Granulocyte transfusions in children with chronic granulomatous disease and invasive aspergillosis

The transfusion of granulocytes to restore host defenses in severely granulocytopenic patients or in patients with defective granulocyte functions has been studied for more than 60 years. However, inadequate dosage of cells and inconsistent efficacy has limited the usage of these transfusions. Recently, the use of mobilizing agents such as granulocyte colony stimulating factors and dexamethasone has renewed interest in these treatment modalities. The present study is conducted to determine an appropriate method of enriched granulocyte collection with Fresenius AS.TEC.204 cell separator (Fresenius, Bad Homburg, Germany) and to evaluate the preliminary clinical results of granulocyte transfusion therapy in patients with chronic granulomatous disease and invasive Aspergillosis in parallel with in vitro granulocyte function. Three patients who have been treated for chronic granulomatous disease and invasive Aspergillosis received a total of 20 granulocyte transfusions. To mobilize granulocytes, healthy donors were given 450 microg of granulocyte colony-stimulating factor (G-CSF) subcutaneously and 8 mg of dexamethasone orally approximately 12 h before collection. Five microg/kg/day of G-CSF was also subcutaneously administered prior to granulocyte transfusions. The first patient received 4; the second, 14 and the third, 2 transfusions. The granulocyte count given to these patients ranged between 0.4 and 3.0 x 10(9)/kg. Most transfusions were well tolerated. The nitroblue tetrazolium (NBT) tests that were done 16-24 h after the transfusion showed 14-46% dye reduction. Two of the three patients survived the infection. Granulocyte transfusions from G-CSF and dexamethasone stimulated donors could be a choice of treatment in chronic granulomatous disease patients, especially with disseminated invasive Aspergillosis.     

Treatment of invasive aspergillosis with itraconazole in a patient with chronic granulomatous disease

An 18-year-old boy with X-linked chronic granulomatous disease (CGD) developed Aspergillus fumigatus pneumonia and multifocal osteomyelitis. Treatment with amphotericin B resulted in only moderate improvement of the lesions and was accompanied by considerable toxicity. In contrast, administration of the new triazole drug itraconazole led to complete disappearance of all signs of infection. We conclude that itraconazole may be a valuable new drug for treating invasive aspergillosis in patients with CGD, although the duration of treatment remains to be established.     

Chronic granulomatous disease in an adult female with granulomatous cheilitis. Evidence for an X-linked pattern of inheritance with extreme lyonization

We describe in this paper a female patient affected by chronic granulomatous disease with all the features of the classic X-linked form of the disease and presenting a mild form of the disease, the major clinical manifestation being a granulomatous cheilitis. The capability of the patient's phagocytes to undergo a respiratory burst in response to different stimuli was markedly depressed and only 10% of the patient's neutrophils were able to reduce nitroblue tetrazolium when stimulated with phorbol myristate acetate to an extent similar to normal cells. With this test, the neutrophils of the patient's mother showed a clear mosaicism, only 40% being able to reduce the dye. Activation of NADPH oxidase in cell-free systems showed that the phagocyte defect was at the level of a membrane component. Difference in spectra revealed that the observed membrane defect was due to a lack of cytochrome b558, the terminal component of NADPH oxidase. Incubation for 2 or 24 h of the patient's neutrophils with human recombinant interferon-gamma and granulocyte macrophage colony-stimulating factor did not correct their defective capability to undergo a respiratory burst However, cultivation of the patient's monocytes with interferon-gamma for prolonged times substantially enhanced their capability to produce hydrogen peroxide.     

Chronic granulomatous disease

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency due to an abnormal function of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase; NADPH oxidase is a key enzyme for the cellular “respiratory burst”, the cellular process that converts molecular oxygen to the oxygen free-radical superoxide. As a consequence of NADPH oxidase defect, CGD patients suffer from recurrent life-threatening infections and from exceeding inflammatory responses leading to granulomas. This article analyzes clinical aspects of CGD. Furthermore, using the CGD model, we focused on the future perspective to reduce atherosclerosis and its complications.     

