Impact of HIV Infection on Tuberculosis

Postgrad Med J 2000;76:259–268 259 Postgrad Med J: first published as 10.1136/pmj.76.895.259 on 1 May 2000. Downloaded from REVIEWS

Impact of HIV infection on tuberculosis

Alimuddin Zumla, Patrick Malon, Jane Henderson, John M Grange

Abstract Keywords: HIV; AIDS; tuberculosis Tuberculosis is increasing in prevalence in many countries and is now the leading Tuberculosis has been recognised since the Centre for Infectious infectious cause of death world wide, dawn of recorded history and during the 19th Diseases, University being responsible for three million deaths century it was among the leading causes of College London, Royal annually. Infection with HIV, likewise Free and University morbidity and mortality in Europe and the College Medical increasing in prevalence, has emerged as USA. Some of many names that have been School, Windeyer the most important predisposing factor given to the various clinical forms of tubercu- Institute of Medical for developing overt tuberculosis in people losis are listed in table 1. Starting in the latter Sciences, Room G41, co-infected with Mycobacterium tubercu- half of the 19th century, the incidence 46 Cleveland Street, losis. Owing to the widespread geographi- declined signiﬁcantly in the industrialised London W1P 6DB, UK cal overlap of these two infections, it is A Zumla nations and by the early 1980s there was a estimated that in 1999, HIV related tuber- widespread opinion that the disease had virtu- Patrick Manson Ward, culosis will reach one million cases and ally been conquered. This complacent attitude University College will cause 30% of the expected 2.5 million was shaken in the early 1990s by the Hospital, London, UK AIDS related deaths. Tuberculosis in HIV occurrence of an upsurge in the incidence of P Malon infected individuals may have unusual J Henderson tuberculosis in New York City. It is now clinical features and can cause diagnostic apparent that, far from being conquered, Imperial College diYculties. Despite the eVectiveness of tuberculosis is one of the most prevalent infec- School of Medicine, modern short course treatment, the mor- tious causes of human suVering and death National Heart and tality of HIV related tuberculosis during world wide. Indeed there are more cases of Lung Institute, and after treatment remains high, and this tuberculosis in the world today than at any Dovehouse Street, may be due to other HIV related infec- London, UK previous time in human history. Because of the J M Grange tions. The “cursed duet” of infection with relentless spread of tuberculosis throughout both HIV and M tuberculosis is generating the world, the World Health Organisation Correspondence to: a threat to human health of unparalleled (WHO), in 1993, took the unprecedented step Professor Zumla (e-mail: proportions which, if not taken seriously 1

of declaring tuberculosis a global emergency. http://pmj.bmj.com/ [email protected]) by health workers and decision makers, Submitted 24 March 1999 could become totally unmanageable. Global burden of tuberculosis Accepted 13 July 1999 (Postgrad Med J 2000;76:259–268) The global burden of tuberculosis is summa- Table 1 Historical names for tuberculosis rised in table 2. Each year, around seven to eight million people develop the disease. Historical name Clinical type of tuberculosis Tuberculosis causes the death of around three Consumption (of the lungs) Pulmonary tuberculosis million people annually. The disease is respon-

Pthisis Pulmonary tuberculosis sible for 7% of all adult deaths and 25% of pre- on September 28, 2021 by guest. Protected copyright. Tabes pulmonalis Pulmonary tuberculosis 2 Tissic Pulmonary tuberculosis ventable adult deaths. Among children, it is Hectic fever Pulmonary tuberculosis now an important cause of morbidity and Asthenia Pulmonary tuberculosis mortality.3 The incidence and prevalence of the Galloping consumption Acute progressive tuberculosis Tabes mesenterica Abdominal tuberculosis disease continues to rise in the developing Scrofula Cervical lymphadenitis countries while many developed countries Struma Cervical lymphadenitis including the USA and UK have witnessed a King’s evil Cervical lymphadenitis Pott’s disease* Spinal tuberculosis reversal of the downward trend that had Prosector’s or Butcher’s wart Primary inoculation skin tuberculosis occurred since the late 19th century. Tuberculous chancre Skin tuberculosis Scrofuloderma Skin tuberculosis secondary to cervical lymphadenitis Lupus vulgaris Chronic skin tuberculosis Aetiology of tuberculosis Most cases of human tuberculosis are caused *Named after Sir Percival Pott (1714–88), a surgeon at St Bartholomew’s Hospital, London. by the human tubercle bacillus, Mycobacterium Table 2 Estimated global burden of tuberculosis (World Health Organisation, 1998) tuberculosis, but in countries where cattle tuberculosis still occurs human tuberculosis is also WHO region Total population No infected Annual incidence* Annual deaths caused by M bovis. In addition, some cases, South East Asia 1 458 000 000 704 000 000 2 800 000 1 095 000 principally in equatorial Africa, are caused by a Western Paciﬁc 1 630 000 000 610 000 000 1 583 000 591 000 rather heterogeneous group of strains termed Africa 611 000 000 293 000 000 1 650 000 770 000 Americas 788 000 000 237 000 000 448 000 160 000 M africanum. Though bearing separate species Europe 859 000 000 205 000 000 342 000 118 000 names, these are really members of a single Eastern Mediterranean 473 000 000 161 000 000 427 000 173 000 species often termed the M tuberculosis Total 5 819 000 000 2 210 000 000 7 250 000 2 907 000 complex.4 Infection usually occurs by inhaling *Estimated number of new cases developing during the course of a year. Being a chronic disease, small droplets of cough aerosol, about 5µ in the total number of cases at a given time is much higher, around 16 million. diameter, containing tubercle bacilli. Infection 260 Zumla, Malon, Henderson, et al

Table 3 Factors determining susceptibility to tuberculosis appear more susceptible while children be- Postgrad Med J: first published as 10.1136/pmj.76.895.259 on 1 May 2000. Downloaded from tween the ages of 5 years and 15 years appear Age Those aged less than 5 years and the elderly are susceptible The 5–15 age group is relatively protected relatively immune from developing Racial and genetic predisposition “Herd immunity” tuberculosis—the “golden age group”. This ? HLA age related variation in protection may be ? Cytokine gene defects Immunological factors HIV infection related to hormonal regulation of immune Steroid therapy responses.7 Cytotoxic drugs Post-transplant immunosuppressive therapy Congenital immunodeﬁciencies Impact of the HIV/AIDS pandemic on the Protein energy malnutrition Chronic medical conditions Diabetes mellitus global burden of tuberculosis Chronic liver or renal disease In addition to the factors mentioned above, Malignancies immunosuppression of any type is a predispos- Lung damage, especially silicosis Stress Endocrine factors ing factor for the development of tuberculosis. Previous exposure to mycobacteria BCG vaccination Since the early 1980s, HIV infection has Exposure to environmental mycobacteria Mycobacterial factors Variation in strain virulence (?) emerged as by far the most important of all the Infective dose predisposing factors.8 In persons co-infected with the tubercle bacillus and HIV, the overall Table 4 Global burden of HIV/AIDS, December 1998 annual risk of developing active tuberculosis rises from about 0.4% to 8%—that is, 20 times Prevalence (%) in 9 Region Persons infected with HIV 15–49 age range the risk. The risk depends, however, on the degree of immunosuppression—the risk of a Sub-Saharan Africa 22 500 000 8.0 North Africa and Middle East 210 000 0.13 patient with AIDS developing tuberculosis is South and South East Asia 6 700 000 0.69 170 times higher than a non- East Asia and Paciﬁc 560 000 0.07 immunosuppressed person. For these reasons, Latin America 1 400 000 0.57 Caribbean 330 000 1.96 infection with HIV and M tuberculosis have Eastern Europe and Central Asia 270 000 0.14 been dubbed “the cursed duet”.10 Western Europe 500 000 0.25 North America 890 000 0.56 At the end of 1998, over 33 million people Australia and New Zealand 12 000 0.1 were estimated to be infected by HIV11 and the Total 33 400 000 1.1 regional distribution of these is shown in table 4. Most of those infected were aged 15 to 49 by M bovis is also acquired by drinking infected years and, as shown in table 4, over 1% of this milk and the primary lesions occur in the phar- age group are HIV positive. Assuming that a ynx or intestine. Rarely, infection occurs by third of these are co-infected with the tubercle traumatic inoculation of bacilli into the skin, bacillus, and that 8% of these develop active particularly in butchers and others handling tuberculosis annually, there could be almost the carcasses of tuberculous animals. one million cases of HIV related tuberculosis in

