Case report of a laryngeal tuberculosis during pregnancy – challenges in diagnosis and management

Abstract

Although tuberculosis is the leading infectious cause of mortality worldwide, it is a rare condition in Switzerland and laryngeal manifestations are easily misdiagnosed. Patients with laryngeal tuberculosis often present with non-specific symptoms like dysphonia, weight loss, dysphagia or odynophagia. We present a case of a 27-year-old pregnant woman with dys- and odynophagia and non-productive cough not responding to conservative treatment. Laryngoscopic examination showed polypoid alterations, erythema and edema of the supraglottic structures. Biopsy was consistent with tuberculosis. Quadruple antitubercular therapy was started as recommended by the World Health Organization and Swiss Lung Association guidelines. Subsequently, the patient fully recovered from the illness and the follow-up was negative for relapse.

Keywords:

• Laryngeal tuberculosis
• dysphagia
• odynophagia
• pregnancy
• case report

Background

Tuberculosis (TB) is a contagious infectious disease of chronic evolution caused by Mycobacterium tuberculosis. Despite progress in disease control, TB is still responsible for approximately 1.5 million deaths every year, and therefore one of the leading causes of mortality worldwide according to the World Health Organization (WHO) [1].

In Europe, incidence and mortality rates of TB have substantially decreased during the last decades. According to the Tuberculosis surveillance and monitoring data published by the European Centre for Disease Prevention and Control (ECDC), Switzerland reported a low incidence of 5.1–7.3 per 100,000 population in the years 2015–2019. Two-thirds of the cases were reported to be of foreign origin [2].

Of all TB cases reported in Switzerland in 2019, two-thirds (68.7%) were pulmonary and one-third (31.3%) extrapulmonary, involving organs or anatomical sites such as pleura, lymph nodes, abdomen, genitourinary tract, skin, joints, bones or meninges. The ECDC classifies laryngeal TB as pulmonary tuberculosis, therefore, data on the prevalence of isolated laryngeal tuberculosis in Europe is lacking [2]. In the United States and Brazil, laryngeal TB account for approximately 1–2% of all TB cases [3–6].

Regarding its pathogenesis, laryngeal TB can be divided into primary laryngeal TB from direct invasion of bacilli into the larynx or secondary laryngeal TB due to direct bronchogenic spread from advanced pulmonary TB or via hematogenous or lymphatic spread from extrapulmonary sources. While older publications from the 1940s reported a vast majority of secondary laryngeal TB, a more recent review revealed a higher proportion of primary laryngeal TB. Due to its rarity and unspecific symptoms, laryngeal TB is easily misdiagnosed. Symptoms may mimic common disorders like laryngopharyngeal reflux (LPR) or malignancy. The most common symptoms of laryngeal TB are dysphonia (96%), weight loss (47%), cough (38%), dysphagia (26%) and odynophagia (25%). Stridor has been described in 9% of the cases with a potential need of tracheotomy for safe airway management [3].

If TB is suspected, definitive diagnosis is based on the identification of a pathogenic species of the M. tuberculosis complex from a biological sample in positive culture and/or nucleic acid amplification test. Based on PCR, nucleic acid amplification techniques can detect M. tuberculosis complex with high sensitivity in less than 2 h. Mycobacterial culture is required for drug susceptibility testing. Since mycobacteria grow slowly, definitive results are only available after several weeks. Microscopic examination of stained tissue samples might point to the diagnosis but have to be confirmed by PCR testing in order to exclude nontuberculous mycobacteria and other acid-fast bacilli [7].

TB is treated with a combination of antituberculosis drugs administered over a period of several months. The WHO and the Swiss Lung Association (SLA) recommend isoniazid, rifampicin, pyrazinamide and ethambutol as the first-line treatment in an initial phase for 2 months, followed by a continuation phase with only isoniazid and rifampicin for 4 months. If any drug resistance is detected, the treatment regime needs to be adapted and the advice of an infectious disease specialist is recommended. In children, pregnant or breast-feeding women and in immunocompromised patients the same standard treatment regime is advised [7,8]. It is safe to continue breastfeeding for women under treatment with the first-line drugs as only minor, non-toxic quantities pass to the breast milk [9].

In this report, we present the case of a 27-year-old pregnant woman with laryngeal TB, discuss the most common differential diagnoses and review the diagnostic and therapeutic procedures.

Case presentation

A previously healthy 27-year-old woman has presented herself to our outpatient otorhinolaryngology clinic with a history of increasing dysphagia, odynophagia and non-productive cough for 5 months. Dyspnea and dysphonia were not present at any time. Although she was in the 35th week of pregnancy, she had lost 4 kg of weight in the past 4 weeks. She did not drink any alcohol and was a non-smoker. The patient had immigrated to Switzerland from Romania six months prior to presentation. Regular outpatient gynecological check-ups before showed a normal pregnancy. Due to her laryngeal symptoms the patient had been referred to an extern otorhinolaryngologist three weeks earlier. She was started on a treatment with pantoprazole, prednisone and co-amoxicillin for 5 days, which led only to a short-term improvement.

