Tuberculosis: trends and the twenty-first century.

The global burden of tuberculosis is enormous, even if estimates are somewhat uncertain. The forces counteracting control measures, namely demographic factors, drug resistance, HIV, migration, poverty and marginalization, are enormous as well. With accelerated reforms in tuberculosis programs important progress can be made towards the control of tuberculosis early in the 21st century. This is confirmed by studying reports from countries where control measures have been implemented and sustained. Well-functioning programs can make good use of technological progress, such as improved tools for diagnosis and treatment, when these become available at an affordable cost. It is important now to use the opportunity of increased resources in order to reform tuberculosis programs. The biggest impact on global tuberculosis control in the 21st century can be made in Asia. Success in this part of the world depends on political commitment. Elsewhere, the main forces counteracting control measures are HIV in Africa and multidrug resistance in parts of Europe and the former Soviet Union. Here solutions are still on the drawing board. The long time-frame for tuberculosis control when using the currently recommended strategy, the uncertain impact of "improved" tools on this time-frame and the constant threat that political commitment will not be sustained are reasons why field workers look towards new technology in hope of progress in vaccine research. Here, the prospects are uncertain and the forecasted time-frame is long. Skeptics even doubt that an effective vaccine can be developed. However, when predicting progress it is important to realize that it is for the most part unpredictable.

Prevalence and annual risk of tuberculosis infection in Laos.

SETTING: Laos, where the implementation of a national tuberculosis program started in 1995. OBJECTIVE: To estimate the prevalence (P) and annual risk of tuberculosis infection (ARTI) and relate this to case rates in the tuberculosis program. METHODS: Tuberculin survey in schools in Vientiane municipality and three provinces. Sampling was not representative, but included schools in accessible districts in provinces with different characteristics. A group of 150 tuberculosis patients were tested for comparison. RESULTS: An intra-dermal tuberculin test (PPD RT23/ Tween80) was applied to 11237 children; 9968 reactions were read, 4035 among first and second grade children with no BCG scar: 818 in Vientiane (mean age 8.4), 803 in Savannakhet (8.9), 1563 in Xiengkhuang (8.4), and 851 in Luangprabang (7.9). If reactions of > or =10 mm are counted, ARTI is estimated as 1.1% for the areas included in the survey with a strong variation by province (Vientiane 1.3%; Savannakhet 1.4%; Luangprabang 0.6%; Xiengkhuang 0.1%). The difference in ARTI is in accordance with differences in reported case rates in the provinces. The ARTI varied from 0.5% to 1.2%, depending on the method used for calculating P (Vientiane 0.6%-1.4%; Savannakhet 0.5-1.5%; Xiengkhuang 0.1%-0.2%; Luangprabang 0.4%-0.9%). CONCLUSIONS: The ARTI is unequally distributed geographically and/or by ethnic group. It is generally higher in south and lower in central and north Laos. Improved methods are needed for estimating the prevalence of infection.

Low failure rate in standardised retreatment of tuberculosis in Nicaragua: patient category, drug resistance and survival of 'chronic' patients.

SETTING: IUATLD collaborative programme, Nicaragua. OBJECTIVE: To analyse reported trends in the retreatment failure rate (2SRHZE/1RHZE/5R3H3E3), and assess demographic characteristics, drug resistance and survival in patients who fail retreatment. DESIGN: A retrospective, descriptive study. Reports from 1988-1996 were analysed and records of 69 patients who failed retreatment were reviewed. RESULTS: The treatment success rate in new cases improved from 71% in 1988-1991 to 79% in 1992-1996, the default rate decreased from 16% to 10%, and the failure rate remained stable at 2-3%. The proportion of previously treated patients among all smear-positives decreased from 20% to 15%. In retreatment patients the failure rate declined from 6.6% to 4.3% and the average annual number of failures from 24 to 13. In 1992-1996, 64 patients, 0.8% of new smear-positive cases treated during this period, failed retreatment; the corresponding figures for 1988-1991 are 95 and 1.6%. Among 69 retreatment failure cases reviewed, there was male predominance and increasing age during the study period. Drug susceptibility results were available for 38, of whom 89% were resistant to isoniazid and rifampicin. The median survival of patients after failure was 3.9 years. CONCLUSION: Treatment results improved over the study period. The proportion of patients on retreatment out of all smear positives treated decreased, as did the absolute number of failures and the retreatment failure rate. Development of multidrug resistance has been largely prevented in Nicaragua; the low failure rate justifies the continued use of the standardised retreatment regimen.

