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Disseminated BCG infection: a four case study
Méd Mal Infect 2001 ; 31 : 549-53 2001 Éditions scientifiques et médicales Elsevier SAS. Tous droits réservés S0399-077X(01)00264-5/FLA
Original article
Disseminated BCG infection: a four case study I. Bahri 1∗ , T. Boudawara 1 , S. Makni 1 , M. Kharrat 1 , A. Triki 2 , S. Ben Hamed 3 , R. Jlidi 1 1 Laboratoire d’anatomie et de cytologie pathologiques, CHU Habib Bourguiba de Sfax, Tunisie ; 2 service de pédiatrie, CHU Habib Bourguiba de Sfax, Tunisie ; 3 service des maladies infectieuses, CHU Habib Bourguiba de Sfax, Tunisie
(Received 10 May 2001; accepted 5 July 2001)
Summary BCG inoculation at birth has been compulsory in our country since 1959. Adverse reactions induced by BCG vaccination are rare, ranging from zero to 23.8%. Disseminated infections are even rarer and their estimated incidence is 0.1 to 4.3 per one million vaccinated children. Lethal disseminated BCG infection is exceptional and affects especially the children presenting an immune deficiency. A familial gene defect may play a role. BCG osteitis is second to suppurative lymphadenitis in clinical forms; it generally develops five months to five years after vaccination. We report four cases of disseminated BCG infection occuring in children from three months to four years of age, leading to death in two cases. Our objective is to discuss the pathologic aspects of BCG infection. 2001 Éditions scientifiques et médicales Elsevier SAS BCG / immune defect / tuberculosis / vaccine
Résumé – Bécégite généralisée : Étude de quatre observations. La vaccination par le Bacille de Calmette et Guérin (BCG) à la naissance est obligatoire dans notre pays depuis 1959. Les réactions secondaires au BCG sont rares variant de zéro à 23,8 %. Les infections disséminées sont encore plus rares et sont observées chez 0,1 à 4,3/million d’enfants vaccinés. Les bécégites mortelles sont exceptionnelles et atteignent surtout les enfants présentant des déficits immunitaires. Le rôle d’une anomalie génétique familiale doit être pris en considération. La bécégite osseuse est retrouvée en deuxième position dans les formes cliniques après les adénites suppurées ; elle survient généralement cinq mois à cinq ans après la vaccination. Nous rapportons quatre observations de bécégites généralisées chez des enfants âgés de trois mois à quatre ans avec une évolution mortelle dans deux cas. Notre objectif est de discuter les aspects anatomopathologiques des bécégites. 2001 Éditions scientifiques et médicales Elsevier SAS BCG / déficit immunitaire / tuberculose / vaccin
Calmette and Guérin discovered BCG in 1906. In Tunisia, BCG vaccination became mandatory in 1959. Post BCG vaccination complications are observed in 0 to 23.8% cases. Disseminated BCG infections are rare. They are observed in 0.1 to 4.3/million vaccinated children. We report four cases with the objective to discuss their anatomoclinical aspect and to insist on the interest prevention.
∗ Correspondence and reprints.
E-mail address: [email protected] (I. Bahri).
CASES Case 1 Infant BN, 3 months old, having received BCG vaccination at birth in the Bir Ali Regional Hospital (lyophilized vaccine made from a weakened strain of Mycobacterium bovis, given by intradermal injection in the upper third of
550
I. Bahri et al.
the left arm), presented with an occlusive syndrome. On examination, he was hypotrophic at minus four standard deviations (−4 SD), pyretic (38◦ C), and presented with abdominal distension and collateral circulation. A thorax X-ray showed a right basal-lobar opacity. Biological assessment revealed a hyperleucocytosis at 20,800, a microcytic hypochrome anemia at 9 g of hemoglobin, and a hypocalcemia at 1.5 mmol/L. Immunity was not explored and there was no history of similar cases in the family. Death came rapidly, due to peritonitis and respiratory deficiency. Autopsy revealed, an ascitis, bilateral pleural effusion, micronodular hepatomegalia and multiple mesenteric hypertrophic lymph nodes. Histological examination of biopsy samples confirmed the disseminated BCG infection because of large areas of caseous necrosis in mesenteric and peripancreatic nodes (figure 1a) associated with tuberculous granuloma in the intestin, spleen, liver (figure 1b), and lungs.
