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					The Australian Tuberculosis
Newsletter
February 2004 Vol 19 no 1




In this edition                                            Editorial
                                                           Twenty years ago Dr AJ Proust of Canberra
 DOTS/not DOTS                                            founded the Australian Tuberculosis Newsletter.
                                                           Tuberculosis (TB) was rapidly declining in
 New risk factors                                         Australia with an annual rate that year of 7.5
 Zoonoses                                                 cases per 100,000 population. Indeed a decline
                                                           across the world caused many to hope that the
 Nuclear amplification                                    disease could be eliminated. This hope led to a
                                                           dismantling of TB services infrastructure in New
Forthcoming meetings                                       York, with as we know disastrous consequences.
                                                           Even the abolition of the National Tuberculosis
                                                           Advisory Council in Australia was later shown to
8th Conference IUATLD North America                        be shortsighted, and had to be remedied years
Austin, Texas                                              later. It was estimated that the annual rate of TB
                                                           would fall to below 4 per 100,000 population by
26 to 28 February 2004
                                                           2001. The admission of refugees and migrants
email: TB@alamc.org                                        from countries of high TB prevalence saw this
                                                           prediction overturned.A re-read of the first edition
3rd Conference of the IUATLD Europe Region                 tells us that some aspects of TB diagnosis,
                                                           control, treatment and prevention change slowly if
Moscow, Russia                                             at all. A study by Mills of Newcastle reviewed his
23 to 26 June 2004                                         experience of “absolute supervision” beginning in
                                                           1969. This subject remains intensely topical.On
email: pulmo@mosmed.ru
                                                           the other hand what appear to be advances in
                                                           knowledge and later found to be incorrect, may
35th Union World Conference                                be exemplified in a report from Canada
                                                           implicating non-steroidal anti-inflammatory drugs
Palais des congres, Paris
                                                           as a risk factor for TB.
28 October to 1 November 2004
                                                           Twenty years ago the editor of this newsletter had
email: union@iuatld.org
                                                           difficulty finding enough articles in the medical
                                                           literature to its nine pages. Today, the editor finds
Editorial group                                            himself overwhelmed by an ocean of papers. To
                                                           fill sixteen pages, criteria for selection had to be
Dr J Thompson         Dr M Hurwitz                         set. They are in order of importance. First, that
Dr V Krause           Dr M Levy                            the topic is of vital importance whatever the
Dr S Nogrady          Dr A Proust                          setting; second, that it originates from Australia,
Letters and other contributions are welcomed,              New Zealand or a neighboring country; thirdly that
but should not exceed 400 words.                           it is an original contribution; and finally that the
                                                           topic is dealt with in a sufficiently rigorous way to
All communications, including letters to the editor,       provide a vehicle for an editorial or short review.
should be sent to:                                         To warrant selection, at least one of these criteria
            Dr John Thompson                               must be satisfied.
            3 Banner Street
            O’CONNOR ACT 2602
tel/fax     02 6249 8446
email       jtandjnj@actewagl.net.au

Sponsored by CHATA –
Community Health and Tuberculosis Australia

                                                       1
World News                                                  Summary: Among communicable diseases,
                                                            tuberculosis is the second leading cause of death
By the time this newsletter reaches you, the
                                                            worldwide, killing nearly 2 million people each
IUATLD will become known as the UNION.
                                                            year. Most cases are in less-developed countries;
                                                            over the past decade, tuberculosis incidence has
                                                            increased in Africa, mainly as a result of the
DOT
                                                            burden of HIV infection, and in the former Soviet
A randomized controlled clinical trial of the               Union, owing to socioeconomic change and
efficacy of family-based direct observation                 decline of the health-care system. Definitive
of anti-tuberculosis treatment in an urban,                 diagnosis of tuberculosis remains based on
developed country setting.                                  culture for Mycobacterium tuberculosis, but rapid
                                                            diagnosis of infectious tuberculosis by simple
MacIntyre et al Melbourne & Sydney Australia.               sputum smear for acid-fast bacilli remains an
Int J Tuberc Lung Dis 2003; 7: 848                          important tool, and more rapid molecular
                                                            techniques hold promise. Treatment with several
Setting: A randomized, controlled clinical trial of         drugs for 6 months or more can cure more than
the effectiveness of a family-based program of              95% of patients; direct observation of treatment, a
directly   observed    treatment    (DOT)       for         component of the recommended five-element
tuberculosis.                                               DOTS strategy, is judged to be the standard of
Methods: TB patients seen in Victoria, Australia,           care by most authorities, but currently only a third
were randomly allocated to DOT observed by a                of cases worldwide are treated under this
family member (FDOT), or to standard supervised             approach. Systematic monitoring of case
but non-observed therapy (ST). The outcome                  detection and treatment outcomes is essential to
measure was compliance, measured by blinded                 effective service delivery. The proportion of
testing of isoniazid levels in urine. An intention to       patients diagnosed and treated effectively has
treat analysis was used.                                    increased greatly over the past decade but is still
                                                            far short of global targets. Efforts to develop more
Results: Of 173 patients, 87 were allocated to              effective tuberculosis vaccines are under way, but
FDOT and 86 to ST. Only 58% in the FDOT                     even if one is identified, more effective treatment
group were able to receive FDOT, the major                  systems are likely to be required for decades.
reason being living alone and not having a family           Other modes of tuberculosis control, such as
member to observe treatment. The rate of non-               treatment of latent infection, have a potentially
compliance was 24% (41/173), with no significant            important role in some contexts. Until tuberculosis
difference between FDOT (22/87) and ST                      is controlled worldwide, it will continue to be a
(19/86). No clinical or socio-demographic variable          major killer in less-developed countries and a
predicted compliance.                                       constant threat in most of the more-developed
Conclusions: We were unable to demonstrate a                countries.
benefit of FDOT in an urban, industrialised
country setting. FDOT may be more appropriate
in developing countries, where extended family              The world-wide increase in tuberculosis:
support is often available and the burden of TB is          how demographic changes, HIV infection
much higher. Poor compliance and the difficulty in          and increasing numbers in poverty are
predicting non-compliance shown in this study               increasing tuberculosis.
highlights the need for DOT for all TB patients.
                                                            Davies PD Liverpool UK
Comment: Like some other studies on DOTS in
                                                            Ann Med 2003; 35: 235
the literature, it is not made clear if the
recommendation for DOT in this study means all              Summary: After more than a century of decline,
five arms of DOT or just the observation arm.               in the mid 1980s tuberculosis began to increase
JT                                                         in some developed countries. Health care
                                                            workers were then forced to look to the
                                                            developing world, where they found tuberculosis
Reviews                                                     to be out of control, in many countries. it is now
                                                            appreciated that tuberculosis is not only
Tuberculosis
                                                            increasing globally but is likely to do so beyond
Frieden et al New York NY USA                               the next decade for three principal reasons. First,
                                                            demographically as the expected population
Lancet 2003; 362: 887
                                                            increase will be greatest in areas of the world
                                                            where tuberculosis is most prevalent, particularly


