Disseminated Disease by Mycobacterium abscessus and Mycobacterium celatum in an Immunocompromised Host.

BACKGROUND Nontuberculous mycobacteria (NTM) are environmental pathogens that cause an increasing number of diseases, in particular in immunosuppressed patients. Diagnosing NTM infections may be difficult because clinical presentation is unspecific and resembles other conditions such as tuberculosis, lymphomas, or septicemia. CASE REPORT We report the case of a 62-year-old male with a recent history of autologous bone marrow transplantation for a follicular lymphoma admitted to our department for long-lasting remittent fever and abscess-like splenic nodules. The patient was diagnosed with mixed systemic infection by Mycobacterium abscessus and Mycobacterium celatum localized in spleen, bone marrow and kidneys. CONCLUSIONS In this case a rare disseminated atypical mycobacteriosis was diagnosed and treated. As far as we know this is the first case in the literature of M. abscessus localization either in the spleen or in the bone marrow. Our patient underwent a complex long-term therapy and had a complete resolution of the disease.

Background

Nontuberculous mycobacteria (NTM) represent an ubiquitous group of micro-organisms with life-threatening effects on elderly and immunocompromised patients, in particular those who underwent immunosuppressive therapy and patients in the Acquired immunodeficiency syndrome (AIDS) population [1]. The awareness on these pathogens is increasing because innovations in molecular techniques have improved the diagnosis of these previously unrecognized diseases [2]. Nevertheless, a NTM diagnosis is still very insidious: infections frequently develop with specific and variable symptoms that can deceive the clinician and can lead to misdiagnosis and delayed treatment.

Among NTM species, the most common rapidly growing myco-bacterium is Mycobacterium abscessus, that causes 5–20% of all NTM infections [3]. It causes pulmonary infections in immuno-compromised patients or inpatients with predisposing lung conditions such as bronchiectasis or cystic fibrosis [4], but it also can involve skin and soft-tissues infections.

Epidemiological data on M. abscessus are lacking, nevertheless, in the literature this mycobacterium is associated with significantly higher fatality rates than any other rapidly growing NTM species [5].

M. celatum is a slow-growing NTM, responsible for localized infections, mostly in the lungs or in lymph nodes as reported by Christiansen et al. in 2004. It is a rare cause of infection in humans, but it can develop into a fatal disease in immunocompromised patients and in immunocompetent patients as well [6].

Here, we report a case of simultaneous M. abscessus and M. celatum disseminated disease in a patient affected with prior B-cell lymphoma and persistent hypogammaglobulinemia.

Case Report

On February 9, 2018, a 62-year-old Caucasian male was admitted to the Unit of Infectious Diseases at the “Garibaldi” Hospital in Catania (eastern Sicily) due to long-lasting remittent fever.

In 1999, he was diagnosed with follicular B-cell non-Hodgkin lymphoma first treated with chemotherapy until 2000 and, after a relapse, with an autologous hematopoietic stem cell transplantation (HSCT) in 2003.

After the HSCT, the patient had persistent hypogammaglobulinemia and reported frequent hospital admissions due to recurrent respiratory infections.

In June 2017, gallbladder hydrops required an abdomen computed tomography (CT) scan (Figure 1) that showed a marked splenomegaly with several abscess-like splenic hypodense nodules (maximum 4 cm diameter). The patient underwent cholecystectomy, and during surgery, a spleen biopsy was performed, but unfortunately showed irrelevant results.

Figure 1.

Accidental spleen nodules. Axial contrast-enhanced abdomen computed tomography scan (2 sections) showing gallbladder hydrops and splenomegaly (spleen bipolar diameter: 14 cm) with parenchymal alterations characterized by several abscess-like splenic hypodense nodules. Presence of peri-splenic fluid collection.

In November 2017, the patient was admitted to the Department of Internal Medicine for a 2-month remittent hyperpyrexia, partially susceptible to steroids and paracetamol. Under the suspicion of non-Hodgkin lymphoma relapse with splenic localization, the patient underwent a splenectomy with histological examination of his spleen. The histopathological examination of the surgical specimens showed multiple granulomatous lesions with necrotic focus and external giant pluri-nuclear cells, with extended vascularized areas, as well as the presence of many fibrotic regions and areas with polymorphic lymphoid infiltrates.

