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Biomedical subjects

H J Milburn

Publications and source records attributed to H J Milburn.

At least 19 recordsLinked to original sources
PubMed2001

Primary tuberculosis.

The natural history of tuberculosis is complex. Primary infection, the initial phase, occurs in people without specific immunity, generally normal children and young adults who have not previously been exposed to Mycobacterium tuberculosis. The initial infection can occur at any time during childhood, but adolescence is the peak time of risk. Primary disease develops within 5 years of the initial infection, which stimulates specific immunity, demonstrated by the development of a positive skin response to purified protein derivative of tuberculin. Although symptoms of primary disease may be few, early detection and treatment are important for both preventing the development of immediate complications, which carry a high risk of morbidity and mortality, and preventing spread of infection following later reactivation of disease. Our understanding of the host's immune response to the primary infection is increasing, and it is hoped this will lead to improved possibilities for vaccines in the future.

Adult↗
PubMed2000

High incidence of primary tuberculosis.

An usually high rate of both tuberculosis infection and active disease is reported in 11 of 38 nursery children in contact with a case of smear positive pulmonary tuberculosis, emphasising the susceptibility of young children to this disease. This report also underlines some important principles in case finding and disease control.

Adult↗
PubMed1998

An outbreak of multi-drug-resistant tuberculosis in a London teaching hospital.

We describe the epidemiology and control of a hospital outbreak of multi-drug-resistant tuberculosis (MDR-TB). A human immunodeficiency virus (HIV)-negative patient with drug-sensitive tuberculosis developed MDR-TB during a period of unsupervised therapy. She was admitted to an isolation room in a ward with HIV-positive patients, but the room, unbeknown to hospital staff, was at positive-pressure relative to the main ward. Seven HIV-positive contacts developed MDR-TB. The diagnosis in the second patient was delayed, partly because acid-fast bacilli in his sputum were assumed to be Mycobacterium avium-intracellulare. All the available Mycobacterium tuberculosis isolates were indistinguishable by molecular typing. Nearly 1400 staff and patient contacts were offered screening, but the screening programme detected only one of the cases. Despite therapy, the index patient and two of the contacts died. HIV-positive patients are more likely than others to develop tuberculosis after exposure, and the disease may progress more rapidly. In these patients the possibility that acid-fast bacilli may represent M. tuberculosis must always be considered. Patients with tuberculosis (suspected or proven) should not be nursed in the same wards as immunosuppressed patients, and should be isolated. MDR-TB cases must be isolated in negative-pressure rooms. Hospital side-rooms may be positive-pressure as a fire safety measure; infection control teams must be aware of the airflows in all isolation rooms, and must be consulted during the design of hospital buildings. Good communication between infection control teams and clinicians is important, and all medical and nursing staff must be aware of the principles of management of patients with proven or suspected tuberculosis and MDR-TB.

AIDS-Related Opportunistic Infections↗
PubMed1997

Corticosteroids restore the balance between locally produced Th1 and Th2 cytokines and immunoglobulin isotypes to normal in sarcoid lung.

