Mycobacterial disease in patients with chronic granulomatous disease: A retrospective analysis of 71 cases.

BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by inborn errors of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex. From the first year of life onward, most affected patients display multiple, severe, and recurrent infections caused by bacteria and fungi. Mycobacterial infections have also been reported in some patients. OBJECTIVE: Our objective was to assess the effect of mycobacterial disease in patients with CGD. METHODS: We analyzed retrospectively the clinical features of mycobacterial disease in 71 patients with CGD. Tuberculosis and BCG disease were diagnosed on the basis of microbiological, pathological, and/or clinical criteria. RESULTS: Thirty-one (44%) patients had tuberculosis, and 53 (75%) presented with adverse effects of BCG vaccination; 13 (18%) had both tuberculosis and BCG infections. None of these patients displayed clinical disease caused by environmental mycobacteria, Mycobacterium leprae, or Mycobacterium ulcerans. Most patients (76%) also had other pyogenic and fungal infections, but 24% presented solely with mycobacterial disease. Most patients presented a single localized episode of mycobacterial disease (37%), but recurrence (18%), disseminated disease (27%), and even death (18%) were also observed. One common feature in these patients was an early age at presentation for BCG disease. Mycobacterial disease was the first clinical manifestation of CGD in 60% of these patients. CONCLUSION: Mycobacterial disease is relatively common in patients with CGD living in countries in which tuberculosis is endemic, BCG vaccine is mandatory, or both. Adverse reactions to BCG and severe forms of tuberculosis should lead to a suspicion of CGD. BCG vaccine is contraindicated in patients with CGD.

Complex regional pain syndrome secondary to leprosy.

INTRODUCTION: Leprosy is a chronic infectious disease caused by Mycobacterium leprae affecting the skin and the nerves. Complex regional pain syndrome (CRPS/Sudeck's dystrophy) is a painful and disabling condition--a triad of autonomic, sensory, and motor symptoms disproportionate to the inciting event (inflammatory, infective, or traumatic nerve damage). CASE: A 20-year-old male presented with continuous pain, aggravated by cold and emotions, loss of fine touch and temperature sensation, redness, swelling, along lateral aspect of left hand and forearm with weakness in the grip of 6 months' duration. There was a 5-year history of sensory loss only over left index finger that he ignored. Examination revealed abnormal sensory and autonomic functions along left radial and median nerve distribution that were confirmed by nerve conduction studies suggestive of mononeuritis multiplex. Radial cutaneous nerve biopsy was suggestive of leprosy. Magnetic resonance imaging and ultrasonography showed no compressive etiology; however, MRI showed involvement of brachial plexus. Antileprosy, anti-inflammatory drugs, and steroids were given in view of neuritis because of lepra reaction with supportive measures of physiotherapy, transcutaneous electrical nerve stimulation, to no avail. A surgical median nerve decompression also failed to relieve the pain. Temporary stellate ganglion block improved the pain scale. Thus, excluding all other causes, the final diagnosis was CRPS secondary to leprosy. There is only one reported case of CRPS with leprosy. CONCLUSION: Leprous neuropathy caused the nerve damage that lead to CRPS type 2. Very rarely leprosy can lead to CRPS. CRPS is a diagnosis of exclusion.

Hansen's disease (leprosy) complicated by secondary mycobacterial infection.

A patient with Hansen's disease received corticosteroids for a type 1 leprosy reaction and subsequently developed a new cutaneous lesion at the original biopsy site from which Mycobacterium fortuitum was cultured. A review of the literature found only two other cases of coinfection with atypical mycobacteria and Mycobacterium leprae, although there are many reports of pulmonary tuberculosis in patients with leprosy. This case highlights the diagnostic difficulties encountered when a patient has two different mycobacterial infections of the skin. The published experience emphasizes that such coinfection is remarkably uncommon in leprosy, despite the frequent use of high doses of corticosteroids for leprosy reactions.

[Human mycobacterial infections: impact of host genetic factors]. / Infections mycobactériennes humaines: impact des facteurs génétiques de l'hôte.

