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Osteomyelitis Because of Mycobacterium Xenopi in an Immunocompetent Child

Kuntz, Martin MD*†; Seidl, Maximilian MD†‡; Henneke, Philipp MD*†

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The Pediatric Infectious Disease Journal: January 2016 - Volume 35 - Issue 1 - p 110-113
doi: 10.1097/INF.0000000000000933

Abstract

Osteomyelitis in children poses a considerable diagnostic challenge, in particular, if environmental organisms and nonbacterial osteitis are considered. We report a child with osteomyelitis of the right foot because of Mycobacterium xenopi, in whom only a repeated histopathologic analysis led to the correct diagnosis.

CASE REPORT

A 6-year-old boy presented with a 4-week history of pain in his right heel. Although he first experienced pain after playing soccer during a vacation in Italy, an injury close to the onset of symptoms was not noticed. Apart from the local pain, the boy was feeling well and did not experience fever or other symptoms. Treatment with oral ibuprofen did not improve his pain.

The patient was born to German, nonconsanguineous parents and had shown normal growth and a normal psychomotor development. The past medical history was significant only for atopic dermatitis and allergic asthma. However, he never had need for long-term medication. Neither the patient himself, nor his family, had a history of invasive infections.

Physical examination revealed a mild redness and swelling distal of the right lateral malleolus. Active and passive movements of the right foot were painful, but the range of motion of the right ankle was not reduced. There were no additional clinical findings. In particular, neither lymphadenopathy nor hepatosplenomegaly was observed. Laboratory work-up showed an elevated erythrocyte sedimentation rate (ESR) of 20 mm/h. Further laboratory results were unremarkable. The C-reactive protein was less than 3 mg/L, and complete blood count and smear were normal (leukocytes 7.7 giga/L: lymphocytes 33%, monocytes 6% and neutrophils 54%). An radiogram of the right foot and ankle showed a radiolucent lesion in the calcaneus of approximately 15 mm in diameter (Fig. 1A). Magnetic resonance imaging (MRI) revealed focal cortical bone destruction, intense bone marrow edema and contrast enhancement affecting the adjacent soft tissue (Fig. 1B). The results of MRI and radionuclide imaging were compatible with osteomyelitis. Yet, a neoplasm could not be excluded. Accordingly, an open biopsy was performed. Histopathology showed a mixed inflammatory infiltrate with macrophages, granulocytes and few lymphocytes accompanied by focal scar formation. Accordingly, the diagnosis of chronic granulating, focally floride osteomyelitis was made (see Fig., Supplemental Digital Content 1, https://links.lww.com/INF/C286). Ziehl–Neelsen stain for acid-fast bacilli was negative. In 1 of 2 bone samples, nested polymerase chain reaction (PCR) and sequencing revealed nucleic acids of M. xenopi. Bacterial culture, including liquid culture for mycobacteria, remained negative. Tuberculin skin test was moderately positive (9 mm induration), and the in-tube gamma-interferon release assay (Quantiferon Gold, Qiagen, Hilden, Germany) was negative. Of note, the patient had not received BCG vaccination. In the light of nonspecific histology and the uncommon mycobacterial species, osteomyelitis because of nontuberculous mycobacteria (NTM) was considered to be a possible, yet less likely, diagnosis than nonbacterial osteomyelitis. Hence, the patient was treated with nonsteroidal antiinflammatory drugs and immobilization and was subsequently kept under close clinical observation.

FIGURE 1
FIGURE 1:
Conventional radiogram in lateral projection depicts a radiolucent calcanear lesion (A) corresponding to an intense contrast enhancement of the calcaneus on postcontrast T1-weighted MRI scans at the time of first presentation (B). Radiogram performed after 6 weeks, before the second biopsy, shows a persistent radiolucent defect (C), whereas MRI reveals slight decrease of lesion size but new fistula at the site of surgical access (D).

In the following 2 weeks, swelling and redness of the right ankle improved, the biopsy wound appeared to be healing well and the ESR improved (7 mm/h). However, 6 weeks after biopsy, the mother observed secretion at the site of the scar. Plain radiogram showed persistent radiolucency with some marginal sclerosis (Fig. 1C). A repeat MRI revealed a reduction of the size of the bone lesion and the surrounding edema when compared with the previous scan. Yet a fistula had developed at the site of the surgical access (Fig. 1D).

Because spontaneous healing of the fistulating process was considered unlikely, surgical revision with a second biopsy was performed 5 days later. Histopathology at this stage showed a granulomatous tissue reaction with giant cells and central necrosis (Fig., Supplemental Digital Content 1, https://links.lww.com/INF/C286). Ziehl–Neelsen stain remained negative. Nested PCR and sequencing again were positive for M. xenopi. An independently performed DNA detection assay also returned a positive result for M. xenopi (LCD-Array MYCO Direct 1.7, Chipron, Berlin, Germany). Furthermore, M. xenopi—together with Staphylococcus aureus—was cultured in a liquid culture of this second biopsy specimen. Given now the characteristic tissue reaction and the repeated detection of M. xenopi in 2 independent laboratories (pathology and microbiology) with different methods, the diagnosis of NTM osteomyelitis was made. S. aureus was considered to be responsible for a bacterial superinfection. Antibiotic therapy with rifampicin, ethambutol, clarithromycin (following recommendations for pulmonary disease because of M. xenopi1) and cefuroxime was initiated. Cefuroxime was continued for 2 weeks, ethambutol for 4 weeks and rifampicin and clarithromycin for 6 months.

