Microscopic polyangiitis secondary to Mycobacterium abscessus in a patient with bronchiectasis: a case report

The incidence and prevalence of Non-Tuberculous Mycobacterial–pulmonary disease (NTM-PD) is increasing [1, 2]. Understanding the spectrum of disease and pathogenicity of differing Non-Tuberculous Mycobacteria (NTM) has advanced in line with developments in microbiological detection highlighting the need to sub-speciate NTM and alter management accordingly [1]. NTM can cause progressive lung disease or reside within the lungs asymptomatically [1]. Treatment regimens are prolonged, toxic and difficult to tolerate. Decisions to commence treatment are based on a number of factors including disease severity, frequency of positive cultures, progression of radiological appearances, underlying lung disease, co-morbidities and pathogenicity of individual species [1].

Guidance on treating NTM-PD was first published in 2007 [3] with no further guidance published until the 2016 Cystic Fibrosis specific consensus document [4] and 2017 British Thoracic Society guidelines [5]. This is due to lack of evidence in this area and to the complexity of the disease. Increasing incidence and prevalence of NTM-PD highlights the need for further research and guidance [1].

Mycobacterium abscessus (M.abscessus) is one of the most pathogenic NTMs, particularly in those with underlying lung disease [5]. It is a multi-resistant organism with limited antibiotic options and is challenging to treat [5]. M. abscessus is a rapid growing NTM which can be sub-speciated into M.a.abscessus, M.a.massiliense and M.a.bolletii [5]. The initial treatment aim is eradication, which commonly fails and therefore long-term chronic suppressive therapy becomes necessary. Development of macrolide resistance is associated with reduced rates of culture conversion and increased chronic infection [5]. Evidence on optimal antibiotic regimes and longer-term outcomes of chronic suppressive treatment are limited [3, 5]. Those with the subspecies M.a.abscessus have much lower rates of culture conversion [5]. The impact of M.abscessus infection on patients should not be underestimated because of prolonged toxic treatment regimens that it requires, the need for stringent infection control precautions and it’s relative contra-indication to lung transplantation [4, 5].

A 70-year-old female had been symptomatic with a persistent non-productive cough and recurrent chest infections for 10 years. At presentation to clinic a CT thorax showed right middle lobe bronchiectasis. She was a life-long non-smoker with no childhood history of respiratory disease and normal baseline investigations for immune deficiency. Clinical stability was achieved with long term Azithromycin and regular airway clearance. Staphyloccocus aureus (S.aureus) was cultured intermittently from sputum samples with repeatedly negative mycobacterial cultures. A repeat CT 6 years after her initial scan demonstrated progression of disease with bi-apical scarring, right middle lobe atelectasis, right upper lobe cylindrical bronchiectasis and reticulo-nodular densities in both lower lobes. (Fig. 1) Nebulised Tobramycin was trialled to suppress S.aureus and stabilise radiological appearances but stopped after 15 months due to worsening cough.

M. abscessus was first isolated from her sputum in November 2013; sub-speciated into M.a. abscessus. Commencement of therapy was under consideration when, 3 months from first isolation of M.abscessus, paraesthesia developed in her hands and feet with associated small joint arthropathy. A subtle purpuric rash was evident on the lower limbs. Nerve conduction studies confirmed an axonal loss sensorimotor neuropathy. Erythrocyte Sedimentation Ratio was elevated at 49 mm/hr, Perinuclear Anti-Neutrophil Cytoplasmic Antibodies (P-ANCA) titre was highly positive at 80 AI and Myeloperoxidase- ANCA (MPO-ANCA) was > 8 AI with Proteinase-3–ANCA (PR3-ANCA) < 0.2 AI. Renal function and urine microscopy were normal. A diagnosis of microscopic polyangiitis was made. Treatment with Cyclophosphamide and high dose Prednisolone was commenced with full resolution of her paraesthesia.

Within 4 months of first isolation, all sputum samples (n = 4) were culture positive and 66% of those samples were smear positive for M. abscessus. C-Reactive Protein was elevated at 86.2 mg/l. A repeat CT thorax showed extensive bronchiectasis with underlying collapse in the right upper and lower lobes. There was extensive tree-in-bud change within the right lower lobe, scattered pulmonary nodules and small areas of ground glass shadowing in both lungs. Deteriorating radiological appearances and commencement of active immunosuppression prompted urgent initiation of M. abscessus treatment.

NTM-PD is increasing in incidence and prevalence. Determining the clinical relevance of NTM isolates can be difficult [2]. M. abscessus is the 3rd most commonly isolated NTM in the USA [5]. It predominantly affects white, female non-smokers over the age of 60 [5]. It can occur in the absence of underlying lung disease where the course can be slow and indolent. In the setting of pre-existing lung disease such as CF or bronchiectasis, it can be fulminant and rapidly progressive [5]. The radiographic picture is of inflammatory nodules, tree-in-bud opacities and cavitation particularly in areas of underlying bronchiectasis [4].