For the persistent fever, the patient was admitted to our department in January 2018. Upon hospital admission, physical examination was irrelevant except for hyperpyrexia (temperature >38°C), a post-surgery paramedian abdominal scar and a remarkable dullness at basal chest percussion on the left lung (Figure 2).

Figure 2.

Lung involvement of the disease. Chest x-ray showing several bilateral parenchymal foci with ill-defined margins, localized mainly in the perihilar regions. Presence of left costophrenic angle blunting.

Blood examinations revealed neutrophilic leukocytosis (white blood cell 13 600 cell/mm3, absolute neutrophil count (ANC) 8300 cell/mm3), normocytic anemia with hemoglobin 11.1 g/dL, thrombocytopenia (62 000 cell/mm3), increased C-reactive protein (CRP) value of 4.04 mg/dL, hypoalbuminemia (2.57 g/dL), severe hypogammaglobulinemia (0.06 g/dL), hyponatremia (128 mEq/lL, increased values of serum ferritin (642 ng/mL) and beta-2 microglobulin (4.37 mg/L). The value of procalcitonin was normal.

Repeated blood cultures and urine cultures were negative for bacteria and fungi. Lung and abdominal CT scan (Figure 3) showed left-sided pleural effusion, bilateral pulmonary ground-glass areas and mild pericardial effusion; in the abdomen, presence of multiple abscess-like hypodense nodules in the kidney, loculated effusion with perivisceral fat thickness and edematous imbibition of the muscles in the left hip.

Figure 3.

Progressive worsening of lung disease. Axial contrast-enhanced thorax computed tomography scan (2 sections) showing left-sided pleural effusion with parenchymal dysventilation; disseminated bilateral pulmonary “ground-glass” areas.

The patient underwent thoracentesis with removal of 1200 mL of clear fluid, analyzed by Ziehl-Neelsen microscopy and GeneXpert test, both were negative for M. tuberculosis. Also, sputum, 24-hour collected urine and peritoneal fluid aspirate were analyzed by smear microscopy (Ziehl-Neelsen stain), myco-bacteria growth indicator tube (MGIT) culture examination and nucleic acid amplification tests (NAATs) by Xpert MTB/RIF assay. All the examinations were negative for mycobacteria.

During hospitalization, the patient’s clinical status progressively deteriorated: hyperpyrexia persisted with peaks >39°C and dyspnea occurred (oxygen saturation was 86% in room air). Thus, oxygen therapy was administered via Venturi mask (FiO2 40%, oxygen saturation 91% with 10 L/minute). He also developed an anasarca-like edema, so both furosemide (50 mg/day) and albumin (10 mg/day) were infused intravenously.

On February 14, smears from previously removed spleen tissue aspirate were deparaffinized and together with bone marrow aspiration were screened “in situ” by multiplex real-time polymerase chain reaction (PCR) assay: both spleen tissue smears and bone marrow aspiration resulted positive for M. abscessus and for M. celatum. Bone marrow aspirate was also cultured on Löwenstein-Jensen agar resulting positive for M. abscessus and M. celatum growth.

On the basis of such findings, starting from February 22, antibiotic treatment was administered with tigecycline 50 mg twice daily intravenously, amikacin 750 mg once daily intravenously, clarithromycin 500 mg twice daily by mouth, ciprofloxacin 500 mg twice daily by mouth, and clofazimine 100 mg once daily.

Within a week from the onset of treatment, the patient’s fever decreased, and his clinical conditions improved with progressive amelioration of dyspnea. One month later, his biochemical examinations demonstrated a complete normalization of inflammatory markers. Tigecycline and amikacin were interrupted, and oral linezolid 300 mg twice daily was introduced. On March 30, the patient was discharged in good clinical status, without fever or dyspnea.

Two months after the discharge, the patient suffered from severe periumbilical abdominal pain, and underwent a pancolonscopy that showed evidence of mucosal redness in the ileal tract. A biopsy of the ileum revealed clofazimine crystal-histiocytes in the lamina propria, thus clofazimine was interrupted. The patient continued with amikacin 750 mg intramuscularly while linezolid (300 mg twice daily), clarithromycin (500 mg twice daily) and ciprofloxacin (500 mg twice daily) orally.