Case 2
Figure 1a. Peripancreatic tuberculous granuloma (HE ×200).
Figure 2a. Ultrasound: multinodular aspect of the liver and increased kidney volume.
Figure 1b. Granulomatous hepatitis (HE ×400).
Figure 2b. Spleen multiple nodules.
Infant ZA, six months old, firstborn and first pregnancy, premature and dysmature, received BCG vaccination at one month of age in a private clinic. The vaccine was made from a weakened strain of Mycobacterium bovis and given by intradermal injection above the insertion of the deltoid muscle. This infant presented with a history of chronic thrush despite treatment. He was admitted to hospital because of a worsening condition and cutaneousmucosa paleness noted over the last month. Examination revealed hypotrophy (−4 DS), hepatosplenomegaly, exophtalmia, and testicular hypertrophy. The liver was multinodular and the kidney volume appeared enlarged at ultrasonography (figure 2a). Blood sample analysis proved a pancytopena with a leucopenia at 1,700/mL and a neutropenia at 850/mL. Sternal puncture was normal. No search for an immune deficit or a familial genetic abnormality was performed, but there was no similar case
551
Disseminated BCG infection below four years of age
Figure 4. Osseous BCG infection: epithelioid granuloma with Langhans giant cells (HE ×400).
Case 4
Figure 3. Radiography of elbows: thickening of the right ulna.
in the family history. Evolution was marked by a quick death. Post mortem histological examination of internal organs internes confirmed the disseminated BCG infection with involvment of the liver, spleen (figure 2b), kidneys, adrenals, lungs, and hematopoietic marrow.
Case 3 Infant AS, 18 months old, received BCG vaccination at birth in the Gafsa Regional Hospital, given by intradermal injection in the upper third of the left arm (vaccine made from a weakened live strain of Mycobacterium bovis). She had no previous history of pathology and presented with painless tumefactions of the right side hand, ankle, and elbow (figure 3) having developed over the last three months. The clinical examination showed a eutrophic child (−1 DS). Radiological exploration revealed the presence of multiple calcifications in the spleen, abdomen, and soft cervical parts, and a delayed bone maturation (bone age: nine months). Biological assessment gave a hyperleucocytosis at 18,400/mL with the predominance of lymphocytes (lymphocytes: 8,500/mL or 46.4% and neutrophils: 7,300/mL or 40%). A biopsy of the ulna revealed a dissociation of the bone by merging tuberculous granuloma, often sites of caseous necrosis; this histological aspect is typical of bone BCG infection. The immunologic assessment was normal (immunoglobulin dosage and serum dosage of the total hemolytic complement and of the C3 and C4 fractions). Evolution under antituberculous treatment was marked by clinical and radiological improvement after 50 days. The patient was then lost to follow-up.
Infant DS, 4 yeards old, born at home, received BCG vaccination at three years of age (dry vaccine made from a weakened strain of Mycobacterium bovis, given by intradermal injection in the upper third of the left arm). One year after this vaccination, 2 erythemato-papulous lesions developed under the left axilla and on the injection site. On clinical examination, he was hypotrophic (−3 DS). Histological examination of the axilla and injection site biopsies was suggestive of BCG infection because of the presence of tuberculous granuloma. Biological assessment gave normal blood counts and a negative HIV serology. An antituberculous treatment was given but stopped by the patient after one month. The evolution was marked by a relapse of cutaneous lesions four years after, with the development of a sternal mass of 8 cm in diameter, cervical pain, and a degradation of the general health state. The probable diagnostic was that of a cutaneous histiocytosis. New cutaneous and bone biopsies of the sternal region were performed so as to diagnose a possible histiocytosis. Histological examination confirmed BCG infection (figure 4). Dosage of the serum complement was normal. Treatment was taken up again, leading to clinical and radiological improvement after ten months, but the patient was then lost to follow-up.