Evaluation of a standardized recording tool for sputum smear microscopy for acid-fast bacilli under routine conditions in low income countries.

SETTING: Laboratories performing sputum smear microscopy for tuberculosis in Benin, Malawi, Nicaragua and Senegal. METHODS: Analysis of computerized laboratory registers to ascertain workload, yield from serial smear examination, and demographic characteristics of examinees. RESULTS: Data from more than 60,000 examinees in 42 laboratories showed that the average number of smears examined per day ranged from 4 to 19 (mean 6) per country. To find one case of tuberculosis, on average 21 smears of suspects were examined (range 8 to 50). Of all cases with ultimately at least one positive result, 87% were already positive on the first examination. Demographic characteristics of cases differed considerably by country and gender. In 35 of 42 laboratories, males were more frequently found to be cases than females, and with increasing age an increasingly larger number of female than male suspects had to be examined to identify one case. CONCLUSIONS: This study demonstrates the usefulness of a standardized recording system for results of acid-fast microscopy in obtaining essential information for program management and on demographic characteristics of persons presenting for examination.

Human papillomavirus (HPV) in an Icelandic population: the role of HPV DNA testing based on hybrid capture and PCR assays among women with screen-detected abnormal Pap smears.

This study was based on 358 cases with abnormal smears referred for colposcopy and HPV DNA testing. We analysed: 1) the frequency of different grades of cyto- and histopathologic findings; 2) the frequency and relative amount of HPV DNA with the hybrid capture assay (HCA) in swabs, and the frequency of HPV with PCR in swabs (-S) and biopsies (-B); and 3) the frequency of HPV types according to the grade of the cyto- and histopathologic findings. Of all cases, 95% were positive with all HPV tests combined. The HCA (HPV: 16, 18, 31, 33, 35, 45, 51, 52 and 56) and the PCR-S and PCR-B (HPV: 16, 18, 31, 33 and 35) tests for high-risk HPV exhibited sensitivities of 57%, 56% and 48%, respectively. The high-grade smears and the high-risk PCR-S HPV had about 80% sensitivity for histologic high-grade lesions compared with around 70% for HCA and the PCR-B. Combining the high-grade smears and the high-risk HPV increased the sensitivity to 93-96%. Among the cervical intraepithelial neoplasia I (CIN I) and the atypical squamous cells of undetermined significance (ASCUS) smears the sensitivity of high-risk HPV for high-grade histologic lesions was 63% for the HCA and 79% for the PCR-S. No correlation was found between the relative amount of HPV DNA detected by HCA and the grade of cyto- and histological lesions. We conclude that the results strongly indicate that HCA is less sensitive than PCR in the diagnosis of high-risk HPV, that swabs are more sensitive than biopsies as a sampling method, that high-risk HPV and high-grade smears are complementary for the diagnosis of high-grade histologic lesions and that the present role of HPV testing in screening could be limited to identifying women with low-grade smears and koilocytotic or low-grade colposcopic biopsies that are at risk of concealing or developing high-grade histologic lesions.

Successful management of a national tuberculosis programme under conditions of war.

