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 Table of Contents  
CASE REPORT
Year : 2019  |  Volume : 8  |  Issue : 3  |  Page : 298-301

Perils with Pirfenidone and “the tuberculosis link”


1 Department of Medicine, Kasturba Medical College, MAHE, Mangalore, Karnataka, India
2 Department of Pulmonary Medicine, Kasturba Medical College, MAHE, Mangalore, Karnataka, India
3 Department of Dermatology, Kasturba Medical College, MAHE, Mangalore, Karnataka, India

Date of Web Publication12-Sep-2019

Correspondence Address:
Dr K Vishak Acharya
Department of Pulmonary Medicine, Kasturba Medical College, MAHE, Mangalore, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmy.ijmy_96_19

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  Abstract 


We report a case of idiopathic pulmonary fibrosis (IPF) treated with pirfenidone who developed tuberculosis (TB) and later had exfoliative dermatitis secondary to an interaction between pirfenidone and rifampicin. This case report highlights the possible risk of developing TB in patients diagnosed with IPF and on antifibrotic therapy like pirfenidone. Furthermore, this case report documents a previously unreported adverse reaction due to the interaction of rifampicin with pirfenidone.

Keywords: Idiopathic pulmonary fibrosis, pirfenidone, rifampicin, tuberculosis


How to cite this article:
Hande MH, Acharya K V, Shreenivasa A, Nayak K, Arun S. Perils with Pirfenidone and “the tuberculosis link”. Int J Mycobacteriol 2019;8:298-301

How to cite this URL:
Hande MH, Acharya K V, Shreenivasa A, Nayak K, Arun S. Perils with Pirfenidone and “the tuberculosis link”. Int J Mycobacteriol [serial online] 2019 [cited 2019 Oct 19];8:298-301. Available from: http://www.ijmyco.org/text.asp?2019/8/3/298/266498




  Introduction Top


The management of tuberculosis (TB) patients presenting with idiopathic pulmonary fibrosis (IPF) is a challenge. Patients with IPF have an increased risk of developing TB.[1] Isolated and sparse data are available in the literature of IPF patients on the treatment of developing pulmonary tuberculosis (PTB). With increasing use of novel therapies such as pirfenidone, there is high likelihood of encountering various new drug toxicities and previously unencountered interactions.


  Case Report Top


A 69-year-old male, nonsmoker, presented with Modified Medical Research Council Grade II dyspnea and cough for 3 months. Examination revealed bilateral basal crepitation. Routine hematological laboratory tests including complete blood counts, liver function tests, and renal function tests were normal. Chest X-ray was suggestive of bilateral mid-zone, lower zone reticular opacities. Pulmonary function tests revealed mild restrictive pattern. High-resolution computed tomography (HRCT) chest showed bibasilar subpleural honeycombing with areas of reticularity and traction bronchiectasis, suggestive of definitive usual interstitial pneumonia (UIP) pattern [Figure 1]. Rheumatoid factor and antinuclear antibodies were negative. Diagnosis of IPF was considered, and the patient was started on incremental doses of pirfenidone and was tolerating a dose of 1200 mg/day of pirfenidone. The patient was on regular follow-up for 8 months during which period he showed symptomatic improvement with amelioration of dyspnea and cough. In addition, his chest radiograph showed marginal clearance and improvement in performance scale with 6-min walk test.
Figure 1: High-resolution computed tomography chest showing bibasilar subpleural honeycombing with areas of reticularity and traction bronchiectasis suggestive of definitive usual interstitial pneumonia pattern

