Extrapulmonary tuberculosis in the northeastern suburbs of Paris: 141 cases

European Journal of Internal Medicine 11 (2000) 145–150 www.elsevier.com / locate / ejim

Original article

Extrapulmonary tuberculosis in the northeastern suburbs of Paris: 141 cases a, c a f d c e O. Fain *, O. Lortholary , V. Lascaux , I. Amoura , P. Babinet , J. Beaudreuil , P. Boudon , P. Cruaud b , J. Desrues f , M. Djouab f , J. Glowinski f , F. Lhote d , A. Kettaneh a , D. Malbec e , E. Mathieu a , C. Taleb a , L. Guillevin c , M. Thomas a a

Department of Internal Medicine, Jean Verdier Hospital, Avenue du 14 Juillet, 93143 Bondy Cedex, France b Microbiology Laboratory, Jean Verdier Hospital, 93143 Bondy Cedex, France c Department of Internal Medicine, Avicenne Hospital, Bobigny, France d Department of Internal Medicine, Delafontaine Hospital, Saint Denis, France e Department of Internal Medicine, Robert Ballanger Hospital, Aulnay sous Bois, France f Department of Internal Medicine, Gonesse Hospital, Gonesse, France Received 1 November 1999; received in revised form 27 January 2000; accepted 29 February 2000

Abstract Background: Big cities were particularly affected by tuberculosis in the 1990s. Methods: We studied 141 cases of extrapulmonary tuberculosis in patients not infected by HIV in the northeastern suburbs of Paris. Results: A total of 84 men and 57 women were included in the study. Their average age at diagnosis was 42.2 years. Some 73.6% of the patients were foreign-born. A total of 182 sites were identified in 141 patients. There was an association with pulmonary tuberculosis in 38 cases. The sites were: lymph node (48.9%), pleural (25.5%), skeletal (22.7%), genitourinary (5.7%), and meninges (5%). Unfavorable social conditions were frequently observed. The average duration of treatment was 10 months. Twenty-four adverse drug effects were noted. Sixty-eight strains of Mycobacterium tuberculosis were isolated. Five cases of primary resistance to at least one antituberculous drug and only one case of multidrug resistance were observed. Some 95.7% of the 93 patients who were not lost to follow up were cured. Conclusion: Independently of HIV infection, extrapulmonary tuberculosis is still present, particularly in the suburbs of big cities, where social conditions are poor. The significant number of patients lost to follow-up demands that measures be adapted for the therapeutic management of these patients.  2000 Elsevier Science B.V. All rights reserved. Keywords: Extrapulmonary tuberculosis; Lymph node tuberculosis; Tuberculous pleural effusion; Tuberculous meningitis; Precariousness

1. Introduction A resurgence of tuberculosis was observed in Europe and in the United States in the 1990s [1]. Human immunodeficiency virus (HIV) infection is a significant risk factor but not the only one for tuberculosis. Poor living conditions with homelessness, unemployment, and inadequate *Corresponding author. Tel.: 133-1-4802-6396; fax: 133-1-48026361. E-mail address: [email protected] (O. Fain)

access to health care, or being a migrant from a country with a high level of endemic tuberculosis, are all important factors that can explain the high incidence of tuberculosis in big cities and their suburbs. In France, the incidence of tuberculosis decreased between 1970 (58 / 100 000 inhabitants) and 1989 (16 / 100 000) [2]. This downward trend persisted until 1991 in certain areas, while in others, notably the Ile de France region, where the incidence of unemployment, migrant status, and homelessness is greater than in other regions of France, figures rose from 1990 onwards [3], with the incidence increasing from 33 per

0953-6205 / 00 / $ – see front matter  2000 Elsevier Science B.V. All rights reserved. PII: S0953-6205( 00 )00076-5

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O. Fain et al. / European Journal of Internal Medicine 11 (2000) 145 – 150

100 000 inhabitants in 1990 to 38 in 1992, and then decreasing slightly to 37.7 in 1994 [4]. In 1994, 42.8% of the disease notifications came from the Ile de France, which represents only 19% of the French population. The Seine Saint Denis area of the Ile de France was the most severely affected region in 1994, with an incidence of 58.2 per 100 000 inhabitants [3]. These facts led us to report our experience of extrapulmonary tuberculosis in patients not infected by HIV in the Ile de France over a 5-year period.

