Pulmonary complications after bone marrow transplantation.

Many of the pulmonary complications that we have described have a nonspecific radiographic appearance. The most crucial information for proper interpretation of the chest radiographs is the chronologic onset of radiographic abnormalities after transplantation. Before and immediately after engraftment, local peripheral opacities accompanied by a surrounding rim of edema are regarded as fungal infections, and therapy with granulocyte transfusions and amphotericin B is initiated. Diffuse interstitial thickening is likely to represent edema, pulmonary hemorrhage, bacterial infection, or ARDS rather than CMV or P. carinii pneumonia in the neutropenic host. After engraftment, diffuse interstitial processes become the predominant lung abnormalities. In allogeneic transplant patients who are serologically positive for CMV or who receive serologically positive donor marrow for CMV, pneumonitis caused by this virus is perhaps the most common treatable lung infection. Idiopathic interstitial pneumonias present in a similar fashion to CMV pneumonia; however, the response to corticosteroid therapy is only occasionally gratifying. The onset of nodular opacities in this period may be due to a number of disorders, such as opportunistic infection, BOOP, PTLPD or recurrent tumor. Open lung biopsy usually is required for definitive diagnosis.

Childhood lymphoma: diagnostic accuracy of chest radiography for severe pulmonary complications.

INTRODUCTION: We sought to determine whether chest radiography can be reliably used to distinguish persistent or relapsing pulmonary lymphoma from a variety of infectious and noninfectious pulmonary conditions that can occur in children receiving treatment for lymphoma. METHODS: We studied chest radiographs of 37 patients (30 with non-Hodgkin's lymphoma, and seven with Hodgkin's disease) who died of paediatric lymphoma or of treatment complications. Pulmonary findings at autopsy comprised lung tumour (n = 14), pleural tumour (n = 12), pneumonia (n = 22), adult respiratory distress syndrome (ARDS; n = 16), haemorrhage (n = 27), and infarction (n = 13). Using a 4-point scale and without knowledge of autopsy findings, three radiologists independently rated antemortem radiographs for the presence of pulmonary tumour, pleural tumour, pneumonia in general, pneumonia caused by viral, bacterial, fungal, and protozoan pathogens, ARDS, pulmonary haemorrhage, and pulmonary infarction. Diagnostic accuracy was defined by the area under the receiver-operating-characteristic curve (AZ). RESULTS: Diagnostic accuracy was good for pulmonary tumour (AZ, 0.71 +/- 0.6), protozoan pneumonia (AZ, 0.77 +/- 0.06), and ARDS (AZ, 0.86 +/- 0.07) but poor for all other conditions. The absence of both pleural effusions and mediastinal/right hilar lymphadenopathy was significantly associated (P < or = 0.04) with the absence of lung tumour. DISCUSSION: The pulmonary processes in these patients can all demonstrate diffuse airspace opacification, and many patients had multiple lung abnormalities at autopsy. The radiologist-readers were unable to identify which pulmonary conditions were responsible for radiographic findings in most patients. The readers were able to identify patients who did not have pulmonary lymphoma. If pulmonary involvement with lymphoma is unlikely, bronchoscopy with bronchoalveolar lavage may be sufficient to establish a diagnosis. When pulmonary lymphoma is a clinical consideration, open lung biopsy is usually required for diagnosis.

Diagnostic utility of thoracentesis for neutropenic children with cancer.

Thoracentesis is a procedure often performed in children with pleural effusions to assist in diagnosis and management. Its safety and utility for immunocompromised patients with neutropenia (absolute neutrophil count, <1,500 polymorphonuclear leukocytes and band forms per microL) is unclear. We reviewed our experience over a 10-year period to evaluate the role of thoracentesis for neutropenic children with cancer who had pulmonary effusions of presumed infectious etiology. Twenty-two patients were identified, and 18 had absolute neutrophil counts of < or = 500/microL. Empirical antibiotics had been administered to 95% of these patients and antifungal agents to 72%. Two patients' cultures were positive for fungal organisms: Aspergillus terreus in one case and Candida albicans in the other. Both of these patients had been receiving antifungal therapy. Therapy was altered for these two patients plus one additional patient in whose pleural fluid tumor cells were unexpectedly found. Eight of the remaining 19 patients underwent another diagnostic procedure, yielding five additional diagnoses. In conclusion, thoracentesis is safe and should be considered as a diagnostic test for febrile neutropenic patients with pulmonary effusions of presumed infectious etiology, although more invasive tests may be warranted.

