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Disseminated Infection with Mycobacterium Avium Complex

Mycobacterium avium complex (MAC) refers to a group of opportunistic pathogens that constitute a major threat to immunocompromised patients. The majority of affected individuals suffers from AIDS, but congenital or acquired disorders of the immune system as well as iatrogenic immunosuppression also predispose for the disease. Treatment consists in prolonged antimycobacterial chemotherapy and an adequate therapy of the primary disorder. If the patients' immune system can be reconstituted, their prognosis is favorable. Ongoing immunodeficiency is a predictor of recurrence.


Presentation

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.

Fever
  • Patients frequently present with fatigue, high-grade fever and profound night sweats, report abdominal pain, loss of appetite, nausea, vomiting, diarrhea, and weight loss.[symptoma.com]
  • Abstract Disseminated Mycobacterium avium complex (MAC) infection presenting as a painful lytic femur lesion with associated fever, night sweats and weight loss occurred in a 45-y-old woman with apparent normal immune function.[ncbi.nlm.nih.gov]
  • The clinical features of DMAC infection are fever, weight loss, abdominal pain, anemia, elevated serum alkaline phosphatase, and elevated serum lactate dehydrogenase. The diagnosis is made by blood cultures; clinical diagnosis is unreliable.[ncbi.nlm.nih.gov]
  • In the prospective study, DMAC was seen only in persons with a CD4 count 3 and was associated with fever ( P .03), anemia ( P .001), weight loss ( P .01), diarrhea ( P .01), and elevated alkaline phosphatase ( P .01).[doi.org]
  • MAC causes disseminated disease in up to 40% of people with human immunodeficiency virus (HIV) in the United States, producing fever, sweats, weight loss, and anemia.[en.wikipedia.org]
Weight Loss
  • Figure 1 An 81-year-old woman was admitted with weight loss (18 kg in 27 months), hemoptysis, and tubular and diffuse granular shadows on her chest radiograph (Panel A).[doi.org]
  • Abstract Disseminated Mycobacterium avium complex (MAC) infection presenting as a painful lytic femur lesion with associated fever, night sweats and weight loss occurred in a 45-y-old woman with apparent normal immune function.[ncbi.nlm.nih.gov]
  • The clinical features of DMAC infection are fever, weight loss, abdominal pain, anemia, elevated serum alkaline phosphatase, and elevated serum lactate dehydrogenase. The diagnosis is made by blood cultures; clinical diagnosis is unreliable.[ncbi.nlm.nih.gov]
  • In the prospective study, DMAC was seen only in persons with a CD4 count 3 and was associated with fever ( P .03), anemia ( P .001), weight loss ( P .01), diarrhea ( P .01), and elevated alkaline phosphatase ( P .01).[doi.org]
  • MAC causes disseminated disease in up to 40% of people with human immunodeficiency virus (HIV) in the United States, producing fever, sweats, weight loss, and anemia.[en.wikipedia.org]
Anemia
  • M. vium -complex infections are a common late consequence of HIV infection, particularly in persons with low CD4 cell counts and anemia.[doi.org]
  • The clinical features of DMAC infection are fever, weight loss, abdominal pain, anemia, elevated serum alkaline phosphatase, and elevated serum lactate dehydrogenase. The diagnosis is made by blood cultures; clinical diagnosis is unreliable.[ncbi.nlm.nih.gov]
  • In the prospective study, DMAC was seen only in persons with a CD4 count 3 and was associated with fever ( P .03), anemia ( P .001), weight loss ( P .01), diarrhea ( P .01), and elevated alkaline phosphatase ( P .01).[doi.org]
  • 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.[symptoma.com]
Lymphadenopathy
  • A low dose of IFN-alpha2b (3 x 10(6) units/m(2) three times weekly subcutaneously) successfully attenuated progressive hepatosplenomegaly and abdominal/retroperitoneal/pelvic lymphadenopathy, although the patient continued to be mycobacteremic.[ncbi.nlm.nih.gov]
  • 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.[symptoma.com]
  • This generally includes a focal lymphadenopathy/lymphadenitis.[en.wikipedia.org]
  • Small pleural effusion and hilar lymphadenopathy are also noted. Bronchoscopic examination shows a polypoid smooth-surfaced mass lesion that completely occluded the lingular division of the left upper lobe bronchus.[ncbi.nlm.nih.gov]