Humans are exposed worldwide to a variety of environmental mycobacteria (EM) and most children are inoculated with live Bacille Calmette-Guérin (BCG) vaccine. Although rarely pathogenic, poorly virulent mycobacteria, including BCG and most EM, may cause a variety of clinical diseases. M. tuberculosis and M. leprae are more virulent, causing tuberculosis, and leprosy, respectively. Remarkably, only a minority of individuals develop clinical disease, even if infected with virulent mycobacteria. There is now accumulating evidence that the large interindividual variability of clinical outcome results in part from variability in the human genes that control host defense. We review here in current knowledge about genetic predisposition to common (leprosy and tuberculosis) and rare (BCG and EM infections) mycobacterial infections.

Genetic dissection of immunity to mycobacteria: the human model.

Humans are exposed to a variety of environmental mycobacteria (EM), and most children are inoculated with live Bacille Calmette-Guérin (BCG) vaccine. In addition, most of the world's population is occasionally exposed to human-borne mycobacterial species, which are less abundant but more virulent. Although rarely pathogenic, mildly virulent mycobacteria, including BCG and most EM, may cause a variety of clinical diseases. Mycobacterium tuberculosis, M. leprae, and EM M. ulcerans are more virulent, causing tuberculosis, leprosy, and Buruli ulcer, respectively. Remarkably, only a minority of individuals develop clinical disease, even if infected with virulent mycobacteria. The interindividual variability of clinical outcome is thought to result in part from variability in the human genes that control host defense. In this well-defined microbiological and clinical context, the principles of mouse immunology and the methods of human genetics can be combined to facilitate the genetic dissection of immunity to mycobacteria. The natural infections are unique to the human model, not being found in any of the animal models of experimental infection. We review current genetic knowledge concerning the simple and complex inheritance of predisposition to mycobacterial diseases in humans. Rare patients with Mendelian disorders have been found to be vulnerable to BCG, a few EM, and M. tuberculosis. Most cases of presumed Mendelian susceptibility to these and other mycobacterial species remain unexplained. In the general population leprosy and tuberculosis have been shown to be associated with certain human genetic polymorphisms and linked to certain chromosomal regions. The causal vulnerability genes themselves have yet to be identified and their pathogenic alleles immunologically validated. The studies carried out to date have been fruitful, initiating the genetic dissection of protective immunity against a variety of mycobacterial species in natural conditions of infection. The human model has potential uses beyond the study of mycobacterial infections and may well become a model of choice for the investigation of immunity to infectious agents.

Infections mycobactériennes humaines: im´pact des facteurs génetiques de lhôte / Human mycobacterial infections: impact of host genetic factors

Humans are exposed worldwide to a variety of environmental mycobacteria (EM) and most children are inoculated with live Bacille Calmette-Guérin (BCG) vaccine. Although rarely pathogenic, poorly virulent mycobacteria, including BCG and most EM, may cause a variety of clinical diseases. M. tuberculosis and M. leprae are more virulent, causing tuberculosis, and leprosy, respectively. Remarkably, only a minority of individuals develop clinical disease, even if infected with virulent mycobacteria. There is now accumulating evidence that the large interindividual variability of clinical outcome results in part from variability in the human genes that control host defense. We review here in current knowledge about genetic predisposition to common (leprosy and tuberculosis) and rare (BCG and EM infections) mycobacterial infections.

Mycobacterium leprae and Mycobacterium lepraemurium infections in domestic and wild animals.

Mycobacterium leprae, the aetiological agent of leprosy in humans, gives rise to a chronic granulomatous disease that affects primarily the skin and peripheral nerves, and secondarily some internal organs such as the testis and the eye; viscera are seldom involved. Depending on host resistance, leprosy may present as a benign disease (tuberculoid leprosy) or as a malignant disease (lepromatous leprosy), with a spectrum of intermediate stages appearing between the two. Immunity against leprosy depends on the cell-mediated immunity of the host, and this is severely compromised in the malignant (lepromatous) form of leprosy. Although culture of M. leprae has never been achieved in artificial media, the bacterium may be grown in several experimental animals, including the armadillo, non-human primates, and to a certain extent, rodents. Naturally acquired leprosy has been reported in wild nine-banded armadillos (Dasypus novemcinctus) and in three species of non-human primates (chimpanzees [Pan troglodytes], sooty mangabey monkeys [Cercocebus atys] and cynomolgus macaques [Macaca fascicularis]), thus qualifying leprosy as a zoonosis. Murine leprosy is a leprosy-like disease of rats and mice, caused by Mycobacterium lepraemurium. The disease affects primarily viscera and the skin, and very rarely peripheral nerves. Depending on the host strain, rodent leprosy may also evolve as 'lepromatous' or 'tuberculoid' leprosy, and strains of mouse that develop intermediate forms of the disease may exist. Growth of M. lepraemurium on conventional media for mycobacteria is not successful, but the bacterium has been cultured on an egg yolk-based medium. Naturally acquired murine leprosy has been observed in rats, mice and cats, but not in humans or any other species. Thus, in contrast to human leprosy, murine leprosy is not a zoonosis.