Physical examination revealed slight tenderness on palpation over the larynx. The transnasal fiberoptic laryngoscopy showed an intense inflammation of the supraglottic larynx with polypoid alterations, erythema and edema of the mucosa (Figure 1). Laboratory investigations revealed normal leukocytes, the C reactive protein was elevated at 99 mg/L.

Figure 1. Fiberoptic evaluation of the patient’s larynx. All supraglottic structures are covered with dense polypoid lesions.

The patient was hospitalized and a biopsy from the larynx was taken under general anesthesia. Polymerase chain reaction (PCR) was positive for Mycobacterium tuberculosis complex. Sputum microscopy revealed massive acid-fast bacilli (Figure 2). Subsequently, cultures grew M. tuberculosis sensitive to all commonly used tuberculostatic agents.

Figure 2. Microscopic examination of the Ziel-Neelsen stained sputum revealed acid-fast bacilli, suspicions for Mycobacterium.

The patient was put on aerosol isolation and a quadruple tuberculostatic therapy with rifampicin, isoniazid, pyrazinamid, and ethambutol as well as vitamine B6 (pyridoxine 40 mg/d) was started [7,10].

Due to ongoing pregnancy, we did not immediately perform a chest x-ray. As a result of a worsening dysphagia, temporary nutrition via nasogastric tube was necessary for several days. After two weeks of treatment, sputum microscopy was negative for acid-fast bacteria and the isolation was terminated.

During the entire stay in the clinic, the patient underwent close gynecological check-ups. On the 18th day of hospitalization, the first contractions occurred and the patient was referred to the obstetric department for delivery. On the same day, a healthy boy was born by cesarean section. Six days after birth, the family was able to leave the hospital.

On follow-up, 21 days after discharge and 5 weeks after first diagnosis, the patient complained of worsening dysphagia. PCR and culture remained negative for M. tuberculosis. A chest x-ray showed no features suggestive of pulmonary TB. In transnasal fiberendoscopy, increased inflammatory reaction was evident. Due to the temporal correlation, we suspected a tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS) triggered by antituberculostatic treatment and postpartal recovery of the immune function. No additional treatment was necessary.

The patient and her son were well and free of disease on follow-up 6 month after diagnosis and completed 6 months of therapy.

Discussion

We report a rare case of primary laryngeal TB in a pregnant woman with delayed diagnosis. Although patient management was challenging due to the impending birth at time of diagnosis and due to the occurrence of IRIS in the further course, the outcomes for both the patient and her newborn was favorable.

Risk factors for TB infection include recent exposure to active TB disease, coming from a high-burden TB country and living and working in a high-risk setting (e.g. correctional facility, health care facility, homeless shelter, nursing home). The risk factors for progression from latent to active TB are immunodeficiency including human immunodeficiency virus (HIV) infection, TB infection in the last 2 years and intravenous drug use [11]. In our case, the patient immigrated to Switzerland from Romania only a few weeks before symptom onset. The incidence of TB in Romania of 82 per 100,000 population is the highest in the European union [2].

Clinicians play a central role in the management of individuals affected by TB. Primary care is often the first point of contact. Tuberculosis should be suspected in patients with symptoms such as loss of appetite, weight loss, fever, night sweats, weakness, coughing for longer than 3 weeks, chest pain or hemoptysis. In patients with primary laryngeal TB, these symptoms may be less pronounced, rendering the diagnosis even more challenging. While Achkar et al. reported a mean duration of symptoms in pulmonary TB prior to diagnosis of 5–10 weeks, Benwill et al. found in their case series of laryngeal TB a mean duration of 19 weeks [3,7,12]. The patient in our case presented with a duration of symptoms of over 25 weeks. This delay in diagnosis is often accompanied by multiple previous visits to doctors, as seen also in our case.

In literature, dysphonia is reported to be the most common symptom of laryngeal TB, followed by weight loss, cough, dysphagia, and odynophagia [3]. We see here a clear correlation of the anatomic affection of the larynx and the clinical presentation. By decreasing incidence rate, the lesions of laryngeal TB are located on the vocal folds, the ventricular folds, epiglottis, subglottis and posterior commissure [3]. In our case the leading symptoms were dysphagia and odynophagia, cough and weight loss but no dysphonia or dyspnea. This is explained by the fact that in our case only the supraglottic larynx (the area of the larynx above the vocal cords) and not the vocal folds was affected.