DISCUSSION BCG is made from a weakened live strain of Mycobacterium bovis. It is harmless in most children. Its protective effect range has been estimated from 0 to 80% in several studies [1, 2]. Nevertheless, secondary complications may occur in 0 to 23.8% of vaccinated children [3, 4]. The most frequent complications are purulent lymphadenitis (0.9 per 1,000 vaccinated children) [3]. Bone BCG infection is the second most frequent, ranging fom 0.39 to 46 per million vaccinated children [5 – 7]. It usually develops
552
I. Bahri et al.
five months to five years after vaccination [8]. Disseminated BCG infection are rare. They account for 6/1,000 of secondary complications after BCG vaccination [9]. They are observed in 0.1 to 4.3 per million vaccinated children [9 – 11] (the two patients from the Sfax region, in our study, were born in 1994 and 1997; the number of children vaccinated during these two years is respectively vaccines 16,416 and 13,971). In our country, the BCG vaccine used is a lyophilized vaccine made from a weakened strain of Mycobacterium bovis; its administration is exclusively intradermal, and it is injected above the distal insertion of the deltoid muscle (around the superior third of the left arm). Disseminated BCG infection is lethal in 50 to 71% of the cases [9, 12]. In ou series, the evolution was fatal in two cases out of four. Various factors are implicated [8, 9, 13, 14]: – virulence of the vaccine strain; – the high number of injected bacilli; – a technical injection mistake which must be strictly intradermal; – a temporary or permanent immune deficiency observed in 86% of the cases [9]; – a low socio-economical status (malnutrition ++) (cases n◦ 1, 2, and 4). For some authors, disseminated BCG infection is defined by the combination of three conditions: – culture and identification of BCG at least; – proved dissemination (by hemoculture or marrow culture, or the affection of two anatomical sites away from the vaccination site); – the presence of a system syndrome compatible with tuberculosis (pyrexia, weight-loss, anemia, and death). Twenty eight cases of disseminated BCG infection were reported in litterature between 1980 and 1997 [9]; the clinical symptomatology is not specific: coughing (72%), pyrexia (61%), anorexia and weight-loss (40%), diarrhea and emesis (33%). The most frequent clinical signs on examination are hepatomegaly (82%), splenomegaly (54%), and adenopathies (46%) [14]. In our cases, bone affection was noted in two cases out of four osseu. In animals and healthy infants, BCG has preferential sites in the liver, lungs, and spleen, with tuberculoid granuloma which remain clinically asymptomatic and evolve to complete cure without calcification [10, 15]. After two to three years, bacilli are only found in satellite lymph nodes [10]. In case of patent immune deficiency, the histological lesions vary depending on the type of deficit (inconstant caracter of epithelioid and giant cells, of the follicular organisation, and of the caseous necrosis) [10, 15]. Recent studies have shown that vaccine administration delayed until the end of the third month is more efficient and gives less secondary complications [16]. Other authors have shown that administration of half of the usual vaccine dose is sufficient and gives a lot less adverse effects [6]. Experimental studies on the murine model have shown a better efficacy of antituberculous vaccination with a DNA
fragment instead of BCG [17, 18]. Disseminated BCG infection was considered as a childhood disease, but, today, cases have been reported in HIV positive adults [9]. Immunodepressed children and late stage AIDS patients present more risks and do not respond as well to standard treatment [9]. Research has allowed identifying a new heredirary immune deficiency, the absence of interferon gamma expression (IFN gamma). This deficit is marked by susceptibility to weakly virulent mycobacteria, whether weakened (BCG vaccine) or atypical (environmental). Indeed, the immune response to BCG is essentially mediated by the macrophages which phagocyte BCG and are then activated by T lymphocytes, leading to the granuloma. This macrophagic activation results mainly from the secretion