Early chemotherapy for non-tuberculous mycobacterial infections in patients with cystic fibrosis.

AIM: To evaluate the response rate to antimycobacterial drug therapy in patients with cystic fibrosis (CF) suffering from infection by non-tuberculous mycobacteria (NTM). METHODS: Ten patients, aged 10-34 y, out of 180 CF patients, were diagnosed with NTM disease. They had been regularly checked and examined for pulmonary symptoms, and had had chest X-rays and sputum cultures (including for mycobacteria) performed. One additional 36-y-old female received her CF diagnosis soon after the NTM diagnosis. RESULTS: Mycobacterium avium-intracellulare complex (MAC) was found in 10 out of 11 patients and M. kansasii in 1 patient. Treatment with antimycobacterial drugs resulted in clinical improvement (weight gain or stabilization of weight and/or improved or stabilized lung function in 8 out of 11 patients) and mycobacterial culture turned negative in 10 out of 1. CONCLUSION: Promising results may be associated with early intervention with antimycobacterial therapy in CF patients.

Lack of T-lymphocytosis and poor interferon gamma production in BAL fluid from HIV-negative immunocompetent patients with pulmonary non-tuberculous mycobacteriosis.

Very little is known about the pathogenesis of pulmonary non-tuberculous mycobacteriosis in immunocompetent individuals. Local inflammatory response was assessed by examining bronchoalveolar lavage fluid from 13 HIV-negative patients (12 F) without known cell-mediated immunosuppression, aged 48-72 y (median age 60 y), with non-tuberculous lung mycobacteriosis. Macrophages, lymphocytes, polymorphonuclear neutrophils and eosinophils in bronchoalveolar lavage fluid were analysed morphologically, and the subsets of T-lymphocytes (CD3+, CD4+, CD8+), HLA-DR+, B-lymphocytes (CD19+) and CD16+/CD56+ cells (natural killer, NK cells) were analysed by flow cytometry. Interleukin-1 beta (IL-1beta), IL-2, IL-4, IL-6, IL-8, IL-10 and interferon-gamma (IFN-gamma) levels were assessed by ELISA. The total number of cells/ml was significantly higher in BAL fluid from the patients (median value=880 x 10(3)/ml) compared to six healthy controls (200 x 10(3)/ml). The polymorphonuclear neutrophil population was significantly increased in the patients both proportionally and in the count/ml. The proportion of macrophages was significantly reduced in the patients but not the count/ml. The count of lymphocytes/ml was significantly higher in the patients but the proportion of lymphocytes was unchanged. No significant difference was seen in the relative proportion of NK cells, B- or T-lymphocytes and HLA-DR+ compared to the healthy controls. The IL-1beta and IL-8 levels were significantly increased in the patients. No differences were seen between the patients and controls in the leukocyte or lymphocyte subsets in peripheral blood. The local inflammatory response in BAL fluid from the studied patients was characterized by granulocytosis, and increase in the IL-1beta and IL-8 levels. There was no specific T-cell response.

Fatal outcome of disseminated Mycobacterium avium infection in childhood. A case of primary incompetent monocyte/macrophage function?

Disseminated BCG infection rarely heals, and disseminated disease caused by the Mycobacterium avium complex usually has a poor prognosis with a short time to death. The case of a boy who died after 9 years of diagnosed disseminated M. avium complex infection is described. He showed no signs of previously known immunodeficiency except an incompetent primary monocyte/macrophage function. This case has been commented on in Acta Paediatrica Scandinavia (1982) as "the first infant to survive a generalized BCG infection".

Prognostic significance of pathological chest radiography in transplant patients affected by cytomegalovirus and/or pneumocystis carinii.

PURPOSE: In order to evaluate the prognostic significance of chest film findings in connection with cytomegalovirus (CMV) and/or pneumocystis carinii infection (PC), a retrospective review was made of the pulmonary charts of 274 recipients of kidney and/or pancreatic grafts transplanted between April 1987 and December 1990. MATERIAL, METHODS AND RESULTS: Positive laboratory findings for CMV and/or PC were seen in 92 patients. In 77 patients only CMV was found, 13 patients had both CMV and PC, and 2 patients had only PC. In 57 patients a chest examination was performed. The films were reviewed by 2 radiologists independently. In 32 patients normal chest film findings were seen, while 25 patients demonstrated pathological changes. Of the patients with pathological changes 3 had only pleuritis while the remaining 22 demonstrated parenchymal infiltrations. No deaths occurred among patients infected with CMV and/or PC, when the chest film findings were normal or pleuritis only was seen, but there were 9 deaths in the group of patients with parenchymal infiltrations. Of the patients who died, 2 had only CMV, 5 had both CMV and PC, and 2 had only PC. The overall mortality, regardless of radiological findings, did not exceed 3% in patients with CMV only, but increased to 38% in patients with both CMV and PC. In patients with parenchymal infiltrations the corresponding mortality figures were increased to 18% and 56%, respectively. CONCLUSION: We conclude that a radiologically verified pneumonia related to the infectious agent influences the prognosis, and that CMV pneumonia has a better prognosis than PC pneumonia.