In this study, we have investigated the balance between Th1- and Th2-like activity in the lungs in sarcoidosis and have determined the effect of corticosteroid treatment on this. Twenty-one patients with acute untreated sarcoidosis were investigated by bronchoalveolar lavage (BAL) and compared with 11 normal volunteers. Sixteen of the sarcoid patients required corticosteroid therapy and seven of these were reinvestigated after 2-3 months' treatment. In order to assess Th1- and Th2-like activity in the lungs, IgG subclasses and IgE were measured in BAL fluid and serum, and IL-2, IL-4 and interferon-gamma (IFN-gamma) in BAL. In patients with untreated sarcoidosis, albumin-corrected BAL/serum ratios for IgG4 and IgE were significantly reduced (IgG4, 1.04 +/- 0.18 (mean +/- s.e.m.); IgE 9.58 +/- 3.11) compared with those in normal controls (IgG4 5.3 +/- 0.72, P < 0.001; IgE 67.7 +/- 28.9, P < 0.01). Estimates of actual levels of immunoglobulins produced in the lungs were also made and showed extremely high levels of total IgG in sarcoid patients (39.56 +/- 8.2 mg/l) compared with controls (1.17 +/- 0.5 mg/l, P < 0.001). Although there was no difference between the groups in amount of IgG4 locally produced, the proportion of total IgG which was IgG4 was greatly reduced in those with sarcoidosis (1.6 +/- 0.4% compared with 38.5 +/- 3.2%; P < 0.001). Lavage levels of IL-4 were also reduced in sarcoid patients (IL-4 2.103 +/- 0.21 pg/ml) compared with those in normals (IL-4 6.8 +/- 1.05; P < 0.001). Levels of IL-2 were lower (7.63 +/- 0.51 pg/ml compared with 9.4 +/- 0.95 pg/ml), but this difference was not significant. IFN-gamma, however, could not be detected above 0.4 pg/ml in any of the normal lavage fluid, but was detectable in 12/21 patients with sarcoidosis (chi2 = 7.74; P < 0.001). These changes reverted towards normal on treatment with oral corticosteroids. The mean albumin-corrected BAL/serum ratio for IgG4 before treatment was 0.88 +/- 0.33 compared with 5.5 +/- 2.1 (P < 0.05) on treatment, and for IgE before treatment 9.52 +/- 2.15 compared with 50.8 +/- 17.9 (P < 0.05) on treatment. Total IgG produced in the lung fell from 26.16 +/- 7.9 to 6.12 +/- 2.4 mg/l (P < 0.001) on treatment, and the proportion of IgG4 locally produced rose from 2.3 + 0.8% to 23.9 +/- 6.1% (P < 0.01). The mean level of IL-4 in lavage before treatment was 2.53 +/- 0.34 pg/ml compared with 4.7 +/- 0.34 (P < 0.001) on treatment. Levels of IL-2 also rose significantly on treatment from 8.74 +/- 0.95 pg/ml before to 14.44 +/- 1.38 pg/ml (P < 0.001) on treatment. Levels of IFN-gamma fell from 1.65 +/- 0.43 pg/ml before treatment to undetectable levels in all patients (P < 0.001) on treatment. These results demonstrate an imbalance between Th1- and Th2-like activity in the lungs in sarcoidosis, with suppression of Th2 and increase in Th1. Corticosteroid therapy restores the normal balance between Th1 and Th2 cytokines and immunoglobulins in the lungs, suggesting an effect on local immune regulation.

Adolescent↗
PubMed1993

Abnormal alveolar macrophage populations in bone marrow transplant recipients with pneumonitis.

The purpose of this investigation was to determine whether there is any relationship between different subsets of alveolar macrophages and type of infection or survival from interstitial pneumonitis following bone marrow transplantation (BMT). The population of alveolar macrophages found in bronchoalveolar lavage fluid (BALF) from 16 BMT recipients with 19 episodes of interstitial pneumonitis was investigated, using immunocytochemical methods. Results were compared with those from seven normal volunteers. The results showed that patients with pneumonitis had significantly higher numbers of total cells in BALF than normals but reduced proportions of macrophages, although the absolute numbers were unchanged. Of the cells present which were morphologically macrophages, there were raised proportions of both RFD1+ cells (interdigitating cells) and RFD7+ cells (mature macrophages) in patients compared with normals, but expansion of these two subsets could be explained, in part, by a significant increase in cells positive for both markers (42% in patients compared with 9% in normals). Proportions of cells with the monocyte phenotype (CD14+, UCHM1) were also significantly raised in patients with pneumonitis (17% compared with 6% in normals). These patients, however, had significantly reduced proportions of macrophage-like cells which were positive for the DR antigen (Class II major histocompatibility complex (MHC) antigen) (47% compared with 88% in normals), and this abnormality was greater still in patients who died from pneumonitis (40%) compared with those who survived (52%). The results of this study indicate a breakdown of local immunoregulation, thus contributing to the high incidence of, and mortality from, opportunistic pulmonary infections in this group.

Adolescent↗
PubMed1993

IgG subclasses in the lungs of patients with interstitial pneumonitis following bone marrow transplantation.