In one of the largest case series of laryngeal TB, Reis et al. describe four categories of videolaryngoscopic appearances of the larynx: nonspecific inflammatory lesions (hyperemic lesions with flat or exophytic appearance with smooth surface), granulomatous lesions (hyperemic lesion with exophytic appearance and rough surface), erosive lesions, and ulcerated lesions [13]. Depending on the clinical presentation, other differential diagnoses have to be considered. Symptoms of laryngeal TB are non-specific and mimic other conditions. Lou et al. reported laryngeal TB to be most likely misdiagnosed as laryngopharyngeal reflux (LPR). Typical symptoms of LPR like globus sensation, throat clearing, dysphonia, hoarseness, cough and dysphagia coincide with laryngeal TB. Also, laryngoscopic presentation with laryngeal edema and hyperemia match the nonspecific inflammatory lesions of laryngeal TB as described by Reis et al. (Figure 3(A)). Failed treatment with proton pump inhibitors should alert the physician. More extended forms of nonspecific inflammatory lesions of laryngeal TB can present similar to a viral laryngitis or epiglottitis (Figure 3(B)). More ulcerated and infiltrating forms can lead to surface epithelium necrosis, ill-outlined borders and foci of caseification. These cases with mass-like lesions can be misdiagnosed as laryngeal carcinoma (Figure 3(C)) or pronounced forms of laryngeal perichondritis (Figure 3(D)) [13–17].

Figure 3. Fiberoptic evaluation of a pregnant woman with laryngophayngeal reflux revealed erythema below the corniculate cartilages (A), a bacterial laryngitis showing erythema, edema and pus of the entire larynx (B). An erosive lesion on the epiglottis with ill-outlined borders in a case of supraglottic laryngeal carcinoma (C). Mass-like lesions in an extent form of laryngeal perichondritis (D).

The debate if pregnancy does increase the likelihood of tuberculosis infection or progression of a latent to an active tuberculosis disease is still unresolved. Studies have failed to demonstrate a clear association [18]. Nevertheless, Gould et al. found the tuberculosis incidence to be significantly higher in the 180 days postpartum. This may be a reflection of the immunologic changes during pregnancy (e.g. suppression of the T-helper inflammatory response) that may actually increase susceptibility to TB. A diagnostic delay may occur to hesitancy to perform radiographs and the similarity of TB symptoms to symptoms commonly reported during pregnancy (e.g. weakness, weight changes, or shortness of breath). Delays in treatment initiation are associated with poorer outcomes for mother and fetus [19].

On the other hand, the impact of tuberculosis on pregnancy is well known and the consequences of delayed or missed diagnosis can be tragic. A systematic review and meta-analysis of pregnant women with active TB showed higher odds of maternal and neonatal adverse outcomes including maternal death, miscarriage, perinatal death, preterm birth and congenital TB infection [20]. The prevalence of TB in pregnant women is not well known. The pregnancy status of females with newly diagnosed TB is not routinely reported and many countries do not screen for TB in pregnancy. The estimated prevalence in low-burden regions like Switzerland is 0.06–0.25% [21]. While treatment of a latent TB in pregnant women can be delayed until 2–3 months post-partum, active TB needs immediate treatment. The risk of an untreated active TB on mother and fetus is considerably higher than the risk of the treatment. The four first line drugs recommended by the WHO and SLA (isoniazid, rifampicin, ethambutol and pyrazinamide) have an excellent safety record in pregnancy and are not associated with human fetal malformations. Drug-induced hepatitis, in particular in association with isoniazid, is a challenge in treatment of TB, but not peculiar to pregnancy. Close monitoring of liver function is recommended [22,23].

The worsening of the patient symptoms 3 weeks postpartum were due to a tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS). TB-IRIS is an abnormal, excessive immune response against alive or dead Mycobacterium tuberculosis. Mostly seen in HIV-infected TB patients, the risk for TB-IRIS is highest if antiretroviral therapy is initiated during TB treatment and immune function improves rapidly leading to systemic or local inflammatory reactions. In our HIV-negative patient, normalization of the immunologic function after pregnancy may have led to TB-IRIS. Treatment is based on the use of anti-tuberculosis drugs sometime with adjunctive corticosteroids [24].

Conclusion

As a consequence of migration and tourism, TB might appear in countries where it was once believed to be eradicated [1]. This case presentation highlights the importance of considering laryngeal TB as a differential diagnosis in a patient with dys- and odynophagia, cough and weight loss – even in Switzerland. In case of compatible symptoms, detailed history taking including screening for risk factors such as recent exposure to active TB disease, coming from a high-burden TB country, living and working at a high-risk setting, immunodeficiency, and intravenous drug use is crucial. While cough and globus sensation are common symptoms in pregnancy, odynophagia and weight loss should prompt physicians to consider the further diagnosis. Early biopsy by an ENT specialist can facilitate early diagnosis and treatment of laryngeal TB. Adequate knowledge about TB should be part of the armamentarium of each physician.

Informed consent statement

I confirm that we have received and archived written consent to publish the details from the individual described in the case report.

Disclosure statement

No potential conflict of interest was reported by the author(s).