Serial pulmonary function studies in children treated for newly diagnosed Hodgkin's disease with mantle radiotherapy plus cycles of cyclophosphamide, vincristine, and procarbazine alternating with cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine.

BACKGROUND: The pulmonary toxicity of bleomycin-containing chemotherapy combined with mantle radiotherapy in children treated for Hodgkin's disease was longitudinally assessed. METHODS: The results of serial pulmonary function studies in 37 children, newly diagnosed and treated at St. Jude Children's Research Hospital between September 23, 1983, and June 30, 1988, with cyclophosphamide, vincristine, and procarbazine (COP) alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) plus low dose mantle radiotherapy are analyzed. All patients had pulmonary function studies at least before the first bleomycin dose, after completion of radiotherapy, and serially upon discontinuation of therapy. Bleomycin therapy was withheld whenever measured carbon monoxide diffusing capacity was less than 50% of the predicted value. RESULTS: Vital capacity, diffusing capacity, and diffusing capacity per unit of alveolar volume declined during the first 6 months of therapy but improved there after. At 2 years postdiagnosis, diffusing capacity per unit of alveolar volume remained significantly reduced. Only one patient was symptomatic at the 2-year point. The survival rate of these patients was 95% at a median follow up of 93 months. CONCLUSION: If bleomycin is with held when diffusing capacity is diminished to 50% predicted, clinical compromise of pulmonary function appears to be minimal in pediatric patients receiving alternating cycles of COP/ ABVD in combination with low-dose mantle radiotherapy. Survival was excellent, even with reduction of the total bleomycin dose.

Oxidation of bromide by the human leukocyte enzymes myeloperoxidase and eosinophil peroxidase. Formation of bromamines.

Myeloperoxidase and eosinophil peroxidase catalyzed the oxidation of bromide ion by hydrogen peroxide (H2O2) and produced a brominating agent that reacted with amine compounds to form bromamines, which are long-lived oxidants containing covalent nitrogen-bromine bonds. Results were consistent with oxidation of bromide to an equilibrium mixture of hypobromous acid (HOBr) and hypobromite ion (OBr-). Up to 1 mol of bromamine was produced per mole of H2O2, indicating that bromamine formation prevented the reduction of HOBr/OBr- by H2O2 and the loss of oxidizing and brominating activity. Bromamines differed from HOBr/OBr- in that bromamines reacted slowly with H2O2, were not reduced by dimethyl sulfoxide, and had absorption spectra similar to those of chloramines, but shifted 36 nm toward higher wavelengths. Mono- and di-bromo derivatives (RNHBr and RNHBr2) of the beta-amino acid taurine were relatively stable with half-lives of 70 and 16 h at pH 7, 37 degrees C. The mono-bromamine was obtained with a 200-fold excess of amine over the amount of HOBr/OBr- and the di-bromamine at a 2:1 ratio of HOBr/OBr- to the amine. In the presence of physiologic levels of both bromide (0.1 mM) and chloride (0.1 M), myeloperoxidase and eosinophil peroxidase produced mixtures of bromamines and chloramines containing 6 +/- 4% and 88 +/- 4% bromamine. In contrast, only the mono-chloramine derivative (RNHCl) was formed when a mixture of hypochlorous acid (HOCl) and hypochlorite ion (OCl-) was added to solutions containing bromide and excess amine. The rapid formation of the chloramine prevented the oxidation of bromide by HOCl/OCl-, and the chloramine did not react with bromide within 1 h at 37 degrees C. The results indicate that when enzyme-catalyzed bromide or chloride oxidation took place in the presence of an amine compound at 10 mM or higher, bromamines were not produced in secondary reactions such as the oxidation of bromide by HOCl/OCl- and the exchange of bromide with chlorine atoms of chloramines. Therefore, the amount of bromamine produced by myeloperoxidase or eosinophil peroxidase was equal to the amount of bromide oxidized by the enzyme. Bromide was preferred over chloride as the substrate for both enzymes.