                                                        2
middle Africa and South Asia. Secondly, the                  Drug dynamics
increase of HIV, which renders the host uniquely
                                                             The bactericidal activity of moxifloxacin in
susceptible to tuberculosis, is occurring in the
same areas of the world and is already causing               patients with pulmonary tuberculosis.
an increase in tuberculosis case rates of up to              Gillespie et al London UK
tenfold. Thirdly, as more and more people are
forced to live in poverty, where poor nutrition and          Am J Resp Crit Care Med 2003; Aug13
crowded conditions lead to the spread of                     Summary: Patients with newly diagnosed AFB
tuberculosis,     the    disease    risk   will   be         smear-positive pulmonary tuberculosis were
compounded. Sound medical management,                        randomised to receive 400 mg moxifloxacin, 300
particularly the use of the five components of               mg isoniazid, or 600 mg rifampin daily for 5 days.
directly observed therapy, will relieve the                  Sixteen hour overnight sputum collections were
situation. But until world conditions of poverty and         made for the 2 days before and for five days of
HIV spread are addressed, it is unlikely that                monotherapy. Bactericidal activity was estimated
tuberculosis can be controlled.                              by the time taken to kill 50% of visible bacilli
                                                             (vt50) and the fall in sputum viable count during
                                                             the first 2 days designated as the Early
Conference Reports                                           Bactericidal Activity (EBA). The mean vt50 of
ASM Australasian Society for Infectious                      moxafloxacin, was 0.88 days (95% CI 0.43-1.33
Diseases March 2003                                          days) and the mean EBA 0.53 (95% CI 0.28-
                                                             0.79). For the isoniazid group the mean vt50 was
Tuberculous arthritis; an important differential             0.46 days (95% CI 0.31-0.61 days) and the mean
diagnosis in paediatric monoarthritis. A case                EBA was 0.77 ( 95% CI 0.54-1.0). For rifampin
report and review of the literature.                         the mean vt50 was 0.71 days (95%CI 0.48-0.95
                                                             days) and mean EBA was 0.28 (95% CI 0.15-
May et al Westmead NSW
                                                             0.41). Using the EBA method isoniazid was
Mycobacterium tuberculosis (Mtb) is a rare cause             significantly more active than rifampin (p<0.01)
of chronic monoarthritis, which can masquerade               but not moxifloxacin. Using the vt50 method
as oligoarticular juvenile idiopathic arthritis (JIA).       isoniazid was more active than both rifampin and
We present a case of a four year old Caucasian               moxifloxacin(p=0.03). Moxifloxacin has an activity
child with tuberculous monoarthritis of the knee in          similar to rifampin in human subjects with
whom the initial diagnosis was delayed due to the            pulmonary tuberculosis suggesting it should
absence of identifiable risk factors for Mtb. We             undergo further assessment as part of a short
reviewed the literature on epidemiological risk              course regimen for the treatment of drug
factors, methods of diagnosis, treatment and                 susceptible tuberculosis.
outcome data from both endemic and non-
                                                             Comment: Let us hope these new quinolones
endemic areas on this condition and identified a
                                                             can rescue us from MDR-tuberculosis. JT
total of 540 cases of tuberculous monoarthritis in
children. Details of individual diagnostic methods
and results was available in 90 patients. Mantoux
                                                             Gatifloxacin and ethionamide as the
testing was found to be positive in 83 (92%)
                                                             foundation for therapy of tuberculosis.
cases, and Mtb was obtained from culture of
synovial fluid in 76%. Five of eleven cases had a            Cynamon et al Syracuse NY USA
positive result for Mtb polymerase chain reaction
                                                             Antimicrob Agents Chemother. 2003; 47: 2442
on biopsy specimens. Ninety one percent of
synovial biopsies performed had supportive                   Summary: The use of gatifloxacin (GAT) in
histological findings. Treatment in advanced                 combination with ethionamide (ETA) with or
disease is surgical , while synovectomy in earlier           without pyrazinamide (PZA) for a 12-week
stages may not be required. Outcome can be                   treatment period followed by an 8-week
partially predicted by changes seen on plain                 observation period was evaluated in a model of
radiographs of the joint, and is often improved by           tuberculosis in mice. Mice treated with GAT at
early treatment. Tuberculous arthritis cannot be             300 mg/kg of body weight in combination with
excluded on the basis of history and radiographic            ETA (25 mg/kg) for 5 days a week had sterile
examination alone.                                           lungs, whereas mice treated with GAT (100
                                                             mg/kg) and ETA (25 mg/kg) had about
                                                             10CFU/lung; however there was regrowth of the
                                                             organisms in both groups at the end of the
                                                             observation period. When PZA (450 mg/kg 5
                                                             days per week) was added to the high-dose GAT-

                                                         3
ETA regimen, no viable mycobacteria were                   individuals, leading to active and contagious
present after the 8-week observation. GAT in               tuberculosis. An estimated 2 billion people
combination with ETA and PZA has great                     worldwide are infected with M.tuberculosis- an
potential for the treatment of tuberculosis.               enormous reservoir of potential tuberculosis
                                                           cases. The establishment and reactivation of
Comment: Certainly in mice. JT
                                                           latent infection depend on several factors, related
                                                           both to host and bacterium. Elucidation of the
                                                           host immune response mechanisms that control
Fluoroquinolones, tuberculosis, and
                                                           the initial infection and prevent reactivation has
resistance.
                                                           begun. The bacillus is well adapted to the human
Ginsburg et al Baltimore MD USA                            host and has a range of evasion mechanisms that
                                                           contribute to its ability to avoid elimination by the
Lancet Infect Dis 2003; 3: 432
                                                           immune system and establish a persistent
Summary: Although the fluoroquinolones are                 infection. We discuss current understanding of
presently used to treat tuberculosis primarily in          both host and bacterial factors that contribute to
cases involving resistance or intolerance to first-        latent and reactivation tuberculosis.
line antituberculosis therapy, these drugs are
                                                           Comment: Thankfully, the authors don’t use the
potential first-line agents and are under study for
                                                           tautology, latent tuberculosis infection (LTBI).
this indication. However, there is concern about
                                                           JT
the development of fluoroquinolone resistance in
Mycobacterium tuberculosis, particularly when
administered as monotherapy or as the only                 Latent tuberculosis in pregnancy:
active agent in a failing multidrug regimen.
                                                           screening and treatment.
Treatment failures as well as relapses have been
documented under such conditions. With                     Bergeron et al Omaha NE USA
increasing numbers of fluoroquine prescriptions
                                                           Curr Womens Health Rep 2003; 3: 303
and the expanded use of these broad-spectrum
agents for many infections, the selective pressure         Summary: Currently most cases of active
of fluoroquine use results in the ready emergence          tuberculosis in the United states are a result of
of fluoroquinolone resistance in a diversity of            activation of latent tuberculosis infection. In this
organisms, including M. tuberculosis. Among M.             article, the history of the epidemiology of
tuberculosis, resistance is emerging and may               tuberculosis and latent tuberculosis infection is
herald a significant future threat to the long-term        reviewed. Previous and current recommendations
clinical utility of fluoroquinolones. Discussion and       for screening and treatment for latent tuberculosis
education regarding appropriate use are                    during pregnancy and the postpartum period are
necessary to preserve the effectiveness of this            discussed. A review of the literature regarding
antibiotic class against the hazard of growing             postpartum and antepartum treatment is included.
resistance.                                                Finally, the question of whether antepartum or
                                                           postpartum treatment is the most beneficial is
Comment: Yes, but what if the horse has already
                                                           discussed.
bolted. JT
                                                           Comment: An important topic revisited. JT

Infection
                                                           Association of initial tuberculin sensitivity,
Latent tuberculosis: mechanisms of host and
                                                           age and sex with the incidence of
bacillus that contribute to persistent infection.
                                                           tuberculosis in South India:
Tufaiello New York USA                                     a 15-year follow-up.
Lancet Infect Dis 2003; 3: 578                             Tuberculosis Research Centre (ICMR),
Summary:        Most    people    infected     with        Chennai India
Mycobacterium tuberculosis contain the initial
                                                           Int J Tuberc Lung Dis 2003; 7: 1083
infection and develop latent tuberculosis. This
state is characterized by evidence of an immune            Objective: To determine the association of initial
response against the bacterium (a positive                 tuberculin sensitivity, age and sex with the
tuberculin skin test) but no signs of active               development of tuberculosis.
infection. It can be maintained for the lifetime of
the infected person. However, reactivation of              Methods: A 15-year follow-up of 280,000
latent infection occurs in about 10% of infected           subjects in south India, where new cases of
                                                           tuberculosis were detected mainly by periodic

