Laryngeal tuberculosis in patients treated with adalimumab: a casual or causal connection?

Abstract

This article presents two consecutive cases of laryngeal tuberculosis in patients treated with a specific anti-tumour necrosis factor-alpha (adalimumab), with a focus on their diagnostic process and therapeutic management. Both patients presented with aspecific chronic laryngeal symptoms that had been worsening for a few months in one case and for almost 1 year in the other one. They were both studied with fibreoptic laryngoscopy and contrast-enhanced CT and MRI scans. In both cases, the laryngeal biopsy proved negative to Ziehl-Neelsen test, while positive to Koch’s bacillus sensitive to rifampicin at PCR test. Both patients completely responded to standard antitubercular antibiotic therapy with rifampicin, isoniazid, pyrazinamide and etambutol protocol.

In the differential diagnosis of such patients, laryngeal tuberculosis should be considered due to the reasonable linkage between the immunosuppressant therapy with adalimumab and the tuberculosis infection/reactivation.

Background

Laryngeal tuberculosis is the most common granulomatous disease of the larynx, and might be localised primarily in the larynx or might be secondary to pulmonary lesions. The endoscopic findings of laryngeal tuberculosis have been classified into five types: perichondritic, ulcerative, granulomatous, polypoid and non-specific inflammatory. Laryngeal localisation of tuberculosis can be explained according to either a bronchogenic direct contamination or a haematogenic and lymphatic route.¹ Among drugs causing tuberculosis reactivation, alongside systemic corticosteroids and antirejection therapies, biological immunosuppressants such as tumour necrosis factor-alpha (TNFα) antagonist monoclonal antibodies and soluble receptors are thought to play an increasingly important role, so international guidelines suggest tuberculosis screening before starting treatment with all biological agents.²

Case presentation

Case 1

A man in his 20s came to our attention due to worsening dysphonia and hoarseness associated with productive cough for 2 months. He had been diagnosed with juvenile rheumatoid arthritis a few years before and treated with adalimumab. He interrupted this treatment a month later due to laryngeal symptoms and due to the increase in the erythrocyte sedimentation rate.

Case 2

A woman in her 60s referred to our clinic with progressive dysphagia, odynophagia and low-grade fever for the past 10 months. The patient had been under treatment with adalimumab due to Crohn’s ileo-colitis until her husband was diagnosed with pulmonary tuberculosis and her Quantiferon test turned out positive.

Investigations

Case 1

Fiberoptic laryngoscopy revealed a relevant oedema and an irregular ulcerated and granulomatous aspect of the epiglottis and both false vocal cords (figure 1A, B). A contrast-enhanced CT scan of the neck and thorax showed a diffuse enhancement of the supraglottis, diffuse cervical adenopathies (figure 2A, B) and multiple pulmonary micronodules with miliariform spreading pattern, without cavitated lesions (figure 2C).

Figure 1.

(A, B) Fibereoptic endoscopic appearance of case #1 at time of ear, nose and throat evaluation. Notice the ulcerated and granulomatous aspect of the epiglottis, aryepiglottic folds and arytenoids. These structures appear enlarged and swollen.

Figure 2.

Contrast-enhanced CT of the neck from case 1. Axial view showing enhancing irregular tissue affecting both vocal folds (A) and the supraglottis (B), without relevant reduction of the airway lumen. Multiple enlarged fusiform lymph nodes are present at both cervical sides. (C) Multiple bilateral pulmonary micronodules with typical miliariform spreading can be seen. No cavitated lesions are present.

The specimens from laryngeal biopsies in microlaryngoscopy resulted negative to the Ziehl-Neelsen test and positive to PCR test for multisensitive Koch’s bacillus. Follow-up fiberoptic image after 1 month of antitubercular medical therapy showed significant improvement of the patient’s condition (figure 3).

Figure 3.

Follow-up fibreoptic image after 1 month of antitubercular medical therapy from case 1 showing improvement of the patient’s condition.