2. Patients and methods This retrospective study was conducted between 1 January 1990 and 31 December 1994 in four departments of internal medicine in Seine Saint Denis and in two departments in the Val d’Oise areas around Paris. All patients with extrapulmonary tuberculosis who were over 15 years of age and not infected by HIV were included. The patients were identified from microbiology laboratory records, pathology records, and discharge diagnoses from each department and hospital.

2.1. Diagnostic criteria All patients had a clinical illness compatible with tuberculous infection and they were all responding to antituberculous therapy. The diagnosis was made when positive Mycobacterium tuberculosis (M. tuberculosis) culture results were obtained and / or histological examination found a caseating granuloma with or without acid-fast bacilli, or when one or more of the following were found: granulomatous inflammation on biopsy, detection of M. tuberculosis DNA by polymerase chain reaction (Amplicor technique), empirical antituberculosis treatment by isoniazid (INH), rifampin (RPM), pyrazinamide (PZA) that was effective in 3 months.

most represented. In this group, the sex ratio (male / female) was 2.21, which is statistically different from that of patients older than 45 years (P,0.02). Some 73.6% of the patients were foreign-born; 33.3% of the French citizens came from the French West Indies. The sex ratio was 0.83 in the French patients and 1.78 in the migrants. Information concerning housing conditions was available in 117 cases: 14 patients lived in a migrant hostel, four lived with more than six people in the same room, 99 lived in a house or a flat (,6 in the same flat), and a total of 18 patients lived in overcrowded conditions. Information about employment was available for 99 patients: 39 were unemployed, 24 were retired, 29 were manual workers, and seven were students. Twenty-one patients were immunodeficient (receiving steroids or immunosuppressive treatment, diagnosed as having diabetes mellitus). Clinical manifestations and details of extrapulmonary tuberculosis are reported in Tables 1–4. A total of 68 strains of M. tuberculosis were isolated, 27 on direct examination and culture and 41 on culture alone. Five cases of primary resistance to at least one antituberculous drug were described (proportion method): INH in four cases (three low-grade resistance), streptomycin (STM) in three cases, and PZA in one case; there was also one case of multidrug resistance [INH, RMP, PZA and ethambutol (EMB)]. These resistant strains were isolated from patients between 19 and 30 years of age, originally from Asia in two cases (Burma, Laos) and from Mali, Haiti and Portugal in one case each. Histological examination found caseating granuloma in 51 patients (36.2%). In these cases, M. tuberculosis was found in 23 patients (45.1%). An isolated granuloma was present in 32 patients (22.7%) with M. tuberculosis in 11 cases (34.4%). M. tuberculosis and caseating granuloma were more frequently identified in patients under 64 years of age than in older patients: 52.1% versus 25% (P50.04) and 38% versus 25% (P50.03), respectively. Fifty percent of patients older than 64 years, and only 6.6% younger than 64 years (P,0.001) received empirical antituberculous treatment.

2.2. Statistical methods 3.1. Treatment A chi-square test with Yates’s correction and Fisher’s exact test for small sample sizes were used.

