Evaluating the use of the interferon-γ response to Mycobacterium tuberculosis-specific antigens in patients with psoriasis prior to antitumour necrosis factor-α therapy: a prospective head-to-head cross-sectional study.

BACKGROUND: Targeted biological therapies have transformed the treatment of chronic inflammatory disease. However, reactivation of latent tuberculosis infection (LTBI) is a significant risk with the use of antitumour necrosis factor (anti-TNF)-α therapy and screening is mandatory prior to treatment. The tuberculin skin test (TST) may be difficult to interpret in patients with inflammatory disease or receiving immunosuppressive therapies. OBJECTIVES: The aim of this study was to evaluate and compare the QuantiFERON(®) -TB Gold In-Tube (QFR) and T-SPOT.TB (TSTB) interferon-γ-release assays (IGRA) against the TST in a cohort of patients commencing anti-TNF-α therapies for chronic inflammatory disease. METHODS: A prospective cross-sectional study was undertaken at a London tertiary referral centre. Demographic data collected included TB risk factors. TST, QFR and TSTB were performed in all patients. RESULTS: Seventy patients with chronic plaque psoriasis were included in the study. Agreement between QFR and TSTB, excluding indeterminate results, was 89% (κ = 0.567), between QFR and TST 85% (κ= 0.313) and 81% (κ = 0.244) between TSTB and TST. There was no significant association with concomitant immunosuppression and either TST or IGRA results. Seven patients received chemoprophylaxis for LTBI diagnosed after clinical risk assessment together with positive TST and/or IGRA. Three patients had positive results in all three tests. CONCLUSIONS: While there was moderate overall agreement between QFR and TSTB and fair correlation between TST, QFR and TSTB, there were a number of discordant results, suggesting that a three-pronged approach using TST, QFR and TSTB may be of additional benefit.

The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement.

Anti-tumour necrosis factor (TNF) monoclonal antibodies or soluble TNF receptors have become an invaluable treatment against chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease and psoriasis. Individuals who are treated with TNF antagonists are at an increased risk of reactivating latent infections, especially tuberculosis (TB). Following TNF antagonist therapy, the relative risk for TB is increased up to 25 times, depending on the clinical setting and the TNF antagonist used. Interferon-γ release assays or, as an alternative in individuals without a history of bacille Calmette-Guérin vaccination, tuberculin skin testing is recommended to screen all adult candidates for TNF antagonist treatment for the presence of latent infection with Mycobacterium tuberculosis. Moreover, paediatric practice suggests concomitant use of both the tuberculin skin test and an interferon-γ release assay, as there are insufficient data in children to recommend one test over the other. Consequently, targeted preventive chemotherapy is highly recommended for all individuals with persistent M. tuberculosis-specific immune responses undergoing TNF antagonist therapy as it significantly reduces the risk of progression to TB. This TBNET consensus statement summarises current knowledge and expert opinions and provides evidence-based recommendations to reduce the TB risk among candidates for TNF antagonist therapy.

Reactivation of tuberculosis and vitamin D deficiency: the contribution of diet and exposure to sunlight.

BACKGROUND: As well as its role in the regulation of calcium metabolism, vitamin D is an immunoregulatory hormone. Epidemiological evidence also suggests a link between vitamin D deficiency and tuberculosis (TB). A study was undertaken to examine serum vitamin D concentrations before treatment in patients with active TB and their contacts from the same ethnic and social background and to investigate the relative contributions of diet and sunlight exposure. METHODS: Serum vitamin D concentrations were measured before treatment in 178 patients with active TB and 130 healthy contacts. The prevalence of vitamin D deficiency and its relation to skin colour, month of estimation and TB diagnosis were determined. 35 patients and 35 frequency-matched contacts completed dietary and sun exposure questionnaires to determine the relative contribution of these to serum vitamin D concentrations. RESULTS: There was a statistically significant difference in serum vitamin D concentrations between patients and contacts (20.1 vs 30.8 nmol/l, 95% CI 7.1 to 14.3; p<0.001) and significantly more patients had severely deficient concentrations (<21 nmol/l) than controls (114/178 (64%) vs 40/130 (31%), p<0.001). There was no association between serum concentrations of vitamin D and skin pigmentation. The healthy contacts showed a predictable seasonal pattern, rising to peak concentrations in the summer months, but this response was absent in patients with TB. Dietary intake was the same in both patients with TB and contacts matched for age, sex and skin colour, but patients with TB displayed a stronger correlation between serum vitamin D concentrations and dietary intake (r = 0.42, p = 0.016) than controls (r = 0.13, p>0.1). There was no difference in sunlight exposure between the groups. CONCLUSIONS: Patients with active TB have lower serum vitamin D concentrations than contacts from similar ethnic and social backgrounds and with comparable dietary intake and sun exposure, and do not show the expected seasonal variation. These observations indicate that other factors are contributing to vitamin D deficiency in patients with TB and suggest abnormal handling of this vitamin.