1999, about 10% of the expected new cases of http://pmj.bmj.com/ Factors determining susceptibility to tuberculosis in that year. It has been estimated tuberculosis that tuberculosis will be the cause of 30% of the Not everyone who is infected with the tubercle expected 2.5 million AIDS related deaths in bacillus develops clinically evident disease. As a 1999.11 broad generalisation, and in the absence of In addition to the high risk of developing obvious predisposing factors, about 5% of reactivation tuberculosis, HIV positive persons those infected develop primary tuberculosis can be primarily infected or reinfected by the within three years of infection and another 5% tubercle bacillus and are at a very high risk of on September 28, 2021 by guest. Protected copyright. develop post-primary tuberculosis at any sub- 12 5 developing active tuberculosis. The risk of sequent period of their lives. Many factors such infection and reinfection tuberculosis is predispose to the development of tuberculosis related to the number of source cases in the and the principal ones are listed in table 3. The community and is therefore low in regions with question of whether resistance to tuberculosis a low prevalence of tuberculosis.13 The exact is genetically determined has generated consid- risk of tuberculosis developing after exposure erable controversy. While various resistance determining genes have been delineated in the of an HIV positive person to a source case is mouse, their relevance to the human situation unknown owing to the diYculty in distinguish- has not been clearly established. Likewise, ing between recent infection and reactivation. there is uncertainty as to whether the decline in Most documented cases follow exposure of the incidence of the disease in the developed patients to source cases during hospitalisation nations over the last century is principally due for AIDS related illness. These patients, by to natural selection or to improving societal implication, are profoundly immunosup- conditions. pressed and their chance of progressing to Environmental factors may also aVect sus- overt tuberculosis after infection approaches ceptibility to progression to tuberculous dis- 100%. Furthermore, the clinical course of the ease. Thus, for example, it has been suggested disease is “telescoped” down to a few months that exposure to environmental mycobacteria rather than years or decades.10 Such exposure may, depending on the nature of the exposure, in hospitals and other institutes has been have a beneﬁcial or detrimental eVect on the responsible for a number of explosive miniepi- relevant immune responses.6 Age also aVects demics, initially in New York City but subse- susceptibility: the elderly and the very young quently in Europe.14 Impact of HIV infection on tuberculosis 261

Prevalence and distribution of HIV Table 5 Comparison of clinical features of tuberculosis in Postgrad Med J: first published as 10.1136/pmj.76.895.259 on 1 May 2000. Downloaded from related tuberculosis HIV infected and non-infected patients The burden of HIV related tuberculosis is not HIV HIV evenly distributed as it is determined by the Feature positive negative overall prevalence of infection by the tubercle Respiratory symptoms +++ +++ bacillus and HIV in the community, in addition Extrapulmonary disease +++ + to the social factors that encourage a crossover Cavitating lung lesions + +++ between the two infections. In the USA, HIV Atypical features on chest radiography +++ ± Negative tuberculin skin tests ++ ± related tuberculosis is largely restricted to Adverse drug reactions ++ ± socioeconomically disadvantaged communities Mortality rate +++ ± in New York City and other large cities.15 It was Relapse after course of treatment ++ ± the occurrence of miniepidemics of HIV associated tuberculosis in New York City in the Langhans’ giant cells but few or no visible early 1990s, and the anxieties generated in the bacilli. As the immune defect increases, and the general population, that led to an upsurge of CD4+ cell count declines, more diVuse lesions interest and concern for this condition. In the with abundant tissue necrosis, few or no UK, HIV related tuberculosis, while not yet a mature epithelioid cells and numerous tubercle major problem, is becoming increasingly com- bacilli are encountered.24 25 Fibrotic reactions mon in both immigrant and indigenous popu- responsible for the walling oV of foci of active lations. Tuberculosis clinics are therefore en- disease are reduced in the more anergic couraged to increase the use of HIV testing16 patients, thereby encouraging local spread and and HIV clinics should always keep tuberculo- widespread dissemination of disease. Cavity sis high on the list of diVerential diagnosis in formation, also the result of an active, though any diYcult clinical case. inappropriate, immune response, is also re- From the global perspective, the region most duced. aVected at the close of the millennium is sub-Saharan Africa, where 83% of all AIDS Clinical features of HIV related related deaths have occurred.17–19 However, the tuberculosis incidence of HIV infection is rapidly increasing The diagnosis of tuberculosis has never been in Asia, where a large percentage of the human easy as there is a very wide range of clinical population infected by the tubercle bacillus features. The advent of HIV related tuberculo- live.17 Within sub-Saharan Africa, East and sis, with many unusual presenting features, has Central African countries are particularly added significantly to the diagnostic diYcul- aVected, with around one in five adults being ties. Heightened clinical awareness remains the infected with HIV.11 In these countries HIV is mainstay of diagnosis. Tuberculosis may de- principally transmitted heterosexually, and velop at any point in the course of the HIV infection in women is as frequent as men. In infection and may thus occur early in the Zambia at least one in four pregnant women course of HIV infection, often before any 20 are HIV seropositive and, as around 50% are significant drop in CD4+ T cell counts occur http://pmj.bmj.com/ also infected with the tubercle bacillus, one in or other clinical conditions suggestive of HIV eight are likely to be co-infected. A recent study infection or AIDS appear. from Zambia indicates that HIV related tuber- The nature, presentation, and the clinical culosis is, after malaria, now the most impor- and radiological features of tuberculosis de- tant non-obstetric cause of maternal death.21 pend on the degree of immunosuppression. In An increasing number of cases of tuberculosis those with relatively good immunity and CD4+ in African children are HIV related. In Zambia, cell counts, and a low viral load, the manifesta- the HIV seroprevalence rate among children tions and presenting symptoms of tuberculosis on September 28, 2021 by guest. Protected copyright. admitted to hospital with tuberculosis rose are essentially similar to those in HIV negative from 18% to 67% over an eight year period up persons. As the immunocompetence decreases, to 1995 while over the same period, the HIV there is an increasing incidence of atypical seroprevalence rate remained at a constant presentations of tuberculosis, and diagnostic 10% in children admitted for surgical diYculties are posed by the rather non-specific conditions.22 presenting features which may be confused with those of other HIV related infections.32627 Pathology of tuberculosis in HIV These atypical forms of tuberculosis include infection rapid progression of clinical disease after infec- The lungs of HIV positive patients dying with tion and a high proportion of extrapulmonary, tuberculosis are characterised by fibrous and multisite, and widely disseminated tuberculo- calcified tuberculosis lesions interspersed with sis. The clinical features of HIV related and newer active lesions containing tubercle non-related tuberculosis are contrasted in table bacilli.23 The latter may be due to either reacti- 5. vation of old lesions or to reinfection. The pre- The most common extrapulmonary mani- cise nature of the immune deficit that leads to festations of tuberculosis are: (a) asymmetrical an enhanced risk of tuberculosis in HIV lymphadenopathy, (b) pericarditis, (c) pleurisy, positive patients has not been established and a and (d) bone and skin. For reasons that are not range of pathological characteristics have been clear, involvement of the central nervous and described. In those with relatively intact genitourinary systems is, relative to the indus- immune function and a relatively high CD4+ trialised countries, uncommon in Africa.28 count, there are classical caseating granulomas More generalised dissemination of disease may characterised by mature epithelioid cells and result in numerous minute lesions throughout 262 Zumla, Malon, Henderson, et al