Subclasses of immunoglobulin G (IgG) were measured in bronchoalveolar lavage (BAL) fluid and serum from five normal volunteers and 25 bone marrow transplant (BMT) recipients, who developed 32 episodes of pneumonitis. Evidence for local production of the four subclasses was sought, to assess whether any observed deficiency was associated with any particular group of pulmonary infections. In the normal volunteers, IgG1 and IgG4 could be detected in BAL fluid from all subjects, with evidence for local production of IgG1 in one, and IgG4 in all five. IgG2 could be detected in BAL fluid from one subject, but IgG3 was undetectable in all normal BAL fluid. The BMT recipients differed from the normal volunteers mainly in the presence of IgG2 and IgG3 in BAL fluid. Furthermore, IgG4 could not be detected in BAL from seven. Furthermore, IgG4 could not be detected in BAL from seven episodes of pneumonitis (six patients). Bacteria, protozoa or fungi alone were isolated from five of these seven lavages, whereas pneumonitis associated with these organisms alone only occurred in 9 of the remaining 25 episodes of pneumonitis (19 patients) where there was also evidence for local production of IgG4. Moreover, 4 out of 7 patients with no detectable IgG4 in lavage developed secondary infections, whilst only 5 out of 19 patients producing IgG4 locally developed secondary infections (p = 0.05). Although there was individual variation within each group, levels of local production of both IgG1 and IgG4 tended, however, to be higher in patients who died from pneumonitis than in those who recovered, suggesting that this may be a poor prognostic marker.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Can lung function measurements be used to predict which patients will be at risk of developing interstitial pneumonitis after bone marrow transplantation?

BACKGROUND: Lung function often deteriorates after bone marrow transplantation for haematological malignancies. Whether pulmonary function measurements are useful for monitoring patients' progress after transplantation and for alerting clinicians to the development of pneumonitis is uncertain. METHODS: Serial pulmonary function measurements were made in 39 patients with a haematological malignancy, and the values from 18 recipients of T cell depleted allogeneic (n = 17) or autologous (n = 1) bone marrow transplants who developed interstitial pneumonitis were compared retrospectively with values from 21 recipients of allogeneic (n = 17) or autologous (n = 4) transplants who did not develop pneumonitis. Lung function was measured at the onset of a further 18 episodes of pneumonitis. RESULTS: Measurements made before transplantation showed no difference in forced expiratory volume in one second (FEV1), transfer factor for carbon monoxide (TLCO), or total lung capacity between the two groups, but the forced vital capacity (FVC) was slightly higher in those who developed pneumonitis (mean (SD)% predicted 104 (12)) than in those who did not (93 (17%)). Six weeks and three months after transplantation all pulmonary function measurements had fallen slightly in both groups but TLCO had fallen considerably more in those who later developed pneumonitis, being 71% (SD 11%) and 77% (7%) of pretransplant values in patients who later developed pneumonitis compared with 109% (38%) and 96% (26%) in those who did not. All lung function measurements were significantly lower at the onset of pneumonitis than three months after transplantation, even in patients with no abnormal signs and a normal chest radiograph. CONCLUSIONS: Serial measurements of gas transfer before and after bone marrow transplantation may be useful for predicting which patients will be at risk of developing pneumonitis and may help to diagnose pneumonitis in breathless patients with no abnormal signs.

Adolescent↗
PubMed1990

Pneumonitis in bone marrow transplant recipients results from a local immune response.