                                                       4
population surveys. Life-table technique was               Productos Biologicos de la Sociedad Espanola de
employed to estimate tuberculosis incidence and            Reumatologia) database, which was launched in
disease risk in survivors. The independent effect          February 2000 by the Spanish Society of
of tuberculin sensitivity, sex and age at intake           Rheumatology. For the estimation of TB risk, the
was determined using Cox’s proportional hazard             annual incidence rate in patients treated with
model.                                                     these agents was compared with the background
                                                           rate and with the rate in a cohort of patients with
Results: Taking subjects with reaction size 0-7
                                                           rheumatoid arthritis(RA) assembled before the
mm to 3 IU PPD-S as reference group, the
                                                           era of anti-TNF treatment.
adjusted relative risk (RR) for developing culture-
positive tuberculosis was 1.1, 1.9, 2.9, 3.6 and           Results: Seventy-one participating centers sent
3.3 for those with indurations of 8-11, 12-15, 16-         data on 1,578 treatments with infliximab (86%) or
19, 20-24 and => 25 mm ( P< 0.01). Considering             etanercept 14%) in 1,540 patients. Drug survival
subjects aged 0-4 years as reference group, the            rates (reported as the cumulative percentage of
adjusted RR for the other groups increased from            patients still receiving medication) for infliximab
1.7 to 10.8 (P < 0.01). Males had a substantially          and etanercept pooled together were 85% and
higher incidence (adjusted RR 3.0, P< 0.001).              81% at 1 year and 2 years respectively. Instances
The risk of culture-positive tuberculosis over 15          of discontinuation were essentially due to adverse
years in survivors was 3.3% (5.0 % in males and            events. Seventeen cases of TB were found in
1.6 % in females), and increased substantially             patients treated with infliximab. The estimated
with tuberculin sensitivity at uptake. In those with       incidence of TB associated with infliximab in RA
>= 12 mm at uptake, the approximate lifetime risk          patients was 1,893 per 100,000 in the year 2000
was 6.1% (8.6% in males and 3.1% in females).              and 1,113 per 100,000 in the year 2001. These
                                                           findings represent a significant increased risk
Conclusion: The incidence of tuberculosis
                                                           compared with background rates. In the first five
increased steadily with tuberculin sensitivity to
                                                           months of 2002, after official guidelines were
PPD-S and age at uptake. Males had a
                                                           established for TB prevention in patients treated
significantly higher risk than females in every
                                                           with biologics, only one new TB case was
PPD-S group and the overall risk was three-fold
                                                           registered.
higher.
                                                           Conclusion:    Therapy     with  infliximab  is
Comment: This is an important study. It suggests
                                                           associated with an increased risk of active TB.
that the cutoff point for tuberculosis infection
                                                           Proper measures are needed to prevent and
(LTBI) is 12 mm for males but higher for females.
                                                           manage this adverse event.
This is true for south India using 3 units of PPD-
S. It may not be true for other countries using            Comment: As more anti-cytokine agents become
different doses of different tuberculins. JT              available, so will such risks continue. JT


Risk Factors                                               Systematic safety follow up in a cohort
                                                           of 107 patients with spondyloarthropathy
Treatment of rheumatoid arthritis with tumour
                                                           treated with infliximab: a new perspective
necrosis factor inhibitors may predispose to
                                                           on the role of host defence in the
significant increase in tuberculosis risk:
                                                           pathogenesis of the disease?
a multicenter active-surveillance report.
                                                           Baeten et al Ghent Belgium
Gomez-Reinno et al Santiago Spain
                                                           Ann Rheum Dis 2003; 62: 829
Arthritis Rheum 2003; 48: 2122
                                                           Background: Recent studies with infliximab
Objective: The long-term safety of therapeutic
                                                           indicate the therapeutic potential of tumour
agents that neutralize tumour necrosis factor
                                                           necrosis factor alpha blockade in spondyloarthro-
(TNF) is uncertain. Recent evidence based on
                                                           pathy(SpA). Because defective host defence is
spontaneous reporting shows an association with
                                                           implicated in the pathogenesis of SpA, the
active tuberculosis (TB). We undertook this study
                                                           potential side effects of this treatment due to
to determine and describe the long-term safety of
                                                           impact on the antimicrobial defence are a major
2 of these agents, infliximab and etanercept in
                                                           concern.
rheumatic diseases based on a national active-
surveillance system following the commerciali-             Objective: To report systematically the adverse
sation of these drugs.                                     events seen in a large cohort of patients with SpA
                                                           treated with infliximab, with special attention to
Methods: We analyzed the safety data actively
                                                           bacterial infections.
collected in the BIOBADASER (Base de Datos de

                                                       5
Patients and Methods: 107 patients with SpA                 was made with the Ziehl-Nielsen staining method.
were treated with infliximab for a total of 191.5           Culture was performed by the conventional
patient years. All serious and/or treatment related         Lowenstein-Jensen method and the Bactec-460
adverse events were reported.                               radiometric method.
Results: Eight severe infections occurred,                  Results: We found mycobacterial infection in
including two reactivations of tuberculosis and             27 patients (2.1%), due to Mycobacterium
three retropharyngeal abscesses, and six minor              tuberculosis in 20 cases, M. kansasii in five
infections with clear bacterial focus. One patient          patients, and M. fortuitum in two patients. The
developed a spinocellular carcinoma of the skin.            mean elapsed time from the renal transplant was
No cases of demyelinating disease or lupus-like             20.5 months; the infection appeared in 18
syndrome were seen. Two patients had an                     patients during the first eight months after
infusion reaction, which however, did not relapse           transplantation. The clinical onset was pulmonary
during the next infusion. Finally, three patients           infection in 17 cases (12 M. tuberculosis and five
with ankylosing spondylitis developed palmar                M. kansasii); five had urinary symptoms (three M.
plantar pustulosis. All patients recovered                  tuberculosis and two M. fortuitum); three case of
completely with adequate treatment, infliximab              tuberculous infection had abdominal symptoms;
treatment had to be stopped in only five patients           another one began with a tuberculous perineal
with severe infections.                                     abscess; the rest of the patients were
                                                            asymptomatic. The types of specimen on which
Conclusions: Although the global safety of
                                                            microbiological identification was carried out
infliximab is good compared with previous reports
                                                            were, in deceasing order: sputum and/or
reports in rheumatoid arthritis and Crohn’s
                                                            bronchial washing/pleural aspiration, urine, feces,
disease, the occurrence of infections such as
                                                            gastric and peritoneal fluids, bone marrow and
tuberculosis and retropharyngeal abscesses
                                                            blood. The first-line drug isoniazid had the highest
highlights the importance of careful screening and
                                                            resistance index in the susceptibility test. Clinical
follow up. Focal nasopharyngeal infections and
                                                            dissemination was observed in eight patients, four
infection related symptoms, possibly induced by
                                                            of whom died. Another three patients had a
streptococci, occurred frequently, suggesting an
                                                            significant impairment in renal function, and in
impairment of specific host defence mechanisms
                                                            one of these patients an allograft nephrectomy
in SpA.
                                                            was necessary due to a severe septic syndrome.
Comment: The TB annual rate of just over 1% is
                                                            Conclusions: Mycobacterial infection, mainly by
only a little less than the Spanish series and
                                                            M. tuberculosis, has an important impact on
remarkably similar to that reported across the
                                                            kidney transplant recipients, particularly in the first
world in the first 2 years after organ transplantion.
                                                            year after surgery. Diagnosis often presents
JT
                                                            some difficulties, and a delay in treatment
                                                            represents a determinant factor for the evolution,
                                                            with a risk of death or permanent damage in renal
Mycobacterial infection in a series of 1261
                                                            function. Therefore, early diagnosis is mandatory.
renal transplant recipients.
                                                            When the Mantoux reaction is positive, anti-
Queipo et al Valencia Spain                                 tuberculous prophylaxis seems advisable.
Clin Microbiol infect 2003; 9: 518                          Comment: Provided the Mantoux test precedes
                                                            immunosuppression. JT
Objective: To describe the incidence and clinical
characteristics of mycobacterial infection in renal
transplant recipients.                                      Nontuberculous mycobacterial infections
Methods: We retrospectively analyzed the cases              in Chinese hematopoietic stem cell
of mycobacterial infection in a series of 1261              transplantation recipients.
renal transplants carried out in our Unit of Renal
                                                            Au et al Hong Kong China
Transplantation from 1980 to 2000. Demographic
parameters and clinical antecedents such as age,            Bone Marrow Transplant 2003; 32:709
cause of end-stage renal disease, time of follow-
                                                            Summary: Between 1995 and 2002, nine cases
up of the graft, previous renal function and type of
                                                            of nontuberculous mycobacterium (NTM) were
immunosuppression were considered. Moreover,
                                                            isolated from 462 allogeneic stem cell transplant
the clinical onset, diagnostic tools, treatment
                                                            (SCT) recipients (1.9%), and none from 139
policy and evolution were studied. The
                                                            autologous cases. They included three cases
pathogenesis of the different types of myco-
                                                            each     of   Mycobacterium      fortuitum   and
bacteria isolated was also analysed. Diagnosis
                                                            M. chelonae, and single cases of M. scofulaceum,