the body. This condition, termed cryptogenic dying from respiratory diseases is currently Postgrad Med J: first published as 10.1136/pmj.76.895.259 on 1 May 2000. Downloaded from disseminated tuberculosis, may be very diYcult underway in Zambia. to diagnose during life. Many unsuspected cases are therefore diagnosed at necropsy and Diagnosis of tuberculosis pose serious risks to the pathologist. Tubercu- In view of the problems encountered in the lin tests may be negative, particularly in the clinical diagnosis of tuberculosis, a huge more severely immunosuppressed, although amount of eVort has been placed in the devel- the extent of induration is not closely related to opment of rapid and sensitive diagnostic tests the CD4+ lymphocyte count and is thus an but serious problems have been encountered. independent marker of immune competence.29 Traditionally, diagnosis has been made by the Blood cultures are positive in between a third microscopical demonstration of acid-fast ba- and a half of patients with disseminated HIV cilli in biological specimens and by in vitro cul- related tuberculosis.30 tivation of tubercle bacilli. Neither approach is A high proportion of African patients with completely satisfactory and attention has re- AIDS develop severe wasting and is thus cently turned to molecular methods of diagno- known locally as “slim disease”. Many such sis. patients have chronic diarrhoea and the condition was thus thought to be caused by MICROSCOPY enteropathy but in one study in Africa almost This is principally applied to sputum but other half the AIDS patients died with “slim disease” specimens include bronchoalveolar lavage and almost half of these were found to have fluid, gastric washings, laryngeal swabs, cere- disseminated tuberculosis on necropsy, com- brospinal fluid, pleural, pericardial and perito- pared with just over a quarter of those dying neal eVusions, fine needle lymph node aspi- without such wasting.31 rates, bone marrow aspirates, and tissue biopsies. Ideally, three sputum specimens HIV related tuberculosis in children collected on successive days should be exam- The clinical diVerences in the disease between ined but, particularly in resource poor coun- HIV positive and HIV negative children are not tries, this encourages non-compliance and as striking as in adults.22 In Africa, a large pro- overburdens the laboratory.4 Children rarely portion of paediatric clinic attendances and produce sputum: only 5% of cases of childhood hospital admissions are for pulmonary diseases pulmonary tuberculosis are smear positive. and distinguishing tuberculosis from the other Gastric aspirates are more likely to be positive causes is never easy and is usually based on but laryngeal swabbing is distressing to the clinical features, tuberculin testing, and a child, exposes the operator to risk of infection, history of exposure to a source case. Labora- and gives a low diagnostic yield. tory investigations are often unhelpful as Microscopy of sputum is rapid, permitting a lesions are usually closed and sputum, even presumptive diagnosis to be made on the when it can be obtained, is almost always nega- patient’s first visit to the clinic, but it is insensi-

tive for acid-fast bacilli on microscopy. Even tive as there must be at least 5000 organisms in http://pmj.bmj.com/ when the most advanced diagnostic facilities 1 ml of sputum to render their detection likely. are available, the diagnosis can only be Microscopy does not permit the distinction confirmed by culture in about half the cases.32 between tubercle bacilli and environmental Positive cultures may be obtained from unusual mycobacteria, but this is not a major problem sites: in a study in South Africa six of 14 HIV in regions where tuberculosis is common. As infected children with culture positive tubercu- mentioned above, patients with HIV related losis had otorrhoea and ear swabs were the tuberculosis, particularly those with more pro- source of the positive cultures in three such found immunosuppression and no cavity on September 28, 2021 by guest. Protected copyright. cases.33 formation, are more likely to be sputum nega- Additional diagnostic diYculties are experi- tive than those with typical cavitating post- enced in HIV positive children as the common primary disease. diagnostic criteria such as chronic cough, weight loss, and failure to thrive may also be CULTURE the result of other HIV related pulmonary By facilitating an identification at species level, infections such as Pneumocystis carinii pneumo- isolation of M tuberculosis in culture provides a nia and disease due to environmental mycobac- definitive diagnosis. The traditional method of teria, especially members of the M avium inoculating solid media such as the egg based complex.34 Likewise, the radiological charac- Löwenstein-Jensen medium is sensitive but teristics of these other infections may be indis- slow as growth may not be visible until after tinguishable from those of tuberculosis. Thus, three or more weeks’ incubation. More rapid in the developing countries, misdiagnosis is results are obtained by the use of commercially common, rendering it diYcult to assess the available culture systems based on the libera-

magnitude of the problem of HIV related tion of radiolabelled carbon dioxide (CO2)or tuberculosis in children. An idea of the true risk changes in the colour or ﬂuorescence of dyes

of tuberculosis in HIV infected children may be due to the liberation of CO2 or consumption of obtained from necropsy studies. One such oxygen.4 study in West Africa suggested a low risk35 but necropsies performed on HIV positive children SEROLOGICAL TESTS in Bulawayo, Zimbabwe, established a diagno- There have been numerous attempts to de- sis of tuberculosis in six out of 122 children velop serological tests for tuberculosis and a (5%).36 A large necropsy study of children few are commercially available but serious Impact of HIV infection on tuberculosis 263

