A rare cause of secondary organising pneumonia

Abstract

Non-tuberculous mycobacterial pulmonary disease may have different clinical manifestations. We report a case of a 64-year-old woman presenting with persistent respiratory complaints, fever and radiological findings. Initially, she was diagnosed with community-acquired pneumonia, but after being submitted to an extensive investigation, including CT-guided transthoracic lung biopsy, a diagnosis of organising pneumonia (OP) was established. The patient was treated with corticosteroids with no favourable response. Subsequently, Mycobacterium avium complex (MAC) was identified in bronchoalveolar lavage culture. The patient was diagnosed with OP secondary to MAC infection and specific antibiotic treatment was initiated. This case represents an infrequent association and illustrates how important it is to investigate primary causes of OP to obtain a satisfactory treatment response.

Background

Organising pneumonia (OP) is an inflammatory lung disease involving the distal bronchioles, respiratory bronchioles, bronchiolar ducts and alveoli. OP may be cryptogenic or secondary to several factors, such as drugs, infections, radiation therapy, malignancy or connective tissue diseases. Several viral and bacterial organisms have been identified as infectious causes of OP.^{1 2}

Non-tuberculous mycobacterial pulmonary disease (NTM-PD), including Mycobacterium avium complex (MAC) infection, is a challenging entity which is becoming increasingly prevalent, particularly in the elderly and patients with underlying lung disease. The diagnosis of NTM-PD relies on the integration of clinical, radiological, microbiological and pathological results. The clinical course of NTM-PD is heterogeneous, ranging from asymptomatic cases without the need for treatment to patients with refractory disease associated with considerable mortality and morbidity.³

This report describes a case of a 64-year-old woman with prolonged history of respiratory complaints, fever and radiological findings and was simultaneously diagnosed with OP and MAC infection.

Case presentation

A 64-year-old woman, non-smoker and a former teacher, presented a past history of arterial hypertension, rheumatic mitral valvular disease with a mechanical valve implanted in 2003, postinfective tubular bronchiectasis, osteoporosis and rhinosinusitis. The patient’s routine medication included warfarin, candesartan, amlodipine, pantoprazole, folic acid, calcium carbonate, alendronic acid and vitamin D. There was no relevant family history or exposure to animals or fungi. There was no recent travel or known contact with tuberculosis. She was previously admitted for multifocal pneumonia in October 2014 and March 2015.

The patient was seen twice in the emergency department in December 2016 and January 2017, complaining of vespertine fever, mucopurulent cough and night sweats, treated with several antibiotics (ß-lactams and cephalosporins) with partial clinical response. In February 2017, she returned to the emergency department with the same complaints, accompanied with exertional dyspnoea, anorexia and weight loss (7% of total body weight) over the previous 3 months. No haemoptysis or pleuritic chest pain was mentioned. Physical examination was unremarkable apart from auricular body temperature of 38.5°C and audible fine crackles in the right middle and left lower lung fields.

After the initial evaluation and due to persistence of clinical complaints, the patient was admitted for aetiological investigation.

Investigations

Blood analysis showed C reactive protein of 249.7 mg/L, erythrocyte sedimentation rate of 106 mm/first hour, but no leucocytosis or neutrophilia. Chest radiograph presented bilateral heterogeneous infiltrates, predominantly in the lower pulmonary fields. Chest CT revealed pulmonary micronodules, tree-in-bud pattern, tubular bronchiectasis, and small consolidations with peripheral, basal and bilateral distribution (figure 1).

Figure 1.

Chest X-ray and CT at diagnosis of Mycobacterium avium complex and organising pneumonia overlap.

Blood cultures, syphilis and viral serologies were negative (including HIV, hepatitis B and C, Epstein-Barr virus, herpes simplex 1 and 2 virus, and parvovirus). Immunological study for autoimmune disease screening was negative, including antinuclear antibodies, antineutrophil cytoplasmatic antibodies and rheumatoid factor. ECG revealed a sinus rhythm with occasional ventricular extrasystoles. Transthoracic echocardiogram excluded valve dysfunction and evidence of infective endocarditis.

Sputum culture isolated an Enterobacter cloacae complex. Sputum acid-fast bacilli (AFB) smear was negative; culture results remained negative (and still in culture) for the duration of hospital stay.

To rule out neoplastic aetiology, the patient’s medical chart was reviewed, revealing normal mammography, thyroid ultrasound and cervical smear test less than 1 year prior to admission. During hospital stay, she underwent abdominal and pelvic CT, upper gastrointestinal endoscopy and colonoscopy and no abnormalities were found.

