En esta nueva sección, he querido compartir algunos CASOS CLINICOPATOLOGICOS interesantes, considero que con la experiencia de cada uno, podremos enriquecerlos aún más aportando comentarios al final, y que aparezcan publicados para inicar asi un foro permanente de Educación Continua.
DR LUIS ALFREDO RUIZ CRUZ
1. Niño de 3 años con episodios recurrentes de insuficiencia respiratoria. NEJM. Vol. 356:398; 2007
2. Niño de 5 años con cefalea y dolor abdominal. NEJM. 355; 24; 2006
3. Infante de 1 mes de edad con neumonia redondeada multilobar. Pediar. Infect. Dis. J. 2006; 25(1):95
Necesitan abrir cuenta en Medscape.com (es gratis)
One-Month-Old Infant With Multilobar Round Pneumonias
Jessica S. Kosut, MD; Naynesh R. Kamani, MD; Barbara A. Jantausch, MD
Pediatr Infect Dis J. 2006;25(1):95,97. ©2006 Lippincott Williams & Wilkins
A 1-month-old male infant presentedto the emergency department with a 1-day history of low grade fever and a 2-day history of fussiness and increased spitting up. He had no diarrhea or history of ill contacts. He had been born at 40 weeks gestation with a birth weight of 8 lbs 5 oz after an uncomplicated pregnancy, delivery and nursery course. He resided with his mother, father, 2 siblings and a cat. He had no history of travel outside the area.
On examination, the infant had a temperature of 38ºC, a pulse of 156 beats/min, a respiratory rate of 35 respirations/min and a weight of 5 kg, with an oxygen saturation of 98% in room air. He was alert and interactive, although intermittently fussy. His examination was remarkable only for abdominal distention, voluntary guarding and increased fussiness with abdominal palpation; he had normoactive bowel sounds. An abdominal radiograph revealed no signs of obstruction. However, incidentally, 2 fluffy appearing perihilar densities were noted in the lungs. A repeat chest radiograph was performed and showed bilateral upper lobe round opacities as well as a left lower lobe infiltrate (Fig. 1. Hematologic studies revealed a white blood cell count of 14,500/mm3 with a differential count of 53% segmented neutrophils, 4% band forms, 33% lymphocytes, 2% eosinophils and 8% monocytes; hemoglobin 11.3 g/dL; and hematocrit 28.2%; platelet count 480,000/mm3. Blood and urine cultures were obtained, and a lumbar puncture was performed. The electrolytes, urine analysis and cerebrospinal fluid studies were all normal. The patient was hospitalized and empirically treated with intravenous ampicillin and cefotaxime.
Posteroanterior (A) and lateral (B) views of the chest depicting bilateral upper lobe and left lower lobe round densities.
A computerized axial tomography scan of the chest revealed 4 heterogeneous well-marginated lesions in the lungs: 1 in the right upper lobe; 1 in the left upper lobe; 1 in the right lower lobe; and 1 in the left lower lobe. The largest mass was within the left lower lobe and measured 2.2 cm. No hilar lymphadenopathy was noted.
Purified protein derivative and anergy panels were both nonreactive. Three gastric aspirates were negative for acid-fast bacilli. Titers for Bartonella henselae were negative. Bronchial alveolar lavage was performed, and specimens were sent for bacterial, fungal and Chlamydia trachomatiscultures, acid-fast smear, influenza A and B antigens, varicella-zoster virus antigen and herpes simplex virus antigen. All of these studies were negative. Pathologic examination of the bronchial lavage specimen showed no hemosiderin-laden macrophages or fungal organisms. An open lung biopsy was performed of the left lower lobe lung mass, which revealed the etiology of this infant’s illness.
Prompted by the unusual radiographic findings, an immunology evaluation was performed before the bronchial alveolar lavage. Quantitative immunoglobulins including IgG, IgA, IgM and IgE and total complement (CH50) were normal. An oxidative burst assay in which dihydrorhodamine 123 fluorescence (DHR) was used found no neutrophils undergoing oxidative burst. The mother, father and siblings were also tested. The mother and sister both had a mixed population of neutrophils where some underwent oxidative burst and others did not, whereas the father and the brother had completely normal oxidative burst assays.