problems of specificity and sensitivity have of the disease and a high degree of clinical sus- Postgrad Med J: first published as 10.1136/pmj.76.895.259 on 1 May 2000. Downloaded from been encountered. Owing to compromised picion is therefore required. immune responses, sensitivity is even lower in patients with HIV related tuberculosis.37 Treatment of HIV related tuberculosis The standard WHO recommended antituber- MOLECULAR METHODS culosis regimen is a six month course of In view of the problems encountered with the rifampicin and isoniazid, with the addition of traditional microbiological methods, the appli- pyrazinamide, together with ethambutol (or cation of nucleic acid (DNA and RNA) ampli- streptomycin) during the first two months of fication techniques—the polymerase chain treatment. Supplementation with daily pyri- reaction (PCR) and the ligase chain reaction doxine (vitamin B6) to prevent isoniazid (LCR)—is the subject of intense research induced neuropathy is now routine. activity. As a result, a number of rapid, Antituberculous regimens based on drugs sensitive, and specific test kits are commercially other than rifampicin, or the use of rifampicin available.38 Problems arise as a result of the only during the first two months, have been presence of inhibiting substances in some used on the grounds that they are cheaper. The clinical specimens which reduce sensitivity, cost diVerence is now not so great and, in terms especially in smear negative sputum specimens, of relapse rates and duration of treatment, the and the unexplained occurrence of a few rifampicin based regimens are ultimately much “false” positive results.4 Another problem is more cost eVective. cross contamination, although this is mini- Thiacetazone based regimens, though mised by closed, isothermal, systems based on cheap, cause an unacceptably high incidence of the amplification of specific messenger RNA severe toxic reactions in HIV infected persons which has a short half life. and they should be universally abandoned. Molecular techniques also permit the rapid There is little or no diVerence in relapse rate identification of mycobacteria other than M between HIV infected and uninfected patients tuberculosis and the determination of rifampicin when rifampicin based short course treatment resistance by detection of mutations in the is used. Thus, in the absence of drug resistance, RpoB gene responsible for resistance.39 the standard short course described above is A further application of molecular technol- recommended.44 Nevertheless, some physi- ogy is the “fingerprinting” of isolates, or PCR cians continue treatment for nine months to products, of M tuberculosis. Such techniques further reduce the risk of relapse.45 46 Unfortu- have been used to investigate miniepidemics of nately, as outlined below, many patients die of HIV related tuberculosis and to diVerentiate other HIV related complications during or between reactivation of old lesions and recent after completion of antituberculosis treatment. infection. It has thus been shown that, particu- In one study, extending rifampicin based treat- larly among HIV positive persons, reinfection ment from six to 12 months reduced the occurs much more frequently than previously relapse rate but did not improve survival.47 40 expected. At the present time, the cost of In addition, owing to a range of human fac- http://pmj.bmj.com/ nucleic based technology rather than technical tors, including negative perception of the problems precludes its use in resource poor disease, its treatment and outcome and the countries. stigmatising nature of the diagnosis, HIV positive patients in some regions are less likely than 48 CHEST RADIOGRAPHY seronegative patients to complete treatment. The radiological appearance of pulmonary Thus it is essential to adopt strategies of tuberculosis in both HIV negative and positive directly observed therapy (DOT) in order to is very variable, but more so in the latter.41 42 ensure completion of treatment.44 This strategy on September 28, 2021 by guest. Protected copyright. Classical chest radiograph appearances of may also help to limit the emergence of drug tuberculosis are seen in approximately one resistant tuberculosis but, in several African third of HIV infected patients while the others countries, even the establishment of national show a range of atypical appearances. Radio- tuberculosis programmes employing DOT logical studies of adult Zairean and Zambian based strategies, is failing to stem the rising tide patients with HIV related tuberculosis show a of tuberculosis. In Botswana, for example, the significantly increased incidence of lymphad- incidence of tuberculosis rose by 120% be- enopathy, pleural eVusions, parenchymal tween 1989 and 1996, paralleling that of the changes, consolidation and miliary disease, but prevalence of HIV infection, despite a decade significantly less cavitary disease and of such strategies and a low prevalence of drug atelectasis.42 Intrathoracic lymphadenopathy, resistance.49 uncommon in HIV uninfected adults with post-primary tuberculosis, is evident in 25%– Adverse eVects of antituberculosis 50% in HIV infected adults with pulmonary chemotherapy tuberculosis.43 The factors determining the Adverse eVects of first line antituberculosis radiological appearance of tuberculosis in HIV drugs occur in both HIV infected and unin- positive patients are poorly understood. Con- fected patients and the patient should be trary to previous opinion, the ability to form monitored carefully for these. Side eVects of cavities and fibrotic changes do not appear to antituberculosis drugs are comparatively more be directly related to the CD4+ cell counts. frequent in the HIV infected tuberculosis The occurrence of atypical radiological mani- patients and very severe and even fatal festations of HIV related pulmonary tuberculo- reactions have been observed in several studies. sis has implications for the accurate diagnosis The most serious problems are encountered 264 Zumla, Malon, Henderson, et al

Table 6 Drug interactions with rifampicin* and usually subside spontaneously. Treatment Postgrad Med J: first published as 10.1136/pmj.76.895.259 on 1 May 2000. Downloaded from should not be modiﬁed but short courses of EVect of drug opposed by rifampicin steroids may be required for severe paradoxical Protease inhibitors Non-nucleoside reverse transcriptase inhibitors 46 Azathioprine Cyclosporin reactions. Diazepam Digoxin Glucocorticoids Haloperidol Imidazole antifungals Oral contraceptives Mortality in patients with HIV related Opiods Phenytoin tuberculosis Propanolol Quinidine There is considerable evidence that HIV sero- Theophylline Tolbutamide Warfarin positive patients with tuberculosis are at a EVects of rifampicin potentiated Cotrimoxazole higher risk of dying than their HIV seronegative counterparts during or after treatment for *Data from Grange updated.52 et al tuberculosis, with death usually being caused with thiacetazone, notably dermal reactions by complications of HIV infection rather than including exfoliative dermatitis and the fre- to tuberculosis itself.54 55 A study in Malawi quently fatal Stevens-Johnson syndrome. In showed the former were 2.5 times as likely to one study of adults from Kenya, thiacetazone die during treatment, with half the deaths toxicity was 18 times more frequent in HIV occurring during the ﬁrst month of treatment.56 positive, than in HIV negative, patients and the The risks of dying for those with smear risk was directly related to the degree of immu- negative and extrapulmonary tuberculosis nosuppression, suggesting an immunological were, respectively, 3.9 and 2.6 higher than basis.50 A study of Zambian children demon- those with sputum positive disease, probably as strated severe fatal reactions to thiacetazone the former tend to be associated with more and highlighted the advantages of profound immunosuppression. The risk of thiacetazone-free regimens.51 Accordingly, as death is related to the antituberculosis regimen mentioned above, regimens containing thia- used. In Uganda, the risk of death within a year cetazone should no longer be used. of starting treatment was 60% higher in patients treated with streptomycin, thiacetazone, and isoniazid than in those receiving Antituberculous drug interactions 57 A number of interactions between antitubercu- rifampicin-based regimens. This may be losis agents and other drugs have been attributable to the prevention of other oppor- described.52 Most interactions are associated tunistic AIDS related infections by the broad with rifampicin due to its ability to induce antimicrobial activity of rifampicin. cytochrome CYP450 enzymes in the liver Nevertheless, it is important to diagnose and which aVect the metabolism of many other treat other opportunistic infections that occur during the course of antituberculosis drugs (table 6). In addition to aVecting the treatment.44 metabolism of antifungals and other drugs that The reason for the high mortality associated HIV positive patients may require, serious with the onset of HIV related tuberculosis, interactions may occur between rifampicin and even when treated vigorously, is not clear. It http://pmj.bmj.com/ antiretroviral drugs (protease inhibitors and may be the result of a poorly understood non-nucleoside reverse transcriptase inhibi- synergy between the two infections which tors). The recommended practice was to stop accelerates the decline in immune competence antiretroviral treatment so that rifampicin and also greatly increases the viral load.58 This could be used to treat tuberculosis but the cur- synergy may be due to an induction of HIV rent recommendation is to replace rifampicin replication by cytokines, including tumour by rifabutin, a much less powerful inducer of necrosis factor-á, induced by the tuberculous