of IFN gamma by T lymphocytes and tumor necrosis factor alpha by macrophages. Experimental studies have shown that after a BCG injection, mice, genetically deprived of one or the other of these two cytokines or of their specific receptor que, are incapable of developing bactericidal granuloma and die rapidly of disseminated BCG infection [13]. Furthermore, the role of interleukine12 (IL12) in the mediation of the immune response to BCG is today well established [19 – 22]. Indeed, experimental studies have demonstrated that this cytokine, produced by macrophages immediately after the infection, increases the production of IFN gamma [21, 22]. Thus, it was shown that adding IL12 to BCG considerably increases its efficacy [19, 21]. These immune deficits seem corelated to a familial genetic anomaly; indeed, an experimental study on a consanguinous Tunisian family, an offspring of which died from disseminated BCG infection, allowed to identify the deletion of a nucleotide in the region coding for the receptor of IFN gamma; this genetic anomaly in inherited in the homozygote state [13]. Other studies have suggested a possible recessive transmission genetic abnormality responsible for an increased susceptibility to infections by mycobacteria; the responsible gene is named NRAMP “natural resistance-associated macrophage protein gene”; it was identified in the rat; in man, this gene was not found but there seems to be a human homologue [11]. In our study, we did not look for an immune deficit or a familial genetic anomaly; nevertheless, pancytopenia in case n◦ 2 and the notion of repeated local candidosis could suggest an undetected immune deficit. Besides these immune deficits, half of the disseminated BCG infection or of the atypical mycobactera in children are idiopathic, without any detectable immune deficiency [13]. In most cases, the medical treatment includes at least isoniazide and rifampicine [9]. Surgery is usd only for rather large purulent and/or ou fistulised lesions. Disseminated BCG infection is a serious disease, lethal in 71% of the cases. The death rate is especially high in case of immunodepression (83%) [9], hence the interest of prevention, diagnostic, and early management for an uncomplicated evolution without sequels.
Disseminated BCG infection below four years of age
REFERENCES 1 Hengster P, Schnpka J, Fille M, Menardi G. Occurence of suppurative lymphadenitis after a change of BCG vaccine. Arch Dis Child 1992; 67: 952-5. 2 Guérin N, Ajjan N. Vaccinations. Encycl Méd Chir (Paris-France), Pédiatrie, 4-002-B-50, 1995, 18 p. 3 Romanus V, Fasth A, Tordai P, Erik Wiholm B. Adverse reactions in healthy and immunocompromised children under six years of age vaccinated with the Danish BCG vaccine, strain Copenhagen 1331: implications for the vaccination policy in Sweden. Acta Pediatr 1993; 82: 1043-52. 4 O’Brien KL, Ruff AJ, Albert Louis M, Desormaux J, Jules Joseph D, Mc Brien M, et al. Bacillus Calmette-Guérin complications in children born to HIV-1-infected women with a review of the literature. Pediatrics 1995; 95: 414-8. 5 Al-Arbi K, Al-Khider ME, Sadiq S. Osteitis of the humerus following BCG vaccination. Tubercle 1984; 65: 305-7. 6 Krepela LV, Galliova J, Kubec V, Marik J. The effect of reduced doses of BCG vaccine on the occurrence of osseous complications after vaccination. Cesk Pediatr 1992; 47: 134-6. 7 Kröger L, Korppi M, Brander E, Kröger H, Wasz-Höckert O, Backman A, et al. Osteitis caused by Bacille Calmette-Guérin vaccination: A retrospective analysis of 222 cases. J of Infect Dis 1995; 172: 574-6. 8 Geissler W, Pumberger W, Wurnig P, Stuhr O. BCG osteomyelitis as a rare cause of mediastinal tumor in a one-year-old child. Eur J Pediatr Surg 1992; 2: 118-21. 9 Talbot EA, Perkins MD, Silva S, Frothingham R. Disseminated Bacille Calmette-Guérin disease after vaccination: case report and review. Clin Infect Dis 1997; 24: 1139-46. 10 Perelman R, Danis F, Nathanson M, Lafay F, Garcia J, Fischer A. A propos d’un cas de “bécégite” généralisée mortelle sans déficit immunitaire apparent. Sem Hop Paris 1980; 56: 480-3. 11 Banac S, Franulovi´c J. Familial liability to complications after BCG vaccination. Acta Pediatr 1997; 86: 899-902.