Mycobacterium smegmatis laminin-binding glycoprotein shares epitopes with Mycobacterium tuberculosis heparin-binding haemagglutinin.

Mycobacterium tuberculosis, the causative agent of tuberculosis, produces a heparin-binding haemagglutinin adhesin (HBHA), which is involved in its epithelial adherence. To ascertain whether HBHA is also present in fast-growing mycobacteria, Mycobacterium smegmatis was studied using anti-HBHA monoclonal antibodies (mAbs). A cross-reactive protein was detected by immunoblotting of M. smegmatis whole-cell lysates. However, the M. tuberculosis HBHA-encoding gene failed to hybridize with M. smegmatis chromosomal DNA in Southern blot analyses. The M. smegmatis protein recognized by the anti-HBHA mAbs was purified by heparin-Sepharose chromatography, and its amino-terminal sequence was found to be identical to that of the previously described histone-like protein, indicating that M. smegmatis does not produce HBHA. Biochemical analysis of the M. smegmatis histone-like protein shows that it is glycosylated like HBHA. Immunoelectron microscopy demonstrated that the M. smegmatis protein is present on the mycobacterial surface, a cellular localization inconsistent with a histone-like function, but compatible with an adhesin activity. In vitro protein interaction assays showed that this glycoprotein binds to laminin, a major component of basement membranes. Therefore, the protein was called M. smegmatis laminin-binding protein (MS-LBP). MS-LBP does not appear to be involved in adherence in the absence of laminin but is responsible for the laminin-mediated mycobacterial adherence to human pneumocytes and macrophages. Homologous laminin-binding adhesins are also produced by virulent mycobacteria such as M. tuberculosis and Mycobacterium leprae, suggesting that this adherence mechanism may contribute to the pathogenesis of mycobacterial diseases.

Models of the within-host dynamics of persistent mycobacterial infections.

We use mathematical models to investigate the within-host dynamics of mycobacterial infections. In particular, we investigate the mechanisms by which bacteria such as Mycobacterium tuberculosis and Mycobacterium leprae persist at low densities for extended periods, and attain high densities much later. We suggest that the persistence of bacteria in face of immune pressure may result from the bacteria having a very slow growth rate, or having a dormant stage. We show that whereas these mechanisms may lead to long-term persistence, this will be obtained at relatively low densities. We then suggest that the long-term persistence of bacteria may result in the loss of immunity because of the deletion of specific T-cells arriving from the thymus, and the exhaustion of the specific T-cells as these cells reach the Hayflick limit and die. This loss of immunity will allow the bacteria to attain a high density. We propose experiments capable of testing our models and discuss the implications of the models for the treatment of infected hosts.

Mycobacterial infections: are the observed enigmas and paradoxes explained by immunosuppression and immunodeficiency?

The enigmas and paradoxes observed in tuberculous patients, in Bacille Calmette-Guérin-vaccinated people and in Bacille Calmette-Guérin-treated cancer patients have been examined, in an attempt to explain them through the mechanisms of immunodeficiency and immunosuppression. A dual effect is postulated: an immunosuppression induced by the infecting mycobacteria that adds to a pre-existing or emerging state of immunodeficiency of the infected individual. The immunological cellular and humoral anergies observed at the beginning of a tuberculous therapy are usually lifted after the first two weeks of treatment. This restoration of immune responsiveness may be attributed to the destruction or to the growth inhibition of immunosuppressive mycobacteria. The observation that drugs cytocidal in vitro do not always sterilize the patients under treatment whereas bacteriostatic drugs do, may find an explanation in the dual immunosuppression induced by cytocidal drugs and mycobacteria. The fact that Bacille Calmette-Guérin applied as an immunotherapy to residual cancer has either a favorable or an unfavorable action may be due to the immunosuppressive activity attached to some Bacille Calmette-Guérin strains and to some cancers. The variable protective activity of Bacille Calmette-Guérin vaccines may be due to the immunological status of the vaccinated people and the compositional differences between strains. The protective activity of subunit vaccines in experimental models can be attributed to the elimination of immunosuppressive factors present in whole killed mycobacteria.

