di
Anna Giulia Cattaneo, M.D.
DBSF, Università dell'Insubria, Via J-H. Dunant, 3 - 21100 Varese

The trend of increasing prevalence of active cases of tuberculosis (TBC) in global populations is a health-threatening problem that reduces the possibilities of control of the disease and imposes specific tuberculosis surveillance measures to organisms for public health.

It is partly due to unusual or multidrug-resistant (MDR) strains of Mycobacteria, reinfection and/or reactivation, and spreading conditions affecting immune competence, like the AIDS.

When aged people are on concern, a number of considerations should be done. In the Western world, old and oldest individuals often spent a part of their life in decades of last centuries in which TBC was a quite common diseases, many of them being survivors to infection. On the other hand, a portion of this population is living in communities, suffers from chronic diseases affecting respiratory functions and immunocompetence, and could represent an under-diagnosed reserve of infection. Attention paid to tuberculosis surveillance and epidemiological studies on TBC in aged persons is sporadic, and generally limited to considerations inter- or extrapolated from studies devoted to general populations.

In this Editorial, focused on description of TBC diffusion in aged people inhabiting Western countries and East Europe, the following points should be discussed:

1. Incidence and prevalence of TBC
2. Diagnostic problems and elusive cases
3. Characterization of the infectious agent: species, strains and clusters
4. Spread of infection or reactivation of old cases
5. Multi-Drug-resistance
6. Preventive measures.
Special attention is paid to the situation in Italy.

Incidence and prevalence of TBC

Different trends can be carried out comparing the notification rate in 32 European countries from 1995 to 2002 (http://www.eurotb.org/). When only two groups of age are taken into account, namely 45-64 years and >64 years, it seems to be evident that higher prevalence of TBC is registered in older individuals. This is true in the majority of countries, with the exception of Romania, Ukraine, Russia and Estonia, where adult are more often affected than aged individuals. In these countries, as in Bosnia Herzegovina, the notification rate is higher than in the other European countries ( 50 up to > 200 x105 in comparison with 10 to 30-50 x105), and rates are increasing.

With minor differences, all other countries in Europe and in USA (http://www.cdc.gov/nchstp/tb/) show a lower notification rate, while higher in older age, a negative trend (reduction of the rate in recent years), or invariant values, especially when very low rates are registered.

Italy presents a quite good situation, with negative trend and values between 4 and 9 x105 in adults, and between 12 and 17 x 105 in people aged more than 64, better than in Germany, France UK and Switzerland. In a near future some differences could be expected, due to the earlier peak of prevalence in resident born out from Europe, as shown in several studies (Journal of Clinical Microbiology, May 2001, p. 1802-1807, Vol. 39, No. 5, http://www.eurotb.org/).

Sex bound differences have been described, with general higher prevalence in males. In a small sample of patient resident in Lombardy higher rates of cases appeared to be located in the 4th decade in females and in the 6th decade in males (Journal of Clinical Microbiology, June 2001, p. 2213-2218, Vol. 39, No. 6).

- Diagnostic problems and elusive cases.

Elusive cases of tubercular infection are especially frequent in frail organisms, in which symptoms and localizations are often unusual. The strain of Mycobacterium responsible for infection is also a cause of misdiagnosis.

Epidemiological data permit to approximate the prevalence of localization:

1. Pulmonary TBC is by far the commonest infection, responsible for 70-75% of cases.
2. Extra pulmonary disease (no more than 20% of all cases) can be localized in the lymphatic apparatus (43%), pleura (18%), bone (11%) peritoneum (6%), and genitourinary apparatus (5%). Miliary TBC, defined as pulmonary and extra pulmonary co infection, represents about 9% of all cases.
   Retarded diagnosis could be quite common in older individuals living alone, or with relatives not trained to take care of the oldest. On the contrary, a large statistics carried out in 2003 in US reports a percentage near to 100% of correct diagnosed cases in residents in long-term care facilities.
   Need for an early and correct diagnosis could be improved by adopting adequate measures for clinical, instrumental and etiological diagnosis, for risk evaluation, and notification of all newly diagnosed cases and "at risk- individuals.
   Associated risks include alcohol abuse, unemployment in the past 24 months and homeless state and residence in metropolitan areas associated to psychosocial or medical frailty. HIV seems to be associated to TBC infection, but at the present it is by far more frequent in young people, aged 25-44 years.