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12 Casanova JL, Blanche S, Emile JF, Jouanguy E, Lamhamedi S, Altare F, et al. Idiopathic disseminated bacillus Calmette-Guérin infection: a french national retrospective study. Pediatrics 1996; 98: 774-8. 13 Casanova JL. Infection disséminée idiopathique par le BCG ou les mycobactéries atypiques. Arch Pediatr 1997; 4: 883-5. 14 Hussey G, Chisholm T, Kibel M. Military tuberculosis in children: a review of 94 cases. Pediatr Infect Dis J 1991; 10: 832-6. 15 Lachaux A, Descos B, Mertani A, Souillet G, Gilly J, Hermier M. Infection généralisée à BCG d’évolution favorable chez un nourrisson de 3 mois sans déficit immunitaire reconnu. Arch Fr Pediatr 1986; 43: 807-9. 16 Ildirim I, Sapan N, Cavusoglu B. Comparison of BCG vaccination at birth and at third month of life. Arch Dis Child 1992; 67: 80-2. 17 Tascon RE, Colston MJ, Ragno S, Stavropoulos E, Gregory D, Lowrie DB. Vaccination against tuberculosis by DNA injection. Nature Medicine 1996; 2: 888-92. 18 Huygen K, Content J, Denis O, Montgomery DL, Yawman AM, Deck RR. Immunogenicity and protective efficacy of a tuberculosis DNA vaccine. Nat Med 1996; 2: 893-8. 19 Freidag BL, Melton GB, Collins F, Klinman DM, Cheever A, Stobie L, et al. CpG oligodeoxynucleotides and interleukin-12 improve the efficacy of Mycobacterium bovis BCG vaccination in mice challenged with M. tuberculosis. Infect Immun 2000; 68: 2948-53. 20 Leal IS, Smedegard B, Andersen P, Appelberg R. Interleukin-6 and interleukin-12 participate in induction of a type 1 protective T-cell response during vaccination with a tuberculosis subunit vaccine. Infect Immun 1999; 67: 5747-54. 21 O’Donnell MA, Luo Y, Chen X, Szilvasi A, Hunter SE, Clinton SK. Rôle of IL-12 in the induction and potentiation of IFN-gamma in response to bacillus Calmette-Guerin. J Immunol 1999; 163: 424652. 22 Mendez-Samperio P, Ayala-Verdin HE, Trejo-Echeverria A. Interleukin-12 regulates the production of Bacille Calmette-Guerininduced interferon-gamma from human cells in a CD40-dependent manner. Scand J Immunol 1999; 50: 61-7.
Original article
Disseminated BCG infection: a four case study I. Bahri 1∗ , T. Boudawara 1 , S. Makni 1 , M. Kharrat 1 , A. Triki 2 , S. Ben Hamed 3 , R. Jlidi 1 1 Laboratoire d’anatomie et de cytologie pathologiques, CHU Habib Bourguiba de Sfax, Tunisie ; 2 service de pédiatrie, CHU Habib Bourguiba de Sfax, Tunisie ; 3 service des maladies infectieuses, CHU Habib Bourguiba de Sfax, Tunisie
(Received 10 May 2001; accepted 5 July 2001)
Summary BCG inoculation at birth has been compulsory in our country since 1959. Adverse reactions induced by BCG vaccination are rare, ranging from zero to 23.8%. Disseminated infections are even rarer and their estimated incidence is 0.1 to 4.3 per one million vaccinated children. Lethal disseminated BCG infection is exceptional and affects especially the children presenting an immune deficiency. A familial gene defect may play a role. BCG osteitis is second to suppurative lymphadenitis in clinical forms; it generally develops five months to five years after vaccination. We report four cases of disseminated BCG infection occuring in children from three months to four years of age, leading to death in two cases. Our objective is to discuss the pathologic aspects of BCG infection. 2001 Éditions scientifiques et médicales Elsevier SAS BCG / immune defect / tuberculosis / vaccine
