has been asymptomatic for more than 10 months. The tumor had two parameters suggesting malignant potential; a local invasion into a bile duct, and high mitotic activity. Chromosomal analysis showed two complex abnormalities, of which double loss of X chromosomes and trisomy for chromosome 3 were common. The complexity and polyclonality may stem from a clonal evolution. The observed abnormalities may provide a crucial clue to the understanding of the developmental process of this neoplasm.

Interstitial pneumonitis probably induced by cyclophosphamide in nephrosis.

A case of interstitial shadows associated with oral cyclophosphamide therapy in a 32-month-old girl with steroid-resistant nephrotic syndrome, who was admitted to the Nishi-Kobe Medical Center with systemic edema, is reported. Due to the lack of response to prednisolone, cyclophosphamide was also administered orally at a dose of 3 mg/kg per day, 4 weeks after the start of steroid therapy. Approximately 3 weeks after the combination treatment she developed a fever, dry cough and cyanosis. Radiographic examination showed diffuse ground-glass shadow in both lungs, presumably indicating that she had interstitial pneumonitis. Her pulmonary signs and symptoms deteriorated despite various antimicrobial treatments. A discontinuation of cyclophosphamide and the administration of high-dose methylprednisolone yielded a dramatic improvement. These findings suggest that the diffuse pulmonary disease in this case was induced by cyclophosphamide. Since interstitial pneumonitis may be fatal and irreversible, attention should be paid to this rare complication even in patients undergoing low-dose oral cyclophosphamide treatment.

Pneumomediastinum in newborns induced by the Elder CPR/demand valve during resuscitation.

Two term and one post-term newborn infants with pneumomediastinum associated with the use of an Elder CPR (cardiopulmonary resuscitation)/demand valve during resuscitation are described. Because of apnea or irregular gasping respiration after vaginal delivery, they received repetitive positive-pressure ventilation with this resuscitator, which is designed to provide 100% oxygen with a limited pressure of up to 40 cmH2O. Following resuscitation, the infants had tachypnea and diminished breath sounds. Roentgenograms and computed tomography of the chest revealed pneumomediastinum in all three and cervical subcutaneous emphysema in one. They required 25-30% oxygen for 3-14 days until they recovered spontaneously. Thus, pressures as low as 40 cmH2O can cause barotrauma, and the Elder resuscitator, even when functioning properly, may injure the lungs of newborn infants.

Cranial polyneuropathy with elevated serum antiganglioside antibody.

We report a 6-year-old girl with cranial polyneuropathy with elevated serum levels of antiganglioside antibodies. She manifested herpetic vesicles around the right upper eyelid and mouth without antecedent infection. She developed facial asymmetry and double vision 5 days after the first appearance of the vesicles. Neurological examination on admission disclosed palsies of the bilateral sixth and twelfth cranial nerves and right third and seventh cranial nerves, but limb muscle weakness, ataxia, and areflexia were not observed. Cerebrospinal fluid examination and MRI of the brain showed no abnormalities. Serum antibodies to gangliosides GQ1b and GT1b, but not GM1, and those to Campylobacter jejuni were significantly increased on admission and on the hospital day 14. These observations suggest that the present case is a variant form of Miller Fisher syndrome or Bickerstaff's brainstem encephalitis subsequent to asymptomatic C. jejuni infection. We treated her with intravenous administration of high-dose methylprednisolone and acyclovir, but almost no effect was observed. All cranial nerve palsies, however, had resolved completely approximately 4 months later. This may be the first pediatric case in which cranial polyneuropathy and antiganglioside antibodies were associated.

Herpes zoster in a normal child after varicella vaccination.

A healthy 5 year old girl developed herpes zoster in the dermatome supplied by the ophthalmic branch of the fifth cranial nerve 40 months after varicella vaccination. She was admitted to our hospital because of high fever and painful vesicular lesions over the left side of her forehead. She was treated successfully with systemic and topical acyclovir without developing herpetic keratoconjunctivitis. Our acute and convalescent phase evaluations showed that non-specific cellular and humoral immunity was normal. This is the fourth case of herpes zoster developing in an immunocompetent child following vaccination. Unlike the previously reported cases, our patient required hospitalization mainly to prevent ocular involvement. The issue concerning whether the universal introduction of varicella vaccination of normal children will reduce the incidence of the subsequent occurrence of herpes zoster must await further studies involving longer follow-up periods.