  • […] head and neck infection in children, ORL J Otorhinolaryngol Relat Spec, 2002 , vol. 64 (pg. 284 - 9 ) 3 Management of atypical mycobacterial lymphadentis in childhood: a review based on 380 cases, J Pediatr, 1979 , vol. 95 (pg. 356 - 60 ) 4 Chronic lymphadenopathy[doi.org]
Fatigue
  • Patients frequently present with fatigue, high-grade fever and profound night sweats, report abdominal pain, loss of appetite, nausea, vomiting, diarrhea, and weight loss.[symptoma.com]
  • Symptoms are similar to tuberculosis (TB), and include fever, fatigue, and weight loss. Pulmonary involvement is similar to TB, while diarrhea and abdominal pain are associated with gastrointestinal involvement.[en.wikipedia.org]
  • […] predispose to lung infection by allowing secretions to collect in the airways, especially in the right middle lobe, which has the longest and narrowest of the lobar bronchi. 3,4 Symptoms of Lady Windermere syndrome include cough, sputum production, and fatigue[mdedge.com]
  • Adverse effects of the medication, such as fever, fatigue, gastrointestinal complaints, and allergic reactions were scored. A follow-up ultrasound was performed by an independent radiologist 12 and 24 weeks after the initiation of therapy.[doi.org]
  • They include, in order of frequency, chronic cough (productive or dry), fatigue, dyspnea, hemoptysis, weakness and chest discomfort [1,8]. Fever and weight loss occur less frequently than in patients with typical tuberculosis [8].[scielo.br]
Diarrhea
  • Patients frequently present with fatigue, high-grade fever and profound night sweats, report abdominal pain, loss of appetite, nausea, vomiting, diarrhea, and weight loss.[symptoma.com]
  • In the prospective study, DMAC was seen only in persons with a CD4 count 3 and was associated with fever ( P .03), anemia ( P .001), weight loss ( P .01), diarrhea ( P .01), and elevated alkaline phosphatase ( P .01).[doi.org]
  • MAC bacteria should always be considered in a person with HIV infection presenting with diarrhea.[en.wikipedia.org]
  • Keywords: Mycobacterium avium complex, Enteritis, HIV A 39-year-old man presented with 3-month history of cough and 1-month history of fever, diarrhea and shortness of breath.[ncbi.nlm.nih.gov]
Abdominal Pain
  • Patients frequently present with fatigue, high-grade fever and profound night sweats, report abdominal pain, loss of appetite, nausea, vomiting, diarrhea, and weight loss.[symptoma.com]
  • The clinical features of DMAC infection are fever, weight loss, abdominal pain, anemia, elevated serum alkaline phosphatase, and elevated serum lactate dehydrogenase. The diagnosis is made by blood cultures; clinical diagnosis is unreliable.[ncbi.nlm.nih.gov]
  • Pulmonary involvement is similar to TB, while diarrhea and abdominal pain are associated with gastrointestinal involvement.[en.wikipedia.org]
Hepatosplenomegaly
  • A low dose of IFN-alpha2b (3 x 10(6) units/m(2) three times weekly subcutaneously) successfully attenuated progressive hepatosplenomegaly and abdominal/retroperitoneal/pelvic lymphadenopathy, although the patient continued to be mycobacteremic.[ncbi.nlm.nih.gov]
  • 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.[symptoma.com]
Night Sweats
  • Patients frequently present with fatigue, high-grade fever and profound night sweats, report abdominal pain, loss of appetite, nausea, vomiting, diarrhea, and weight loss.[symptoma.com]
  • Abstract Disseminated Mycobacterium avium complex (MAC) infection presenting as a painful lytic femur lesion with associated fever, night sweats and weight loss occurred in a 45-y-old woman with apparent normal immune function.[ncbi.nlm.nih.gov]
  • Monitoring Patients Receiving Therapy for Disseminated MAC Clinical manifestations of disseminated MAC -- such as fever, weight loss, and night sweats -- should be monitored several times during the initial weeks of therapy.[cdc.gov]
  • Therapy should continue for the lifetime of the patient if clinical and microbiologic improvement is observed.Clinical manifestations of disseminated MAC—such as fever, weight loss, and night sweats—should be monitored several times during the initial[en.wikipedia.org]
  • The clinical features of isolated pulmonary MAC infection in patients with HIV include: fever, cough, and night sweats, and are often accompanied by dyspnea, hemoptysis, and/or weight loss.[ncbi.nlm.nih.gov]
Forgetful
  • Our husbands would really forget our existence if we didn't nag at them from time to time, just to remind them that we have a perfect legal right to do so. LORD DARLINGTON.[wilde.thefreelibrary.com]

Workup

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].

Liver Biopsy
  • Diagnosis was proven by histologic examination of hepatic biopsy and culture of the liver biopsy material. Two years later the patient underwent allogeneic bone marrow transplantation (BMT) from an HLA-matched sibling donor.[ncbi.nlm.nih.gov]

Treatment

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].

Prognosis

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.

Etiology

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.

Epidemiology

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.

Sex distribution
Age distribution

Pathophysiology

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].

Prevention

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].

Summary

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].

Patient Information

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.

References

Article

  1. Clark H, Khatri G, Kapur P, Pedrosa I. Splenic Involvement in Disseminated Mycobacterium avium-intracellulare Infection: Magnetic Resonance Imaging Findings. J Comput Assist Tomogr. 2018; 42(1):151-154.
  2. Deshpande D, Gumbo T. Pharmacokinetic/pharmacodynamic-based treatment of disseminated Mycobacterium avium. Future Microbiol. 2011; 6(4):433-439.
  3. Daley CL. Mycobacterium avium Complex Disease. Microbiol Spectr. 2017; 5(2).
  4. Gruenberg DA, Añover-Sombke S, Gern JE, et al. Atypical presentation of IL-12 receptor beta1 deficiency with pneumococcal sepsis and disseminated nontuberculous mycobacterial infection in a 19-month-old girl born to nonconsanguineous US residents. J Allergy Clin Immunol. 2010; 125(1):264-265.
  5. Ishii T, Tamura A, Matsui H, et al. Disseminated Mycobacterium avium complex infection in a patient carrying autoantibody to interferon-gamma. J Infect Chemother. 2013; 19(6):1152-1157.
  6. Sharma VK, Pai G, Deswarte C, et al. Disseminated Mycobacterium avium complex infection in a child with partial dominant interferon gamma receptor 1 deficiency in India. J Clin Immunol. 2015; 35(5):459-462.
  7. Yabes JM, Farmer A, Vento T. Disseminated Mycobacterium avium complex in an immunocompetent host. Int J Mycobacteriol. 2017; 6(2):202-206.
  8. Graviss EA, Vanden Heuvel EA, Lacke CE, Spindel SA, White AC, Jr., Hamill RJ. Clinical prediction model for differentiation of disseminated Histoplasma capsulatum and Mycobacterium avium complex infections in febrile patients with AIDS. J Acquir Immune Defic Syndr. 2000; 24(1):30-36.
  9. Lee MR, Chien JY, Huang YT, et al. Clinical features of patients with bacteraemia caused by Mycobacterium avium complex species and antimicrobial susceptibility of the isolates at a medical centre in Taiwan, 2008-2014. Int J Antimicrob Agents. 2017; 50(1):35-40.
  10. Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007; 175(4):367-416.
  11. Nightingale SD, Byrd LT, Southern PM, Jockusch JD, Cal SX, Wynne BA. Incidence of Mycobacterium avium-intracellulare complex bacteremia in human immunodeficiency virus-positive patients. J Infect Dis. 1992; 165(6):1082-1085.
  12. Ogunremi T, Taylor G, Johnston L, et al. Mycobacterium chimaera infections in post-operative patients exposed to heater-cooler devices: An overview. Can Commun Dis Rep. 2017; 43(5):107-113.
  13. Scriven JE, Scobie A, Verlander NQ, et al. Mycobacterium chimaera infection following cardiac surgery in the United Kingdom: clinical features and outcome of the first 30 cases. Clin Microbiol Infect. 2018.

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Last updated: 2019-07-11 19:53