The immunology of mycobacterial infections.

Mycobacteria are endowed with substances that profoundly affect the immune system. Leprosy and tuberculosis exemplify broad spectra of useful and detrimental immune responses of mycobacterial infections that range from intense potentiation to severe specific adn nonspecific suppression of humoral and cellular immune elements. The cellular hypersensitivity induced by mycobacteria serves as a classical model for the analysis of specific and nonspecific immune mechanisms. Mycobacterial disease are prevalent worldwide and rank among the most important bacterial diseases. The kaleidoscope of immunologic events induced by injected mycobacteria and during infections will be reviewed from the standpoint of pathogenesis, pathology, in vitro and in vivo effects on cellular and humoral arms of the immune response, diagnosis, classification, potentiation and suppression.

Pathogenicity of cultivated murine leprosy bacilli of Hawaiian-Ogawa strain in mice. 4) Visceral lesions in mice produced by intraperitoneal infection.

The pathogenicity of two substrains (HO-R and HO-S) of cultivated murine leprosy bacilli was examined by intraperitoneal inoculation to various strains of mice (C3H, KK, BALA/c, DDD and C57BL/6). HO-R (Rough Form) was first isolated on 1% Ogawa's egg yolk medium from the leprous lesions produced by original Hawaiian strain (H bacilli). HO-S (Smooth Form) was dissociated in vitro during the 9th to 15th subculture of HO-R on the same kind of medium. In all the mice tested, intraperitoneal inoculation with HO-R bacilli produced progressively severe visceral lesions in the manner similar to H bacilli harvested from subcutaneous leproma. The only exception was, however in DDD strain of mice H bacilli produced only slight visceral lesions even in the later stage of infection. HO-S was much lower in the pathogenicity than the above two strains of murine leprosy bacilli. Visceral lesions produced by intraperitoneal inoculation with HO-S used to be very slight in all the strains of mice except BALB/c. BALB/c strain mice were highly susceptible to intraperitoneal as well as subcutaneous infection with HO-S. From the above observations, it is concluded that the characteristic features of pathogenicity of cultivated murine leprosy bacilli, such as mouse strain differences, are all the same regardless of infection route.

Pathogenicity of cultivated murine leprosy bacilli Hawaiian-Ogawa strain in mice. 1. The pathogenicity of bacilli from rough colonies.

This paper deals with the pathogenicity of cultivated murine leprosy bacilli from rough colonies of Hawaiian-Ogawa strain in mice. This strain was isolated by Ogawa, in 1970, on Ogawa's 1% egg yolk medium [1], from mice previously inoculated with Hawaiian strain of murine leprosy bacilli which has been maintained by passages from mice to mice. The pathogenicity of Hawaiian-Ogawa strain was found to belong to the same pattern as Hawaiian strain when the subcutaneous inoculation test was carried out in C57BL/6 and C3H mice, the former being representative of the benign type and the latter being representative of the malignant type. In KK mice of the intermediate type with Hawaiian bacilli, however, Hawaiian-Ogawa bacilli produced the lesions with malignant features in almost all the male mice, while the female mice were divided into two groups roughly half showing the intermediate or malignant type. In DDD mice of the benign type with Hawaiian bacilli, some cases of the male mice showed the malignant features, whereas almost all the female mice were of the benign type in the same experimental conditions. The pathogenicity of Hawaiian-Ogawa bacilli in mice did not revert into that of Hawaiian bacilli even after serial mouse passage. There are slight but definite differences in the mouse pathogenicity between Hawaiian-Ogawa and Hawaiian strains.