Fungal pneumonia: the predominant lung infection causing death in children undergoing bone marrow transplantation.

The study included 6 children (aged 4-14 years) receiving a conditioning regimen for bone marrow transplantation (BMT) and 14 children (aged 2 14 years) with bone marrow transplants (13 allogeneic, 1 autologous). The children underwent flexible fibre-optic bronchoscopy (FFB) with bronchoalveolar lavage during 6 and 17 episodes of pneumonia, respectively. The aim was to compare the results of the two groups with respect to bronchoscopy findings, pneumonia-causing agents and outcome. During the conditioning regimen, the aetiological agents were recovered by bronchoscopy in 1/6 (17%) episodes and revealed by autopsy in another episode. In three episodes where the aetiology was uncertain, bacterial pneumonia was suspected in two, and Candida pneumonia in one. In episodes after transplantation the aetiological agents were recovered from bronchoscopy material in 14/17 (82%) patients. Autopsy confirmed the premortal diagnosis in the four children who died. In three episodes, bacterial pneumonia was clinically suspected. Based on clinical manifestations, FFB and autopsy findings, bacterial and fungal pneumonia were the most common diagnoses both during conditioning and after BMT. Fungal pneumonia was the most common cause of death in both groups.

Lack of T-helper lymphocytes in BAL fluid from a HIV-negative patient with recurrent non-tuberculous mycobacterial lung infections.

We describe here a previously healthy, 42 year old, HIV-negative woman. Following a seemingly successful 2-year antimycobacterial regimen for a lung infection caused by Mycobacterium avium/intracellulare she acquired a lung infection caused by M. chelonei. Characterization of alveolar cells from bronchoalveolar lavage fluid using flow cytometry revealed a total lack of T-cell subset CD4+ helper lymphocytes in spite of a normal proportion of the CD3+ and CD4+ T-cells in peripheral blood. The levels of Th2 cytokines such as IL-4, TGF-beta and G-CSF were higher in the patient's alveolar cells than in the cells of 4 healthy controls. This imbalance of cells and cell cytokines may contribute to the patient's susceptibility for non-tuberculous mycobacteria and her failure to eradicate these microorganisms.

Treatment of mycobacterial infections in HIV-negative immunocompromised patients.

Rifabutin is a useful drug in the treatment of patients with rifampicin-resistant mycobacteriosis or with rifampicin intolerance. Rifabutin is the preferable drug in patients infected with mycobacteria who concomitantly receive immunosuppressive drugs, because interactions with these are less prominent than with rifampicin.

Rapid detection of cytomegalovirus antigen on alveolar cells in bronchoalveolar fluid from transplant patients with cytomegalovirus pneumonia.

Cytomegalovirus-specific mouse monoclonal antibodies and immunomagnetic beads conjugated with sheep anti-mouse immunoglobulin G were used to screen for cytomegalovirus (CMV) antigen expressed on the surface of alveolar cells in bronchoalveolar lavage (BAL) fluid from 23 transplant recipients with interstitial pneumonia. The beads formed rosettes around the cells when CMV antigen was present on the cell surface. Results could be evaluated by light microscopy within 2 hours of receiving the specimen. Cells in BAL fluid obtained from 15 immunocompetent individuals served as controls. Cytomegalovirus antigen was expressed on the surface of the alveolar cells from 12 transplant recipients and detected by this method as rosette formation on 1-8% of the cells. CMV was isolated from culture of cells in BAL fluid and blood from all these patients except 1, while intracellular CMV antigen was detected by monoclonal antibodies and immunofluorescence in 3 only. Serological changes, indicating an active CMV infection, were present in 11/12 patients. One patient with a CMV pneumonia, later confirmed by autopsy, failed to respond with any antibody titer. No rosette formation occurred on alveolar cells from any of the 15 immunocompetent controls. Thus, the method studied appears to be a valuable complement to other diagnostic methods for CMV pneumonia in transplant recipients. When correlated with the isolation of CMV from culture, the sensitivity was 100% and specificity 92%.

Mycobacterium avium complex develop resistance to synergistically active drug combinations during infection.