Childhood leukemia: diagnostic accuracy of bedside chest radiography for severe pulmonary complications.

PURPOSE: To determine the diagnostic accuracy of bedside chest radiography in patients who develop severe pulmonary complications while undergoing therapy for leukemia. MATERIALS AND METHODS: The authors studied 45 patients, aged 21 years and younger, who died of leukemia or of treatment complications and for whom autopsy findings were available. Pulmonary findings at autopsy comprised pneumonia (n = 25), adult respiratory distress syndrome (ARDS) (n = 16), hemorrhage (n = 38), infarction (n = 18), and leukemic cellular infiltration (n = 11). Four radiologists who were unaware of the autopsy diagnoses independently rated antemortem bedside chest radiographs. RESULTS: Diagnostic accuracy for each disease was as follows: ARDS, 0.81 +/- .03 (standard error); all pneumonias, 0.56 +/- .04; hemorrhage, 0.47 +/- .07; infarction, 0.50 +/- .12; and pulmonary leukemic cellular infiltration, 0.38 +/- .12. CONCLUSION: The specific radiographic appearance of ARDS permits excellent diagnostic accuracy.

Cunninghamella infections: review and report of two cases of Cunninghamella pneumonia in immunocompromised children.

Infections caused by Cunninghamella bertholletiae are being identified with increasing frequency in immunocompromised patients. We have treated two children with cancer for pulmonary infections caused by this rare fungus. Cunninghamella infection is found in a variety of populations of patients, including both children and adults undergoing chemotherapy. Clinical signs and symptoms are indistinguishable from those of other forms of zygomycosis. Outcome is poor: only three of 17 patients with such infection (including one of the two children described herein) have survived. Treatment involves aggressive surgical excision and administration of amphotericin B.

Postoperative outcome following thoracotomy in the pediatric oncology patient with diminished pulmonary function.

Surgical resection of pulmonary metastatic disease is often indicated in pediatric malignancies. Although several adult studies document increased postoperative morbidity in adults with diminished pulmonary function, there is little information in the pediatric population or in patients with restrictive lung disease. We reviewed the postoperative course following thoracotomy in patients with diminished pulmonary function (FVC, FEV1, or TLC less than 80% predicted). Thirty-two thoracotomies were performed in 19 patients. The preoperative FVC (% predicted) was 68 +/- 3.6 with a postoperative value of 60 +/- 2.4 (P < 0.01). The preoperative FEV1 was 69 +/- 4.2 with a postoperative value of 60 +/- 3.8 (P < 0.01). Although there was a significant drop in pulmonary function tests (PFTs) following surgery, there was not a significantly greater loss when comparing patients with mild, moderate, and severe disease. When considering postoperative morbidity, there were 3 events (prolonged oxygen requirement, need for postoperative ventilation, or persistent air leak) following 20 surgeries in patients with mild preoperative respiratory dysfunction, 5 events (including one death) in the 7 patients with moderate dysfunction, and 3 events following 5 surgeries in patients with severe dysfunction. There was no correlation with a decrease in any specific PFT and the occurrence of postoperative morbidity. Our limited review suggests that aggressive surgical treatment of metastatic pulmonary disease is tolerated even in patients with severe decreases in pulmonary function.

Inhibition of the human leukocyte enzymes myeloperoxidase and eosinophil peroxidase by dapsone.