Résumé – Bécégite généralisée : Étude de quatre observations. La vaccination par le Bacille de Calmette et Guérin (BCG) à la naissance est obligatoire dans notre pays depuis 1959. Les réactions secondaires au BCG sont rares variant de zéro à 23,8 %. Les infections disséminées sont encore plus rares et sont observées chez 0,1 à 4,3/million d’enfants vaccinés. Les bécégites mortelles sont exceptionnelles et atteignent surtout les enfants présentant des déficits immunitaires. Le rôle d’une anomalie génétique familiale doit être pris en considération. La bécégite osseuse est retrouvée en deuxième position dans les formes cliniques après les adénites suppurées ; elle survient généralement cinq mois à cinq ans après la vaccination. Nous rapportons quatre observations de bécégites généralisées chez des enfants âgés de trois mois à quatre ans avec une évolution mortelle dans deux cas. Notre objectif est de discuter les aspects anatomopathologiques des bécégites. 2001 Éditions scientifiques et médicales Elsevier SAS BCG / déficit immunitaire / tuberculose / vaccin
Calmette and Guérin discovered BCG in 1906. In Tunisia, BCG vaccination became mandatory in 1959. Post BCG vaccination complications are observed in 0 to 23.8% cases. Disseminated BCG infections are rare. They are observed in 0.1 to 4.3/million vaccinated children. We report four cases with the objective to discuss their anatomoclinical aspect and to insist on the interest prevention.
∗ Correspondence and reprints.
E-mail address: [email protected] (I. Bahri).
CASES Case 1 Infant BN, 3 months old, having received BCG vaccination at birth in the Bir Ali Regional Hospital (lyophilized vaccine made from a weakened strain of Mycobacterium bovis, given by intradermal injection in the upper third of
550
I. Bahri et al.
the left arm), presented with an occlusive syndrome. On examination, he was hypotrophic at minus four standard deviations (−4 SD), pyretic (38◦ C), and presented with abdominal distension and collateral circulation. A thorax X-ray showed a right basal-lobar opacity. Biological assessment revealed a hyperleucocytosis at 20,800, a microcytic hypochrome anemia at 9 g of hemoglobin, and a hypocalcemia at 1.5 mmol/L. Immunity was not explored and there was no history of similar cases in the family. Death came rapidly, due to peritonitis and respiratory deficiency. Autopsy revealed, an ascitis, bilateral pleural effusion, micronodular hepatomegalia and multiple mesenteric hypertrophic lymph nodes. Histological examination of biopsy samples confirmed the disseminated BCG infection because of large areas of caseous necrosis in mesenteric and peripancreatic nodes (figure 1a) associated with tuberculous granuloma in the intestin, spleen, liver (figure 1b), and lungs.
Case 2
Figure 1a. Peripancreatic tuberculous granuloma (HE ×200).
Figure 2a. Ultrasound: multinodular aspect of the liver and increased kidney volume.
Figure 1b. Granulomatous hepatitis (HE ×400).
Figure 2b. Spleen multiple nodules.
Infant ZA, six months old, firstborn and first pregnancy, premature and dysmature, received BCG vaccination at one month of age in a private clinic. The vaccine was made from a weakened strain of Mycobacterium bovis and given by intradermal injection above the insertion of the deltoid muscle. This infant presented with a history of chronic thrush despite treatment. He was admitted to hospital because of a worsening condition and cutaneousmucosa paleness noted over the last month. Examination revealed hypotrophy (−4 DS), hepatosplenomegaly, exophtalmia, and testicular hypertrophy. The liver was multinodular and the kidney volume appeared enlarged at ultrasonography (figure 2a). Blood sample analysis proved a pancytopena with a leucopenia at 1,700/mL and a neutropenia at 850/mL. Sternal puncture was normal. No search for an immune deficit or a familial genetic abnormality was performed, but there was no similar case
551
Disseminated BCG infection below four years of age
Figure 4. Osseous BCG infection: epithelioid granuloma with Langhans giant cells (HE ×400).
Case 4
Figure 3. Radiography of elbows: thickening of the right ulna.
in the family history. Evolution was marked by a quick death. Post mortem histological examination of internal organs internes confirmed the disseminated BCG infection with involvment of the liver, spleen (figure 2b), kidneys, adrenals, lungs, and hematopoietic marrow.