OBJECTIVE: To compare treatment results before and after introduction of short course tuberculosis chemotherapy and to identify factors affecting the results. DESIGN/SETTING: An eight-month chemotherapy regimen for smear-positive pulmonary tuberculosis was introduced in Nicaragua in 1984 with external financial assistance. We performed a retrospective record review to compare treatment results before and after introduction of short-course chemotherapy. Information on support services and programme administration, availability of hospital beds for tuberculosis patients, access to health services and the economic and war situation in the two periods was assessed. RESULTS: The overall success ratio improved by 39% between the two periods reviewed, in spite of evidence of a deteriorating economy and escalation in civil war. A success ratio of 71% was achieved and we estimate that between 80 and 90% of registered cases stopped transmitting tuberculosis. The best results were obtained in the treatment of previously untreated patients with eight-month chemotherapy and in retreatment of relapses. The worst results were obtained in retreatment of defaulters. Analysis of the findings by region suggests that short-course chemotherapy was important, but not enough by itself to guarantee success. Factors likely to have influenced treatment results are: commitment by health authorities in guaranteeing personnel and hospital beds, training of personnel, and supervision of service delivery. Possibilities for further improvement are discussed. CONCLUSIONS: Good results were achieved in tuberculosis control with the introduction of short-course chemotherapy in spite of poverty and war. Government commitment and simultaneous improvement in supportive services and programme management is important when introducing short-course chemotherapy in low income countries.

Rapid deformation of the South flank of kilauea volcano, hawaii.

The south flank of Kilauea volcano has experienced two large [magnitude (M) 7.2 and M 6.1] earthquakes in the past two decades. Global Positioning System measurements conducted between 1990 and 1993 reveal seaward displacements of Kilauea's central south flank at rates of up to about 10 centimeters per year. In contrast, the northern side of the volcano and the distal ends of the south flank did not displace significantly. The observations can be explained by slip on a low-angle fault beneath the south flank combined with dilation deep within Kilauea's rift system, both at rates of at least 15 centimeters per year.

[Cytomegalovirus infections in healthy adults.].

BACKGROUND: Primary cytomegalovirus (CMV) infections in healthy adults are considered extremely rare. To study the extent of this problem in Iceland we undertook a two year (1989-1990) retrospective study of all new CMV infections in adults. METHODS: All positive tests for CMV antibodies in clinical samples (194) were identified in the sole virology laboratory in Iceland. Patients younger than 16 years and all patients with underlying diseases that could cause immunosuppression were excluded (154). The 40 remaining patients were contacted, their case histories reviewed and their serology for CMV, Epstein-Barr and HIV antibodies remeasured. Primary CMV infection was not confirmed in 14 patients leaving 26 immune competent patients who fullfilled our criteria for primary sym-tomatic CMV infection by the presence of IgM anti-CMV antibodies. RESULTS: Duration of illness in the 26 study patients varied from 1 to 25 weeks, usually 7-10 weeks. Fifteen patients were hospitalized. Diagnostic delay was considerable. Immunological tests (DTH skin test, serum immunoglobulines and lymphocyte differential counts) done 172-2 years after the illness did nor reveal any persistent immune abnormalities except for an absolute increase in the number of CD8+ T lymphocytes Conclusions: We conclude that primary CMV infections in adults are not uncommon and probably underdiagnosed. When adult patients present with non-specific symptoms such as low grade fever, malaise and unexplained fatigue, CMV should be considered or excluded with appropriate serological tests.

Tuberculosis case-finding in Nicaragua: evaluation of routine activities in the control programme.

SETTING: The new International Union against Tuberculosis and Lung Disease (IUATLD) tuberculosis strategy developed in the 1980s in Tanzania, Malawi and Mozambique, was simultaneously implemented in Nicaragua. OBJECTIVE: Present results of case-finding, identify trends in incidence and limitations in case-finding and reporting. DESIGN: Data are based upon the traditional reporting system until 1987, replaced as the programme was reorganized. Data were also collected directly from the Central Laboratory, Programme and Laboratory registers during supervision of health centres. RESULTS: Quality control of sputum smears shows 1.8% discordance between peripheral and central laboratories. Notification rate of smear-positive tuberculosis declined 1.7% yearly 1983-1991 and 2.6% for all cases. Half of the patients are new smear-positive pulmonary cases, 40% smear-negative pulmonary cases. Relapses represent 11-13% of all smear-positive patients, children 7-30% of all cases. One-third of extrapulmonary tuberculosis cases are pleural effusions, another third lymphadenitis. 41% of adult patients entered as smear-negative in the programme had no smear reported in the laboratory. CONCLUSIONS: Quality control of sputum smears was established and the reporting system improved in spite of adverse conditions. Notification rate declined gradually. Smears should be done in all patients classified as smear-negative pulmonary tuberculosis.