Chronic granulomatous disease

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency due to an abnormal function of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase; NADPH oxidase is a key enzyme for the cellular "respiratory burst", the cellular process that converts molecular oxygen to the oxygen free-radical superoxide. As a consequence of NADPH oxidase defect, CGD patients suffer from recurrent life-threatening infections and from exceeding inflammatory responses leading to granulomas. This article analyzes clinical aspects of CGD. Furthermore, using the CGD model, we focused on the future perspective to reduce atherosclerosis and its complications.     

Successful treatment of invasive aspergillosis in chronic granulomatous disease by granulocyte transfusions followed by peripheral blood stem cell transplantation

Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder characterized by impaired microbial killing and susceptibility to bacterial and fungal infections. Cure of the disease can be achieved by stem cell transplantation when performed early in its course, and before severe infections have developed. Invasive aspergillosis constitutes a very high risk for transplantation. We report a 4-year-old boy with X-linked CGD who underwent successful HLA-identical peripheral blood stem cell (PBSC) transplantation during invasive pulmonary aspergillosis and osteomyelitis of the left fourth rib, which was unresponsive to antifungal treatment. During the 2 months prior to the transplant he received G-CSF-mobilized granulocyte transfusions (GTX) from unrelated donors three times a week in addition to the antifungal treatment. This resulted in clinical improvement in his respiratory status. He also received GTX during the aplastic period after the conditioning regimen, until he had engrafted. Post-transplant superoxide generation test revealed that neutrophil function was within normal range. One year post transplant the CT scan showed almost complete clearance of the pulmonary infiltrates and a marked improvement in the osteomyelitic process. Based on other reports and our own experience, GTX can serve as important treatment in patients with CGD who have failed conventional anti-fungal treatment and for whom stem cell transplantation is the only chance for cure.     

Esophageal dysmotility in an adult with chronic granulomatous disease

Chronic granulomatous disease (CGD) is a group of hereditary disorders of impaired intracellular destruction of phagocytosed bacteria. Gastrointestinal manifestations are present, with hepatic abscess being the most common. In this case report, we present an adult with CGD with esophageal involvement, which has been described in only one other adult. The clinical history, modalities of diagnosis (including endoscopy, barium radiography, and esophageal manometry), and therapeutic strategies pertaining to the esophageal manifestations of CGD are discussed. A review of the pertinent available literature is provided.     

Recurrent Nocardia pneumonia in an adult with chronic granulomatous disease

The diagnosis of chronic granulomatous disease was made for the first time in a young adult when he presented with Nocardia asteroides pneumonia. Treatment with trimethoprim/sulfamethoxazole for 10 wk brought about an apparent cure of the infection. Two and one half years later N. asteroides pneumonia recurred and resulted in death from respiratory failure. Antibiotic susceptibility studies suggested that both episodes were caused by the same organism. This suggestion was supported by endonuclease restriction analysis, which showed that the plasmids from both Nocardia isolates were identical. Late recurrence of pneumonia caused by N. asteroides occurs only rarely. In this patient, recurrent infection appeared to be related to persistence of colonizing organisms in the host.     

Chronic granulomatous disease in three siblings

A family of 7 persons is described in which one male and two female siblings have chronic granulomatous disease (CGD). The CGD diagnosis was established by histories of recurring infections, typical histopathology, deficient nitroblue tetrazolium (NBT) reduction and deficient neutrophil killing of Staphylococcus aureus. Noteworthy infections were liver abscesses, pneumonia, pleurisy, lymphadenitis, skin pustules, urinary tract infection and dental abscesses. The affected boy was the most severely ill with liver abscesses. One sister also had liver abscesses with Staph. aureus and both were treated with cloxacillin in combination with fucidin and surgical intervention. A survey of the closest relatives with the NBT test disclosed no further cases. In this family in the heredity seems to be of the recessive type.     

Selective immunoglobulin M deficiency in an adult with Streptococcus pneumoniae sepsis and invasive aspergillosis.