The therapy was well tolerated, and the patient experienced complete clinical recovery. Given the unusual course of an invasive NTM osteomyelitis, immunological investigations were initiated to identify possible immunodeficiency. Repeated microscopic differential leukocyte counts were normal, especially with regards to lymphocyte and monocyte levels. HIV serology was negative. Moreover, a detailed immunological work-up was performed and showed normal results. This included phenotyping of lymphocyte subsets (CD4/CD8 T cells, natural killer cells and B cells) and immunoglobulin isotype levels. In addition, a defect in the interferon-gamma/interleukin-12 axis in monocytes was ruled out by normal interferon-gamma receptor expression, interferon-gamma–dependent upregulation of CD80 and interleukin-12 production and interleukin-12–dependent production of interferon-gamma. NADPH oxidase activity was proven to be normal by showing normal oxidative burst of granulocytes and monocytes in vitro. Finally, defects in nuclear factor-κB activation and toll-like receptor function were ruled out by assessing normal cytokine production of monocytes in response to various stimulants. Altogether, no known causes for susceptibility to mycobacterial infection could be identified.

Three years after recovery, the patient presented again with pain in his right heel. ESR was elevated (18 mm/h), and MRI confirmed the recurrence of a lesion with morphological properties similar to those seen 3 years earlier. Surgical debridement was performed, yielding mostly liquid material. Unfortunately, the quality of the material obtained did not allow for proper histological evaluation, and microbiological investigations remained without specific results. However, given the strong clinical suspicion of a relapse of the mycobacterial infection and the lack of alternative explanations, the patient was again started on combinational anti-mycobacterial therapy with rifampicin and clarithromycine for 12 months. After 8 months of treatment, he is without symptoms, and the MRI shows substantial regression of the lesion.

DISCUSSION

The case presented here is notable and instructive in several respects. First, NTM infection in otherwise healthy children usually presents as lymphadenitis colli.2 In contrast, soft tissue and bone infections have almost exclusively been reported in immunocompromised individuals or after direct inoculation.3 To our knowledge, only 1 other case of an otherwise healthy child with osteomyelitis because of M. xenopi has been published.4 Remarkably, the calcaneus was also the site of infection. It is important to note that when the case description by Martínez-Roig et al was accepted for publication, genetic defects resulting in specific susceptibility to mycobacteria, and functional tests to exclude them, were not yet known.5 Hence, it remains undetermined whether the child reported suffered from aberrations in interleukin-12/interferon-gamma signaling.

Most importantly, our case illustrates the challenge that the identification of NTM by highly sensitive molecular methods may pose to clinicians. Because NTM are environmental microorganisms, they are known contaminants of material used in diagnostic laboratories. Of note, retrospectively, M. xenopi had never been detected as a contaminant in our institution. At the time of the first biopsy, our patient had experienced symptoms for 6 weeks already. In the following 8 weeks, the tissue reaction progressed from a nonspecific inflammatory response to a granulomatous reaction indicative of a mycobacterial infection. Accordingly, the case highlights the importance of repeated diagnostic workup because typical histological findings may not be present at the beginning of an NTM infection. The case presented here also underlines the fact that infections with slow-growing mycobacteria can be difficult to treat and may relapse even after a long interval of suspected recovery.

NTM species isolated from usually sterile sites in children differ considerably across Europe, with Mycobacterium avium being by far the most common isolate in Germany.6 A recent epidemiological study on the geographic distribution of NTM species isolated from patients with chronic lung disease reported on a high incidence of M. xenopi in Italy,7 which our patient repeatedly had visited during vacations. Accordingly, a detailed travel history may be important when assigning pathogenic value to a NTM species identified in a tissue sample. Of similar, if not greater, importance is the difficult clinical task involved in identifying common microbial contaminants as potential pathogens, including nontuberculous mycobacteria. Knowledge of specific local contaminants may be decisive in this context. Mycobacteria thrive in the biofilm of water taps, and sterilization does not necessarily remove nucleic acids. Given the challenges of microbiological diagnostics, we propose that misdiagnosis of NTM osteomyelitis as aseptic osteomyelitis is not a rarity, but may happen on occasion. This hypothesis is based on the concept that NTM are of low virulence and that they may be cleared by the immune system over time, even without specific antimicrobial therapy. This would be in analogy to many children with NTM lymphadenitis.8 Currently, however, NTM osteomyelitis has been very rarely reported in healthy children, and it may be the first sign of an underlying condition with a potentially life-threatening course. Thus, specific immunodeficiency, in particular HIV, monocytopenia,9 dendritic cell dysfunction10 and aberrations, in interleukin-12/interferon-gamma signaling5,11 should be excluded in all children with NTM osteomyelitis.

As seen in our case, invasive NTM infections can continue for years. Given the lack of systematic data on the effectiveness of specific anti-mycobacterial regimes and the consecutive lack of stringent clinical guidelines, management of children with invasive NTM infections still relies on individual decisions by infectious disease specialists. A meticulous diagnostic work-up and reporting of children with invasive NTM infections will hopefully result in novel algorithms that safely discriminate between NTM infections as sporadic incidences and those indicative of profound immunodeficiency.

ACKNOWLEDGEMENTS

The authors would like to thank several physicians who helped in the management of this complex case and who also made important contributions to the manuscript. Drs. Katharina Schuster, Helga Löffler, Roland Elling, Markus Hufnagel and Abdelrehim El Tayeh took part in the clinical management of our patient. Prof. Martin Werner supervised the histopathological analysis. Dr. Christian Schneider supervised the microbiological analysis of the surgical specimens. Dr. Julia Geiger analyzed the MRI scans and conventional radiograms and assisted in the preparation of Figure 1.

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Keywords:

non-tuberculous mycobacteria; osteomyelitis; histopathology; granulomatous tissue reaction; relapse; immunodeficiency

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