- Characterization of the infectious agent: species, strains and clusters

TBC causative agents are included in the Mycobacterium tuberculosis complex, represented by five mycobacterial species: M. tuberculosis, M. bovis, M. africanum, M. microti, and M.canetti, almost identical in DNA homology studies and in terms of their ability to cause clinical disease and to be transmissible from person to person. Therefore, diseases caused by any of the five organisms are classified as tuberculosis, with the only exception of the BCG (Bacillus of Calmette-Guerin) strain M. bovis, whose transmission is usually jatrogenic, following cancer immunotherapy.
Infections with Mycobacteria other than those cited before (as M. avium, M.intracellulare, M. kansasii, M. marinum and other) are more appropriately included in "atypical mycobacterium, or NTM (Non Tuberculosis Mycobacteria) infections- . They are different from TBC both clinically and epidemiologically. Molecular biology methods can improve diagnosis.

- Re-infection or reactivation of old cases

A consistent portion of people ageing at the present time, and even more those reaching oldest age, survived in their youth a tubercular infection. The 70% of a large sample considering 90% of all population affected by TBC in Norway was distributed in two decades, between 70 and 89 years of age.
Analysis of infection clustering (multiple isolates with an identical DNA pattern) can be done by the restriction fragment length polymorphism technique: a cluster identifies an infective outbreak, while diversity states instead reactivation of latent TBC. The situation seems to be very similar in a number of countries with low prevalence of infection, included Italy (15% of clustering, Eur. J. Epidemiol. 1997, 13:845-851; 16%, Journal of Clinical Microbiology, 2001, 39: 2213-2218), Norway (11%, Journal of Clinical Microbiology, 2001, 39: 1802-1807), and Switzerland (17%, Eur. Respir. J. 1998, 11:804-808), in which relapse due to reinfection seems to be the rule, and transmission possible but only in marginal cases. Unexpectedly, in Denmark the prevalence of cluster is by far higher (49%), and large cluster are present, documenting a wide spread of infection (J. Clin. Microbiol. 1998, 36:305-308). The rather higher frequency of TBC, and even of multiresistant strains, in recent immigrates from high prevalence countries does not seems a threatening for spreading of new infections among population in countries like Norway, in which the control is good (Eur. J. Epidemiol. 2000, 13:845-851). On the contrary, a half of all new cases of TBC seems to be transmitted from foreign to native individuals in the Netherlands (Am. J. Epidemiol. 1998, 147:187-195). In a large study carried out in Great Vancouver, Canada, age was not found to be linearly associated to clustering, but clusters were significantly more frequent in groups in which higher prevalence of TBC is usually found: aged individuals, non-Aboriginal, or Aboriginal in their adulthood appeared to be clustered, and this fact suggests a possible role played by these subjects in transmission on tuberculosis. (CMAJ. 2002 August 20; 167 (4): 349-352).

- Single- and Multi-Drug-resistance (SDR and MDR)

This health threatening problems includes old and new phenomena. The resistance developed by Mycobacteria to Streptomycin and that more recent to Isoniazid are in fact well-known and frequent phenomena, to which the newly developed resistance to other antitubercular drugs has been added. An evaluation of the phenomenon on a worldwide scale has shown a prevalence of 6,6% SDR and of 1,4% of MDR in all cases of primary developed resistance. Mean prevalence for SDR if 12.2% and that for MDR is 13.0% of all cases of acquired resistance. These last show a lower frequency in population than primary developed resistance. In its all, resistance phenomena are more frequent in patients treated more than once, and in those affected by AIDS, in which acquired resistance is greater. Great differences in trend between different countries have been found; Italy was not evaluated (NEJM, 1998, 338:1641-1649).

- Preventive measures.

The first prevention seems to be an early diagnosis of new cases and new epidemics: this concept is not so obsolete as it could seem. In fact, a recent study carried out in London shows a diagnostic delay ranging from 14 and 104 days, with different trend in relation to age, sex, social and racial provenience of subjects. No selected data obtained in older people are shown in this study, age being only considered as more or less than 40 years (BMJ. 2003, 326(7395): 909-910.)
Other important preventive measures should principally remove risk factors (mainly social frailty, physical decline due to not unavoidable conditions, like poverty or careless, AIDS infection - rare in person aged at the present, but growing in future generations -, and alcoholism), errors in drug assumption and early abandonment of therapy, in addition to general hygienic measures for isolation of active cases.

Improving notification, diagnostics and epidemiological knowledges also in the oldest layers of populations seems to be a good purpose for the future.