Disseminated Infection with Mycobacterium Avium Complex

Disseminated infection with MAC generally manifests in non-specific, constitutional symptoms. Patients frequently present with fatigue, high-grade fever and profound night sweats, report abdominal pain, loss of appetite, nausea, vomiting, diarrhea, and weight loss [1] [2]. During the physical examination, diffuse lymphadenopathy and hepatosplenomegaly may be noted. If palpable lymph nodes are not involved in the disease, lymphadenopathy may still be observed in thoracic and abdominal images [3]. Images showing the upper abdomen may reveal the presence of multiple lesions in liver and spleen, which require further characterization.

Laboratory analyses of blood samples may reveal anemia, leucopenia, and/or thrombocytopenia. At the same time, serum levels of alkaline phosphatase, hepatic transaminases, and γ-glutamyl transferase are usually elevated [2] [3]. Inflammatory parameters such as levels of C-reactive protein and the erythrocyte sedimentation rate may be altered, too.

The majority of patients has a medical history of immunodeficiency. Affected individuals may be infected with the human immunodeficiency virus or have developed AIDS, may be on immunosuppressive therapy, or suffer from hematological malignancies. In immunocompetent individuals, disseminated infections with MAC are increasingly rare, and suspicion arises that these individuals suffer from as-of-yet undiagnosed disorders of the immune system. Furthermore, disseminated infections with have occasionally been reported to be the presenting symptoms of immunodeficiency, so the confirmation of MAC in otherwise "healthy" patients should entail diagnostic measures to assess the condition of their immune system [2] [4] [5] [6].

As indicated above, the histological characterization of hepatic or splenic lesions may provide important clues as to the nature of the disease [1] [7]. The respective tissue samples are obtained by guided biopsy. MAC induce granuloma formation, and granulomatous lesions eventually become necrotic. Pancytopenia may prompt bone marrow biopsies, and the examination of bone marrow specimens may also suggest granulomatous inflammation [3]. In any case, Ziehl-Neelsen staining confirms the presence of acid-fast bacilli, thereby supporting the tentative diagnosis of mycobacteria infection. Of note, additional staining for fungal organisms is recommended. Mycosis may manifest in a similar manner and generally affects the immunocompromised, much as MAC does [8].

In order to confirm mycobacteriosis and to identify the species involved, bacterial cultures and molecular biological analyses should be performed. Single blood cultures have a sensitivity of approximately 90%, and although it takes weeks until the results are available, growth of mycobacteria remains an essential step in the diagnosis of infections with MAC: The appearance of bacterial colonies, the results of biochemical tests and serotyping may allow for the identification of the species or at least for its classification as MAC. Furthermore, the pathogens' resistance to determined antibiotics can best be assessed in cultures, and data regarding their susceptibility may determine the outcome. The inability to predict antibiotic susceptibility based on the results of genetic studies is a major drawback of this approach. However, specific probes may be used to rapidly identify the causative agent [3]. There are genus-specific probes and probes binding to species-specific rpoB genes and 16S-23S rRNA internal transcribed spacer regions; alternatively, these DNA sections may be sequenced [9].

The therapy of disseminated infections with MAC is based on the administration of antimycobacterial agents and strengthening of the patients' immune system, ideally by fighting the primary disorder. With regards to the former, the drugs of choice are bacteriostatic macrolide antibiotics and ethambutol. They may be combined with rifamycins in the following way [10]:

• 250 mg of azithromycin per day or 1,000 mg of clarithromycin per day, plus
• 15 mg ethambutol per kg and day, plus
• Up to 4350 mg rifabutin per day.

All these drugs are administered orally.

Fluoroquinolones like moxifloxacin are recommended as second-line agents in the treatment of disseminated infections with MAC. Rifamycins are known for complex interactions with drugs commonly administered to transplantation patients, which is why quinolones may be preferred as third agents in these cases [3].

However, regardless of the regimen, cure rates are far below optimum: With regards to mycobacteria in macrophages, the efficacy of antibiotics is severely restricted. Most patients require antibiotic therapy for months or even years to overcome the infection, if cure can be achieved at all. The success of antibiotic treatments largely depends on the patients' response to additional therapies aiming at the reconstitution of their immune system [2]. Before the discontinuation of antimycobacterial chemotherapy, the patient should be asymptomatic, and blood cultures should yield negative results [3].

Of note, the high incidence of disseminated infections with MAC among severely immunocompromised patients and the tedious workup may justify an empiric therapy against this type of mycobacteria [1].

In industrialized nations, AIDS-related MAC infections are associated with a favorable prognosis. This is due to significant improvements in antiretroviral therapy, which nowadays allows for an immune reconstitution even in patients with advanced disease. In developing countries, where the access to medical care is limited, disseminated infections with MAC continue to be a major cause of death in AIDS patients.

If refractory to therapy, primary disorders other than AIDS usually signify a poor outcome. Chances are good that disseminated infections with MAC can be controlled if the patient's defenses can be strengthened by treating the underlying disease.

MAC is ubiquitously distributed in the environment and has been detected in soil, house dust, water, and distinct kinds of food [3]. The complex comprises a growing number of species, with Mycobacterium avium and its distinct subspecies, Mycobacterium chimaera, and Mycobacterium intracellulare being the most important human pathogens. Beyond these species, the following are currently considered part of the MAC:

• Mycobacterium arosiense
• Mycobacterium bouchedurhonense
• Mycobacterium colombiense
• Mycobacterium marseillense
• Mycobacterium timonense
• Mycobacterium vulneris
• Mycobacterium yongonense

These species differ with regards to sources of environmental exposure, degrees of pathogenicity, and susceptibility to antibiotic treatment. Thus, specification is a crucial step in the workup of MAC infections - the adaptation of the therapeutic regimen may determine the outcome. Nevertheless, it shall be mentioned that Mycobacterium avium accounts for >95% of cases of disseminated infections with MAC.