                                                        6
M. gordonae and M. avium complex. Seven cases             links, but most notably identified previously
were respiratory, including five cases requiring          unrecognized inter-village transmission. This
treatment, and two involved infected catheters            study     demonstrates    significant   ongoing
and vascular conduits. Compared with the nine             transmission in a geographically isolated, low-
cases of Mycobacterium tuberculosis (MTB)                 density population. In a resource-rich country
isolated in the same period, NTM isolation                such as Canada, these communities illustrate
occurred later after HSCT and involved more               some of the persistent challenges of TB control
unrelated donors. Important risk factors for NTM          and elimination.
infection included significant a GVHD (p=0.043),
                                                          Comment: This study could so easily be set in
leukemia relapse (p=0.022), MUD and mismatch
                                                          Australia. JT
SCT(p <0.0010 and existence of BO ( p<0.001).
Coinfection with aspergillus was common.
Invasive NTM disease required prolonged
                                                          Short Review
antimicrobial treatment in five cases due to M.
fortuitum and M. chelonae. With better MTB                What do we do when the sputum smears
prophylaxis, intensive immunosuppression and              are negative?
better awareness, NTM has become an emerging
                                                          The year 2001 saw 558 cases of pulmonary
threat in oriental allogeneic HSCT recipients. The
                                                          tuberculosis reported in Australia. 58% of these
cutoff between colonization and infection, and the
                                                          were sputum smear positive. This left 34% whose
threshold for starting treatment is unclear. NTM
                                                          sputum was smear and culture negative. In some
isolation     is     a    marker    for     severe
                                                          of these bronchoscopic washings were smear
immunosuppression and poor prognosis. When
                                                          and culture positive. Because of overlap between
there is doubt over species identity or extent of
                                                          sputum and bronchial washing examinations we
infection, broad-spectrum cover may be prudent.
                                                          are only able to say that a sizable minority
Comment: Prudent certainly: but do we know                presumably had their diagnosis largely made on
what is effective cover for NTM disease? JT              the basis of chest Xray appearance by competent
                                                          and experienced clinicians. The suspected case
                                                          of tuberculosis who is already hospitalised
Risk Groups                                               presents a dilemma. Should they be rigidly
                                                          isolated particularly if sputum smears are
Tuberculosis in the Inuit community
                                                          negative and until culture results are available?
of Quebec, Canada.
                                                          Tattevin et al addressed this issue using chest
Nguyen et al Montreal Canada                              Xray appearance, medical history, HIV status and
                                                          social factors as criteria for isolation. Each factor
Am J Resp Crit Care Med 2003; Sept 18
                                                          showed a correlation with active disease of
Summary: In low incidence countries targeting             varying significance, but their overall predictive
TB elimination, tuberculosis remains a problem of         values were very modest indeed.
a few high-risk groups. In Canada, Aboriginals,           In Australia the sputum smear negative case
and particularly the Arctic Inuit communities, have       seems to be increasingly subject to broncho-
witnessed dramatic decreases in TB during the             scopic washing examination for Mtb. In 2001,
1960-70s, but rates remain at least 10-20 times           nearly a third of all Mtb positive respiratory
higher than the national average. We are                  secretions came from bronchoscopy. Yet studies
describing the results of an integrated traditional       from New Zealand and other countries now show
and molecular epidemiology study of all culture           that the yield from induced sputum is equally as
positive M. tuberculosis cases in the Arctic Inuit        good as from bronchoscopy, and far more cost
communities of Quebec from 1990 until 2000.               effective. Indeed a report from Turkey suggests
The demographic characteristics of the 46 TB              that examination of gastric lavage specimens for
cases included in the study were most notable for         AFB produces the same number of positive
a bimodal age distribution (48% under 25 years of         findings as bronchoscopic lavage. Such an old
age). Genotyping analysis using multiple                  technique is likely to be cheaper than
modalities (IS6110 RFlp, spoligotype, MIRU-               bronchoscopy.
VNTR) showed that 76% (35/46) of TB cases
were clustered (6 clusters, median size 4 cases),         It is becoming clear that nuclear amplification
and estimated that at least 62.5% of TB cases             techniques to detect Mtb in respiratory secretions
were due to ongoing transmission. By integrating          should not be carried out as a routine even in
the epidemiologic and genotyping data, we                 wealthy countries. Their sensitivity may vary a
observed that the genotyping clustering results           little according to the commercial kit used, but is
were concordant with recognized epidemiologic             over 95% where the secretions are smear
                                                          positive. Sensitivity falls greatly where secretions

                                                      7
are culture positive only and vary between 50 and           pneumonia. The absence of cavitation on chest
75%. However, if the sputum smear is positive,              X-ray, presence of intrathoracic lymphadenopathy
an Amplicor or similar test should be carried out if        or lower lobe infiltrates may still be consistent with
the chest Xray appearance is either not typical of          a diagnosis of TB. Current clinical scoring
tuberculosis or there is likelihood of non-                 systems and algorithms don’t seem highly
tuberculous mycobacterial disease. Sarmiento et             predictive. There are now sufficient studies to tell
al felt that where bronchial secretions were smear          us that HIV and smear-negative tuberculosis in
negative and tuberculosis was possible, nuclear             the one person has such a poor outcome in poor
amplification or PCR examinations were                      countries that improved diagnostic measures are
advisable. Where sputum smear is negative, only             sorely needed.
a high clinical probability of active tuberculosis
                                                                                                John Thompson
can justify ordering a PCR test. There is no
evidence to justify the use of nuclear amplification        Ref: Kanaya et al Chest 2001,120:349. Lumb et
to monitor treatment. Lim et al have shown PCR              al CDI 2002; 26: 173. Miller et al CDI 2002;
is a valuable adjunct to clinical decision making,          26:525. Lim et al Chest 2003; 124: 902.
but does not replace it. It does seem to have a             Sarmiento et al J Clin Microbiol 2003; 41: 3233.
place in HIV1 positive individuals who have                 Colebunders et al Int J Tuberc Lung dis 2000; 4:
become sufficiently immunosuppressed as to                  97. Conde et al Am J Respir Crit Care Med 2000;
have only mediastinal lymphadenopathy or even               162: 2238. Pek et al Ann Acad Med Singapore
normal chest X-ray as the outward manifestation             2002; 31: 92. Chen et al Int J Tuberc Lung Dis
of their tuberculosis (TB). If the latter, a CT scan        2002; 6: 350. Maartens Curr Opin Pulm Med
may well show enlarged nodes.                               2002; 8: 173. Palmieri et al Infection 2002; 30: 68.
                                                            Tattevin et al Chest 1999; 115: 1248. Okutan et al
These considerations are all very well in a
                                                            Yonsei Med J 2003; 44: 242. Lim et al
wealthy country, or even a less affluent one
                                                            Respirology 2002; 7: 351. Lambert et al Int J
where tuberculosis is common and clinicians have
                                                            Tuberc Lung Dis 2003; 7: 485. Siddiqi et al
gained     considerable  expertise    in   X-ray
                                                            Lancet infect Dis 2003; 3: 288
interpretation.
What of the sputum smear negative person in a
poor country, particularly if they present at a local       Epidemiology
or even district level, where such expertise is not
                                                            A cluster of tuberculosis associated with use
available? The local microscopist is unlikely
                                                            of a marijuana water pipe.
diagnose the 58% of cases as seen in an
Australian reference laboratory. Siddiqi et al              Munckhof et al Brisbane Queensland
discuss the various criteria, algorithms and
scoring systems that have been proposed to deal             Int J Tuberc Lung Dis 2003; 7: 860
with the smear negative person. Those criteria of           Setting: New cases of pulmonary tuberculosis
little use include the tuberculin test, follow up of        (TB) were noted in a cluster of young Caucasian
smear negative cases, except if the person is HIV           males, an unusual ethnic group for this disease in
positive, haematological and biochemical markers            Queensland, Australia. It was noted that
such as ESR. Response to a trial of                         marijuana water pipe (bong) smoking was
antituberculosis drugs is not recommended as a              common amongst cases and contacts.
criterion for diagnosis. The authors are less
enthusiastic than WHO in recommending a trial of            Objective: To report the cluster of TB and to
antibiotics to exclude pneumonia, particularly              investigate whether a shared use of a marijuana
where penicillin resistance occurs and the use of           water pipe was associated with transmission of
macrolides and quinolones may suppress the                  TB.
tuberculous process and lead to apparent                    Design: All contacts were identified and screened
improvement. The patient is falsely thought to              according to standard protocols. Cases were
have pneumonia.                                             asked to list contacts with whom they had shared
Sputum concentration improves the yield of                  a marijuana water pipe.
positive smears, but may not be practicable                 Results: Five cases of open pulmonary TB were
because of the extra resources needed.                      identified clinically and on sputum culture, and all
An analysis of the studies available suggest that           isolates of Mycobacterium tuberculosis were
where the prevalence of HIV infection and                   identified on typing. Of 149 contacts identified,
tuberculosis is high, cough for longer than three           114 (77%) completed screening, and 57 (50%)
weeks, chest pain, cervical adenopathy, no                  had significant tuberculin skin test (TST)
sputum and dyspnoea suggest TB rather than                  reactions on follow-up. Of 45 contacts who had