cytochrome enzymes, and to start or continue on September 28, 2021 by guest. Protected copyright. 46 process. In addition, tuberculosis per se is asso- with the antiretroviral drugs. Even if rifabutin ciated with a reduction in the CD4+ lym- is substituted for rifampicin, care should be phocyte count which may be additive to that exercised in the use of the protease inhibitor resulting from the HIV infection. In view of the saquinavir and the non-nucleoside reverse deleterious eVect of tuberculosis on the course transcriptase inhibitors as rifabutin decreases of HIV infection, all forms of tuberculosis are their levels, with the risk of selection of drug classified as AIDS defining conditions.59 resistant viruses.8 Another problem encountered with the simultaneous administration of Drug resistant tuberculosis antiretrovirals and antituberculosis chemo- A further complicating factor is the occurrence therapy is the temporary exacerbation of the of drug resistant tuberculosis. Many of the symptoms and signs of tuberculosis—the cases in these outbreaks reported in New York so-called paradoxical reactions.53 These, which City were multidrug resistant which, by defini- have been ascribed to hypersensitivity reactions tion, are resistant to rifampicin and isoniazid to antigen released by bacilli killed by the with or without resistance to other drugs.60 chemotherapy, manifest as fever, enlargement This was the result of poor medical care previ- of aVected lymph nodes, and a worsening of ously received by the patients who were mostly the radiological appearance. They are occa- from socioeconomically underprivileged sec- sionally encountered in HIV seronegative tors of the community. HIV infection per se is patients but their incidence is higher in HIV not a predisposing factor for the development seropositive patients, particularly those given of multidrug resistance and, in many other antiretroviral drugs, probably as a result of parts of the world, such an association does not improving immune responsiveness. These re- occur.61 62 Tests for drug susceptibility are often actions are not indicative of treatment failure not possible in developing countries but they Impact of HIV infection on tuberculosis 265

should certainly be performed in the industr- lem in regions, including many African coun- Postgrad Med J: first published as 10.1136/pmj.76.895.259 on 1 May 2000. Downloaded from ialised nations.44 tries, where the prevalence of HIV infection is high and where cattle tuberculosis has not been Infection control in health care settings eradicated.73 As several miniepidemics of HIV related tuberculosis, including multidrug resistant forms, BCG vaccination in HIV infected persons have followed exposure to source cases within There is a risk that vaccination with Bacille hospitals and clinics, well defined policies for Calmette-Guérin (BCG), a living attenuated the prevention of transmission of tuberculosis vaccine, will cause infectious complications in within such institutions, including isolation of HIV positive persons.74 There is a small known and suspect infectious patients, are increase in the incidence of adverse eVects of essential.63 BCG in the children of HIV infected women, but most such eVects are mild.75 In one study, Prophylaxis against tuberculosis in complications occurred in nine of 68 HIV co-infected persons infected children three to 35 months after neo- In view of the very high risk of a co-infected natal BCG vaccination. Regional lymphaden- person developing active tuberculosis, and the opathy with or without fistula formation adverse eVect of this disease on the immune occurred in seven and systemic disease in two.76 status and survival of the patient, there is a very Accordingly, the safety of BCG vaccination in good theoretical case for provision of prophy- regions with a high incidence of HIV infection lactic treatment for those at risk. In practice, requires consideration. The WHO has advised serious problems have been encountered in that, while persons known to be HIV positive diagnosing dual infection, ruling out active should never be given BCG, routine immunisa- tuberculosis, and ensuring compliance with tion of infants should nevertheless continue in treatment without breach of confidence or areas with a high incidence of tuberculosis and 63 64 enhancement of stigma. HIV infection.77 In the UK it is recommended In the initial studies, a 12 month course of infants born to mothers known or suspected to isoniazid was found to lower the incidence of be HIV positive that should not receive BCG 65 66 tuberculosis in co-infected persons. Subse- unless they are subsequently shown to be HIV quently, shorter combination regimens have negative.78 also been shown to be eVective. These include a three month course of a rifamycin (rifampicin Conclusions or rifabutin) plus isoniazid and a two month The emergence of the HIV pandemic over the course of a rifamycin plus pyrazin- last two decades has had a devastating e ect on 46 67–69 V amide. A study in Zambia revealed that tuberculosis world wide, but principally in sub- the two month combination regimens or six Saharan Africa. In 1999, around 10% of all months of isoniazid, administered twice cases of tuberculosis will be HIV related, rising weekly, reduced the incidence of tuberculosis to over 20% in Africa. In addition, 30% of the by about 40% compared with a placebo group, expected 2.5 million AIDS related deaths in http://pmj.bmj.com/ although the overall mortality due to all causes 70 1999 will be due to tuberculosis. It is expected was not reduced. Prevention was more eVec- that the problem will likewise become extensive tive in those with relatively limited immuno- in Asia over the next decade. Many African suppression (positive tuberculin tests, high countries report that their health care facilities lymphocyte counts, and high haemoglobin are overwhelmed by the additional burden of concentrations). By 18 months, the incidence HIV related tuberculosis and urgent action is of tuberculosis in those who had received

therefore required to stem this epidemic before on September 28, 2021 by guest. Protected copyright. prophylaxis was similar to that in the placebo it becomes totally unmanageable, with devas- group; probably due to reinfection and thus tating human and economic consequences indicating the need to consider repeated which will be felt throughout the world. courses or, perhaps, lifelong prophylactic treat- The diYculties in diagnosis posed by the ment. varied clinical manifestations of tuberculosis and the particularly high incidence of atypical HIV infection and tuberculosis of bovine presentations in HIV positive patients, together origin with the problems of management, must be Tuberculosis due to M bovis is transmitted borne in mind by the practising physician. As from cattle to humans and, occasionally from the incidence of tuberculosis, especially of humans to cattle, but the evidence for human 71 cases that are HIV related, continues to to human transmission is weak and anecdotal. escalate world wide, physicians and patholo- This has led to the concept, never formally gists must keep tuberculosis high on the list of proved, that M bovis is less virulent for humans diVerential diagnoses in any problematic clini- than M tuberculosis. There have, however, been cal case. reports of a high incidence of HIV related tuberculosis due to M bovis among Mexicans arriving in the USA72 and also a report of a 1 World Health Organisation. TB—a global emergency.Ge- neva: WHO, 1994. miniepidemic resulting from exposure in an 2 Murray CJ, Styblo K, Rouillon A. Tuberculosis in develop- AIDS unit to a patient infected with a tubercle ing countries: burden, intervention and cost. Bulletin of the 14 International Union of Tuberculosis and Lung Disease 1990;65: bacillus closely resembling M bovis. If con- 6–24. ﬁrmed, an increased susceptibility of HIV 3 Chintu C, Zumla A. Pediatric tuberculosis and the HIV epi- infected persons to this form of tuberculosis demic. In: Zumla A, Johnson M, Miller RF, eds. AIDS and respiratory medicine. London: Chapman and Hall, 1997: could generate a serious human health prob- 153–63. 266 Zumla, Malon, Henderson, et al