3. Results (Tables 1–4) Because this study was retrospective, HIV serology was not available in 33 patients. These patients had no obvious risk factors for HIV infection and presented no manifestations associated with HIV infection during treatment. A total of 141 patients were studied during this period, and 182 extrapulmonary sites were detected. Over the same period and in the same departments, 45 patients with extrapulmonary tuberculosis who were also infected with HIV were detected. The 25–44 year age group was the

A total of 92 patients (65.2%) were initially treated with a four-drug regimen consisting of INH, RMP, EMB and PZA. Forty-nine patients (34.8%) were placed on a threedrug regimen with INH and RMP in 48 cases, EMB in 25 cases, and PZA in 22 cases. STM was used in three cases of lymph node and pulmonary tuberculosis after stopping INH or RMP because of adverse effects in two cases. Fluoroquinolones were prescribed in four cases, due to resistance to antituberculous agents (INH or RMP) in two cases and to adverse effects in two cases. Adverse drug effects were noted in 24 patients. Corticosteroids were used in 15 patients (10.6%): in 11 cases from the onset and in four cases because of increasing initial lesions. Prednisone was used at a median daily dose of 0.6 mg / kg per

O. Fain et al. / European Journal of Internal Medicine 11 (2000) 145 – 150

147

Table 1 Characteristics of 141 patients with extrapulmonary tuberculosis Site Patients: Localizations:

Lymph nodes n569 n581

Sex ratio (male / female) % Migrants % Isolated site % Associated pulmonary tuberculosis % Associated extrapulmonary tuberculosis % Detection of M. tuberculosis from the site % Direct examination positive % Histological diagnosis from the site % Empirical treatment % Constitutional symptoms Fever Weight loss Sweats Positive tuberculin skin test (%) Erythrocyte sedimentation rate .30 mm (%) Lymphopenia ,1000 / mm 3 (%) Delay a (days) Diagnosis delay b (days) Duration of treatment in months (range) a b

Skeletal n532 n535

1.09

Pleuritis n536 n536

1.91

76.6 55.1 31.9 30.4 38.2 10.6 58 7.2 71 36.2 50.7 23.2 92 69 20.3 125.2 30.8 9.5 (6–19)

Meningitis n57 n57

3

86.6 18.7 31.2 75 25 9.3 55 18.7 84.4 68.7 71.9 40.6 81.5 32 28.1 90.7 53.9 11.2 (6–19)

1.33

70.9 61.1 33.3 27.8 19.4 9.3 68.2 25 86.4 72.7 63.6 13.6 66.6 36 47.2 62.8 14.2 8.5 (6–12)

57.1 57.1 42.8 42.9 42.9 0 0 14.3 100 57.1 51.1 14.3 80 71.4 57.1 56 20.3 9.8 (8–12)

Urological n58 n58

Total n5141 n5182

0.6

1.47

62.5 12.5 37.5 75 62.5 0 0 25 62.5 37.5 37.5 0 80 100 16.7 44.2 25.7 10.2 (6–18)

73.6 55.3 44.7 60.2 48.2 19 58.9 16.3 78 53.2 26.2 61 78.6 66.7 29.5 99 31.3 10 (6–19)

Delay between the first clinical signs and the first medical consultation. Delay between the first medical consultation and the date of tuberculosis diagnosis.

day for a mean duration of 2 months. Surgery was performed in 22 patients (15.6%).

3.2. Outcome Some 48 patients (34%) were lost to follow-up, 35 of them (24.8%) just after discharge from hospital, and 13 after 1–4 months of treatment. Seventy-nine patients were cured without sequelae and 10 with sequelae. Five new sites with bacteriological evidence appeared during treatment; in four patients this occurred after a median interval of 75.7 days (range 20–102 days). No predisposing factors were detected. All patients had good compliance and

normal immune reactions, and the strains were sensitive to all antituberculous drugs. All patients were cured by prolonged treatment (median 17 months). Four of our 141 patients died, three of a cause unrelated to tuberculosis. In all, 95.7% of the patients who were not lost to follow-up were cured (63% of all patients).