                                                        8
shared a marijuana water pipe with a case,              Comment: A convincing study, yet rates of TB
29 (64%) had a significant TST reaction.                remain high even in those who received
                                                        treatment. JT
Conclusion: Sharing a marijuana water pipe with
a case of pulmonary TB was associated with
transmission of TB (OR 2.22, 95% CI 0.96-5.17),
                                                        Danish bacille Calmette-Guerin
although the most important risk factor for
                                                        vaccine-induced disease in human
acquiring TB infection in this cluster was close
household contact with a case (OR 4.91, 95% CI          immunodeficiency virus-infected children.
1.13-20.70).                                            Hesseling et al Cape Town South Africa
Comment: In Arab countries, such as Egypt,              Clin Infect Dis 2003; 37: 1226
sharing a water pipe (ghoza) has long been
recognized as an agent for transmitting TB. JT         Summary: An analysis of isolates of
                                                        Mycobacterium        tuberculosis    complex     was
                                                        performed to determine the prevalence of bacille
HIV and TB                                              Calmette-Guerin (BCG) disease among human
                                                        immunodeficiency virus (HIV)-infected children.
Efficacy of secondary isoniazid preventive              Speciation was done with polymerase chain
therapy among HIV-infected Southern                     reaction; 183 isolates from mycobacterial cultures
Africans: time to change policy?                        for 49 HIV-infected patients were analyzed/ The
                                                        Danish Mycobacterium bovis BCG strain was
Churchyard et al South Africa, UK, USA,
                                                        isolated from 5 patients. No cases of Tokyo M.
France
                                                        bovis BCG strain disease were detected. All
AIDS 2003; 17: 2063                                     patients were asymptomatic at birth, <12 months
                                                        of age, and severely immunodeficient at
Objective: To determine the efficacy of secondary
                                                        presentation. Four patients had regional axillary
preventive therapy against tuberculosis (TB)
                                                        adenitis ipsilateral to the vaccination site, and two
among gold miners working in South Africa.
                                                        had pulmonary BCG disease. Two patients with
Design: An observational study.                         regional axillary adenitis had simultaneous
                                                        pulmonary M. tuberculosis infection. Although
Setting: Health service providing comprehensive
                                                        chest radiographic features were similar to those
care for gold miners.
                                                        in patients with tuberculosis, BCG disease should
Methods: The incidence of recurrent TB was              be considered in HIV-infected infants with right
compared between two cohorts of HIV-infected            axillary adenitis ipsilateral to the vaccination site.
miners: one cohort (n=338) had received                 Young, symptomatic, HIV-infected infants are at
secondary prevention therapy with isoniazid(IPT)        risk for BCG-related complications. Controlled,
and the other had not (n= 221).                         population- based studies are needed to assess
                                                        the risk of BCG in HIV-infected children.
Results: The overall incidence of recurrent TB
was reduced by 55% among men who received               Comment: Even though BCG adenitis occurs
IPT compared with those who did not (incidence          amongst the HIV-negative children of the poor in
rates 8.6 and 19.1 per 100 person-years,                any country, I am surprised that live vaccines are
respectively; incidence rate ratio, 0.45; 95%           still administered to the HIV positive. JT
confidence interval 0.26-0.78). The efficacy of
isoniazid preventive therapy was unchanged after
controlling for CD4 cell count and age. The             Imaging
number of person-years of IPT required to               Imaging features of musculoskeletal
prevent one case of recurrent TB among
                                                        tuberculosis.
individuals with a CD4 count <200 /106/L, and >/=
200 /106 cells/L was 5 and 19, respectively.            De Vuyst et al Duffel Belgium
Conclusion: Secondary preventive therapy                Eur Radiol 2003; 13: 1809
reduces TB recurrence: the absolute impact
                                                        Summary: The purpose of this article is to review
appears to be greatest among individuals with low
                                                        the imaging characteristics of musculoskeletal
CD4 cells counts. International TB preventive
                                                        tuberculosis.
therapy guidelines for HIV-infected individuals
need to be expanded to include recommend-               Skeletal tuberculosis represents one-third of all
ations for secondary preventive therapy in              cases of tuberculosis occurring in extrapulmonary
settings where TB prevalence is high.                   sites. Hematogenous spread from a distant focus
                                                        elsewhere in the body is the cornerstone in the


                                                    9
understanding        of   imaging     features      of        Zoonoses
musculoskeletal tuberculosis. the most common
                                                              Mycobacterium bovis subsp. caprae caused
presentations       are  tuberculous     spondylitis,
arthritis, osteomyelitis and soft tissue involve-             one-third of human M. bovis-associated
ment. The diagnostic value of the different                   tuberculosis cases reported in Germany
imaging techniques, which include conventional                between 1999 and 2001.
radiography, CT and MR imaging, are                           Kubica et al Borstel Germany
emphasized. Whereas conventional radiography
is the mainstay in the diagnosis of tuberculous               J Clin Microbiol 2003; 41: 3070
arthritis and osteomyelitis, MR imaging may                   Summary: The prevalence of the Mycobacterium
detect associated bone marrow and soft tissue                 bovis subsp. caprae and M. bovis subsp. bovis
abnormalities. MR imaging is generally accepted               among German tuberculosis cases caused by the
as the imaging modality of choice for diagnosis,              bovine tubercle bacillus from 1999 to 2001 was
demonstration of the extent of the disease of                 determined. Isolates from 166 patients living in
tuberculous spondylitis, and soft tissue tuber-               Germany and 10 animals were analyzed by
culosis. Moreover it may be very helpful in the               conventional laboratory procedures, spoligo-
differential diagnosis with pyogenic spondylo-                typing, and partly by PCR-restriction fragment
discitis, as it may easily demonstrate anterior               length polymorphism analysis of the gyrB gene.
corner destruction, the relative preservation of the          By spoligotyping, 55 of 176 isolates (31%) could
intervertebral disc, multilevel involvement with or           be identified as M. bovis subsp caprae, and 121
without skip lesions, and a large sof tissue                  (69%) were confirmed as M.bovis subsp. bovis. In
abscess, as these are all arguments in favor of a             general, a low variability of spoligotypes with 59
tuberculous spondylitis. On the other hand, CT is             distinct patterns and a cluster rate of 77% (136
still superior in the demonstration of calcifications,        isolates/ 19 clusters) was determined. About half
which are found in chronic tuberculous                        of all isolates were grouped in the three main
abscesses.                                                    clusters with 29, 30, and 35 isolates, respectively.
Comment: A welcome review of the topic for                    Differences in age and gender between the
those countries rich enough to possess these                  patient groups infected with M. bovis subsp. bovis
facilities. JT                                               and M. bovis subsp. caprae did not reach
                                                              statistical   significance.   However,     marked
                                                              differences in the geographical prevalence of
Tuberculosis of the central nervous system:                   M. bovis subsp. caprae were observed, ranging
overview of neuroradiological findings.                       from fewer than 10% of all M. bovis isolates in the
                                                              north up to more than 80% of isolates in the south
Bernaerts et al Antwerp Belgium                               of Germany. In conclusion, M. bovis subsp.
Eur Radiol 2003; 13: 1876                                     caprae accounts for a high ratio of human M.
                                                              bovis-associated tuberculosis cases in Germany
Summary: This article presents the range of                   and was more frequently found in the southern
manifestations of tuberculosis (TB) of the                    part.
craniospinal axis. Central nervous system (CNS)
infection with Mycobacterium tuberculosis occurs              Comment: The members of M. tuberculosis
either in a diffuse form as basal exudative                   complex continue to increase. JT
leptomeningitis or in a localized form as
tuberculoma, abscess or cerebritis. In an addition
to an extensive review of computed tomography                 Tuberculosis in seals caused by a novel
and magnetic resonance features, the patho-                   member of the Mycobacterium tuberculosis
genesis and relevant clinical setting are                     complex: Mycobacterium pinnipedii sp. nov
discussed. Modern imaging is a cornerstone in                 Cousins et al Perth W.A. Australia
the early diagnosis of CNS tuberculosis and may
prevent unnecessary morbidity and mortality.                  Int J Syst Evol Microbiol 2003; 53: 1305

Contrast-enhanced MR imaging is generally                     Summary: A comparison of Mycobacterium
considered as the modality of choice in the                   tuberculosis complex isolates from seals
detection and assessment of CNS tuberculosis.                 (pinnipeds) in Australia, Argentina, Uruguay,
                                                              Great Britain and New Zealand was undertaken
Comment: Obviously the initial MR scan needs to               to determine their relationships to each other and
be done and reported on within one or two hours               their taxonomic position within the complex.
of the patient’s admission. How many Australian               Isolates from 30 cases of tuberculosis in six
public tertiary institutions can satisfy such a               species of pinniped and seven related isolates
demand? JT                                                   were compared to representative and standard