Current difficulties in the diagnosis and management of spinal tuberculosis.

BACKGROUND: The diagnosis of spinal tuberculosis (ST) is difficult and it commonly presents at an advanced stage. The management and follow up is complicated by a lack of guidance on the appropriate use and interpretation of spinal magnetic resonance studies (MR). AIMS: A retrospective study was performed at a UK centre to identify the demographic and presenting features of a spinal TB population, their response to treatment, and the value of follow up MR studies. PATIENTS AND RESULTS: Twenty one patients were identified with mean symptom duration of 11 (1.5-36) months having been assessed by a health practitioner on 3.2 (0-10) occasions before referral for investigation for ST. Twenty were born outside the UK. Their mean duration of residence in the UK was 6.67 (0.75-20) years, and six (32%) were resident for more than 10 years. Most (85.7%) did not have a medical history and one was HIV positive. Back pain, neurological, and constitutional symptoms were found in 100%, 29%, and 38% respectively. Musculoskeletal and neurological signs were found in 29% and 19% respectively. Spinal MR performed between 6 and 12 months suggests that six months of chemotherapy (for a fully sensitive organism) may not be sufficient to achieve disease resolution. CONCLUSIONS: Awareness of the demographic, clinical, and laboratory features of an ST population may facilitate earlier diagnosis. Guidance is required on the appropriate use and interpretation of MRI in the follow up of these patients.

G-CSF enables completion of tuberculosis therapy associated with iatrogenic neutropenia.

Neutropenia is a rare complication of anti-tuberculous therapy and is usually due to a single agent, most frequently isoniazid. The current case describes a previously healthy immunocompetent patient with tuberculosis of the lymph nodes who developed neutropenia due to a number of first line antibiotics (rifampicin, isoniazid and ethambutol) and streptomycin when introduced in combination and individually thus resulting in repeated treatment disruption. The introduction of twice-weekly subcutaneous granulocyte-colony stimulating factor to correct iatrogenic neutropenia facilitated the continuation and eventual completion of therapy without adverse effect. This is the first description of the use of granulocyte-colony stimulating factor to correct iatrogenic neutropenia due to anti-tuberculous antibiotics and the second description of the occurrence of iatrogenic neutropenia to more than anti-tuberculous antibiotic in an individual.

Management of multiple drug-resistant tuberculosis.

There has been a worldwide increase in multiple drug-resistant tuberculosis (MDR-TB) which has in the past been associated with a poor prognosis. In the U.K., about half of the cases live in the London area and we have set out to obtain further information on their treatment and outcome. We examined the risk factors, drug resistance, drug treatment, sputum conversion, and outcome in patients with MDR-TB at three hospitals in South London and diagnosed during the period June 1995-January 1999. Human Immunodeficiency Virus (HIV)-positive patients were excluded. There were 760 patients resident in Lambeth, Southwark and Lewisham Health Authority (LSLHA) who were notified as tuberculosis (TB) during the time period and who were of negative or unknown HIV status. (The population of LSLHA is approx.750,000.) There was a total of 13 patients with MDR-TB, known or presumed to be HlV negative. Their median age was 28 years (range 15-53); nine (69%) were born outside the U.K. and 11 had pulmonary disease; they had organisms resistant to a median of two first-line drugs (range 2-4) and to a median of four of all drugs tested (range 2-10). They received treatment with a median of six drugs (range 3-9). Eight were followed up for at least 3 years (range 3-6) after the completion of treatment; at their last assessment none had features of active TB and all were sputum negative (smear and culture). Two returned to their countries of origin during treatment; they were sputum negative at that time. Two patients are well and continue on treatment in the U.K. One patient (known HIV negative) died following treatment failure. In conclusion, we obtained disease-free survival in eight cases of MDR-TB, known or presumed to be HIV negative and followed up for 3 years or more. The prognosis for patients treated at specialised centres is good (and better than is generally believed). We describe a new protocol for the detection and management of MDR-TB.

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.

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.

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.

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.

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.

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)

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.

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.

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.