Dapsone (4,4'-diaminodiphenylsulfone) is an antimicrobial substance that also has anti-inflammatory activity, which has been attributed to inhibition of the leukocyte enzyme myeloperoxidase (MPO). We observed that dapsone was a much better inhibitor of the eosinophil peroxidase (EPO) in an assay that measured peroxidase-catalyzed oxidation of tetramethylbenzidine at pH 5.4. To clarify the specificity and pH-dependence of dapsone inhibition of the purified enzymes under more physiologic conditions, we studied peroxidase-catalyzed oxidation of chloride to the antimicrobial and cytotoxic agent hypochlorous acid. Taurine was added as a trap for hypochlorous acid, to prevent inactivation of the enzymes or chlorination of dapsone by hypochlorous acid. Dapsone was much more effective as an inhibitor of both MPO and EPO when chloride rather than tetramethylbenzidine was the substrate. Inhibition of both enzymes was greater at neutral pH than at acid pH (pH 7 vs pH 5), but EPO was more sensitive to inhibition than MPO regardless of pH. Inhibition was increased by lowering chloride, raising hydrogen peroxide, or lowering the enzyme concentration. Inhibition was accompanied by irreversible loss of enzyme activity, which was correlated with loss of the heme absorption spectrum, indicating chemical modification of the enzyme active site. EPO, but not MPO, was partially protected against inactivation by adding physiologic levels of bromide along with chloride. The results suggest that dapsone could prevent MPO- and EPO-mediated tissue injury at sites where the peroxidase enzymes are secreted and diluted into the neutral pH environment of the tissue interstitial space. Dapsone might not inhibit peroxidase-mediated antimicrobial activity, which occurs at high enzyme concentrations in the acid environment of phagolysosomes.

Postsepsis bradycardia in children with leukemia.

OBJECTIVE: We observed sinus bradycardia in a small number of children with hematologic malignancies who were recovering from sepsis. Our objective was to define this symptom complex and attempt to delineate its etiology. DESIGN: Retrospective chart review. SETTING: A pediatric ICU in a children's oncology hospital. PATIENTS: Children admitted to the ICU over a 24-month period who developed persistent bradycardia (heart rate less than 5% for age for greater than 1 hr) after an episode of sepsis. MEASUREMENTS AND MAIN RESULTS: Seven children developed postsepsis bradycardia. Six patients had a primary diagnosis of acute myelogenous leukemia and one patient had acute lymphocytic leukemia. All patients had positive blood cultures (Streptococcus mitis, n = 4; Escherichia coli, n = 2; and Klebsiella pneumoniae, n = 1). All seven children were clinically recovering from sepsis when the bradycardia developed. Neither hypotension nor other symptom was associated with the bradycardia. No therapy was given for the bradycardia. Echocardiograms and ECGs were normal in all patients, except for the presence of bradycardia. Bradycardia persisted for 24 to 72 hrs. After that time, heart rates slowly increased to the normal range for age. CONCLUSIONS: We speculate that this syndrome may result from alterations in beta-adrenergic receptor function or an unidentified humoral factor produced by the invading organism or as part of the host's response to sepsis. Prior drug therapy or the underlying illness may predispose to this condition, since all the patients had acute leukemia. As the bradycardia was clinically insignificant, invasive therapeutic or diagnostic strategies were not indicated.

Vincristine-induced recurrent laryngeal nerve paralysis in children.

Stridor developed in 2 children during vincristine therapy for malignancies. Indirect laryngoscopy revealed left vocal cord paralyses in both patients. One child had generalized neurotoxicity from vincristine including hypotonia, decreased gastrointestinal motility, and painful paresthesias while laryngeal nerve paralysis was the only neurotoxic manifestation in the other patient. Stridor resolved in both patients after discontinuing or decreasing the dose of vincristine. Visualization of the airway not only confirms the diagnosis, but also rules out treatable causes of stridor in the febrile, immunocompromised patient.

Assay of the human leukocyte enzymes myeloperoxidase and eosinophil peroxidase.