                                                         10
strains of the M. tuberculosis complex. The seal           Comment: This is work in progress, and not
isolates could be distinguished from other                 another reason to ban pigeons from city squares.
members of the M. tuberculosis complex,                    JT
including the recently defined ‘Mycobacterium
canetti’ and ‘Mycobacterium caprae’ on the basis
of host preference and phenotypic and genetic              Mycobacterium bovis bacille Calmette-Guerin
tests. Pinnipeds appear to be the natural host for         vaccination of cattle: activation of bovine
this ‘seal bacillus’, although the organism is also        CD4 (+) and gammadelta TCR (+) cells and
pathogenic in guinea pigs, rabbits, humans,                modulation by 1,25-dihydroxyvitamin D (3).
Brazilian tapir (Tapirus terrestris) and possibly
cattle. Infection caused by the seal bacillus is           Waters et al Ames IA USA
predominantly associated with granulomatous                Tuberculosis (Edinb) 2003; 83: 287
lesions in the peripheral lymph nodes, lungs,
pleura, spleen and peritoneum. Cases of                    Setting:            1,25     dihydroxyvitamin D3
disseminated disease have been found. As with              (1,25(OH)(2)D(3)) is a potent modulator of
other members of the M. tuberculosis complex,              immune responses and may be beneficial in the
aerosols are the most likely route of transmission.        treatment of tuberculosis. Recent evidence
The name Mycobacterium pinnipedii sp nov. is               suggests that 1,25 (OH)(2)D(3) may effect
proposed for this novel member of the M.                   T-dependent responses in cattle; however,
tuberculosis complex(the type strain is 6482 (T)=          mechanisms by which this vitamin modulates
ATCCBAA-NCTC 13288(T).                                     activation of bovine T cells are unclear.

Comment: Presumably those cases of TB in                   Objective: Determine the effects of 1,25
seals that were transmitted to humans, were                (OH)(2)D(3) on the expression of CD25, CD44,
caused by this bacillus. JT                               and CD62L by bovine T cell subsets proliferating
                                                           in response to antigen stimulation.
                                                           Design: Antigen-specific recall responses of
Experimental inoculation of pigeons                        Mycobacterium bovis bacille Calmette-Guerin
(Columba livia) with Mycobacterium bovis.                  (BCG) vaccinated cattle were used as a model
Fitzgerald et al E. Lansing MI USA                         system to evaluate effects of 1,25(OH)(2)D(3) on
                                                           the proliferation and activation of bovine T cell
Avian Dis 2003; 47: 470                                    subsets.
Summary: The purpose of this pilot study was to            Results: CD4(+) and gammadelta TCR(+) cells
determine if pigeons (Columba livia) are                   were the predominant T cell subsets responding
susceptible to infection with Mycobacterium bovis          to soluble crude bovis-derived antigens (ie:
by either oral or intratracheal inoculation and to         purified protein derivative and a BCG whole cell
assess their possible role in the lateral                  sonicate) by proliferation and activation-induced
transmission of bovine tuberculosis. Six pigeons           alterations in phenotype. These subsets exhibited
were orally inoculated with 1.3 x 10(5) colony-            increased CD25 and CD44 mean fluorescence
forming units of M.bovis, six pigeons were                 intensity (mfi) and decreased CD62L mfi on
intratracheally inoculated with the same dose, and         antigen stimulation. Addition of 1,25(OH)(2)D(3)
six pigeons served as non inoculated controls.             inhibited proliferation of CD4(+) cells and
The study continued for 90 days post inoculation           decreased the expression of CD44 on responding
(PI), with groups of birds necropsied at 30-day            (ie: proliferating) CD4(+) and gammadelta(+)
intervals, and fecal samples and tissues were              cells.
collected for mycobacterial culture. Two pigeons,
one intratracheally inoculated and one orally              Conclusion: These findings suggest that the
inoculated, shed M. bovis in their feces at day PI,        production of 1,25(OH)(2)D(3) by macrophages
and one one intratracheally inoculated bird shed           within     tuberculous  lesions   would    inhibit
M. bovis in its feces 60 days PI. Whereas no               proliferation and CD44 expression by co-localized
illness or weight loss was present during the              CD4(+) and gammadelta TCR(+) cells.
course of the study, 2 of 12 inoculated birds              Comment: To think that we once treated TB with
exhibited microscopic lesions of mycobacteriosis,          vitamin D compounds! JT
and the organism was isolated from tissues of
three inoculated birds. Pigeons are susceptible to
infection with M. bovis after high dose inoculation
and can shed the organism in their feces for up to
60 days.



                                                      11
Diagnostic methods                                             histopathologic findings of pleural fragments
                                                               obtained by biopsy. The diagnosis of pTB was
Diagnostic accuracy of nucleic amplification
                                                               confirmed in any patient presenting with positive
tests for tuberculous meningitis: a systematic                 culture findings of Mycobacterium tuberculosis,
review and meta-analysis.                                      either on the pleural fluid or other biological
Pai et al Berkeley California USA                              material, or the presence of histopathologic
                                                               findings suggestive of pTB on pleural biopsy, and
Lancet Infect Dis 2003; 3:                                     also, in the absence of negative laboratory
Summary: Conventional tests are not always                     results, those patients with clinical improvement
helpful in making a diagnosis of tuberculous                   after empirical treatment.
meningitis. We did a systematic review and meta-               Results: We studied 45 patients with pleural
analysis to establish the summary accuracy of                  effusion. Of these, 16 patients met the diagnosis
nucleic amplification (NAA) tests for tuberculous              of pTB by our broad case definition. PCR findings
meningitis. We searched six electronics                        were positive in six patients. The reaction was
databases and contacted authors, experts, and                  also positive in a patient whose diagnosis of
manufacturers. Measures of diagnostic accuracy                 tuberculosis could not be confirmed. ADA activity
were pooled using a random effects model. Forty-               was considered positive in 11 patients with pTB.
nine studies met our inclusion criteria. The                   The combined use of PCR and ADA activity
summary estimates in 14 studies with commercial                confirmed pTB in 14 patients; however when
NAA tests were: sensitivity 0.56 (95% CI                       analysed in combination with the conventional
0.46,0.66), specificity 0.98 (0.97,0.99), positive             methods, diagnosis of pTB was achieved in all 16
likelihood ratio 35.1 (19.0, 64.6), negative                   patients.
likelihood ratio 0.44 (0.33, 0.60), and diagnostic
odds ratio 96.4 (42.8, 217.3). In the 35 studies               Conclusion: Our results show that, even in a
with in-house (“home-brew”) tests, the summary                 highly endemic area neither PCR nor ADA activity
accuracy could not be established with                         should be relied on as a single test that
confidence because of wide variability in test                 substitutes for the diagnostic methods already
accuracy. On current evidence, commercial NAA                  available, but rather they should be used as an
tests show a potential role in confirming                      extra tool in the diagnosis of pTB.
tuberculous meningitis diagnosis, although their               The combined analysis of PCR and ADA activity,
overall low sensitivity precludes the use of these             however, is a very useful diagnostic approach to
tests to rule out tuberculous meningitis with                  achieve a more rapid and precise diagnosis in the
certainty.                                                     cases of pTB.
Comment: We        must    still   rely   on   clinical        Comment: The diagnostic dilemma largely
judgment. JT                                                  remains, particularly where solitary tuberculous
                                                               effusions may undergo spontaneous resolution.
                                                               JT
Combined use of the polymerase chain
reaction and detection of adenosine
deaminase activity on pleural fluid improves                   Stability of DNA patterns and evidence
the rate of diagnosis of pleural tuberculosis.                 of Mycobacterium tuberculosis reactivation
Lima et al Sao Paulo Brazil                                    occurring decades after the initial infection.
Chest 2003; 124: 909                                           Lillebaek et al Copenhagen Denmark
Study Objectives: Evaluation of the combined                   J Infect Dis 2003; 188: 1032
use of polymerase chain reaction (PCR) and                     Summary: Two hundred three freeze-dried
adenosine deaminase (ADA) activity on the                      strains of Mycobacterium tuberculosis collected
diagnosis of pleural tuberculosis (pTB) in a region            during the 1960s were compared with 4102
of high prevalence of tuberculosis.                            strains collected during the 1990s, and 14 DNA
Patients: PCR and determination of ADA activity                patterns identified among the “historical strains”
were performed on the pleural fluid of every                   were 100% identical to patterns identified among
patient presenting with pleural effusion suspected             the “recent strains”. They were isolated from 41
to be associated with tuberculosis. The case                   and 40 patients who had tuberculosis during the
definition of pTB involved parameters including                1960s and 1990s respectively. The patients’
the combination of clinical and radiological                   mean age differed by >30 years, a finding
findings; biochemical, microbiological, and cyto-              strongly suggesting that the patients from the
logic examination of the pleural fluid; and the                1990s experienced reactivation of M. tuberculosis