Eighteen recipients of allogeneic T cell-depleted bone marrow who developed 22 episodes of interstitial pneumonitis were investigated by bronchoalveolar lavage for the cause of pneumonitis. The cells obtained were examined using a panel of monoclonal antibodies with immunocytochemical techniques to identify lymphocyte subsets and the presence of surface molecules indicative of lymphocyte activation. The majority of patients had an excess of lymphocytes in lavage and most of these cells were positively stained with the McAb recognizing the CD8 antigen (suppressor/cytotoxic type T cells). Although the proportions of CD4+ (helper type) T cells were below normal, the absolute numbers were within normal limits, thus the CD4:CD8 ratio was consistently 1:1 or less. A large proportion of the CD8+ cells displayed HLA-DR molecules (RFDR1+), interleukin-2 (IL-2) receptors (CD25+) and high concentration of CD7 antigen (RFT2+). Further analysis revealed that most CD8+ cells were CD5+ (RFT1+) yet a large proportion (20-40%) were CD5-. A majority of CD8+ cells was also CD38+ (RFT10+) and Leu7+. No clear correlation between the emergence of a raised proportion of activated CD8+ cells and diagnosed cytomegalovirus infection was found. These results demonstrate, however, that cells with the phenotype of the resident T cells of the bronchial epithelium (CD8+CD5-) emerge to the air spaces and express activation markers. This raises the intriguing paradox of an aggressive local immune response occurring in an otherwise immunosuppressed group of patients.

Adolescent↗
PubMed1990

Controlled trial of natamycin in the treatment of allergic bronchopulmonary aspergillosis.

Allergic bronchopulmonary aspergillosis often requires treatment with oral corticosteroids to control the host response to Aspergillus fumigatus. In a double blind study 25 patients with allergic bronchopulmonary aspergillosis taking maintenance oral corticosteroids were randomly allocated to receive 5 mg natamycin or placebo by nebuliser twice daily for one year. The primary aim of the study was to assess the steroid sparing potential of natamycin. Standardised reductions in corticosteroid dosage were therefore undertaken every five weeks, unless clinically contraindicated. Five patients were withdrawn in the first four months: two (1 natamycin, 1 placebo) died, two (1 natamycin, 1 placebo) had suspected drug reactions, and one (natamycin) was non-compliant. The pretreatment characteristics of the 20 patients (10 in each group) who completed the study were similar, 17 (9 natamycin, 8 placebo) having evidence of recent disease activity. At the end of the study prednisolone dose had been reduced by a similar amount in each group (median natamycin 2.25 mg, placebo 2.5 mg). Evidence of disease activity during the study year (transient shadowing on the chest radiograph, blood eosinophilia, or increases in antibodies to A fumigatus, or any combination of these) was observed in similar numbers of patients in each group (5 natamycin, 7 placebo). There was no evidence that natamycin conferred benefit on these patients with allergic bronchopulmonary aspergillosis.

Adult↗
PubMed1989

Pulmonary cell populations in recipients of bone marrow transplants with interstitial pneumonitis.

The immunological basis of the inflammatory response in the lungs of patients with pneumonitis after bone marrow transplantation has been investigated by means of bronchoalveolar lavage. Ten episodes of pneumonitis associated with cytomegalovirus and nine episodes due to various other infectious and non-infectious causes were investigated in 16 patients (three patients had two episodes of pneumonitis). Total lavage cell counts and differential cell counts were determined and compared with results from normal control subjects. In most patients with pneumonitis the total cell yield was greater than normal (mean 6.8 (SD 6.0) x 10(5) cells/ml; normal 1-2 x 10(5) cells/ml). The percentage distribution of these cells was 71.9 (17) macrophage like cells, 24.1 (15.8) lymphocytes, 5.0 (5.0) polymorphonuclear cells, and 0.7 (1.0) eosinophils. None of the patients had peripheral lymphocytosis despite the increased number of lymphocytes in the lavage fluid. Further analysis of the lymphocyte population using monoclonal antibodies with immunocytochemical techniques showed that B cells were generally present in normal proportions, whereas the proportion of cells expressing T lymphocyte markers (CD2+, CD5+, CD8) were reduced in nine out of 19 cases. In 10 of the 19 episodes there were substantial numbers of cells expressing none of the B or T cell antigens studied ("null" cells). These abnormalities bore no relation to survival. The total cell yield, the proportion and number of lymphocytes, and the proportion and number of T cells in the bronchoalveolar lavage fluid were all lower in the group with cytomegalovirus infections than in those with pneumonitis from other causes. These results suggest that the pneumonitis in recipients of bone marrow transplants is associated with a local immune response despite the fact that the individuals are otherwise immunosuppressed.

Adolescent↗
PubMed1988

Presence of a partially acid-labile alpha-interferon in bronchoalveolar lavage fluid of patients with cytomegalovirus pneumonitis is associated with a poor prognosis.