Characterization of immune complexes in multiple sclerosis by an antigen-specific immune complex radioimmunoassay.

Serum and cerebrospinal fluid samples from multiple sclerosis (MS) patients containing various levels of Clq-reactive immune complexes (IC) and samples from age- and sex-matched controls were tested by an antigen-specific IC radioimmunoassay which detects IC containing myelin membrane-related antigens. Positive reactivity in the assay was significantly associated with IC-containing MS sera (P less than 0.005) but such an association was not observed with MS cerebrospinal fluid. Analysis of longitudinal specimens revealed that the levels of the antigen-specific serum IC fluctuated with time. Significant correlation between serum levels of Clq-reactive IC and serum levels of IC containing myelin membrane-related antigens was observed (r = 0.62; P less than 0.001). Sucrose gradient centrifugation of sera from 1 patient showed that the IC had a peak density of 1.075 g/ml, indicating the presence of lipid material. The results suggest that serum IC of MS patients frequently contain myelin membrane-related antigens and that these antigens may be lipids or lipid-associated.

Mitogen and antigen stimulation of multiple sclerosis cerebrospinal fluid lymphocytes in vitro.

Responses of cerebrospinal fluid (CSF) and peripheral blood (PB) lymphocytes from 20 MS patients to phytohemagglutinin (PHA), measles, rubella, mumps and herpes simplex virus antigens were followed during periods of from 6 to 13 months. Up to 6 examinations, each with 1-5 stimulants, were performed with a lymphocyte blast transformation test. Most of the patients responded with their CSF cells to PHA (14/19) and at least to some of the viral antigens tested (15/20) during the follow-up. Although the maximal responses of CSF and PB cells to PHA and measles virus antigen were of the same magnitude, non-reactive or weakly responding lymphocytes were more common in CSF than in PB. In 7 of 15 patients having viral antigen responsive CSF cells simultaneous reactivity to several antigens could be shown. The stimulation results of CSF lymphocytes did not correlate with the numbers of CSF leukocytes or the intrathecal IgG synthesis. A negative correlation was observed between the strength of the CSF cellular response to PHA or measles virus antigen and the rate of intrathecal antibody synthesis to measles virus antigen, suggesting that the stimulated cells may at least partially represent suppressor cells.

Antibodies to measles virus in ankylosing spondylitis.

IgG antibodies to measles virus were measured by a solid-phase radio-immunoassay in serum specimens from 31 patients with confirmed ankylosing spondylitis (AS), from 8 patients with symptoms and signs resembling AS and from 39 patients hospitalized for various non-rheumatological disorders. The patients with AS and without iritis/uveitis had a 4-fold increased amount of measles antibodies in their serum specimens compared with the control patients (p less than 0.01). The AS patients with iritis and the patients with symptoms and signs resembling AS were, in this respect, similar to the control patients.

Intrathecal synthesis of virus antibodies in multiple sclerosis patients.