                                                          12
infection acquired during the 1960s. The half-life        Summary: The growing list of fully sequenced
of IS6110 DNA patterns during latency was                 genomes, combined with innovations in the fields
estimated to be 36 years (95% confidence                  of structural biology and bioinformatics, provides
interval, 25-54 years). Thus, this comparison of          a synergy for the discovery of new drug targets.
historical and recent strains yields molecular            With this background, the TB Structural
epidemiological evidence of M. tuberculosis               Genomics Consortium has been formed. This
reactivation spanning decades and suggests that           international consortium is comprised of
the rate of change of DNA patterns during latency         laboratories from 31 universities and institutes in
is much longer than that during active disease.           13 countries. The goal of the consortium is to
This has important implications for the                   determine the structures of over 400 drug targets
interpretation of clustering, especially for the          from the genome of Mycobacterium tuberculosis
extent of recent transmission.                            and analyze their structures in the context of
                                                          functional information. We summarise the efforts
Comment: Another swing of the pendulum in the
                                                          of the UCLA consortium members. Potential drug
reinfection reactivation debate. JT
                                                          targets were selected using a variety of
                                                          bioinformatics methods and screened for certain
                                                          physical and species-specific properties to yield a
Combined use of serum and urinary antibody
                                                          starting group of protein targets for structure
for diagnosis of tuberculosis.
                                                          determination. Target determination methods
Singh et al New York NY USA                               include protein phylogenetic profiles and Rosetta
                                                          Stone methods and the use of related
J Infect Dis 2003; 188:371
                                                          biochemical pathways to select genes linked to
Summary: Efforts to devise immunoassays for               essential prokaryotic genes. Criteria imposed on
tuberculosis (TB) that can be adapted to rapid            target selection included potential protein
formats are ongoing. The present study was                solubility, protein or domin size, and targets that
aimed at determining whether urinary anti-                lack homologs in eukaryotic organisms. In
Mycobacterium tuberculosis antibodies are                 addition, some protein targets were chosen that
present in patients with TB, to evaluate the              are specific to M. tuberculosis, such as PE and
feasibility of developing a urine antibody- based         PPE domains. Thus far , the UCLA group has
diagnostic test. Urinary antibodies directed              cloned 263 targets, expressed 171 proteins and
against the culture filtrate proteins of m.               purified 40 proteins, which are currently in
tuberculosis, MPT32, and the 81-kDa GkB protein           crystallization trials. Our efforts have yielded 13
were detectable in patients with TB, although the         crystals and eight structures. Seven structures
sensitivity of antibody detection was lower (53%-         are summarized here. Four of the structures are
64%), compared with serum antibodies (68%-                secreted proteins: antigen 85B; MTP63, which is
77%). Surprisingly, with all three antigens, the          one of the three major secreted proteins of M.
use of paired urine and serum samples provided            tuberculosis. a thioredoxin derivative Rv2878c;
higher sensitivities of antibody detection than           and potentially secreted glutamate synthetase.
either single specimen, and anti-GkB antibodies           We also report the structures of three proteins
were present in the serum and/or urine of 39              that are potentially essential to the survival of M.
(90%) of 43 smear-positive with TB. Although,             tuberculosis: a protein involved in the folate
with the current methods and antigens, the level          biosynthetic pathway (Rv3607c): a protein
of sensitivity is insufficient to design a urinary        involved in the biosynthesis of vitamin B5
antibody diagnostic, these studies provide the            (Rv3602c); and a pyrophosphatase, Rv2697c.
foundation for further studies on the development         Our approach to the M. tuberculosis structural
of a urine antibody-based immunoassay for TB.             genomics project will yield information for drug
                                                          design      and     vaccine    production    against
Comment: For many years we have been looking
                                                          tuberculosis. In addition, this study will provide
for the ‘perfect’ antibody. Are we any further
                                                          further insights into the mechanisms of
ahead? JT
                                                          mycobacterial pathogenesis.
                                                          Comment: Very exciting! One assume that these
Molecular Biology                                         proteins are species or even subspecies specific.
                                                          JT
Structural genomics of Mycobacterium
tuberculosis: a preliminary report of progress
at UCLA.
Goulding et al Los Angeles CA USA
Biophys Chem 2003; 105: 361

                                                     13
The TB structural genomics consortium:                       splicing and its inhibition is based on purified
a resource for Mycobacterium tuberculosis.                   proteins and measures the formation of Green
                                                             Fluorescent Protein or its inhibition. The
Terwilliger et al Los Alamos NM USA                          advantages of inteins as antimycobacterial
Tuberculosis (Edin) 2003; 83: 223                            targets are discussed.
Summary: The TB Structural Genomics                          Comment: Watch this space! JT
Consortium is an organization devoted to
encouraging, coordinating, and facilitating the
determination and analysis of structures of                  Social Issues
proteins from Mycobacterium tuberculosis. The                Public health impact of detention
Consortium members hope to work together with                of individuals with tuberculosis:
other M. tuberculosis researchers to identify M.
                                                             systematic literature review.
tuberculosis proteins for which structural
information could provide important biological               Coker R London UK
information, to analyze and interpret structures of
                                                             Public Health 2003; 117: 281
M. tuberculosis proteins, and to work collabor-
atively to test ideas about M. tuberculosis protein          Summary: As the world witnesses ever-
function that are suggested by structure or related          increasing rates of tuberculosis, particularly of
to structural information. This review describes             drug-resistant strains affecting some of society’s
the TB Structural Genomics Consortium and                    most marginalized individuals, policy makers and
some of the proteins for which the consortium is             legislators may again visit the statute book in
in the process of determining three-dimensional              order to strengthen their armamentarium of tools
structures.                                                  to protect public health. This paper assesses the
                                                             evidence in support of the sanction to detain
Comment: Such collaboration is admirable; but
                                                             those with tuberculosis who are perceived as
at the end of the day who will own M. tuberculosis
                                                             posing a public health threat, and shows that little
and its proteins? JT
                                                             research has been conducted to inform policy,
                                                             probably because traditional epidemiological
                                                             methods used to assess the impact of
Inteins as targets for potential
                                                             interventions are not feasible.
antimycobacterial drugs.
                                                             Comment: Is it always appropriate to invoke EBM
Paulus H Watertown MS USA
                                                             to make political decisions? JT
Front Biosci 2003; 8: s1157
Summary: Protein splicing is a self-catalyzed                Gender differences in pulmonary disease.
process mediated by inteins. The observation that
inteins occur only in microorganisms and that                Caracta C New York NY USA
they often interrupt genes that play an essential            Mt Sinai J Med 2003; 70: 215
role in nucleic acid metabolism makes them
attractive as potential antibacterial targets.               Summary: Epidemiologic evidence points to
because mycobacteria are the only intein-                    gender-based differences in incidence, risk,
containing bacteria associated with human hosts,             histology, and pathogenesis of certain lung
intein would represent highly specific anti-                 diseases in women as compared to men. Gender
mycobacterial       targets.   In    Mycobacterium           influences not only physiological differences, but
tuberculosis, two important proteins of DNA repair           also the social, economic, and cultural context in
and replication, RecA and DnaB, respectively, are            which men and women coexist. Central to these
interrupted by inteins that must be excised by               differences is the role of sex hormones, which
protein splicing before these proteins can                   may contribute to the pathogenesis of disease or
function. This review describes the screening                serve as protective factors. This paper seeks to
systems for the detection of mutations or                    review the role of gender in major areas of
inhibitors that interfere with proteins splicing that        pulmonary disease and explore the mechanisms
have been developed and published to date. In                that may underlie gender differences in asthma,
three of these experimental systems, inteins have            chronic obstructive pulmonary disease and
been inserted into proteins that are toxic under             mycobacterial     disease    (tuberculosis    and
certain conditions. Protein splicing therefore leads         Mycobacterium avium intracellulare infection) and
to conditional growth inhibition or cell death and           lung cancer.
its inhibition can be monitored in terms of
bacterial growth. A fourth assay for protein