In 30 patients with pneumonitis, 16 of whom had undergone bone marrow transplantation, 13 episodes of cytomegalovirus (CMV) pneumonitis were diagnosed. In three of these, alpha-interferon, which in two cases was partially acid-labile, was detected in bronchoalveolar lavage fluid. All three of these patients died. Only two deaths occurred in ten patients without detectable levels of alpha interferon in the lavage fluid. CMV pneumonitis in immunocompromised patients appears to stimulate the local production of a partially acid-labile alpha-interferon, and its presence is associated with a poor prognosis. Gamma-interferon was not found in the lavage fluid of any patient with pneumonitis.

Bone Marrow Transplantation↗
PubMed1988

Is the measurement of virus-specific antibody in the lungs of transplant recipients with cytomegalovirus pneumonitis of diagnostic or prognostic value?

We have investigated 12 transplant recipients (nine bone marrow transplants, three renal) with 15 episodes of pneumonitis caused by cytomegalovirus (CMV) and ten patients (eight bone marrow transplant recipients, two renal transplant recipients) with 12 episodes of interstitial pneumonitis in whom no CMV was detected, to determine whether levels of CMV-specific IgG in the lung are diagnostic of infection. We have also assessed whether a vigorous specific local antibody response is important for survival. CMV-specific IgG and herpes simplex (HSV)-specific IgG were measured in bronchoalveolar lavage (BAL) fluid and serum using albumin to correct for simple diffusion from serum into the lung. We have found evidence for local production or facilitated transport of CMV-specific IgG in ten patients with CMV pneumonitis but also in six patients with pneumonitis where no CMV was detected. Similar results were found for HSV-specific IgG although only one patient had a demonstrable HSV infection. There was a tendency for those patients producing large amounts of immunoglobulin in the lung to survive compared with those who died, but there were wide variations between patients in each group. The local humoral immune response in transplant patients with pneumonitis was not specific to the infecting agent and is most probably the result of polyclonal B cell activation or facilitated transport of IgG from serum to lung secretions. Measurement of CMV-specific IgG response in the lung should not, therefore, be used for diagnostic or prognostic purposes.

Adolescent↗
PubMed1988

Humoral immune responses within the lung of bone marrow transplant recipients studied by bronchoalveolar lavage.

We investigated 20 bone marrow transplant recipients with pneumonitis using bronchoalveolar lavage (BAL) to assess the humoral immune response in the lung. We measured the levels of total IgG, IgM and IgA in bronchoalveolar lavage fluid and serum, and albumin measurements were used to correct for simple diffusion of immunoglobulins from serum into the lung. We found evidence for the local production of immunoglobulins G, M and A in 15 patients. This was independent of the cause of the pneumonitis. We also found that, although seven patients who recovered from their pulmonary problem had evidence of considerable local production of immunoglobulin, eight patients who died were also producing immunoglobulins in the lung. Death due to pneumonitis in BMT recipients cannot, therefore, be ascribed to a failure of the local humoral immune response.

Adolescent↗
PubMed1987

Role of bronchoalveolar lavage in the evaluation of interstitial pneumonitis in recipients of bone marrow transplants.

Forty episodes of pneumonitis in 30 recipients of allogeneic bone marrow transplants were investigated by fibreoptic bronchoscopy and bronchoalveolar lavage. A positive diagnosis was made in 32 episodes of pneumonitis (24 patients), giving a diagnostic yield of 80%. In 31 of these the diagnosis was made within 24 hours of bronchoscopy and this enabled the appropriate treatment to be instituted early. Eighteen patients recovered from their primary infection, although two died subsequently of respiratory failure due to postpneumonic lung destruction. Ten patients later developed a second episode of pneumonitis and a diagnosis was made in nine of these. Only three survived a second episode. Bronchoalveolar lavage was well tolerated by all patients and there was no morbidity or mortality that could be directly attributed to the procedure. Bronchoalveolar lavage is a safe and valuable early diagnostic procedure for the investigation of pulmonary complications in patients who have received bone marrow transplants.

Adolescent↗