Isolates of Mycobacterium avium complex from five patients on longterm (3-5 yrs) anti-mycobacterial drug treatment were collected during the early and late phase of disease, and studied in vitro for their susceptibility to anti-mycobacterial drugs and drug-combinations. All isolates were resistant or moderately resistant to ethambutol, rifampicin and streptomycin when given singly; however, all strains isolated early in the disease were susceptible to the combination of ethambutol with either rifampicin or streptomycin. All late isolates had developed resistance to one or both of these combinations. Three of the patients died within a year after the last isolation of M. avium complex, and the two remaining patients still have severe chronic disease. It is concluded that the susceptibility of M. avium strains to combinations of drugs should be monitored during the course of treatment, in order to guide the selection of effective drug-combinations throughout the infection.

Seroreactivity to Pneumocystis carinii in patients with AIDS versus other immunosuppressed patients.

The aim was to study the humoral response to Pneumocystis carinii and its diagnostic use in patients with P. carinii pneumonia (PCP). The antibody response was measured by indirect immunofluorescence in AIDS patients versus other immunosuppressed patients with 122 episodes of confirmed PCP. During the early acute stage of the pneumonia, anti-P. carinii antibodies were found in 17% of AIDS and 24% of other immunosuppressed patients. In the second serum sample, antibodies were still found in 17% of the AIDS patients but in as many as 56% of the otherwise immunosuppressed patients. Antibodies were also found in 17% of HIV-positive and 15% of other immunosuppressed control patients, but only in 3% of immunocompetent controls (p < 0.001). Paired sera were available from 55 patients during 58 PCP episodes. Seroconversion or a fourfold rise in titre was detected in only 1/36 (3%) AIDS patients but in 10/22 (45%), (95% c.i.: 24-66%) other immunosuppressed patients (p < 0.001). We conclude that AIDS patients seem to have lost their ability to develop a humoral response to P. carinii during pneumonia, whereas many other immunosuppressed patients do respond. In these patients the serological test against P. carinii was of no diagnostic value in the acute phase of the infection, whereas when analysing paired sera it was a useful complement to the clinical diagnosis.

Disseminated Mycobacterium malmoense infection in a patient with chronic granulocytic leukaemia.

Mycobacterium malmoense is an atypical mycobacterium previously isolated from lymph nodes in children and from adults with pulmonary disease. Disseminated infection is extremely rare and bone marrow involvement has never previously been described. We report a patient with chronic granulocytic leukaemia and persistent fever with granuloma in the bone marrow due to disseminated M. malmoense infection. The patient initially received treatment with isoniazid, ethambutol and rifampicin with clearance of mycobacteria in the bone marrow and clinical improvement. Sensitivity in vitro was established for streptomycin, amikacin, ethambutol and rifabutin. The patient eventually expired as a result of progressive respiratory failure from other opportunistic infections. At autopsy staining of samples from lung parenchyma revealed fungal hyphi but staining for Pneumocystis carinii and myobacteria were negative.

Treatment of non-tuberculous mycobacterial infections in patients without AIDS.

This report summarizes the results of an 8-year study of the treatment of non-tuberculous mycobacterial infections and the long-term efficacy of this treatment in patients without AIDS. Of 25 patients, aged 10-82 years, 24 had pulmonary involvement; in 5 cases as part of disseminated disease. One patient had a renal infection only. Predisposing factors were identified in 16 patients. M. avium-intracellulare and M. malmoense were isolated in 17 and 7 patients, respectively, and M. kansasii in 1 patient. Three patients were subjected to lobectomy and 22 received multiple drug chemotherapy for 18-60 months. Chemotherapy was initially effective in 17/22 patients and surgery in 3/3. However, in the end 10 patients died of their mycobacterial infection, and 6 are still suffering from chronic infection. Only 7 patients appear to be free of disease more than 2 years after completing chemotherapy.

Aetiology of pulmonary diseases in immunocompromised patients.

Fibreoptic bronchoscopy with bronchoalveolar lavage (BAL), transbronchial lung biopsy (TBB) and brushing was performed, in 134 episodes of pulmonary disease in 118 compromised patients. Sixty eight of the patients were infected with immunodeficiency virus type 1 (HIV-1), 18 were renal and pancreas transplant recipients, 7 were liver and 15 were bone marrow transplant recipients, and 10 patients were undergoing immunosuppressive and/or cytotoxic drug therapy. Pneumocystis carinii (PC) was the predominant pathogen in HIV-1 infected patients. It was considered to be the aetiological cause of pneumonia in 54/82 (66%) episodes of lung complications noted in these patients. Cytomegalovirus (CMV) was the most common micro-organism in transplant recipients. CMV pneumonia was diagnosed in 22/42 episodes of pulmonary disease in these patients. CMV was detected by bronchoscopy procedures at a relatively high frequency of 36/82 (44%) episodes in HIV-1 infected patients. However, after analysis of clinical information, cultures from leucocytes and autopsy findings, CMV seemed to be involved in the pathogenicity of pneumonia in only two out of the 36 patients. Bacterial aetiology, including mycobacterial agents, was unusual, but was the major cause of pulmonary infections in 6/10 episodes in patients undergoing extensive immunosuppressive and/or cytotoxic drug therapy. Bronchoscopy was helpful in establishing correct aetiology in 98/134 (73%) episodes of pulmonary disease. Growth of Candida albicans and bacteria should always be viewed sceptically because of the possibility of contamination from colonization in the upper respiratory tract.