4 Collins CH, Grange JM, Yates MD. Tuberculosis bacteriology. 37 Wilkins EGL. Antibody detection in tuberculosis. In: Davies Postgrad Med J: first published as 10.1136/pmj.76.895.259 on 1 May 2000. Downloaded from Organization and practice. 2nd Ed. Oxford: Butterworth PDO, ed. Clinical tuberculosis. London: Chapman and Hall, Heinemann, 1997. 1998: 81–96. 5 Raviglione MC, Snider DE, Kochi A. Global epidemiology 38 Tan MF, Ng WC, Chan SH, et al. Comparative usefulness of of tuberculosis. Morbidity and mortality of a worldwide epi- PCR in the detection of Mycobacterium tuberculosis indif- demic. JAMA 1995;273:220–6. ferent clinical specimens. J Med Microbiol 1997;46:164–9. 6 Fine PEM. Variation in protection by BCG: implications of 39 Drobniewski FA, Wilson SM. The rapid diagnosis of isoni- and for heterologous immunity. Lancet 1995;346:1339–45. azid and rifampicin resistance in Mycobacterium 7 Rook GAW, Hernandez-Pando R, Baker R, et al. Human tuberculosis—a molecular story. J Med Microbiol 1998;47: and murine tuberculosis as models for immuno-endocrine 189–96. interactions. In: Rook GAW, Lightman S, eds. Steroid 40 van Embden JDA, Cave MD, Crawford JT. Strain hormones and the T cell cytokine profile. London: Springer, identification of Mycobacterium tuberculosis by DNA 1997: 193–220. fingerprinting: recommendations for a standardised meth- 8 Havlir DV, Barnes PE. Tuberculosis in patients with human odology. J Clin Microbiol 1993;31:406–9. immunodeficiency virus infection. N Engl J Med 1999;340: 41 Daley CL. The typically “atypical” radiographic presenta- 367–73. tion of tuberculosis in advanced HIV disease. Tuber Lung Dis 9 Dolin PJ, Raviglione MC, Kochi A. Global tuberculosis 1995;76:475–6. incidence and mortality during 1990–2000. Bull World 42 Tshibwabwa-Tumba E, Mwinga A, Pobee JOM, et al. Health Organ 1994;72:213–20. Radiological features of pulmonary tuberculosis in 963 10 Chretien J. Tuberculosis and HIV. The cursed duet. Bull Int HIV-infected adults at three central African hospitals. Clin Union Tuberc Lung Dis 1990;65:25–8. Radiol 1997;52:837–41. 11 UNAIDS. AIDS epidemic update, December 1998. Geneva: 43 Saks AM, Posner R. Tuberculosis in HIV positive patients in World Health Organisation, 1998. South Africa: a comparative radiological study with HIV 12 Alland D, Kalkut GE, Moss AR, et al. Transmission of negative patients. Clin Radiol 1992;46:387–90. tuberculosis in New York City—an analysis by DNA finger- 44 Scientific Statement. Treatment regimens in HIV-infected printing and conventional epidemiologic methods. N Engl J tuberculosis patients. An oYcial statement of the Inter- Med 1994;330:1710–16. national Union Against Tuberculosis and Lung Disease. 13 Leitch AG, Rubilar M, Watt B, et al. Why disease due to International Journal of Tuberculosis and Lung Disease 1998;2: Mycobacterium tuberculosis is less common than expected 175–8. in HIV-positive patients in Edinburgh. Respir Med 1995;89: 45 Murray JF. Tuberculosis and HIV infection: a global 495–7. perspective. Respiration 1998;65:335–42. 14 Bouvet E, Casalino E, Mendoza-Sassi G, et al. A nosocomial 46 Centers for Disease Control. Prevention and treatment of outbreak of multidrug-resistant Mycobacterium bovis tuberculosis among patients infected with human immuno- among HIV-infected patients. A case-control study. AIDS deficiency virus: principles of therapy and revised recom- 1993;7:1453–60. mendations. MMWR Morb Mortal Wkly Rep 1998;47(RR- 15 Coker R. Lessons from New York’s tuberculosis epidemic. 20):1–58. BMJ 1998;317:616. 47 Perriens JH, St Louis ME, Mukudi MB, et al. Pulmonary 16 Coker R, Miller R. HIV associated tuberculosis. BMJ 1997; tuberculosis in HIV-infected patients in Zaire: a controlled 314:1847. trial of treatment for either 6 or 12 months. N Engl J Med 17 World Health Organisation. The world health report 1998. 1995;32:779–84. Geneva: WHO, 1998. 48 Ackah AN, Coulibaly D, Digbeu H, et al. Response to treat- 18 Ustianowski A, Mwaba P, Zumla A. Tuberculosis and ment, mortality, and CD4 lymphocyte counts in HIV- HIV—perspectives from sub-Saharan Africa. In: Porter infected persons with tuberculosis in Abidjan, Cote d’Ivoire. JDH, Grange JM, eds. Tuberculosis—an interdisciplinary Lancet 1995;345:607–10. perspective. London: Imperial College Press, 1999. 49 Kenyon TA, Mwasekaga MJ, Huebner R, et al. Low levels of 19 BlinkhoV P, Bukanga E, Syamalevwe B, et al. Under the drug resistance amidst rapidly increasing tuberculosis and mupundu tree. Strategies for Hope Series No 14. London: human immunodeficiency virus co-epidemics in Botswana. Actionaid, 1999. International Journal of Tuberculosis and Lung Disease 1999;3: 20 Fylkesnes K, Musonda RM, Kasumba K, et al. The HIV 4–11. epidemic in Zambia: socio-demographic prevalence pat- 50 Nunn P, Kibuga D, Gathua S, et al. Cutaneous hypersensi- terns and indications of trends among childbearing women. tivity reactions due to thiacetazone in HIV-1 seropositive AIDS 1997;11:339–45. patients treated for tuberculosis. Lancet 1991;337:627–30. 21 Ahmed Y, Mwaba P, Grange JM, et al. A study of maternal 51 Luo C, Chintu C, Bhatt G, et al. HIV-infection in Zambian mortality at the University Teaching Hospital, Lusaka, children with tuberculosis: changing seroprevalence and Zambia: the emergence of tuberculosis as a major evaluation of a thiacetazone-free regimen. Tuber Lung Dis non-obstetric cause of maternal death. International Journal 1994;75:111–15. of Tuberculosis and Lung Disease 1999;3:1–6.. 52 Grange JM, Winstanley PA, Davies PDO. Clinically signifi- http://pmj.bmj.com/ 22 Chintu C, Zumla A. Childhood tuberculosis and infection cant drug interactions with antituberculosis agents. Drug with the human immunodeficiency virus. J R Coll Phys Lond Saf 1994;11:242–51. 1995;29:92–94. 53 Narita M, Ashkin D, Hollender ES, et al. Paradoxical wors- 23 Lucas S, Nelson AM. Pathogenesis of tuberculosis in ening of tuberculosis following antiretroviral therapy in human immunodeficiency virus-infected people. In: Bloom patients with AIDS. Am J Respir Crit Care Med 1998;158: BR, ed. Tuberculosis: pathogenesis, protection and control. 157–61. Washington: ASM Press, 1994: 503–13. 54 Perriens JH, Colebunders RL, Karahunga C, et al. Increased 24 Lucas S, Wamukota W. HIV and the local African mortality and tuberculosis treatment failure rate among population. In: Pounder RE, Chiodini PL, eds. Advanced human immunodeficiency virus (HIV) seropositive com- medicine. London: Balliere-Tindall, 1987: 102–11. pared with HIV seronegative patients with pulmonary

