Disseminated bacillus Calmette-Guerin infection and immunodeficiency.

To the Editor: Disseminated bacillus Calmette-Guerin (BCG) infection has been noted in patients with primary immunodeficiency. Incidence rates have ranged from 0.06 to 1.56 cases per million vaccinated, and mortality rates have remained at [approximately equal to]60% (1-7). Of 946 patients with primary immunodeficiency, including 29 with severe combined immunodeficiencies, diagnosed from 1980 through 2006 at the Children's Memorial Health Institute in Warsaw, adverse events after BCG vaccination were observed in 16 (8,9). All 16 were children who had been vaccinated at birth with BCG, Brazilian strain (Biomed, Lublin, Poland).

Four patients with severe combined immunodeficiency showed adverse reactions to BCG. Patient M.K. had mild inflammation at the site of the BCG injection and was successfully treated with rifampin. The patient subsequently received a bone marrow transplant, and 2 months later poor appetite, failure to thrive, and subfebrile condition were noted. Disseminated skin changes (with pus formation in the subcutaneous layer), osteomyelitis, and multiple lesions in the liver were found. A skin biopsy showed tuberculoma formations, which were PCR-positive for Mycobacterium tuberculosis complex (Amplified Mycobacterium Tuberculosis Direct [MTD] Test, Gen-Probe, Inc., San Diego, CA, USA) but had negative culture results. Complete recovery, including full immunologic reconstitution, was reached after 12 months of treatment with triple antituberculosis (TB) therapy (rifampin, isoniazid, and ciprofloxacin). Patient M.C., a 6-month-old boy, was admitted to an intensive care unit because of respiratory insufficiency. An unhealed BCG vaccination site was noted. Bronchopulmonary lavage samples were tested for M. bovis; positive PCR and culture results led to the diagnosis of disseminated BCG infection. Despite intensive anti-TB therapy, the child died of multiple organ failure. Autopsy showed typical granuloma formations and a hypoplastic thymus, typical for severe combined immunodeficiency. Male patients S.D. and C.G. were admitted to intensive care units at 6 and 8 months of age, respectively, with lymphadenopathy and multiple organ insufficiency. Each boy died of multiple organ failure; postmortem examination found granuloma formation and a hypoplastic thymus in each (8).

Eight patients with severe combined immunodeficiency had local adverse events after vaccination with BCG. Inflammation at the vaccination site was observed for all 8. For all except 1, dual anti-TB therapy (rifampin, isoniazid) or monotherapy was successful. For 1 of these patients, anti-TB treatment was stopped 3 months after bone marrow transplant, but increasing inflammation and lymphadenitis appeared 1 month later, with positive PCR and negative culture results for Mycobacterium spp. After 12 months of triple anti-TB therapy, this patient fully recovered.

In 2-month-old female patient, W.M., who had interferon-[gamma]-receptor deficiency, axillary lymphadenopathy with normal healing of the vaccination site was noted 7 weeks after BCG vaccination. Tuberculous lymphadenitis was diagnosed by histopathologic methods. Despite dual anti-TB therapy and streptomycin administration, the girl died. At autopsy, multiple tuberculous granulomas were found (5).

In 4-month-old female patient M.K., who had interleukin-12-receptor deficiency, axillary lymphadenopathy with positive results from Mycobacterium typing was noted. Dual anti-TB therapy for 12 months produced good results.

In 7-month-old female patient B.B., who also had interleukin-12-receptor deficiency, axillary lymphadenopathy was noted. Mycobacteria PCR-positive for the M. tuberculosis complex were found in the purulent secretion. Despite dual anti-TB therapy, the patient experienced 2 episodes of relapse. After another 2 years of anti-TB therapy, disseminated BCG infection, with pulmonary consequences, developed.

In patient R.C., a 6-month-old boy, osteomyelitis was diagnosed, and delayed healing of the BCG vaccination scar was noted. Investigation of his immunologic status showed no abnormalities. However, because granulomatous inflammation was present in a bone biopsy sample and staining for BCG produced a positive result, triple anti-TB therapy was provided for 12 months, with good results.

The literature describes >200 cases of disseminated BCG infection in patients with primary immunodeficiency (1-7). The diagnostic difficulties described for 8 of our patients with primary immunodeficiency have been noted by others (1-6,8-10). In only 2 cases was the Mycobacterium species successfully isolated and identified as the M. bovis BCG strain. We propose novel criteria for the diagnosis of disseminated BCG infection in persons with primary immunodeficiency (Table). These criteria have recently been submitted to the European Society for Immunodeficiencies.

We believe that patients with severe combined immunodeficiency and any form of mild local changes at the BCG injection site should be given single or double anti-TB therapy, which should be continued until complete immunologic reconstitution occurs after bone marrow transplant. Severe local BCG infection with regional lymph node involvement needs at least triple anti-TB therapy followed by long-term prophylaxis. Disseminated BCG infection needs anti-TB therapy, including [greater than or equal to]4 anti-TB drugs, until the patient fully recovers.

Acknowledgments

E.A.B. thanks Peter Folb, Dina Pfeifer, and Adwoa Bentsi-Enchill for encouragement in writing this article.

The investigation was supported by grant EURO-POLICY-primary immunodeficiency SP23-CT-2005-006411 and national project no. PBZ-KBN-119/PO5/04.

References

(1.) Newport MJ, Huxley CM, Huston S, Hawrylowicz CM, Oostra BA, Williamson R, et al. A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection. N Engl J Med. 1996;335:1941-9.