                                                        14
Comment: Gender difference in tuberculosis                 major antimicrobial mechanisms of macrophages:
prevalence will remain an important issue in high          phagolysosome fusion and the production of toxic
incidence countries. JT                                   reactive nitrogen intermediates. M. tuberculosis
                                                           also modulates antigen presentation to prevent
                                                           the detection of infected macrophages by CD4 (+)
Microbiology                                               T cells.
Optimization of acid fast smears for the direct
detection of mycobacteria in clinical samples.             Interleukin-15 as an immune adjuvant to
Murray et al Newcastle U K                                 increase the efficacy of Mycobacterium
                                                           bovis bacillus Calmette-Guerin vaccination.
J Clin Pathol 2003; 56: 613
                                                           Umemurra et al Kiyose Japan
Aims: Despite its long history, the acid fast stain
remains unstandardised. Technical variations in            Infect Immun 2003; 71: 6045
both the preparation of clinical material and
                                                           Summary: Interleukin-15 (IL-15) transgenic mice
subsequent staining mean that smear sensitivity
                                                           which had been inoculated with Mycobacterium
relative to culture may vary from 50% to over
                                                           bovis bacillus Calmette-Guerin (BCG) 24 weeks
80%. This study assessed the sensitivity of acid
                                                           previously showed resistance against airborne
fast microscopy at each of five stages of sample
                                                           infection with Mycobacterium tuberculosis H37Rv
preparation and by both commonly used staining
                                                           accompanied by an increased CD8 (+)-Tcl-cell
methods.
                                                           response. IL-15 may be used as an immune
Methods: Sputum samples thought for varying                adjuvant given with BCG vaccination to enhance
reasons to be highly likely to be culture positive         its biologic efficacy.
were used to prepare a series of smears in which
                                                           Comment: Encouraging, but difficult to translate
the    effects  of     digestion    (liquefaction),
                                                           to humans. JT
concentration (centrifugation), and decontami-
nation (sodium hydroxide) could be assessed,
together with a comparison of staining by the
                                                           Extra pulmonary Tuberculosis
auramine/phenol and Ziehl-Nielsen techniques.
                                                           Kikuchi-Fujimoto disease in Nepal:
Results: The most effective method for the
                                                           a study of 6 cases.
demonstration of acid fast organisms in sputum
was found to be an auramine phenol stain applied           Adhikari et al Khathmandu Nepal
to a liquefied, concentrated sample and examined
                                                           Arch Pathol Lab Med 2003; 127: 1345
before the decontamination process.
                                                           Context: Kikuchi-Fujimoto disease is a benign
Conclusions: The auramine phenol stain applied
                                                           disorder, predominantly affecting young women
to a liquefied, concentrated sample and examined
                                                           with a predilection for cervical lymphadenopathy.
before the decontamination process is the most
                                                           Although the disease has been recognized
effective method for the demonstration of acid
                                                           worldwide, to our knowledge no cases have been
fast organisms in sputum.
                                                           reported previously from Nepal.
Comment: What method does our laboratory
                                                           Objectives: To determine the prevalence of
use? JT
                                                           Kikuchi-Fujimoto disease in Nepal and to analyze
                                                           clinicopathological features.
Immunity                                                   Methods: We reviewed six cases of Kikuchi-
                                                           Fujimoto disease recorded at 3 different hospitals
Immune evasion by Mycobacterium
                                                           in Nepal during a period from June 1998 to June
tuberculosis: living with the enemy.
                                                           2002. Clinical data and histopathology are
Flynn et al Pittsburgh PA USA                              presented.
Curr Opin Immunol 2003; 15: 450                            Results: This study included five females and
                                                           one boy, aged 13 to 32 years. These patients
Summary:      Mycobacterium    tuberculosis is
                                                           presented with prolonged fever and lymph-
successful as a pathogen because of its ability to
                                                           adenopathy. The five female patients had cervical
persist in an immunocompetent host. This
                                                           lymphadenopathy, and the boy had axillary
bacterium lives within the macrophage, a cell
                                                           lymphadenopathy. Complete blood counts
whose function is the elimination of microbes.
                                                           revealed raised erythrocyte sedimentation rates in
Recent     advances    have     improved      our
                                                           all patients and anaemia in two patients. The size
understanding of how M. tuberculosis evades two

                                                      15
of excised lymph nodes ( in greatest dimension)             Screening
ranged from 1.5 to 5 cm. Typical histological
                                                            Assessment of tuberculosis screening and
features were seen, namely, architectural
effacement due to presence of pale nodular                  management practices of large jail systems.
lymphohistiocytic foci with karyorrhectic debris,           Reichard et al Atlanta GA USA
coagulation necrosis, eosinophilic debris, and the
absence of granulocytic infiltration. In a follow up        Public Health Rep 2003; 118: 500
of the cases, disease recurrence was not found.             Objective: This descriptive study sought to
Conclusion: Our study emphasizes that Kikuchi-              explore the use and timeliness of tuberculosis
Fujimoto disease should be considered as one of             (TB) screening and management activities in jail
the differential diagnoses in patients with                 facilities.
prolonged fever and cervical lymphadenopathy                Methods: Study personnel visited 20 large US jail
and that it should be differentiated from                   systems and reviewed the medical records of 56
tuberculous lymphadenitis in regions where                  inmates who had recently been evaluated for TB
tuberculosis is prevalent.                                  disease and 376 inmates who were diagnosed
Comment: Which is why this report is included in            with or confirmed to have latent TB infection
the newsletter. JT                                         (LTBI). Data from these records were analyzed to
                                                            determine completion and timeliness of
                                                            screening, diagnostic and treatment activities.
Catastrophe corner                                          Results: In 14% of 56 inmates evaluated for TB
Ethambutol and optic neuropathy                             disease and 24% of 376 i1nmates with LTBI,
                                                            chest radiographs were either not performed or
Chuenkongkaew et al Bangkok Thailand                        not documented. Of 48 inmates evaluated for TB
J Med Assoc Thai 2003; 86: 622                              disease who were not receiving treatment when
                                                            admitted to jail, 10 had no record of sputum
Purpose: To demonstrate the association                     collection being done. A mean delay of 3.1 days
between ethambutol and optic neuropathy.                    occurred from symptom report to respiratory
Method: Thirteen patients who developed optic               isolation. Time from tuberculin skin test reading to
atrophy after being treated with ethambutol for             chest radiograph reading was a mean of 5.3 days
tuberculosis of the lung or lymph node at Siriraj           in inmates evaluated for TB disease and a mean
Hospital between 1997 and 2001 were retro-                  of 7 days in inmates with LTBI. Follow-up was
spectively reviewed. The clinical characteristics           arranged for 91% of released inmates who were
and initial and final visual acuity were analyzed to        on treatment for TB disease and only 17% of
determine visual outcome.                                   released inmates who were on treatment for
                                                            LTBI.
Results: All patients had optic neuropathy
between 1 to 6 months (mean 2.9 months) after               Conclusions: Jail health information systems
starting ethambutol therapy at a dosage ranging             should be augmented to better document and
from 13 to 20 mg/kg/day (mean 17 mg/kg/day).                monitor inmate health care related to TB.
Seven of the 13 patients experienced visual                 Completion rates and timeliness of TB screening,
recovery after stopping the drug. Of 6 patients             diagnostic, and treatment measures should be
with irreversible visual impairment, 4 patients had         evaluated to identify areas needing improvement.
diabetes mellitus, glaucoma and a history of                Finally, mechanisms for continuity of care upon
heavy smoking.                                              inmate release should be enhanced to promote
                                                            therapy completion and prevent transmission in
Conclusion: Early recognition of optic neuro-               the community.
pathy should be considered in patients with
ethambutol therapy. A low dose and prompt                   Comment: The last recommendation is most
discontinuation of the drug is recommended                  important but so hard to implement. JT
particularly in individuals with diabetes mellitus,
glaucoma or who are heavy smokers.
Comment: It is as concerning that only half the
patients recovered their eyesight as that they all
developed this complication with a dose of less
than 25 mg/kg/day. JT




                                                       16
Index


Editorial .................................................... 1
World Reviews ......................................... 2
DOT ......................................................... 2
Conference Reports ................................. 3
Drug Dynamics ......................................... 3
Infection ................................................... 4
Risk factors .............................................. 5
Risk groups .............................................. 7
Short review ............................................. 7
Epidemiology ............................................ 8
HIV and TB............................................... 9
Imaging .................................................... 9
Zoonoses ............................................... 10
Diagnostic Methods ................................ 12
Molecular Biology ................................... 12
Social Issues .......................................... 14
Microbiology ........................................... 15
Immunity................................................. 15
Extra pulmonary TB ................................ 15
Catastrophe Corner ................................ 16
Screening ............................................... 16




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