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After 11 months of diagnosis and treatment with pirfenidone, he reported with new onset of cough and low-grade fever of 10 days' duration. Chest X-ray showed bilateral consolidation [Figure 2], and the patient was treated with broad-spectrum antibiotics. HRCT revealed extensive consolidation in the left upper lobe, cavitation, and mediastinal lymphadenopathy. Sputum for acid-fast bacilli by Ziehl–Neelsen staining was positive. A diagnosis of sputum-positive PTB was made, and the patient was started on TB treatment consisting of isoniazid, rifampicin, ethambutol, and pyrazinamide as per body weight and pirfenidone was discontinued. On day 3 of anti-TB treatment (ATT), pirfenidone was restarted and the patient started developing erythema and exfoliation involving more than 85% of the body surface area with conjunctivitis [Figure 3] and [Figure 4]. The patient also had worsening of hypoxia, toxemia, and fever. He was hospitalized and started on oxygen, noninvasive ventilatory support, and parenteral antibiotics. All four ATTs and pirfenidone were discontinued, and the patient was started on oral prednisolone 1 mg/kg/body weight and antihistamines as per the dermatologist's advice. The skin exfoliation started regressing from day 5 after discontinuing ATT. On day 10, the patient's hypoxia improved and was weaned off oxygen and antibiotics. Pirfenidone was restarted and no new eruptions were observed. ATT rechallenge was started on the 14th day with sequential initiation of isoniazid, ethambutol, rifampin, and pyrazinamide. He developed pruritus, erythema, and new crop of skin lesions on restarting of rifampicin. The lesion abated after discontinuing rifampicin. Subsequently, he received isoniazid, ethambutol, pyrazinamide, and moxifloxacin and his skin and ophthalmic lesions cleared up over 2 weeks, during which period prednisolone was also tapered and stopped. The patient completed 6 months of ATT with 4 months of continuation phase with isoniazid, ethambutol, and moxifloxacin. The patient is presently on pirfenidone 1800 mg/day with stable clinical, radiological parameters preserved lung functions and no further skin-related adverse reactions.
Figure 2: Bilateral consolidation and left upper zone cavitatory lesion

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Figure 3: Extensive erythema and exfoliation involving more than 85% of the body surface area

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Figure 4: Extensive erythema and skin exfoliation

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  Discussion Top


IPF is a chronic, progressive, idiopathic fibrosing interstitial pneumonia limited to the lung and associated with a pattern of UIP on HRCT or histologic appearance on lung biopsy.[2]

Pirfenidone is a novel orally available antifibrotic drug approved by the FDA in 2014 for the treatment of IPF. It has significant antifibrotic and anti-inflammatory effects.[3] It has been evaluated in four phase III double-blinded, randomized controlled trials which demonstrated that pirfenidone slows disease progression and reduces mortality in patients with IPF. It acts by inhibiting transforming growth factor-beta and tumor necrosis factor-alpha, which play an active role in fibrosis and inflammation.[4]

Pirfenidone has been generally well tolerated, with primary drug-related adverse effects being gastrointestinal upset (nausea, vomiting, and diarrhea) and skin disturbance (rash and photosensitivity).[5]

The structural changes and reduced local immunity in patients with IPF render them susceptible to PTB, with the incidence of TB in patients with IPF being 4 times greater than the general population.[1] Research studies in a mouse model of TB showed that adjunctive pirfenidone use leads to reduced bacterial clearance, increased cavitation, development of isoniazid-monoresistant bacilli, and increased relapse rates.[6] A large single study on 795 patients with IPF showed that Mycobacterium tuberculosis and nontuberculous mycobacteria were found in 35 (4.4%) and 16 patients (2.0%), respectively, with a prevalence rate than that found in the general population. TB also was observed to be more common in patients treated with immunosuppressant therapy for IPF than in those who did not receive any kind of immunosuppressants (2.6% vs. 1.4%, P = 0.12). Among the IPF patients who received immunosuppressant, they developed TB within 1 year after treatment with immunosuppressants, while those subjects who did not receive immunosuppressants, it occurred later than 2 years after diagnosis of IPF.[1] In our case, the patient was not on immunosuppression for IPF and developed TB after 11 months after diagnosis and treatment of IPF with pirfenidone alone. In such a clinical context, it is worthwhile to probe the possibility of pirfenidone alone predisposing to TB. Our case, along with prior reported cases of reactivation of PTB in two patients treated with pirfenidone,[7] suggests that pirfenidone may predispose to TB. Both the reported cases in the literature like our patient developed cavitation approximately 10–18 months after starting pirfenidone. The only difference was that the reported cases were smear negative but polymerase chain reaction positive, while our case was smear-positive PTB. However, this association needs to be validated with larger-sized randomized trials.