25 Nambuya A, Sewankambo N, Mugerwa J, et al. Tuberculous tuberculosis treated with “standard” chemotherapy in Kin- on September 28, 2021 by guest. Protected copyright. lymphadenitis associated with human immunodeficiency shasa, Zaire. Am Rev Respir Dis 1991;144:750–5. virus infection in Uganda. J Clin Pathol 1988;41:93–6. 55 van den Broek J, Mfinanga S, Moshiro C, et al. Impact of 26 Huebner RE, Castro KG. The changing face of tuberculo- human immunodeficiency virus on the outcome of treat- sis. Ann Rev Med 1995;46:47–55. ment and survival of tuberculosis patients in Mwanza, Tan- 27 Whalen C, Horsburgh CR, Hom D, et al. Accelerated course zania. International Journal of Tuberculosis and Lung Disease of human immunodeficiency virus infection after tuberculo- 1998;2:547–52. sis. Am J Resp Crit Care Med 1995;151:129–34. 56 Harries AD, Nyangulu DS, Kang’ombe C, et al. Treatment 28 Harries AD. Tuberculosis in HIV-infected persons with spe- outcome of an unselected cohort of tuberculosis patients in cial emphasis on sub-Saharan Africa. J Infect 1998;37:205– relation to human immunodeficiency virus status in Zomba 9. Hospital, Malawi. Trans R Soc Trop Med Hyg 1998;92:343– 29 Diagbouga S, Fumoux F, Ledru E, et al. Lack of direct cor- 7. relation between CD4+ lymphocyte counts and induration 57 Okwera A, Whalen C, Bykewaso F, et al. Randomised trial of sizes of the tuberculin skin test in human immunodeficiency thiacetazone and rifampicin-containing regimens for pul- virus type 1 seropositive patients. International Journal of monary tuberculosis in HIV-infected Ugandans. Lancet Tuberculosis and Lung Disease 1998;2:317–23. 1994;334:1323–8. 30 Di Lonardo M, Isola NC, Ambroggi M, et al. Mycobacteria 58 Goletti D, Weissman D, Jackson RW, et al.EVect of in HIV-infected patients in Buenos Aires. Tuber Lung Dis Mycobacterium tuberculosis on HIV replication: role of 1995;76:185–9. immune activation. J Immunol 1996;157:1271–6. 31 Lucas SB, de Cock KM, Hounnou A, et al. Slim disease in 59 Centers for Disease Control. The 1993 revised classification Africa: the contribution of tubeculosis. BMJ 1994;308: system for HIV infection and expanded surveillance case 1531–3. definition for AIDS among adolescents and adults. MMWR 32 Starke JR, Taylor-Watts RT. Tuberculosis in the paediatric Morb Mortal Wkly Rep 1993;41(17):1–19. population in Houston, Texas. Pediatrics 1989;84:28–35. 60 Kochi A, Vareldzis B, Styblo K. Multidrug-resistant 33 Schaaf HS, Geldenduys A, Gie RP, et al. Culture-positive tuberculosis and its control. Res Microbiol 1993;144:104–10. tuberculosis in human immunodeficiency virus type 61 Gordin FM, Nelson ET, Matts JP, et al. The impact of 1-infected children. Pediatr Infect Dis J 1998;17:599–604. human immunodeficiency virus infection on drug resistant 34 Donald PR. Clinical manifestations of tuberculosis. In: tuberculosis. Am J Respir Crit Care Med 1996;154:1478–83. Donald PR, Fourie B, Grange JM, eds. Tuberculosis in child- 62 Mitike G, Kebede D, Yenneneh H. HIV infection and hood. Pretoria: JL van Schaik, 1999: 61–102. antituberculosis drug resistance among pulmonary tubercu- 35 Lucas SB, Peacock CS, Hounnou A, et al. Disease in losis patients in Harar Tuberculosis Centre, Ethiopia. East children infected with HIV in Abidjan, Cote-d’Ivoire. BMJ Afr Med J 1997;74:154–7. 1996;312:335–8. 63 International Union of Tuberculosis and Lung Disease/ 36 Ikeogu MO, Wolf B, Mathe S. Pulmonary manifestations in World Health Organisation. Statement: tuberculosis preven- HIV seropositivity and malnutrition in Zimbabwe. Arch Dis tive therapy in HIV-infected individuals. Tuber Lung Dis Child 1997;76:124–8. 1994;75:96–8. Impact of HIV infection on tuberculosis 267

64 O’Brien RJ, Perriens JH. Preventive therapy for tuberculosis (B) Extending antituberculosis treatment Postgrad Med J: first published as 10.1136/pmj.76.895.259 on 1 May 2000. Downloaded from in HIV infection: the promise and the reality. AIDS 1995;9: 665–73. from six to 12 months results in a lower 65 Pape JW, Jean SS, Ho JL, et al.EVect of isoniazid relapse rate and an improved survival rate. prophylaxis on incidence of active tuberculosis and progression of HIV infection. Lancet 1993;342:268–72. (C) Rifampicin interacts with antiretrovirals 66 Hawken MP, Meme HK, Elliott LC, et al. Isoniazid preven- by inhibiting the cytochrome CYP450 tive therapy for tuberculosis in HIV-1 infected adults: results of a randomised controlled trial. AIDS 1997;11:875–82. enzyme thus reducing the levels of the 67 Wilkinson D, Squire SB, Garner P. EVect of preventive antiretroviral drugs. treatment for tuberculosis in adults infected with HIV: sys- tematic review of randomised placebo controlled trials. BMJ (D) Current recommendations state that anti- 1998;317:625–9. retrovirals should be continued while a 68 Rose DN. Short-course prophylaxis against tuberculosis in HIV-infected persons. A decision and cost-eVectiveness patient is being treated for tuberculosis. analysis. Ann Intern Med 1998;129:779–86. (E) HIV positive patients with tuberculosis 69 Halsey NA, Coberly JS, Desormeaux J, et al. Randomised trial of isoniazid versus rifampicin and pyrazinamide for experience more hypersensitivity reactions prevention of tuberculosis in HIV-1 infection. Lancet 1998; than HIV negative patients with tubercu- 351:786–92. 70 Mwinga A, Hosp M, Godfrey-Faussett P, et al. Twice weekly losis. tuberculosis preventive threrapy in HIV infection in Zambia. AIDS 1998;12:2447–57. 71 Grange JM, Collins CH. Tuberculosis and the cow. Journal Q4. The following statements with regards to of the Royal Society of Health 1997;117:119–22. tuberculosis are true: 72 Dankner WM, Waecker NJ, Essey MA, et al. Mycobacte- rium bovis infections in San Diego: a clinicoepidemiological (A) HIV positive patients are more likely to be study of 73 patients and a historical review of a forgotten “smear positive” than HIV negative pa- pathogen. Medicine 1993;72:11–37. 73 Daborn CJ, Grange JM, Kazwala RR. The bovine tubercu- tients. losis cycle—an African perspective. J Appl Bacteriol (Sympo- (B) Identiﬁcation of acid fast bacilli on micro- sium Supplement) 1996;81:27–32S. 74 Talbot EA, Perkins MD, Silva SFM, et al. Disseminated scopy enables the diagnosis of tuberculosis bacille Calmette-Guérin disease after vaccination: case to be made. report and review. Clin Inf Dis 1997;24:1139–46. (C) Children with tuberculosis are less likely 75 O’Brien KL, RuV AJ, Louis MA, et al. Bacillus Calmette- Guerin complications in children born to HIV-1-infected to be smear positive than adults. women with a review of the literature. Pediatrics 1995;95: 414–8. (D) Rifampicin resistance can be reliably pre- 76 Besnard M, Sauvion S, OVredo C, et al. Bacillus Calmette- dicted using molecular methods to detect Guérin infection after vaccination of human immuno- mutations in the gene. deﬁciency virus-infected children. Pediatr Infect Dis 1993;12: RpoB 993–7 (E) Serology is of use in the diagnosis of 77 World Health Organisation. HIV and routine childhood tuberculosis in HIV positive patients. immunization. Wkly Epidemiol Rec 1987;62:297–9. 78 Report. Subcommittee of the Joint Tuberculosis Committee of the British Thoracic Society. Guidelines on the management of tuberculosis and HIV infections in the United Q5. Which of the statements are true: Kingdom. BMJ 1992;304:1231–3. (A) Mycobacterium bovis is a recognised cause of primary pulmonary tuberculosis. (B) Those aged between 5 and 15 years old are Multiple choice questions at particular risk of tuberculosis. Q1. The following statements are true: (C) HIV positive patients, once infected with (A) In patients co-infected with tuberculosis tuberculosis, are at high risk of reinfection