Therapy was scheduled to be continued for as long as 12 months (Figure 4). On January 12, 2019, a thoracic and abdominal CT scan demonstrated the complete reabsorption of the intra-abdominal abscesses. It also showed the complete recovery of pericardial and pleural effusions, and of the ground-grass lung infiltrates. On February 15, 2019, therapy was interrupted after 12 months of continuous administration. The patient had an excellent clinical status, apart from subclinical hearing loss as assessed by pure-tone audiometry, which was performed in a standard soundproof cabin. He has returned to his job and to low-intensity sports training.

Figure 4.

Improvement after 6 months of therapy. Axial contrast-enhanced thorax computed tomography scan (2 sections) showing fairly complete resolution of bilateral “ground-glass” areas, persistence of few small foci in the middle lobe. Minimum left-sided pleural effusion.

Discussion

Our clinical case describes a disseminated disease by M. abscessus/celatum in a severely immunocompromised individual. Immune suppression was provoked either by HSCT or by a persistent hypogammaglobulinemia, which required periodical immunoglobulin intravenous infusions.

NTM infections are 50 to 600 times more frequent in solid organ transplantation [7], HSCT recipients [8] than in the general population, and also the mortality rate is higher in the first population than in the latter one. M. avium complex (MAC) is the most frequent NTM species to cause disseminated infections in transplanted population. Allogeneic HSCTs are greater risk factors for NTM infections than autologous transplantations. Causes of NTM infections are mainly unrecognizable: in HSCT, there are very little possibilities that the donor bone marrow could be infected by NTM and could transmit to recipient. In 2017 a M. abscessus outbreak occurred in a hospital in North Carolina (USA) and caused 126 infections, 5 cases of which in HSCT recipients [9]. Compared to Mycobacterium tuberculosis, in HSCT NTM are more correlated to Central venous catheter–associated infections. In HSCT population, the most common NTM infections are localized in lungs, with nodules, necrotizing pneumonia, cavitation, or pleural effusions. Other NTM infections can involve skin, gastrointestinal tract and hematopoietic system with necrotizing granulomas [10]. Complete recovery from NTM disease is seldom possible and new infections with other strains of NTM or even relapse of the original NTM is not uncommon.

M. abscessus complex might cause pulmonary, cutaneous, and disseminated infections in solid organ transplant recipients as reported by Smibert et al. 2016 [11]. In 2018, Salvator et al. [12] reported a pulmonary M. abscessus infection soon after allogeneic HSCT. Also, Morales in 2010 [13] described 8 clinically relevant cases of M. abscessus infection with both cutaneous and respiratory localizations among bone marrow transplant recipients. Nevertheless, as far as we know there are no reports of bone marrow localization by M. abscessus in literature.

Thus, the present case represents the first reported case of M. abscessus localization either in the spleen or in the bone marrow. Also, no human case of M. celatum splenic, bone marrow, and renal infection has been described so far. Even in our experience we could not assess the actual role of M. celatum whether as a co-pathogenic agent or as a mere innocent bystander.

In our clinical case, the patient was successfully treated for as long as 12 months with a complex drug combination, which started with tigecycline, amikacin, clarithromycin orally, ciprofloxacin orally, and clofazimine orally, then shifted towards oral linezolid, clarithromycin, and ciprofloxacin.

As reported by Griffith et al. in 2007 [14], macrolides are the only oral agents reliably active in vitro against M. abscessus. These authors declared that this mycobacterial infection generally has low or intermediate minimum inhibitory concentrations (MICs) to amikacin, cefoxitin, linezolid, and clofazimine. More recently, Ryu et al. [15] suggested the efficacy of macro-lide therapy in addition to fluoroquinolone, linezolid, clofazi-mine, or amikacin for long-term treatments, but never shorter than 12 months comprehensively.

It should be remarked that our patient suffered a severe abdominal distress due to intestinal deposition of crystallized clofazimine. Crystallization of clofazimine in high dosage over prolonged periods is a rare but well-recognized condition known to occur in various tissues [16]. The prompt withdrawal of clofazimine administration is required in order to avoid a life-threatening evolution. In the present case, this unusual side effect forced us to return towards intramuscular amikacin in order to maintain an effective and synergic drug combination. Unfortunately, yet expectedly, a mild hearing loss was ascertained after the 12-month treatment course.

Conclusions

This article has discussed the protracted management of both M. abscessus and M. celatum infections in an immunosup-pressed patient. Infections caused by these mycobacteria localized either in the spleen or in the bone marrow represent a clinical challenge because of the poor prognosis of the condition and the small number of cases described in the literature. Our case report may be considered a model for the management of other similar conditions.