There is wide variation in how patients with M. abscessus NTM-PD are treated [4]. An intensive induction phase consisting of three IV antibiotics administered for several weeks in combination with an oral agent is common [4, 5]. This is usually followed by at least two oral antimicrobials in addition to a macrolide antibiotic and inhaled antibiotic(s) [4]. Side effects of antimicrobial therapy are significant and can limit treatment options over a prolonged treatment period. In one study 65% patients stopped at least one antibiotic due to adverse events or toxicity [6]. In this case the additive toxicity of both anti-microbial and immunosuppressive agents further increased the side effect profile (Table 2).

The association between vasculitis and chronic suppurative lung conditions [7, 8] is thought to result from excessive humoral immune responses secondary to circulating immune complexes [8]. Pulmonary infection may trigger vasculitis through induction of ANCA antigen expression on the surface of neutrophils [9]. The temporal relationship between M.abscessus growth, ANCA positivity and vasculitic symptoms reduces the chance of the two being unrelated, suggesting M.abscessus was a causative trigger for the vasculitides. S.aureus had been chronically cultured since presentation with no prior evidence of vasculitis reducing the likelihood of S.aureus being a causative factor. Previous case reports have described ANCA-positive vasculitis secondary to M.avium complex [10]. Leukocytoclastic vasculitis linked to Salmonella has been reported in children with genetic Interferon-gamma deficiency [11]. Leukocytoclastic vasculitis in an individual with interferon-gamma autoantibodies and disseminated M. abscessus has also been reported [12]. Increased susceptibility to mycobacterial disease has been reported in genetic interferon defects but a causal link with associated vasculitides has not been established [13]. It is possible the reduction in IFN-γ seen in this case may have contributed both to development of vasculitis and poor treatment response.

The use of IFN-γ had been considered in this case. IFN-γ production is integral to mycobacterial defence through activation of both innate and adaptive immune systems via the interleukin12-IFN-γ pathway [13, 14]. IFN-γ facilitates mycobacterial killing by enhancing phagocytosis and expression of oxygen free radicals [14]. Administration is associated with a flu like syndrome [15‐17]. Intramuscular IFN-γ as adjuvant therapy for M. avium complex resulted in clinical benefit over antibiotics alone [5, 15] but of insufficient magnitude to warrant recommending routine use [5]. IFN-γ therapy in management of M. abscessus disease is limited to case reports of use in disseminated disease [16, 18].

Rituximab has been successfully used in disseminated M. abscessus disease refractory to antibacterial chemotherapy in those with IFN-γ autoantibodies [12, 19]. It can restore IFN-γ signalling in these individuals [12, 19]. Whether this is true in those without autoantibodies, as in this case is unknown, as is any potential interaction between Rituximab and IFN-γ therapy. In this case monitoring Rituximab response first was considered of lowest risk but the addition of IFN-γ could be re-visited.

Treatment regimens for systemic vasculitis comprise high dose induction immunosuppression followed by oral maintenance therapy for 12–18 months [9]. The challenge in this case was balancing adequate immunosuppression with sufficient antimicrobial therapy to maintain clinical stability alongside smear and culture negativity. Reductions in immunosuppression triggered vasculitic flares with sight threatening consequences whilst increases in immunosuppression led to a deterioration in NTM-PD.

This case highlights the complex interplay between immune function and NTM-PD both as a complication and a cause of disease [13, 14, 20]. Defects in IFN-γ pathways, both acquired and genetic are associated with NTM-PD [14, 20]; as are defects in macrophage and dendritic cell function and cytokine signalling [5, 13]. Whole genome sequencing has demonstrated higher rates of genetic variants in immune, Cystic Fibrosis Transmembrane Conductance Regulator, cilial function and connective tissue categories in people with NTM-PD. [21] Screening for immune defects in those with NTM-PD who fail to respond to “standard” treatment is increasingly recommended [5] and may allow better prognostication and management in the future. Equally, those with known immune dysfunction should be screened for NTM.

Striking the balance between managing infection and immunosuppression is an increasing issue in clinical medicine with rising numbers of patients receiving biologics, immunosuppressive agents and increasing lifespan post haematological and solid organ transplants [5, 22, 23]. Oral corticosteroid use is up to eight times higher amongst cases of NTM infection [22]. Rates of NTM-PD are five to ten fold higher in patients on anti-TNF alpha therapies [23]. Whilst other biological agents, carry a theoretical increased risk of NTM there is little data on infection rates [15]. Acquisition of NTM infection is likely due to disruption or depletion of cell mediated immunity which is a critical component of host defence against mycobacterium [14]. Adequate screening of high-risk populations for NTM is necessary to further understanding of disease rates and facilitate appropriate intervention [1, 5, 22] (Table 3).

Effective treatment of NTM-PD requires effective communication and team working between specialities treating this complex group of patients. Balancing immunosuppressive with anti-microbial regimes and their relative toxicities is challenging and requires frequent assessment, monitoring and treatment adjustment. Further research will refine management approaches and improve our understanding of the role of innate, adaptive and auto-immune dysfunction and the incidence of related complications including vasculitis.