and HIV the overall annual risk of as well as reactivation. http://pmj.bmj.com/ developing active tuberculosis rises on (D) Tuberculosis is expected to cause 30% of average twofold. the expected AIDS related deaths in 1999. (B) In sub-Saharan Africa, there are twice as (E) In babies infected with HIV it is safe to many men as women infected with HIV. give BCG vaccination. (C) In Zambia, HIV is the second commonest cause of non-obstetric maternal death. Q6. In the year 1999 what percentage of the (D) AIDS patients with active pulmonary expected 2.5 million AIDS related deaths are tuberculosis predominantly exhibit cavi- estimated to be due to tuberculosis? on September 28, 2021 by guest. Protected copyright. tating granulomatous lung lesions. (A) 10% (E) Mortality associated with tuberculosis is (B) 30% similar in patients with HIV and in those (C) 50% without HIV. (D) 70% (E) 90% Q2. In patients disseminated tuberculosis co-infected with HIV: Q7. The overall annual risk of developing active (A) Tuberculin skin tests may be negative. tuberculosis infection in persons co-infected with (B) Blood cultures for mycobacteria are rarely the tubercle bacillus and HIV,compared with positive. persons not infected by HIV,is increased by about: (C) Pericarditis is a common extrapulmonary (A) 10 times manifestation. (B) 20 times (D) Central nervous system involvement is (C) 30 times invariably seen. (D) 40 times (E) Patients are less prone to weight loss than (E) 50 times patients with non-HIV associated tuberculosis. Q8. The region currently most aVected by HIV and tuberculosis co-infection (the “cursed duet”) is: Q3. With regards to treatment for tuberculosis in (A) South East Asia HIV infected patients the following are true: (B) North Africa (A) Addition of pyridoxine to antituberculosis (C) Sub-Saharan Africa regimens prevents ethambutol induced (D) USA neuropathy. (E) Europe 268 Zumla, Malon, Henderson, et al

Q9. Which ONE of the following statements is Q3: Postgrad Med J: first published as 10.1136/pmj.76.895.259 on 1 May 2000. Downloaded from false? (A) False. Neuropathy is a side eVect seen with (A) The standard WHO recommended anti- isoniazid not ethambutol. tuberculosis treatment is six months with (B) False. Survival in HIV positive patients with rifampicin, isoniazid, pyrazinamide, and active tuberculosis is not aVected by in- ethambutol/streptomycin. creasing the length of course of treatment. (B) HIV positive patients are less likely (C) False. Rifampicin is an enzyme inducer— than non-HIV infected patients to com- not inhibitor. plete the course of antituberculosis treat- (D) True. ment. (E) True. (C) Side eVects of antituberculosis treatment are comparatively more common in HIV Q4: infected patients with tuberculosis. (A) False. HIV positive patients with active (D) Protease inhibitors and rifampicin rarely tuberculosis are less likely to be smear interact. positive. (E) Drug resistant tuberculosis is by definition (B) False. Distinction between tuberculosis resistant to isoniazid and rifampicin. and other mycobacterial species (for example, M avium intracellulare) cannot reliably be made on microscopy. The gold standard remains culture of the organism. Answers to multiple choice questions: Molecular methods can also be used. Q1: (C) True. (A) False. The risk is much greater—being in (D) True. the region of 20 times greater. (E) False. Serology lacks both specificity and (B) False. There is a roughly equal prevalence sensitivity especially in HIV positive pa- among the sexes with heterosexual sex tients. being the commonest mode of transmis- Q5: sion. (A) False. M bovis causes primary infection in (C) True. The commonest is malaria. the pharynx or intestine (via drinking (D) False. HIV infected patients with active infected milk) rather than the lung. Al- pulmonary tuberculosis experience necro- though isolated institutionalised outbreaks tising rather than granulomatous lung have been reported among HIV infected lesions that are not walled oV by fibrous patients there is no firm evidence that the changes as in tuberculosis in non-HIV spread was via primary lung infection. patients. This leaves the patient more (B) False. Those within this age group have a prone to local invasion and disseminated relative protection against infection with disease throughout the body (cryptogenic tuberculosis— the “golden age group”. disseminated tuberculosis). (C) True.

(E) False. Mortality is higher in those with (D) True. http://pmj.bmj.com/ HIV. (E) False. There is an increased incidence of infectious complications with use of this Q2: live attenuated vaccine. (A) True. Although the extent of induration is Q6: not related to CD4 count. (B) True 30% (WHO estimates). (B) False. Between one third and one half of cases will be blood culture positive. Q7: (C) True. Pericarditis is the second common- (B) True 20 times. on September 28, 2021 by guest. Protected copyright. est extrapulmonary manifestation after Q8: asymmetrical lymphadenopathy. (C) True. While many regions are aVected, (D) False. Central nervous system involve- sub-Saharan Africa appears to bear the brunt ment is actually quite rare in those African of the cursed duet of tuberculosis and HIV. patients with HIV and disseminated tuberculosis. Q9: (E) False. Severe wasting in Africans with HIV (D) True. Rifampicin induces enzymes in the known as “slim disease” is thought to be cytochrome P-450 system and leads to interac- associated with tuberculosis. tions between these drugs.