A study has also demonstrated that usage of pirfenidone is associated with higher tendency for cavitatory formation in TB in murine models. The effectiveness of adjunctive pirfenidone during TB drug therapy was evaluated using a murine model of chronic TB. The study revealed that adjunctive pirfenidone use leads to reduced bacterial clearance, relapse rates with the emergence of isoniazid-monoresistant bacilli, increased cavitation, and significant lung pathology.[6]

In TB-epidemic countries like India, wherein the incidence of IPF is also on the rise and there is increasing usage of pirfenidone, this possible association poses new challenges to treating physicians, more so as there is overlap of pulmonary and constitutional symptoms, leading to delayed or mistaken diagnosis. Another aspect which makes the management of IPF challenging is the presence of new and previously unreported drug interactions. There are case reports of exfoliative dermatitis secondary to antitubercular drugs,[8] as well as pirfenidone-induced skin rashes individually.

In our case, the patient was on pirfenidone for over a year with no skin toxicity. Later, the patient developed active PTB, and on initiating four-drug ATT (isoniazid, rifampicin, pyrazinamide, and ethambutol) along with pirfenidone, he developed severe exfoliative dermatitis which necessitated hospitalization and stopping all antitubercular drugs and pirfenidone. Subsequent drug challenge with sequential introduction of ATT while continuing pirfenidone suggested rifampicin to be the offending agent. Naranjo score [9] was 3 indicating a possible drug interaction. Hence, we believe that the exfoliative dermatitis was secondary to an interaction between pirfenidone and rifampicin. No similar interactions have previously been reported. Definite mechanism for this interaction is not known and requires further study.


  Conclusion Top


  1. IPF is an independent risk factor for the development of TB. Addition of pirfenidone may increase the susceptibility to develop TB, an association that needs to be supported by larger-sized randomized studies
  2. Patients on pirfenidone with ATT should be carefully monitored for probable drug interactions. Rifampicin and pirfenidone interaction may lead to severe generalized exfoliative dermatitis as reported in our patient
  3. In high TB-prevalent countries like India, health systems should consider this possible TB and IPF association and formulate operational guidelines for initiating chemoprophylaxis for IPF patients on pirfenidone in the presence of latent TB.


Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Park SW, Song JW, Shim TS, Park MS, Lee HL, Uh ST, et al. Mycobacterial pulmonary infections in patients with idiopathic pulmonary fibrosis. J Korean Med Sci 2012;27:896-900.  Back to cited text no. 1
    
2.
Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official ATS/ERS/JRS/ALAT statement: Idiopathic pulmonary fibrosis: Evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011;183:788-824.  Back to cited text no. 2
    
3.
Schaefer CJ, Ruhrmund DW, Pan L, Seiwert SD, Kossen K. Antifibrotic activities of pirfenidone in animal models. Eur Respir Rev 2011;20:85-97.  Back to cited text no. 3
    
4.
Macías-Barragán J, Sandoval-Rodríguez A, Navarro-Partida J, Armendáriz-Borunda J. The multifaceted role of pirfenidone and its novel targets. Fibrogenesis Tissue Repair 2010;3:16.  Back to cited text no. 4
    
5.
Cottin V, Maher T. Long-term clinical and real-world experience with pirfenidone in the treatment of idiopathic pulmonary fibrosis. Eur Respir Rev 2015;24:58-64.  Back to cited text no. 5
    
6.
Ahidjo BA, Maiga MC, Ihms EA, Maiga M, Ordonez AA, Cheung LS, et al. The antifibrotic drug pirfenidone promotes pulmonary cavitation and drug resistance in a mouse model of chronic tuberculosis. JCI Insight 2016;1:e86017.  Back to cited text no. 6
    
7.
Khan M, Alghamdi M, Al-Jahdali H. Reactivation pulmonary tuberculosis in two patients treated with pirfenidone. Int J Mycobacteriol 2017;6:193-5.  Back to cited text no. 7
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8.
Dua R, Sindhwani G, Rawat J. Exfoliative dermatitis to all four first line oral anti-tubercular drugs. Indian J Tuberc 2010;57:53-6.  Back to cited text no. 8
    
9.
Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.  Back to cited text no. 9
    


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