Conditions were optimized for measuring the activity of myeloperoxidase (MPO) and the eosinophil peroxidase (EPO) with tetramethylbenzidine (TMB) as the substrate. Detergents caused a small increase in the measured activity of the purified enzymes and were required when isolated neutrophils or eosinophils were assayed. Sharp concentration optima were observed with both ionic and non-ionic detergents. Activity was also influenced by halide ions. Bromide or iodide caused up to a 7-fold increase in EPO activity and a 1.5-fold increase in MPO activity. The effect of bromide is notable because the bromide-containing detergent CETAB is often used to extract the enzymes for assay and purification. Stimulation by bromide or iodide was consistent with peroxidase-catalyzed oxidation of the halides to hypohalous acids (HOBr and HOI), which oxidized TMB. MPO catalyzes the oxidation of chloride to hypochlorus acid (HOCl), which also oxidized TMB, but chloride up to 20 mM had little effect on the assay. Both MPO and EPO catalyze thiocyanate oxidation, but the product (HOSCN) was a poor oxidant for TMB, and thiocyanate inhibited the measured activities. Stimulation by bromide or iodide could be used to facilitate detection of EPO and to distinguish between MPO and EPO. Activities could also be distinguished based on the greater sensitivity of EPO to inhibition by thiocyanate, azide, aminotriazole, and dapsone. Methods reported here may prove useful for measuring leukocyte influx into inflamed tissues, detecting MPO or EPO deficiencies, and measuring enzyme synthesis and secretion.

Role of flexible bronchoscopy in the diagnosis of pulmonary infiltrates in pediatric patients with cancer.

We reviewed 60 consecutive flexible bronchoscopies done during a 36-month period in 48 pediatric cancer patients with undiagnosed pulmonary infiltrates. Diagnostic procedures during bronchoscopy included 40 brushings, 50 bronchoalveolar lavages, and 6 transbronchial and mucosal biopsies. A total of 16 specific diagnoses were made by bronchoscopy (27% diagnostic yield), including infection (12), pulmonary leukemia (3), and lymphoma (1). The largest proportion of specific diagnoses came from lavage (14/50) and the smallest from brushings (1/40). Biopsies were also useful for selected patients. The low overall yield for bronchoscopy was probably due to the routine use of empiric broad-spectrum antibiotics and antifungal therapy, as well as trimethoprim-sulfamethoxazole prophylaxis for Pneumocystis carinii pneumonitis. Subsequent specific diagnoses were obtained by other procedures (open biopsy, needle aspiration, or autopsy) for 10 patients with negative bronchoscopy results and 3 patients with diagnostic bronchoscopies. These additional diagnoses included 7 infections (Pneumocystis carinii (1), Candida tropicalis (1), cytomegalovirus (1), and Aspergillus (4), and 6 other diagnoses with nonspecific histologic findings. A positive bronchoscopy result may be useful, but negative bronchoscopy findings do not justify delaying other diagnostic procedures or discontinuing antibiotic and antifungal therapy in children with cancer and pulmonary infiltrates.

Oxidant-mediated inhibition of ligand uptake by the macrophage mannose receptor.

We have investigated the effect of oxidants on ligand recognition and internalization by the macrophage mannose receptor. Rat bone marrow macrophages were treated with increasing concentrations of H2O2 for 30 min at 37 degrees C. Fifty percent inhibition of ligand uptake was observed at 250 microM, with only 10% of control uptake remaining following exposure to 1 mM H2O2 for 30 min. Electron micrographic analysis of macrophages following H2O2 treatment showed no morphological alterations compared to untreated cells. Ligand uptake was also inhibited by the following H2O2 generating systems: menadione, xanthine/xanthine oxidase, glucose/glucose oxidase, and phorbol 12-myristate 13-acetate-stimulated polymorphonuclear leukocytes. Inhibition could be blocked by catalase plus or minus superoxide dismutase. Treatment of macrophages at 4 degrees C with H2O2 had no effect on ligand binding, whereas treatment with H2O2 at 37 degrees C reduced binding to 15% of control levels and decreased the number of surface receptors to one-third of control cells. H2O2 treatment inhibited ligand degradation by macrophages, but did not prevent ligand movement from the surface to the interior of the cell. In addition, ligand delivery to lysosomes was blocked by oxidant treatment. These results suggest that treatment of macrophages with reagent H2O2 or H2O2-generating systems inhibits the normal ligand delivery and receptor recycling process involving the mannose receptor. Potential mechanisms might include receptor oxidation, alterations in ATP levels, or membrane lipid peroxidation.

Unilateral analgesia following epidural and subarachnoid block.

A case of unintentional unilateral analgesia following both epidural and subarachnoid block is presented. It is suggested that the presence of an anomalous congenital midline diffusion barrier in both the epidural and subarachnoid spaces could explain this phenomenon.