The patient was treated with piperacillin/tazobactam for 14 days (in line with drug sensitivity of the isolated E. cloacae complex) without evidence of clinical and/or radiological improvement. Consequently, bronchoscopy was performed, showing no airway abnormalities. Bronchoalveolar lavage (BAL) revealed a neutrophilic (33.2%) and lymphocytic (31.2%) alveolitis. BAL bacteriological and AFB smear were negative, and no malignant cells were identified. Mycobacterial BAL culture was ongoing. The patient was then submitted to CT-guided transthoracic lung biopsy and the histological examination showed a pattern suggestive of OP (figure 2).

Figure 2.

Pathological evaluation of transthoracic CT-guided lung biopsy: (A) thickened alveolar septa and intraluminal plugs; immunohistochemistry for cytokeratin highlights the alveolar lining (*); (B) thickened alveolar septa with lymphocytes and histiocytes; and (C) intraluminal plugs, composed of granulation tissue and fibroblasts.

The case was referred to the local interstitial lung disease multidisciplinary team (MDT) meeting, where the diagnosis of cryptogenic organising pneumonia (COP) was established.

Treatment

Treatment with prednisolone (0.75 mg/kg/day) was started and the patient was discharged. On follow-up at the interstitial lung disease outpatient clinic, the patient presented poor response to glucocorticoid therapy, with maintenance of cough and exertional dyspnoea. Furthermore, there was evidence of progression of the pulmonary infiltrates on chest X-ray.

When reviewing the ongoing mycobacterial culture results, the BAL sample revealed the presence of MAC strain. Drug sensitivity testing confirmed its sensitivity to clarithromycin. Consequently, the patient was rediscussed in the MDT meeting, leading to the final diagnosis of OP secondary to MAC infection. On referral to the outpatient clinic for tuberculosis and non-tuberculous mycobacteria, treatment was started with weight-adjusted doses of clarithromycin, rifampicin and ethambutol. The glucocorticoids were concurrently slowly tapered and stopped.

The patient was referred for respiratory rehabilitation and nutrition counselling. Regarding non-pharmacological treatment, she had already taken antipneumococcic and annual influenza vaccines.

Outcome and follow-up

During treatment and follow-up, several challenges ensued. Regarding adverse effects of medication, the main complaint was sustained nausea, which slightly improved with symptomatic medication. She also presented with a modification in chromatic vision at 7 months of treatment. After ophthalmological evaluation, ethambutol was stopped and the ocular symptoms resolved.

Despite clinical improvement, radiological response was slow, motivating the repetition of bronchoscopy with BAL for microbiology at 12 months of treatment and the prolongation of antibiotic therapy until 18 months. Bacterial, mycobacterial and fungal BAL samples and routine sputum cultures were negative.

Chest CT at the end of treatment demonstrated persistence of tubular bronchiectasis with a discrete tree-in-bud pattern, greatly improved when compared with the first CT (figure 3). Spirometry revealed a small airway ventilatory defect with a moderate decrease in diffusing capacity for carbon monoxide and no desaturation on 6 min walking test.

Figure 3.

Chest X-ray and CT after completing treatment for Mycobacterium avium complex.

The patient is still under clinical, microbiological and radiological follow-up at the outpatient clinic for tuberculosis and non-tuberculous mycobacteria and no recurrence of OP or infection has occurred to date (currently in the second year of follow-up after completing MAC treatment).

Discussion

We report the case of a patient who developed MAC pulmonary infection and secondary OP. This association has been rarely reported in the literature, as only two clinical cases were found showing the coexistence of these two entities.^{4 5} In both, the authors report the cases of two women in their late 50s and mid-60s who were investigated for persistent respiratory symptoms and fever. The case from Hamada et al⁵ was also initially diagnosed as community-acquired pneumonia, but the patient did not present any underlying lung disease unlike our patient or the one of Jones et al,⁴ who had bronchiectasis and chronic obstructive pulmonary disease, respectively.⁶ Not infrequently cases of NTM are initially misdiagnosed and the patient may refer multiple times to healthcare facilities with persistent respiratory and constitutional symptoms as in our case.