The open lung biopsy revealed extensive suppurative granulomas with giant cell formation, eosinophilia with focal eosinophilic abscess formation, as well as necrotic microabscess formation. Gomori methenamine silver stain demonstrated fungal hyphal forms highly suggestive of Aspergillus. A diagnosis of chronic granulomatous disease (CGD) with round pneumonias caused by Aspergillusspp. was made. Therapy with voriconazole was initiated. The patient was also given daily prophylactic therapy with trimethoprim-sulfamethoxazole. Repeat computerized axial tomography (CT) scan of the lung showed some improvement after 7 days of antifungal therapy. The patient continued on voriconazole therapy with follow-up chest CT scans to evaluate the response of the lung lesions. About 9 months after the diagnosis was made, the patient underwent a bone marrow transplant (BMT) from his 4-year-old HLA-matched healthy brother. His voriconazole was discontinued 4 months after BMT, and he is currently free of infection and with full donor neutrophil engraftment.
First described in 1957, CGD is an inherited immunodeficiency resulting in a defect in phagocytic cell function. Although neutrophil chemotaxis and phagocytosis are intact, the phagocytes are unable to use reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to generate reactive oxygen species and thus cannot kill the organism ingested by the phagocyte. This leads to recurrent infections with catalase-positive pathogenic bacteria and fungi. Organisms such as Aspergillus spp., Staphylococcus aureus, Pseudomonas spp., Salmonella spp., Aerobactor spp., Candida albicans, Burkholderia cepacia and Serratia marcescens produce catalase, which causes the breakdown of hydrogen peroxide within the cell. Without the presence of this hydrogen peroxide, the phagocyte must be able to generate its own oxygen radicals to kill the infecting organism. Thus in patients with CGD, no death of the organism occurs.
Testing for CGD previously was done primarily with the use of the nitroblue tetrazolium (NBT) test, which qualitatively assesses NADPH oxidase activity. In normal neutrophils stimulated in vitro, the superoxide that is generated reduces NBT to formazan, which creates a dark blue precipitate in the cells. Normal oxidase function results in at least 95% of the cells turning blue in the assay. Currently flow cytometry techniques with the use of dihydrorhodamine 123 fluorescence (DHR) have largely supplanted the NBT test for diagnostic purposes. DHR detects oxidant production because it increases fluorescence when oxidized by H2O2, and the fluorescence is quantitated. Genetic testing is also available. CGD results from mutations in any 1 of the 4 subunits of the NADPH oxidase complex. In our patient’s family, the infant had the X-linked form of CGD, whereas the mother and sister were carriers for the disease as demonstrated by the mixed population of neutrophils found on their flow cytometry testing.
The typical presentation for CGD is recurrent pyogenic infection either in the first 5 years of life or in early adulthood. Infections of the lung, skin and lymph nodes tend to predominate. The most common pathogens in these patients include Aspergillus spp. (pneumonia), S. aureus (suppurative adenitis, subcutaneous infections, liver abscess) and Serratia spp. (osteomyelitis and pneumonia). Many of the patients remain asymptomatic until the infection is advanced.
Antibiotic therapy, both prophylactic and therapeutic, is the mainstay of therapy. Prophylactic trimethoprim-sulfamethoxazole should be initiated soon after the diagnosis of CGD is made. Trimethoprim-sulfamethoxazole reduces the rate of severe infections by at least 50% in patients with CGD because it has activity against S. aureus, Serratia marcescens, Burkholderia spp., and Nocardia spp. Itraconazole has been studied and found to be effective in prophylactic regimens against fungal infections. Furthermore γ-interferon is an effective adjunctive therapy and can reduce the number of severe infections by 70%. In those patients with life-threatening infections not responding to antimicrobial therapy, growth factor or granulocyte transfusions can improve outcomes.
BMT is the only curative therapy currently available. A European retrospective study documented that 23 of 27 patients survived post-BMT, and 22 of those 23 were cured of CGD. Research on gene therapy is being performed with the current focus being on vectors and retroviruses, and it holds great promise for the future treatment of CGD.
Jessica S. Kosut, MD,* Naynesh R. Kamani, MD,† Barbara A. Jantausch, MD‡
*Department of Pediatrics, the †Division of Stem Cell Transplantation and Immunology, Department of Pediatrics and Immunology, Center for Cancer and Blood Disorders, and the ‡Division of Infectious Diseases, Department of Pediatrics, Children’s National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC