An Unusual Presentation of Mycobacterium fortuitum: Massive Isolated Empyema in a Patient With HIV

Introduction

The nontuberculous mycobacteria (NTMB) are ubiquitous environmental organisms that only rarely cause disease in humans.[1] An atypical NTMB, Mycobacterium fortuitum, previously called Mycobacterium chelonae, is a low-grade pathogen that is increasing in prevalence in patients with or without HIV infection. M fortuitum was first isolated from a turtle in 1905, and subsequently identified as the cause of a cutaneous infection in a patient in 1938. The bacterium is found worldwide in soil and tap water and is an infrequent human pathogen. Few cases of parapneumonic pleurisy connected with M fortuitum have been reported in the literature.[2] We report a case of M fortuitum-related massive empyema in a patient with HIV, which to the best of our knowledge is the first reported case of isolated pleural empyema of M fortuitum.

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Case Report

A 56-year-old black man, known to have HIV with a last CD4+ T lymphocyte count of 13 cells/mcL, presented with a 2-month history of anorexia, 30-pound weight loss, and generalized weakness. He reported low-grade fever and increasing cough and expectoration in the preceding 3 days. He denied hemoptysis. His medical history included anemia. He was not taking any medication. He reported a history of 1 pack per day smoking for 35 years. The patient denied using illicit drugs, or alcohol. Physical examination revealed a temperature of 39.2 °C, a heart rate of 130 beats per minute, blood pressure of 150/94 mm Hg, and resting oxygen saturation of 95% in room air. The patient appeared to be in minimal respiratory distress. Examination of head, ears, eyes, nose, and throat was unremarkable. There was no lymphadenopathy. Chest examination revealed dullness of the left hemithorax with decreased breath sounds. There was no clubbing of the extremities or hepatosplenomegaly. The remainder of the physical examination was unremarkable. Laboratory data revealed white blood cell (WBC) count of 4890/L with a differential of 65% neutrophils, 22% lymphocytes, and 2% monocytes.

Hemoglobin was 7.6 g/dl, with mean corpuscular volume of 71.7 fl, mean corpuscular hemoglobin of 22.3 pg, and mean corpuscular hemoglobin concentration 31.1 g/dl. Iron studies revealed an iron concentration of 13 mcg/dL, ferritin 3372 ng/dL, transferrin 123 mg/dL, total iron-binding capacity (TIBC) 226, normal levels of vitamin B12 and folate, and a reticulocyte count of 2%. Results of platelet count, coagulation panel, serum electrolytes, renal function, and urinalysis were all normal. Blood gas showed a mild respiratory alkalosis. The sedimentation rate was 122 mm/hr. Electrocardiography showed sinus tachycardia. The chest radiograph (Figure 1) and CT scan (Figure 2) revealed a massive left-sided pleural effusion and secondary passive collapse of the majority of the left lung with air bronchograms. A small right-sided pleural effusion, and several mediastinal lymph nodes were also noted. No pulmonary nodules or infiltration were noted in the lungs. CT scans of the abdomen, pelvis, and head were negative. Diagnostic thoracocentesis, followed by bilateral therapeutic chest tube placement yielded 800 mL cloudy fluid initially. Furthermore, during the next 8 hours, another 500 mL pus was drained. The fluid contained 225 WBC/dL, with a differential of 99% lymphocytes and 1% polymorphonuclear cells, and 2700 red blood cells. The fluid color was yellow. Chemistry studies revealed glucose of 98 mg/dL (serum glucose, 103 mg/dL), lactate dehydrogenase of 830 U/L (serum lactate dehydrogenase, 347 U/L), and protein of 4.7 g/dL (serum protein, 7.3 g/dL). Stains revealed many leukocytes but no malignant cells, bacteria or acid-fast bacilli, or fungi. Smears and cultures of sputum, pleural effusion, and tissue from the left pleura were obtained, which all were negative for Mycobacterium tuberculosis (MTB) at 10 weeks, Mycobacterium avium complex (MAC), nontuberculous bacteria, and fungi at 4 weeks, but positive for M fortuitum. Results of repeat testing by DNA probe were negative for MTB and MAC.

Figure 1.

Chest radiograph showing massive left side and small right side pleural effusion.

Figure 2.

CT scan of chest. Note: Small black arrows show mediastinal lymph nodes; crosses show left-side massive and right-side small pleural effusion.

While awaiting the results of the biopsy, mycobacterium tuberculosis pleurisy was suspected, and antituberculosis treatment was started, which included isoniazid 300 mg orally once a day, rifampin 600 mg orally once a day, ethambutol 1200 mg orally once a day, and pyrazinamide 1500 mg orally once a day. In addition, 25 mg pyridoxine orally once a day, and highly active antiretroviral therapy (HAART) was introduced, which included coformulated tenofovir + emtricitabine (1 tablet orally once a day) and efavirenz 600 mg orally at bedtime.

Subsequently, using polymerase chain reaction amplification technique, mycobacterium tuberculosis and MAC were ruled out. Using biochemical tests* M fortuitum was identified from the tissue biopsy specimen. Therefore, antimycobacterial agents were discontinued, and azithromycin 500 mg orally once a day plus doxycycline 100 mg orally once a day were started. The patient's symptoms improved significantly during the next week, and the chest tube was discontinued 11 days after it had been placed. A follow up CD4+ count in 3 weeks showed an increase to a count of 215 cells/mcL.

Epidemiology and Pathogenesis

Epidemiology

NTMB have begun to appear with increasing frequency, particularly in the regions of the world where tuberculosis is in decline. Patients with underlying lung disease such as chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, and pneumoconiosis are more susceptible to NTMB infection. Esophageal motility disorders such as achalasia have been found in significant association with pulmonary disease caused by rapidly growing NTMB, M fortuitum.[1,3] These organisms are acquired from water, soil, or nosocomial sources. M fortuitum has frequently been recovered from soil and can be obtained from sink and faucet samplings. It has also been found in sputum and saliva of normal persons, and from milk, fish, and domestic or wild animals. There is obviously no evidence of person-to-person spread of this infection.[3] Pulmonary infection with M fortuitum occurs more often in middle-aged women without underlying pulmonary disease rather than in immunocompromised patients or male patients who smoke.[2] There are also reports of increase of NTMB infection in patients with rheumatoid arthritis, diabetes mellitus, alcoholism, or nonpulmonary malignancies.[4]

Shih and colleagues[5] retrospectively reviewed the records of patients from the Mycobacteriology Laboratory at the National Taiwan University Hospital between January 1992 to June 1996; culture specimens from these patients had grown NTMB and were associated with clinically significant disease. NTMB were isolated and identified using conventional methods – mediums such as Lowenstein-Jensen slant (from 1992 through 1995) and Middlebrook 7H10 (from 1996). Blood and bone marrow aspirate specimens were isolated using an Isolator lysis-centrifugation system. Interestingly, Shih and colleagues reported that M fortuitum is the most common NTMB in Taiwan. In total, 42.5% of all cases of NTMB disease were caused by M fortuitum, and it accounted for most of the keratitis and cutaneous infections, while pulmonary infection was rare and occurred only in elderly nonsmoking female patients.[5]

Despite the severe degree of immunosuppression associated with AIDS, few M fortuitum infections in patients with AIDS have been described in the literature. Recent data show that infections with M fortuitum have been increasing in frequency during the past 2 decades.[2]

Pathogenesis

A large number of different NTMB have been isolated from patients with AIDS. Three rapidly growing NTMB species are prominent in reports of human infection and colonization: M abscessus, M chelonae, and M fortuitum. These organisms share significant structural and biochemical similarities with their more pathogenic relative, M tuberculosis.[1] In general, immunocompetent patients tend to experience limited infections associated with low mortality, although not necessarily low morbidity. Deep organ involvement and disseminated infections occur in immunocompromised patients or patients with a comorbid condition and manifest both high mortality and high morbidity.[2] Decline of CD4+ T lymphocyte count below 100 cells/mcL has been identified as a significant risk for the development of disseminated NTMB infections. Because the CD4+ T lymphocytes are major producers of interferon-gamma (IFN-gamma) as well as other cytokines, it is believed that IFN-gamma might be important in the control of NTMB infections.[1] Smith and colleagues[2] in a retrospective study of 10 cases of coexistent AIDS and M fortuitum reported a median CD4+ cell count of 33 cells/mcL at the time of diagnosis of M fortuitum infection.[2]

M fortuitum is a thin, branching bacillus, stained inconsistently in direct smears and histopathologic preparations. M fortuitum may be weakly acid-fast and therefore could be easily mistaken for Nocardia species. M fortuitum is resistant to netilmycin and grows on Sabouraud agar.[2] On reviewing the literature, it is clear that a large number of mycobacteria have been isolated from patients with AIDS and from HIV-negative patients, as well as from environmental sources. Also, the use of molecular technologies, and improved isolation methods may lead to the description of new species, as well as redefinition of existing ones (for example, the proposal to divide M fortuitum into 2 species, M fortuitum senso stricto and M peregrinum).[6] However, it is important to bear in mind that many mycobacteria are present in the environment and may colonize damaged tissues, especially the respiratory tract, without causing clinical infection. The mere isolation of a given species of “atypical mycobacteria” on a single occasion is not necessarily indicative of pathogenicity; this is true even if the patient is immunocompromised. Assessment of the pathogenicity of a given isolate depends on several factors including the site of isolation, number of times isolated, nature of the patient, and previous history. Most important of all is close liaison between clinician and laboratory. The official statement of the American Thoracic Society gives a detailed review of infections by NTMB as well as criteria for assessing the significance of the isolates.[7]

Clinical Considerations

Clinical Features

M fortuitum causes infections most commonly in patients who have defects in cellular immunity or are receiving glucocorticoid therapy. Disseminated cutaneous infections and abscesses are perhaps the most common clinical manifestation.[3] There are sporadic reports of M fortuitum presentations in patients with AIDS such as soft tissue infections, keratitis or corneal ulcers, cervical lymphadenitis, and rarely endocarditis, meningitis, or hepatitis. Smith and colleagues[2] reported that cervical lymphadenitis was the most common initial sign of M fortuitum infection, and it was found in 9 cases of 11 patients. This entity has been associated with previous dental extraction in patients with AIDS or without AIDS. Other rare reported cases include peritonitis in patients with continuous ambulatory peritoneal dialysis, catheter related sepsis in cancer patients, and localized pulmonary infections in patients with structural lung disease such as bronchiectasis or cystic fibrosis.[2] M fortuitum has been isolated from renal dialysis circuits, being associated with disseminated lesions in a patient undergoing dialysis.[7] Localized cutaneous infection develops in surgical or traumatic wounds, from contaminated injections, or after body piercing in normal hosts. Cutaneous lesions are cellulitic or nodular; are typically erythematous, indurated, and tender, and may progress to ulceration and purulent drainage. Pulmonary NTMB infection is increasing in prevalence.[8] Multiple cases of pleural effusions secondary to underlying pneumonia caused by M fortuitum have been reported in the literature. However, to the best of our knowledge, there has been no report in the literature of isolated empyema without any other coexisting infection or pneumonia caused by M fortuitum.

Diagnosis

The rapidly growing NTMB species may be isolated from clinical specimens submitted for routine microbiologic testing. However, reliable evaluation requires inoculation onto special mycobacterial media and an extended incubation period. Because rapidly growing NTMB species are also common laboratory contaminants, numerous false alarms in the form of pseudoepidemics have been reported.[2]

Smith and colleagues used 15 different diagnostic procedures including fine-needle aspiration (FNA), bronchoalveolar lavage (BAL), different staining and biopsies of infected tissues. Gram or Gram-Wright stain demonstrated branching, beaded, gram-positive bacilli in 2 of the 5 prepared samples. Similarly, a Kinyoun stain showed characteristic fuchsin-positive filamentous rods with short branches only in 3 samples of a total of 6 slides.[2]

Shih and colleagues[5] reported that introduction of the Middlebrook 7H10 agar and the Isolator system in 1996 has resulted in a dramatic increase in the number of NTMB isolated from different samples. The Isolator system lyses the cells and releases the intracellular mycobacteria. The availability of PCR technique facilitates the diagnosis of M fortuitum infections.[5]

Culture specimens from sputum or BAL fluid can be falsely positive or negative. Therefore appropriate diagnosis of NTMB includes (1) high clinical suspicion, (2) positive culture results of sputum or bronchoalveolar lavage, and (3) satisfactory clinical response to treatment.[8]

Treatment

M fortuitum is resistant to the standard antituberculous drugs. Local measures, such as debridement, incision, and drainage, and sometimes excision are the treatment for cutaneous infections and abscesses.[9]

M fortuitum strains have been documented to be susceptible to new quinolones (no specific agents were noted), and to new aminoglycosides SCH21420 and SCH22591. The macrolides, notably clarithromycin and azithromycin, have in vitro activity against M fortuitum and many other NTMB.[7]

Holland and colleagues[1] showed a similar results of successful cure rate (58%) of NTMB with either clarithromycin 500 mg twice daily for 4 months or azithromycin 600 mg/day as monotherapy, except that with azithromycin toxicities (mostly gastrointestinal effects and altered hearing) were greater, and there was no development of macrolide resistance.

In a retrospective study, Shih and colleagues[5] noted 86 clinically significant isolates of NTMB from different organs between January 1992 and June 1996. The most common organism was M fortuitum (42.5%). Most of the infections included keratitis and cutaneous infections. Lung infections were seen in 4 of 11 cases, mostly men. Shih and colleagues used a combination of rifampicin and ethambutol plus ciprofloxacin or clarithromycin (or both) for more than 1 year for the treatment of MAC. Surgery is generally indicated for patients with lesions with extensive cutaneous involvement, abscess formation, or poor response to chemotherapy.

It is clear from animal models and human studies that IFN-gamma is a critical factor in control of mycobacteria. Trials of IFN-gamma in the treatment of non-HIV-related disseminated MAC has been very encouraging. Holland and colleagues[1] conducted a trial with use of subcutaneous IFN-gamma (50 mcg/m², 3 times weekly for up to 1 year) in addition to best-tolerated conventional therapy in patients with pulmonary NTMB infections refractory to the standard treatments.[1] Others also used aerosolized IFN-gamma or interleukin-2 with clinical improvement.[10]

The other antimicrobials used successfully include intravenous imipenem and cefoxitin, and oral rifampicin, ciprofloxacin, clarithromycin, doxycycline, trimethoprim-sulfamethoxazole, and amikacin. The duration of the therapy is not well defined, but treatment for a minimum of 6 to 12 months should be considered.[10]

Current recommendations[11] for treatment of NTMB are to administer intravenous amikacin (5-7.5 mg/kg every 12 hours) and cefoxitin (3 g every 6 hours) with oral clarithromycin (500 mg twice daily) and to continue treatment for 6 to 12 months. Surgery can be considered for localized disease. In general, susceptibility tests should be performed and used to guide antibiotic selection. M fortuitum is usually susceptible to clarithromycin, amikacin, cefoxitin, imipenem, doxycycline, and fluoroquinolones. Patients with localized cutaneous disease may respond to a single active agent (eg, clarithromycin, 500 mg twice daily by mouth for ≥ 2 weeks). Up to 6 months of therapy may be optimal for bacteremic or disseminated cutaneous disease, and a second agent should be added on the basis of susceptibility tests. Pulmonary disease requires prolonged parenteral therapy.

Discussion

M fortuitum is a member of group IV NTMB, designated by Runyon as rapid growers. NTMB can be found in the environment and may colonize damaged tissues, especially the respiratory tract, without causing clinical infection.[7] Colonies of M fortuitum attain full growth in only 3 to 5 days; this is how this organism has acquired its so-called “rapid growing” name. It is a saprophytic and ubiquitous organism. The virulence of NTMB is greatly enhanced by the presence of lipid material such as dietary fat or mineral oil in the lungs. M fortuitum is associated with conditions, which could predispose the patients for aspiration such as achalasia, colonic interposition esophagoplasty, esophageal obstruction, or bronchography with oily materials.[9]

Isolation of any mycobacterial species, especially M fortuitum, from sites other than blood has to be evaluated on an individual basis, including the patient"s immune state. This makes the diagnosis of NTMB infection very difficult. Definitive diagnosis may require biopsy and PCR amplification. M fortuitum is often resistant to standard anti-mycobacterial drugs. Newer macrolides and quinolones may offer promise. Surgical removal of infected tissues or catheter is clearly important in treatment; however, eradication may be difficult even after removal of infected tissues.

Isolated empyema is a presentation of M fortuitum, which to the best of our knowledge has not been described in the literature, and this condition should be considered in any immunocompromised patient, in particular AIDS patients, especially if the CD4+ cell count is less than 100 cells/mcL.