Primary selective immunoglobulin (Ig) M deficiency usually presents early in life with recurrent or severe infections caused by encapsulated and gram-negative organisms. Primary selective IgM deficiency in adults is rare and is usually associated with autoimmune diseases or malignant neoplasm. We performed an extensive immunological analysis of innate and adaptive immunity in an adult patient with possible primary selective IgM deficiency who presented with life-threatening Streptococcus pneumoniae septic shock and invasive Aspergillus fumigatus infection. The patient had no evidence of autoimmune disease or malignant neoplasm. Serum IgG, IgA, and IgE were normal; however, serum IgM levels and specific antibody titers against all 14 pneumococcal polysaccharide serotypes were consistently low. Complement CH50, C3, C4, and neutrophil phagocytosis and oxidative burst were normal. Toll-like receptor expression on monocytes was also normal. Therefore, adult patients with serious life-threatening and unusual infections should be investigated for possible selective primary IgM deficiency.     

Chronic necrotizing pulmonary aspergillosis following an infection by Mycobacterium malmoense

Pneumonia due to Mycobacterium malmoense is rare and usually occurs in damaged lung as is the case with Aspergillus infections. We report the case of a patient who developed chronic necrotizing pulmonary aspergillosis following an infection by atypical mycobacteria. A 53-year-old woman was hospitalized because of weight loss and fever. Direct examination of sputum smear was positive for acid fast bacilli and PCR and culture led to the diagnosis of infection with M. malmoense. Treatment was begun with clarithromycin, rifampicin and ethambutol. Despite initial improvement and excellent adherence to treatment, fever and weight loss recurred 6 months later. Relapse of the mycobacterial infection was excluded and the final diagnosis was necrotizing pulmonary aspergillosis. Infection with A. fumigatus complicating the treatment of M. malmoense is unusual. The management is challenging because of strong interactions between voriconazole and rifampicin, and thus requires a multidisciplinary and specialized approach.     

Fatal invasive aspergillosis in an adolescent with cystic fibrosis

We report on a 13-year-old girl with cystic fibrosis (CF) who developed refractory airflow obstruction despite high-dose steroids. She developed invasive aspergillosis and died despite oral and intravenous antifungal therapy. We speculate that the increasing use of immunosuppressive strategies and aggressive antipseudomonal therapy in CF may lead to an increase in aspergillus lung disease, including invasive aspergillosis in the future.     

Intravenous itraconazole followed by oral itraconazole in the treatment of invasive pulmonary aspergillosis in patients with hematologic malignancies, chronic granulomatous disease, or AIDS.

The pharmacokinetics, efficacy, and safety of intravenous (iv) itraconazole (2 days at 400 mg/day, 12 days at 200 mg/day), followed by 12 weeks of oral capsules (400 mg/day) were studied in 31 immunocompromised patients with pulmonary invasive aspergillosis. All patients received iv itraconazole (median duration, 14 days), and 26 then received oral itraconazole (median duration, 78.5 days). After receiving iv itraconazole, concentrations increased rapidly, with trough plasma levels > or =250 ng/mL in 91% of patients and in all patients by day 7. Concentrations > or =500 ng/mL were observed in 64% of patients by day 2. Mean trough concentrations after 2 and 14 days were 670 and 850 ng/mL, respectively. Therapeutic levels were maintained after switching to oral capsules. A complete or partial response was seen at the last on-treatment assessment in 15 (48%) of 31 patients, with 6 (19%) showing stable disease. Itraconazole was well tolerated, with no unexpected effects. Overall iv/oral itraconazole was safe and effective in invasive aspergillosis.     

Lymphocytic bronchiolitis as presenting disorder in an undiagnosed adult patient with chronic granulomatous disease

Chronic Granulomatous Disease (CGD) is a rare primary immunodeficiency disease. Although the most affected patients are diagnosed in childhood, there are several reports of the disease presenting in adult patients. Here we present a 40 years old man who was admitted in hospital due to respiratory symptoms and ground glass pattern in high resolution computed tomography of lung. Open lung biopsy revealed lymphocytic bronchiolitis. Because of past medical history of granulomatous lesion in lung and recurrent abscesses of skin and soft tissue, NBT test was conducted which its result revealed that the disorder was compatible with CGD and then it was confirmed by fluorescent cytometry.