Fiberoptic bronchoscopy and sputum examination for diagnosis of pulmonary disease in AIDS patients in Stockholm.

For diagnosing pulmonary disease on 82 occasions in 68 patients (64 males) aged 39 (23-73) years infected with HIV-1 we used flexible fiberoptic bronchoscopy (FFB) with bronchoalveolar lavage (BAL) or washing with or without transbronchial lung biopsy (TBB) and brushing. A clinical diagnosis of lower respiratory tract disease was obtained in 68/82 episodes (83%). An etiological diagnosis was reached by FFB in 59/82 episodes (72%). Pneumocystis carinii (PC), the dominating pathogen causing pneumonia in 54/82 episodes (66%), was detected by FFB in 51/54 (94%). In spite of being isolated in bronchoscopy material in 36/82 episodes (44%) cytomegalovirus (CMV) seemed to be the cause of pneumonia only in 2/36 (5%) episodes. Except PC and CMV, only bacteria (including mycobacteria) were found as infectious etiological agents. Kaposi's sarcoma and pulmonary edema were diagnosed in one patient each. For detection of PC in 37 episodes we compared staining of BAL fluid with indirect immunofluorescence (IF) using monoclonal antibodies (MoAB) with staining of BAL material by silver methenamine (Grocott). Staining with IF MoAB alone of BAL fluid only seemed to be even more sensitive than silver methenamine staining of BAL, TBB and brushing material. When using IF MoAB staining of BAL fluid, TBB and brushing added nothing to the result, except in the patient with Kaposi's sarcoma, diagnosed by TBB. Sputum investigation using IF MoAB for detection was increasingly adopted during the study time. It was very useful (sensitivity approximately 74%) and reduced the number of required FFBs.

Cytomegalovirus the predominant cause of pneumonia in renal transplant patients. A two-year study of pneumonia in renal transplant recipients with evaluation of fiberoptic bronchoscopy.

The microbiological etiology of pneumonia in 34 renal transplant patients with clinical and X-ray evidence of pulmonary parenchymal disease was studied. Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL), transbronchial lung biopsy (TBB) and brushing was performed on 18 patients. Laboratory evaluation included histological and cytological methods, cultures for bacteria, fungus and virus and immunofluorescence techniques for the detection of Pneumocystis carinii, cytomegalovirus (CMV) and legionella. Serum samples were obtained concomitantly for antibody studies. CMV, the most common etiology, was considered to be the cause of disease in 18/34 patients. All but one of these patients had positive CMV isolates in culture on leucocytes. Pulmonary edema was found in 7 patients, bacterial pneumonia in 11 patients, P. carinii in 4 patients and Candida albicans in 1 patient. Multifactorial etiology was found in 12/34 cases. The overall mortality was 32%. Bronchoscopy gave correct diagnosis in 13/14 patients with infectious pulmonary diseases (93%). Bronchoscopy procedures were well tolerated and should be considered in transplant patients with evidence of pulmonary parenchymal disease.

Fiberoptic bronchoscopy for diagnosis of opportunistic pulmonary infections after bone marrow transplantation.

As a part of the diagnostic procedure for 16 suspected pulmonary infections in 15 marrow transplant recipients fiberoptic bronchoscopy with bronchoalveolar lavage (BAL), transbronchial lung biopsy (TBB) and brushing were performed. Cytomegalovirus (CMV) was the most common microorganism and CMV pneumonia was diagnosed in 8/16 (50%) episodes of pulmonary disease studied. Pneumonias were diagnosed as caused by Candida or Aspergillus species in 6 episodes and by gram-positive cocci in 2 cases. Adenovirus and Pneumocystis carinii was also isolated in 1 patient each. Three noninfectious diseases (pulmonary oedema, idiopathic pneumonia and pulmonary embolism) were diagnosed by methods other than bronchoscopy. The use of fiberoptic bronchoscopy with BAL and TBB allowed correct identification of 14/18 microorganisms involved. Brushing was less useful. Four patients' pneumonias had a multiple etiology. The bronchoscopy methods used were well tolerated even by patients whose condition was poor.