In 1992, the annual incidence of disseminated infections with MAC among AIDS patients with <100 CD4+ T cells per µl of blood has been estimated at 20% [11]. The large-scale provision of antiretroviral agents and prophylactic use of antibiotics considerably increased average CD4+ T-cell counts and reduced the incidence of disseminated MAC infections: By now, it has dropped to less than a tenth of the aforementioned value [3].

Disseminated infections with MAC may be diagnosed in female and male patients of any age, but are more common in adults. Affected children are likely to suffer from congenital disorders of the immune system, even if an underlying mutation cannot be identified. Adult patients may be assumed to have acquired immunodeficiency.

MAC is acquired via the oral route. Due to the unusual composition of their cell wall, ingested pathogens are resistant to gastric acid and eventually reach the intestine. Acid resistance is particularly pronounced in Mycobacterium avium, but is slightly weaker in other species of the MAC, which may contribute to the predominance of Mycobacterium avium in disseminated infections with MAC [3]. Occasionally, MAC may enter the body through direct inoculation secondary to trauma or surgery [12] [13].

After their passage through the stomach, mycobacteria are enclosed by macrophages present in the intestinal lamina propia, but this type of phagocyte may be unable to kill MAC in its phagosomes. What's more, macrophages may be used as a means of dissemination, and bacteremia may ensue. The fate of mycobacteria within macrophages - destruction, persistence, or replication - depends on the interplay between phagocytes, T cells, and natural killer cells. Accordingly, CD4+ T-cell counts are indicators of the likelihood of MAC infections in AIDS patients [3]. Congenital disorders of the immune system may also facilitate the dissemination of MAC, and such has been shown for mutations affecting interleukin-12 and interferon-γ signaling [3] [4] [6].

Upon severe immunodeficiency, MAC spread through the patient's body, with highest bacterial burdens being reached in the reticuloendothelial system, namely in lymph nodes and spleen [2].

Two strategies may be followed to prevent disseminated infections with MAC:

• On the one hand, acquired immunodeficiency should be treated to enable the patient's immune system to kill opportunistic pathogens like MAC. Those diagnosed with AIDS should be provided antiretroviral therapy, so that CD4+ T-cell counts rise above the critical value of 200 per µl of blood. In order to prevent iatrogenic immunodeficiency, severely immunosuppressive drugs should be avoided whenever possible.
• Autoimmune disease interfering with the patient's quality of life, transplantations of organs, and other conditions may leave no alternatives to immunosuppression. In these cases, the prophylactic use of antibiotics may help to prevent life-threatening infections with MAC. In this context, 1,200 mg of azithromycin may be administered once a week, or 1,000 mg of clarithromycin per day. Rifabutin is also effective but less well tolerated [10].

MAC refers to an ill-defined group of slowly growing, non-tuberculous mycobacteria. MAC share phenotypical and biochemical features but differ genetically, so that the identification of individual species depends on the availability of DNA sequences. Members of the MAC are opportunistic pathogens that are best known for causing respiratory infections in patients with preexisting lung diseases. In immunocompromised individuals, entry via the respiratory tract is of minor importance. Mycobacteria are typically ingested, phagocytosed by macrophages in the intestinal wall, and disseminated throughout the whole body be these same cells.

Before the advent of efficient antiretroviral therapies, disseminated infections with MAC had been a major cause of death in patients infected with the human immunodeficiency virus. Large shares of cases are still related to AIDS (and insufficient access to medical care), but awareness rises that other primary disorders similarly predispose to the disease: congenital disorders of the immune system, non-infective acquired immunodeficiency, and therapeutic immunosuppression likewise prevent the patient's immune system from effectively fighting mycobacteria. Although disseminated infections with MAC are occasionally reported in immunocompetent hosts, they are sometimes considered definite manifestations of immunodeficiency, regardless of clinical and laboratory findings [10].

Mycobacterium avium complex refers to a group of mycobacteria that are very difficult to distinguish and that may cause infections of the respiratory tract. The patient's immune system sees to it that the infection doesn't spread to other organ systems. By contrast, the immune system of patients with immunodeficiency is unable to prevent the systemic spread of mycobacteria. A disseminated infection with Mycobacterium avium complex typically starts in the intestines, where bacteria arrive after being ingested with foods or water, and subsequently involves the lymphatic system, liver, and spleen. It results in constitutional symptoms like fatigue, fever, and night sweats. Patients may suffer from abdominal pain, loss of appetite, nausea, vomiting, and diarrhea, and they may lose weight.

The respective clinical findings don't reveal the nature of the disease. It is important to relate the aforementioned symptoms to a medical history of immunodeficiency - most commonly to an infection with the human immunodeficiency virus or AIDS, but possibly to congenital or acquired disorders of the immune system or the administration of immunosuppressive drugs. Diagnostic imaging is employed to visualize changes in lymph nodes, liver, and spleen, and samples must be obtained from lesions seen in images. In specimens obtained by biopsy, an infection with mycobacteria can be demonstrated.

The antibiotic treatment of a disseminated infection with Mycobacterium avium complex is tedious and often frustrating. The success of therapy largely depends on the management of the underlying immunodeficiency: If a reconstitution of the patient's immune system can be achieved, the infection may probably be overcome. Thanks to considerable advances in the management of AIDS, the prognosis for disseminated infections with Mycobacterium avium complex has significantly improved.

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