4. Discussion This study is a reminder of the importance of tuberculosis, especially in big cities and their suburbs, independently of HIV infection. In the case of the Ile de

Table 2 Characteristics of extrapulmonary tuberculosis: our study (S) and the literature (L) Site

Sex ratio

Migrants (%)

Bacteriology proof from the site (%)

Histologic diagnosis from the site (%)

Associated pulmonary tuberculosis (%)

S

L

S

L

S

L

S

L

S

L

Lymph nodes [16,36,37]

1.1

0.8

76.6

79

38.2

70–75

58

100

31.9

7–42

Skeletal [20,38,39]

1.9

2

86.6

68

70

83

55

95

31.2

30

Pleuritis [40–42]

3

2.4–3

70.9

–

25

13–70

68.2

97

33.3

22–50

Neuromeningeal [14,15,43]

1.3

1.2–4.1

57.1

80–87

42.9

40–86

0

0

42.8

25–74

Total [5,7,9,10,44,45]

1.47

1.09

73.6

37–54

48.2

58–71

58.9

81.5

44.7

18–67

O. Fain et al. / European Journal of Internal Medicine 11 (2000) 145 – 150

148

Table 3 Characteristics of extrapulmonary tuberculosis: our study (S) and the literature (L) Lymph nodes

Superficial (%) Cervical (%) Deep (%) Mediastinal (%) Mesenteric (%)

Skeletal (%) S

L [44]

68.1 49.3 31.9 18.8 13

77.8 51.8 22.3 14.8 7.4

Peripheral Spine Soft tissue Abscess associated

France area, 9–23% [5] of cases of tuberculosis were detected in HIV-infected patients. Extrapulmonary tuberculosis accounts for 15–30% of all cases of tuberculosis in the literature [6]. In the Seine Saint Denis area, the increase in the number of cases of tuberculosis between 1984 and 1994 was mainly due to the increase in extrapulmonary forms, which rose to 38% in 1994 from a mere 15.2% in 1984 [7]. In the United States, among HIVinfected patients, 70% of cases of tuberculosis infection appearing at the stage of AIDS are extrapulmonary [1]. In the Seine Saint Denis area, the figure is lower since 48.3% of cases of tuberculosis were extrapulmonary in HIVinfected patients [7]. According to many studies [8–10], young men are at greatest risk, particularly those in the 25–44 year age group. Immigrants are most frequently affected: 73.6% of cases, although they only represent 12.9% of the Ile de France population and 18.9% of the Seine Saint Denis population in 1990. This fact is mainly due to the high level of endemic tuberculosis in their countries of origin and to their poor living conditions. Migrants who came from sub-Saharan Africa or Asia were more frequently men (64% in our study, 74% in Seine Saint Denis between

Other localizations (%) S

L [14,44]

25 78.1 50

50 50 40

Liver Peritoneum Colon Spleen Pericardium Bone marrow Parotiditis Cavum Larynx Skin

S

L [9,44]

8.5 2.8 1.4 0.7 1.4 2.1 0.7 0.7 0.7 0.7

6.6 8 0.7 – 3 2.6 – – 0.7 0–7.9

1989 and 1993) [5,7]. For North Africans, the sex ratio was 0.73, similar to that of the French patients (0.83). The sub-Saharan Africans and Asians were younger than the North Africans and the French. This reflects the characteristics of immigration in France: more longstanding for North Africans than for sub-Saharan Africans or Asians. For the French group, the French West Indians were younger (P,0.05). In our study, 14.2% of the patients were older than 64 years. In France in 1994, the incidence was 28 / 100 000 in this age group, with a 16% progression between 1992 and 1993 [11]. This age group consisted of 50% French, 16% North Africans, 11.1% Asians, and 5.5% sub-Saharan Africans. The high incidence of tuberculosis in young migrants and elderly French subjects, together with the fact that poor living conditions were detected in our patients, emphasizes the primordial role of social conditions in the progression of this disease. In New York City, Brudney and Dobkin [12] noted 68% homelessness and 82% unemployment among 224 patients affected by tuberculosis. In the Ile de France in 1995, risk factors associated with tuberculosis transmission were male gender and homelessness. Homelessness was a factor of poor compliance and induced an increased risk of resistant

Table 4 Characteristics of extrapulmonary tuberculosis Our study

Average age at diagnosis (years) Age group 25–44 years (%) Migrants (%) Sub-Saharan Africans a Asians a North Africans a Predisposing factors or immunodepression (HIV excluded) (%) Alcoholism (%) a

% Among migrants.