Case 2

A diffuse oedema of the glossoepiglottic valleculae and suprahyoid epiglottis was detected during fibreoptic laryngoscopy, in association with a fine granular appearance of the mucosa, with whitish patches covering the laryngeal surface of the epiglottis. Both the contrast-enhanced CT scan and contrast-enhanced MRI of the neck revealed obliteration of the glossoepiglottic valleculae, with a hypertrophic and contrast-enhancing aspect of the supraglottis (figure 4A, B). After a first laryngeal biopsy performed at another centre detecting chronic inflammation negative for malignancy, the second laryngeal biopsy performed via microlaryngoscopy confirmed a chronic granulomatous inflammatory process with negative Ziehl-Neelsen test and positive Mycobacterium PCR test.

Figure 4.

Endoscopic and radiological appearance of the larynx from case 2. (A) A swollen aspect of the epiglottis and the aryepiglottic folds and arytenoids is visible on fibreoptic examination. (B) Contrast-enhanced CT scan of the neck showing vivid contrast enhancement of the base of the tongue, lingual surface of the epiglottis and right aryepiglottic region.

Treatment

In both cases, due to the multisensitivity of the Mycobacterium isolated through the PCR test of the specimens, the medical treatment consisted of a fourfold antibiotic therapy with a traditional protocol consisting of rifampicin, isoniazid, pyrazinamide and etambutol³ in solitary confinement for 2 weeks. After the first 2 months of therapy, the patients suspended etambutol and pyrazinamide. After a rheumatologist and gastroenterologist consultancy, respectively, they could restart adalimumab for their background immune disease approximately 6 months after the initial interruption.

Outcome and follow-up

At the latest follow-up, approximately 6 months from the diagnosis, they were continuing maintenance therapy with rifampicin and isoniazid, and both laryngeal symptoms and endoscopic appearance of the larynx had improved significantly.

Discussion

The present study is the first series of two cases of laryngeal tuberculosis diagnosed in patients treated with a specific anti-TNFα, adalimumab, for two different autoimmune diseases (rheumatoid arthritis and Crohn’s colitis).

Patients with dysphonia, hoarseness and dysphagia anytime during adalimumab treatment should be evaluated with direct laryngoscopy to detect the presence of any laryngeal change. Any laryngeal lesion in a patient affected by an autoimmune disease treated with immunomodulatory therapy should be accurately evaluated and sent for biopsy to make the proper differential diagnosis. This is particularly relevant in such patients, not only for the risk of infectious disease activation due to the combination of the autoimmune disease itself and the immunomodulatory treatments, but also for a higher risk of malignant neoplasms in immunocompromised patients.

TNFα plays a central role in the host defences against mycobacteria and in the pathogenesis of chronic inflammatory diseases. There are three main checkpoints in which TNFα is involved to contain and eliminate intracellular pathogens: recruitment of inflammatory cells, major macrophage activation and regulation of the inflammatory response. First, TNFα stimulates the production of chemokines and adhesion molecules to accumulate immune cells in the site of infection, creating a granuloma to contain the spreading of the infection. Second, it activates the phagocytic and intracellular killing capacity of the macrophages, in synergy with interferon gamma (IFNγ). Eventually, TNFα can either induce apoptosis in case of excess of inflammatory response or maintain the macrophage viability, acting as a survival factor.

According to Robert and Miossec,⁴ chronic inflammation produces a reduction of Th1 response in peripheral circulation while an increase in its activity in joints in rheumatoid arthritis. This decrease of Th1 expression in peripheral circulation can explain a lower production of interleukin 12 and IFNγ responsible for a higher sensitivity to tuberculosis reactivation of these patients, compared with the general population. In this regard, patients with both chronic inflammation with lower Th1 response and anti-TNFα treatment might have two aggregate mechanisms of higher risk of tuberculosis reactivation.