A follow-up study on the intrathecal synthesis of viral antibodies in multiple sclerosis patients was made on 28 patients over a period of about 2 years. Serial serum and cerebrospinal fluid specimens were assayed for antibodies against measles, rubella, parainfluenza type 2, respiratory syncytial, mumps, influenza A, influenza B, adeno, and herpes simplex viruses by employing a solid-phase enzyme immunoassay technique. All patients had local antibody synthesis against one or more of the antigens studied. Rubella and measles virus antibodies were found with the highest frequency and were synthesized at the highest rate. Simultaneous intrathecal antibody synthesis against the greater number of the viruses studied was associated with higher local immunoglobulin G synthesis. A good overall correspondence in the fluctuations of the different viral antibodies synthesized intrathecally was usually found. Sometimes the changes in intrathecal antibody levels correlated well with the changes in immunoglobulin G index and sometimes not. These fluctuations could not be correlated with the clinical course of the disease. The results of this study suggest that the viral antibodies studied are not relevant to the etiology or the pathogenesis of multiple sclerosis.

Circulating immune complexes in patients with multiple sclerosis. A longitudinal study of serum and CSF by C1q and platelet binding tests.

Two hundred and twenty-eight paired serum and CSF samples collected from 31 patients with MS during a 2-3-year follow-up were analyzed for the presence of immune complexes (IC) by C1q RIA and PIPA (platelet [125I]protein A) techniques. One hundred and forty-four sera from 11 healthy individuals were analyzed as controls. In almost all patients (29/31) IC were detectable during some period of the disease, as tested by either of the techniques. The results obtained by C1q RIA and PIPA correlated positively with each other in MS when mean serum values of each patient were compared. The mean CSF IC levels detected by C1q RIA appeared to correlate to the mean IgG indexes, an indicator of the intrathecal rate of IgG synthesis. The amount of IC in serum and CSF fluctuated independently in MS. The results of the PIPA test for MS serum IC correlated significantly to the duration of the disease. The PIPA test results also showed that patients in stable or chronic phases of MS displayed IC in serum and CSF more often than patients with a relapsing/remitting course of disease but there was no clear correlation between fluctuations in IC levels in individual patients measured by C1q RIA or PIPA techniques and the disease course. Because of the lack of a clear correlation between the presence, quantity and fluctuation of IC and the clinical picture we suggest that those IC detected in the present study are probably not a precipitating factor in the pathogenesis of multiple sclerosis.

Myelin basic protein antibodies in the serum and CSF of multiple sclerosis and subacute sclerosing panencephalitis patients.

A solid-phase radioimmunoassay was developed for the detection of myelin basic protein antibodies of immunoglobulin G (IgG) class. Purified basic protein of myelin (MBP) was adsorbed onto polystyrene beads, followed by incubation in dilutions of serum or cerebrospinal fluid (CSF). 125I-labelled anti-human IgG was used to quantify antibodies bound to the solid-phase. The assay was optimized in tests with rabbit antibodies to MBP and with 125I-labelled anti-rabbit IgG. Serum and CSF specimens from 41 multiple sclerosis (MS), 16 subacute sclerosing panencephalitis (SSPE) and 58 control patients were tested for MBP antibodies. No statistically significant differences were found between MS and control patient groups, but the subgroup of acute MS patients had slightly elevated (P 0.02) antibody levels in their CSF specimens. The SSPE patients had markedly elevated levels (P 0.001) of antibodies to MBP in their CSF specimens.

Measles and rubella virus antibodies in patients with multiple sclerosis. A longitudinal study of serum and CSF specimens by radioimmunoassay.

A longitudinal study on rubella, measles, and respiratory syncytial virus antibodies in serial serum and CSF specimens from 20 multiple sclerosis (MS) patients was performed, using solid-phase radioimmunoassay. Albumin and immunoglobulin G (IgG) levels were also measured to check the integrity of the blood-brain barrier and the intrathecal IgG production. All the patients had local IgG production in their CNA. A local antibody production against one or more of the viruses studied was evident in 15 patients. Fluctuations in the intrathecal viral antibody synthesis were evident in eight patients. No correlation was found between these changes and the clinical course of the disease. The results suggest that the intrathecal antibody synthesis in MS is only partially against any given virus, and in most patients the bulk of the oligoclonal CSF antibodies is against antigens other than those studied here.