42.2 54.6 73.6 39 23 21 19

6.4

Ile de France [5]* Seine Saint Denis [7]** Paris [10]*** 49* 37.3* 38* 10.4* 28*

56** 56** 43**

Other studies

52*** 46***

58 [9] 39.5 [9] 37 [9]

29***

13.6 [20] 26.3 [9] 44 [32] 53 [12]

28**

O. Fain et al. / European Journal of Internal Medicine 11 (2000) 145 – 150

strains [13]. The median delay between the first clinical signs and the first medical consultation was 99 days. Comparison with other series is only possible for meningitis: 56 days in our study, 10 days for Kent [14] and 14 days for Ogawa [15]. Our longer delay is probably related to difficulties of access to health care in our area. Like studies in England [16], the United States [17] and Canada [18], lymph node tuberculosis was frequently observed in Asians (62% of cases). Mediastinal sites were mainly described in migrants, particularly sub-Saharan Africans. Spondylitis was more often described in men and migrants. Multifocal sites were noted in only one patient (3.1%). This frequency is close to that observed in North America or Europe [19], but lower than that in ‘developing countries’: 10–15%. In France, 20% of multifocal sites (31%) were reported in sub-Saharan Africans and 10% in French patients (P,0.01) [20]. Tuberculous pleuritis occurred more frequently in men in two age groups: 20–40 years and older than 65 years [21]. Pleural effusion was more frequently related to reactivation of old tuberculosis: 19% [22] to 46% of cases [23]. Meningitis represented 86% [24] of neuromeningeal tuberculosis, brain abscess 12% [14] to 35% [25]. Brain abscess was associated with meningitis in 30% of cases [25]. Bacteriological proof of extrapulmonary tuberculosis was obtained more frequently in sub-Saharan Africans: 61% in our study, 58% of Cabie´ et al.’s cases [26]. Only one strain of M. tuberculosis was multiresistant among 141 patients (68 strains isolated), i.e. 0.7% of patients. Fortyeight multiresistant strains were isolated in 1992 in France (0.5% of cases) [27], although the prevalence in New York City was 19% [28] and in Rome 5.7% in 1990–1992 [29]. In France, multidrug-resistant organisms were isolated from men (sex ratio 3), 25- to 44-year-old (48% of cases) immigrants in 50% of cases [30]. Thirty-four percent of our patients were lost to follow-up, compared to 24% of those of Brechot in Paris [31] and 89% of those of Brudney and Dobkin in New York City [12]. A favorable course was observed in 95.7% of our patients not lost to follow-up; this was seen in 74.8% [31] to 96% [26] in Parisian studies. Tuberculous meningitis was cured in only 48.9% [15] to 75.9% [14] of patients. Mortality is now uncommon in tuberculosis: 0.7% (our study) to 5.7% [6], but higher in neuromeningeal forms: 7% [14] to 31% [15]. In our series, as in other retrospective studies [32], median treatment time exceeded 6 or 9 months (10 months). However, as the bacillary burden in extrapulmonary tuberculosis is lower than that in cavitary pulmonary disease, and as antituberculous drugs effectively penetrate into most tissues, 6 months of treatment is often effective [1]. In lymph node tuberculosis, 6 months of treatment, including INH, RMP and PZA, is as effective as 9 or 12 months [33]. In miliary, meningeal, or skeletal tuberculosis, more prolonged therapy is recommended, but no studies have demonstrated any advantage of prolonging treatment beyond 6 months. In the studies by Dautzenberg

149

et al. [34] and Cohn et al. [35], no relapse was noted after 6 months of treatment for pulmonary and extrapulmonary tuberculosis. This study shows that tuberculosis is still a public health problem in the suburbs of Paris, one that is linked to poor social conditions and not necessarily secondary to HIV infection. Better early detection and a more efficient follow-up service to assist patient compliance, combined with better living conditions, would limit the growth of the disease and the multiplication of multiresistant strains.

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