In patients receiving anti-TNFα (ie, infliximab or adalimumab) treatment, the relative risk of tuberculosis infection varies from 1.5 to 17 and, in comparison, TNFα receptor therapy (ie, etanercept) presents a lower risk of tuberculosis infection than anti-TNFα.⁵ According to a Brazilian systematic review,⁶ there seems to be no difference in the incidence of tuberculosis among the various rheumatic diseases treated with anti-TNFα drugs. In countries with low incidence of tuberculosis infection, the risk of tuberculosis under anti-TNFα therapy in comparison with the general population is from 8 to 12 times higher, while in countries with high incidence of tuberculosis infection, this risk rockets from 24 to 40 times.⁶

Regarding the different forms of tuberculosis infection in patients under TNFα blockage, 38% of the patients developed a pulmonary tuberculosis while 62% developed an extrapulmonary form.⁷ The median time of tuberculosis onset after starting a TNFα receptor therapy (ie, etanercept) is three to five times (12–21 weeks) longer than in anti-TNFα therapy, and the median rate of reactivation of a latent tuberculosis is 12 times higher for the latter one.⁷ According to a French perspective study⁷ and a British research,⁸ adalimumab has the highest annual incidence rate of tuberculosis infection (215.0 (0.0 to 521.0) out of 100.000) but the longest median time from the start of the therapy to the tuberculosis diagnosis (18.5 months). In addition, it has been shown that anti-TNFα antibodies carry higher risk of reactivation of latent tuberculosis than TNFα soluble receptors even if they both have comparable risk of new tuberculosis infection.⁹

A biphasic distribution of active tuberculosis during anti-TNFα can be explained along two different rationales^{10 11}: the first peak at 3–6 months within the start of the anti-TNFα drug can be referred to a false negative in the screening test (Quantiferon and Tuberculin Skin Test), while the second peak after more than 20 months can be classified as a new primary active tuberculosis infection.⁴ Jauregui-Amezaga et al¹² demonstrated that even with a negative latent tuberculosis infection screening test, during the period of the anti-TNFα treatment, the patient can develop active tuberculosis infection, just like the two cases of our series who both tested negative at the latent tuberculosis infection screening.

On one hand, among the youngsters, due to the extreme rarity of laryngeal malignancy, which accounts for less than 0.1% of head/neck malignancies, we should consider different non-malignant causes of laryngeal lesions. Apart from squamous cell carcinoma or rhabdomyosarcoma, laryngeal granulomatous and ulcerated lesions could be caused by inflammatory diseases such as sarcoidosis, benign vascular neoplasms like haemangiomas¹³ or infectious diseases (either mycobacterial, fungal or protozoan, such as laryngeal leishmaniasis).¹⁴ On the other hand, among adults, particularly those with risk factors, differential diagnosis between laryngeal granulomatous infections like tuberculosis and laryngeal malignant neoplasms should be considered since TNFα inhibitors lead to an increase in both opportunist infections and malignancies.¹⁵

Patient’s perspective.

Patient 1: Due to my medical history, my general practitioner convinced me to see an ENT specialist quickly after I explained her my symptoms. The whole diagnostic process took less than a month and at the end of summer I could start antitubercular therapy. After the diagnosis of tuberculosis, I also persuaded my family and friends to get tested for tuberculosis. I think everyone around me has learned to not underestimate trivial symptoms especially if they last a little longer than a common flu or sorethroat. Eventually, thanks to the medical therapy, my voice improved a lot in the first weeks of treatment even if I haven’t fully recovered yet, but maybe it’s just a matter of time and of retraining with the speech therapist who is helping me.

Patient 2: After almost one year of underestimating symptoms such as low grade fever and difficulty in swallowing, when my husband got diagnosed with pulmonary tuberculosis I decided to fully investigate my condition, following my general practitioner’s advice. Luckily I was soon sent to a third level center after a few outpatient visits and a laryngeal biopsy. Here, the medical team could study my case thoroughly and, after the diagnosis of laryngeal tuberculosis, I promptly started the antitubercular therapy. In this way I could go back to my social life, but most importantly I could restart maintenance therapy with monoclonal antibody for my Crohn disease, which was my main concern at the time.

Learning points.

• Do not underestimate aspecific laryngeal symptoms in selected patients with autoimmune disease or under immunomodulatory treatment.

• A negative screening test before starting the immunomodulatory treatment in immunocompromised patients cannot rule out a latent tuberculosis infection.

• In selected patients, laryngeal tuberculosis should always be considered in the differential diagnosis of cancer and vice versa.

Ethics statements

Patient consent for publication

Obtained.