(2.) Casanova JL, Jouanguy E, Lamhamedi S, Blanche S, Fischer A. Immunological conditions of children with BCG disseminated infection. Lancet. 1995;346:581.

(3.) Casanova JL, Blanche S, Emile JF, Jouanguy E, Lamhamedi S, Altare F, et al. Idiopathic disseminated bacillus Calmette-Guerin infection: a French national retrospective study. Pediatrics. 1996;98:774-8.

(4.) Fieschi C, Dupuis S, Catherinot E, Feinberg J, Bustamante J, Breiman A, et al. Low penetrance, broad resistance, and favourable outcome of interleukin 12 receptor [beta] 1 deficiency: medical and immunogical implications. J Exp Med. 2003;197:527-35.

(5.) Liberek A, Korzon M, Bernatowska E, Kurenko-Deptuch M, Rydlewska M. Vaccination-related Mycobacterium bovis BCG infection. Emerg Infect Dis. 2006;12:860-2.

(6.) Heyderman RS, Morgan G, Levinsky R, Strobel S. Successful bone marrow transplantation and treatment of BCG infection in two patients with severe combined immunodeficiency. Eur J Pediatr. 1991;150:477-80.

(7.) Gonzalez B, Moreno S, Burdach R, Valenzuela MT, Herinquez A, Ramos MI. Clinical presentation of bacillus Calmette-Guerin infections in patients with immunodeficiency syndromes. Pediatr Infect Dis J. 1989;8:201-6.

(8.) Wolska-Kusnierz B, Pac M, Pietrucha B, Heropolitanska-Pliszka E, Klaudel-Dreszler M, Kurenko-Deptuch M, et al. Twenty five years of investigation into primary immunodeficiency diseases in the Department of Immunology, Children's Memorial Health Institute, Warsaw. Central European Journal of Immunology. 2005;30:104-14 [cited 2007 Mar 19]. Available from http://www. termedia.pl/magazine.php?magazine_ id=10&article_id=6799&magazine_ subpage=ABSTRACT.

(9.) Bonilla FA, Bernstein IL, Khan DA, Ballas ZJ, Chinen J, Frank MM, et al. Practice parameter for the diagnosis and the management of primary immunodeficiency. Ann Allergy Asthma Immunol. 2005;94 (5 Suppl 1):S1-63.

(10.) Folb PI, Bernatowska E, Chen R, Clemens J, Dodoo AN, Ellenberg SS, et al. A global perspective on vaccine safety and public health: the Global Advisory Committee on Vaccine Safety. Am J Public Health. 2004;94:1926-31.

Address for correspondence: Ewa Anna Bernatowska, Children's Memorial Health Institute, Department of Immunology, Av. Dzieci Polskich, 20 Warsaw, 04-730 Mazovia, Poland; email: [e-mail]

Ewa Anna Bernatowska, * Beata Wolska-Kusnierz, * Malgorzata Pac, * Magdalena Kurenko-Deptuch, * Zofia Zwolska, ([dagger]) Jean-Laurent Casanova, ([double dagger]) Barbara Piatosa, * Jacques van Dongen, ([section]) Kazimierz Roszkowski, ([dagger]) Bozena Mikoluc, ([paragraph]) Maja Klaudel-Dreszler, * and Anna Liberek ([paragraph])

* Children's Memorial Health Institute, Warsaw, Poland; ([dagger]) National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland; ([double dagger]) University Rene Descartes, Paris, France; ([section]) University Medical Center, Rotterdam, the Netherlands; and ([paragraph]) Medical University of Bialystock, Bialystock, Poland

Table. Suggested diagnostic criteria for disseminated bacillus
Calmette-Guerin (BCG) infection in persons with primary
immunodeficiency *

Diagnosis                            Clinical

Definitive         Systemic symptoms such as fever or subfebrile
                    status, weight loss, or stunted growth, and
                 [greater than or equal to] 2 areas of involvement
                   beyond the site of BCG vaccination ([dagger])

Probable                Systemic symptoms such as fever or
                         subfebrile status, weight loss or
                 stunted growth, and [greater than or equal to] 2
                    areas of involvement beyond the site of BCG
                              vaccination ([dagger])

Possible           Systemic symptoms such as fever or subfebrile
                   condition, weight loss or stunted growth, and
                  [greater than or equal to] areas of involvement
                   beyond the site of BCG vaccination ([dagger])

Exclusion        Any inflammation without typical histopathologic
criteria          changes, with no isolation of M. tuberculosis
                  complex by PCR analysis in patient with primary
                                 immunodeficiency

Differential      Severe, long-term inflammation with granuloma
diagnosis       formation in patient with primary immunodeficiency

Diagnosis                           Laboratory

Definitive     Identification of Mycobacterium bovis BCG substrain
               from the patient's organs by culture and/or standard
               PCR, as well as typical histopathologic changes with
                            granulomatous inflammation

Probable        Identification of M. tuberculosis complex from the
                organs by PCR, without differentiation of M. bovis
               BCG substrain or other members of the M. tuberculosis
                complex and negative mycobacterial cultures, with
                 the presence of typical histopathologic changes
                          with granulomatous inflammation

Possible           No identification of mycobacteria by PCR and
                 culture, with presence of typical histopathologic
                      changes with granulomatous inflammation

Exclusion
criteria

Differential
diagnosis

* Male or female patient with or without genetic confirmation of
severe combined immunodeficiency, interferon-[gamma]-receptor
deficiency, interleukin-12-receptor deficiency, or other primary
immunodeficiency.

([dagger]) Areas of involvement may include lymph nodes, skin,
soft tissues, lungs, spleen, liver, bones.