The diagnosis of NTM-PD depends on the integration of clinical, radiological and microbiological findings, summarised in the American Thoracic Society and Infectious Diseases Society of America (ATS/IDSA) criteria, which have become the accepted disease definition.⁷ The presenting symptoms of NTM-PD are non-specific. The radiological patterns compatible with pulmonary non-tuberculous mycobacterial disease on high-resolution CT (HRCT) are usually fibrocavitary disease or nodular bronchiectasic disease.^{7 8} On the other hand, OP HRCT patterns usually include patchy and peripheral consolidation and/or ground-glass opacities. In the article by Jones et al,⁴ the patient’s HRCT presented a cavitated lesion on the left upper lobe, typical of MAC fibrocavitary disease, and a lower lobe consolidation with air bronchogram. The HRCT descriptions revealed patchy, bilateral consolidations, surrounded by ground-glass opacifications and micronodules, in accordance with the findings of Hamada et al.⁵

Correct identification of the NTM species is of paramount importance, as species differ in their potential to cause pulmonary disease and in the type of treatment needed.³ Unlike tuberculosis, in which one positive culture is usually sufficient to define infection, to meet the ATS/IDSA criteria for NTM-PD a patient must have characteristic symptoms, compatible radiology, and two or more positive sputum samples of the same NTM species or one positive bronchial wash/lavage or compatible histopathological findings with one positive culture.⁷ Other potential causes of pulmonary disease must also be excluded. A limitation of our diagnostic approach was that a sample of the lung CT-guided biopsy should have been sent to the microbiological laboratory. A positive AFB could have indicated a possible NTM infection, despite the absence of granulomas in the histological evaluation.

According to the statement on the International Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias, the diagnosis of OP requires the presence of compatible clinical and radiological features in addition to a high BAL lymphocyte count (>40%) and/or typical pathological aspects.^9–11 In the previous reports,^{4 5} the histological sample was obtained by conventional transbronchial biopsy, while in our case it was obtained by transthoracic approach. Both techniques are valid options for the diagnosis of OP.

When the diagnosis of OP is made by lung biopsy, the next step is to determine whether the disease is cryptogenic or secondary to another process. It is difficult to differentiate COP from secondary OP based on radiological or pathological findings alone.¹¹ Thus, a careful review of the patient’s history, physical examination, medication usage, potential exposures and underlying diseases is needed to determine whether OP is indeed cryptogenic.

Furthermore, BAL may have a role in identifying a secondary cause of OP or a differential diagnosis, such as alveolar haemorrhage, malignancy or infection. In our case, BAL was crucial in the identification of MAC as an aetiological cause of OP. BAL findings have been reported in a limited number of patients with OP. The total number of cells recovered is greater and usually presents a ‘mixed pattern’ with an increase in lymphocytes, in concordance with our case.¹

It is thought that OP is a consequence of alveolar epithelial injury.¹ The initial injury is followed by leakage of plasma proteins, recruitment of fibroblasts and fibrin formation within the alveolar lumen. MAC is known to induce the production of cytokines such as interleukin 8 and to adhere to fibronectin in areas of denuded extracellular matrix in the respiratory mucosa, via fibronectin attachment protein.¹² Both interleukin 8 and fibronectin genes are also increasingly expressed in OP, suggesting a role for cytokine activation by alveolar macrophages in the inflammatory process.¹³ Moreover, it is widely accepted that aerosolised MAC can cause reactions called ‘hot tub lung’—resembling hypersensitivity pneumonitis clinically, radiologically and pathologically and generally responding to corticosteroid treatment.^{14 15} Therefore, it may be possible that MAC has the potential to trigger an OP reaction, as other micro-organisms.

Although corticosteroids are considered the gold standard treatment for COP, dosing and treatment duration are more controversial and recommendations are based only on clinical series.^{1 11} Interesting data have also been published about treatment with macrolides in OP; however, evidence is limited to case reports and they are usually used in association with other immunosuppressive agents, rendering it impossible to evaluate their actual efficacy.¹⁶ Considering secondary OP, the treatment should be directed to the identified cause and some authors defend the use of concomitant corticosteroids with rapid tapering. In our case, the initiation of corticosteroids as for COP did not lead to a favourable clinical response and only with MAC treatment was clinical improvement achieved. Combined treatment for MAC includes a macrolide, which may simultaneously contribute to regulating the inflammatory process of OP.

To our knowledge, this is one of the first cases stating the association between MAC infection and OP. We recommend a systematic investigation of potential aetiological agents in cases thought to have COP, particularly in individuals with pre-existing lung disease.

Further studies are required to confirm whether MAC has a causal relationship with OP, thus representing another clinical and pathological manifestation of MAC pulmonary involvement.

Learning points.

• Insidious respiratory and constitutional symptoms in a patient with structural lung disease and typical radiological features (bronchiectasis, tree-in-bud or nodules) should raise the suspicion of a non-tuberculous Mycobacterium infection.

• Mycobacterium avium complex (MAC) may be included as a cause of organising pneumonia (OP).

• The systematic evaluation of aetiological causes after the diagnosis of OP is crucial to achieve a correct diagnosis and choose the appropriate treatment.

• Follow-up is fundamental to evaluate adverse events associated with MAC treatment and potential disease relapses.