Case 3 Infant AS, 18 months old, received BCG vaccination at birth in the Gafsa Regional Hospital, given by intradermal injection in the upper third of the left arm (vaccine made from a weakened live strain of Mycobacterium bovis). She had no previous history of pathology and presented with painless tumefactions of the right side hand, ankle, and elbow (figure 3) having developed over the last three months. The clinical examination showed a eutrophic child (−1 DS). Radiological exploration revealed the presence of multiple calcifications in the spleen, abdomen, and soft cervical parts, and a delayed bone maturation (bone age: nine months). Biological assessment gave a hyperleucocytosis at 18,400/mL with the predominance of lymphocytes (lymphocytes: 8,500/mL or 46.4% and neutrophils: 7,300/mL or 40%). A biopsy of the ulna revealed a dissociation of the bone by merging tuberculous granuloma, often sites of caseous necrosis; this histological aspect is typical of bone BCG infection. The immunologic assessment was normal (immunoglobulin dosage and serum dosage of the total hemolytic complement and of the C3 and C4 fractions). Evolution under antituberculous treatment was marked by clinical and radiological improvement after 50 days. The patient was then lost to follow-up.
Infant DS, 4 yeards old, born at home, received BCG vaccination at three years of age (dry vaccine made from a weakened strain of Mycobacterium bovis, given by intradermal injection in the upper third of the left arm). One year after this vaccination, 2 erythemato-papulous lesions developed under the left axilla and on the injection site. On clinical examination, he was hypotrophic (−3 DS). Histological examination of the axilla and injection site biopsies was suggestive of BCG infection because of the presence of tuberculous granuloma. Biological assessment gave normal blood counts and a negative HIV serology. An antituberculous treatment was given but stopped by the patient after one month. The evolution was marked by a relapse of cutaneous lesions four years after, with the development of a sternal mass of 8 cm in diameter, cervical pain, and a degradation of the general health state. The probable diagnostic was that of a cutaneous histiocytosis. New cutaneous and bone biopsies of the sternal region were performed so as to diagnose a possible histiocytosis. Histological examination confirmed BCG infection (figure 4). Dosage of the serum complement was normal. Treatment was taken up again, leading to clinical and radiological improvement after ten months, but the patient was then lost to follow-up.
DISCUSSION BCG is made from a weakened live strain of Mycobacterium bovis. It is harmless in most children. Its protective effect range has been estimated from 0 to 80% in several studies [1, 2]. Nevertheless, secondary complications may occur in 0 to 23.8% of vaccinated children [3, 4]. The most frequent complications are purulent lymphadenitis (0.9 per 1,000 vaccinated children) [3]. Bone BCG infection is the second most frequent, ranging fom 0.39 to 46 per million vaccinated children [5 – 7]. It usually develops
552
I. Bahri et al.
five months to five years after vaccination [8]. Disseminated BCG infection are rare. They account for 6/1,000 of secondary complications after BCG vaccination [9]. They are observed in 0.1 to 4.3 per million vaccinated children [9 – 11] (the two patients from the Sfax region, in our study, were born in 1994 and 1997; the number of children vaccinated during these two years is respectively vaccines 16,416 and 13,971). In our country, the BCG vaccine used is a lyophilized vaccine made from a weakened strain of Mycobacterium bovis; its administration is exclusively intradermal, and it is injected above the distal insertion of the deltoid muscle (around the superior third of the left arm). Disseminated BCG infection is lethal in 50 to 71% of the cases [9, 12]. In ou series, the evolution was fatal in two cases out of four. Various factors are implicated [8, 9, 13, 14]: – virulence of the vaccine strain; – the high number of injected bacilli; – a technical injection mistake which must be strictly intradermal; – a temporary or permanent immune deficiency observed in 86% of the cases [9]; – a low socio-economical status (malnutrition ++) (cases n◦ 1, 2, and 4). For some authors, disseminated BCG infection is defined by the combination of three conditions: – culture and identification of BCG at least; – proved dissemination (by hemoculture or marrow culture, or the affection of two anatomical sites away from the vaccination site); – the presence of a system syndrome compatible with tuberculosis (pyrexia, weight-loss, anemia, and death). Twenty eight cases of disseminated BCG infection were reported in litterature between 1980 and 1997 [9]; the clinical symptomatology is not specific: coughing (72%), pyrexia (61%), anorexia and weight-loss (40%), diarrhea and emesis (33%). The most frequent clinical signs on examination are hepatomegaly (82%), splenomegaly (54%), and adenopathies (46%) [14]. In our cases, bone affection was noted in two cases out of four osseu. In animals and healthy infants, BCG has preferential sites in the liver, lungs, and spleen, with tuberculoid granuloma which remain clinically asymptomatic and evolve to complete cure without calcification [10, 15]. After two to three years, bacilli are only found in satellite lymph nodes [10]. In case of patent immune deficiency, the histological lesions vary depending on the type of deficit (inconstant caracter of epithelioid and giant cells, of the follicular organisation, and of the caseous necrosis) [10, 15]. Recent studies have shown that vaccine administration delayed until the end of the third month is more efficient and gives less secondary complications [16]. Other authors have shown that administration of half of the usual vaccine dose is sufficient and gives a lot less adverse effects [6]. Experimental studies on the murine model have shown a better efficacy of antituberculous vaccination with a DNA
fragment instead of BCG [17, 18]. Disseminated BCG infection was considered as a childhood disease, but, today, cases have been reported in HIV positive adults [9]. Immunodepressed children and late stage AIDS patients present more risks and do not respond as well to standard treatment [9]. Research has allowed identifying a new heredirary immune deficiency, the absence of interferon gamma expression (IFN gamma). This deficit is marked by susceptibility to weakly virulent mycobacteria, whether weakened (BCG vaccine) or atypical (environmental). Indeed, the immune response to BCG is essentially mediated by the macrophages which phagocyte BCG and are then activated by T lymphocytes, leading to the granuloma. This macrophagic activation results mainly from the secretion of IFN gamma by T lymphocytes and tumor necrosis factor alpha by macrophages. Experimental studies have shown that after a BCG injection, mice, genetically deprived of one or the other of these two cytokines or of their specific receptor que, are incapable of developing bactericidal granuloma and die rapidly of disseminated BCG infection [13]. Furthermore, the role of interleukine12 (IL12) in the mediation of the immune response to BCG is today well established [19 – 22]. Indeed, experimental studies have demonstrated that this cytokine, produced by macrophages immediately after the infection, increases the production of IFN gamma [21, 22]. Thus, it was shown that adding IL12 to BCG considerably increases its efficacy [19, 21]. These immune deficits seem corelated to a familial genetic anomaly; indeed, an experimental study on a consanguinous Tunisian family, an offspring of which died from disseminated BCG infection, allowed to identify the deletion of a nucleotide in the region coding for the receptor of IFN gamma; this genetic anomaly in inherited in the homozygote state [13]. Other studies have suggested a possible recessive transmission genetic abnormality responsible for an increased susceptibility to infections by mycobacteria; the responsible gene is named NRAMP “natural resistance-associated macrophage protein gene”; it was identified in the rat; in man, this gene was not found but there seems to be a human homologue [11]. In our study, we did not look for an immune deficit or a familial genetic anomaly; nevertheless, pancytopenia in case n◦ 2 and the notion of repeated local candidosis could suggest an undetected immune deficit. Besides these immune deficits, half of the disseminated BCG infection or of the atypical mycobactera in children are idiopathic, without any detectable immune deficiency [13]. In most cases, the medical treatment includes at least isoniazide and rifampicine [9]. Surgery is usd only for rather large purulent and/or ou fistulised lesions. Disseminated BCG infection is a serious disease, lethal in 71% of the cases. The death rate is especially high in case of immunodepression (83%) [9], hence the interest of prevention, diagnostic, and early management for an uncomplicated evolution without sequels.
Disseminated BCG infection below four years of age
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