Supraclavicular Lymphadenopathy as the Presenting Feature of Disseminated Mycobacterium Tuberculosis
1Pulmonary Critical Care Fellow, Swedish Hospital, Part of Northshore University Health System, Chicago, IL
2Pulmonary Critical Care and Interventional Pulmonology, Swedish Hospital, Part of Northshore University Health System, Chicago, IL
3Pulmonary Critical Care and Fellowship Program Director, Swedish Hospital, Part of Northshore University Health System, Chicago, IL
Supraclavicular lymphadenopathy as the presenting feature of disseminated mycobacterium tuberculosis. Consultant. 2023;63(6):e5. doi:10.25270/con.2023.05.000001
Received January 31, 2023. Accepted May 2, 2023. Published online May 9, 2023.
The authors report no relevant financial relationships.
The authors would like to acknowledge Lizabeth Giese, medical librarian at Swedish Hospital, A Part of North Shore University Health System, for assistance with literature review and the construction of the discussion section.
Matthew Nemoy, DO, Department of Medical Education, Swedish Hospital, A Part of North Shore University Health System, 5140 N. California Avenue, Chicago, IL 60625 (email@example.com)
A 64-year-old woman with diaphoresis presented to a community medical center following 2 days of pain due to a lump on the left side of her neck.
History. The patient was born in Mexico but currently resides in Chicago, IL. She had a past medical history significant for diabetes mellitus type 2 and rheumatoid arthritis (RA). Six months before her presentation to the community medical center, she was prescribed certolizumab pegol by her rheumatologist following a negative tuberculosis (TB) interferon gamma release assay.
In addition to the lump, she reported associated headaches, subjective fevers, chills, and cold sweats on and off for 1 month prior to presentation. She had also been suffering from abdominal pain for which she had seen her rheumatologist at another hospital in the Chicagoland area. An outpatient ultrasound for the abdominal pain prior to admission revealed hepatic steatosis. The outpatient rheumatology team noted increased levels of liver enzymes during her recent laboratory work.
The patient’s physical examination revealed a firm, mobile supraclavicular lymph node on the left side of her neck, measuring roughly 2 cm in diameter. No associated hepatomegaly, splenomegaly, or presence of any meningeal signs were observed on admission.
The patient explained that she did not present to the hospital sooner because she was attempting to have her work-up completed as an outpatient. However, when her symptoms were not improving after many weeks, she elected to present to the hospital. She denied any known sick contacts, potential exposure to tuberculosis, or recent travel to endemic areas. There were no known local outbreaks of Mycobacterial tuberculosis (MTB) at the time of her presentation.
Diagnostic testing. On hospital admission, she underwent further computed tomography (CT) scans of the chest, abdomen, and pelvis with contrast, which revealed a consolidative opacity in the anterior perihilar left upper lobe; numerous punctate and small pulmonary nodules throughout the lungs; mediastinal, left hilar, supraclavicular adenopathy; nonspecific small hypodense foci in the spleen; sigmoid colon diverticulosis; and fat-containing umbilical hernia (Figure 1).
Figure 1. Transverse CT image on abdominal window displaying enlarged lymph node in the left supraclavicular region.
At this point, pulmonary specialists were consulted to evaluate the lung infiltrate and lymphadenopathy that was noted on CT. Neither a brain imaging scan nor a cerebrospinal fluid analysis for the patient’s headaches was available for review at the time of pulmonary consultation. Such tests would have been used to determine whether there was evidence of tuberculosis meningitis. Complete blood count did not reveal evidence of leukocytosis. Additionally, the patient’s work-up revealed an aspartate transaminase level of 80 U/L, an alanine transaminase level of 75 U/L, and an alkaline phosphatase of 182 U/L.
To help better define the nature of her lymphadenopathy, arrangements were made for her to undergo a biopsy of her enlarged left supraclavicular lymph node. She underwent ultrasound-guided biopsy with interventional radiology specialists (Figure 2). A total of four samples of a 1.8 x 2.5 cm supraclavicular lymph node on the left were obtained using an 18-gauge core biopsy needle. Pathology revealed evidence of necrosis with epithelioid granulomas (Figure 3).
Figure 2. Ultrasonogram image of enlarged lymph node and 18-gauge core biopsy needle from interventional radiology biopsy procedure.
Figure 3. Slide demonstrating epithelioid granulomas.
Throughout this work-up, the patient continued to report night sweats, decreased appetite, and weight loss. The decision was made to obtain acid-fast bacilli (AFB) smear and sputum culture and to repeat the interferon gamma release assay. The patient was discharged home at this time with plans for her care team to follow-up her results as an outpatient. The interferon gamma release assay was indeterminate and AFB smears were negative within 1 week of specimen collection. The patient was hesitant to initiate empiric therapy without confirmatory testing as she was in the process of transferring her care to another health care system to keep her specialty care within one health care network. However, 4 weeks after the date of collection, her AFB sputum culture grew mycobacterium tuberculosis in three out of three samples.
Differential Diagnoses. Initial differential of signs and symptoms included viral and bacterial pneumonia, pulmonary and extra-pulmonary mycobacterial infection, meningitis (given the reported headaches), malignancy (particularly lymphoma), and complications of rheumatoid arthritis.
Bacterial and viral pneumonia and meningitis diagnoses became less likely as the patient’s laboratory work did not reveal evidence of leukocytosis. Malignancy was ruled out as pathology from the supraclavicular lymph node biopsy did not exhibit evidence of malignant cells. Complications of the patient’s rheumatoid arthritis became less likely throughout her hospitalization as she did not experience joint involvement.
Treatment and management. The patient and her family were notified of the AFB culture results immediately and she was started on rifampin, isoniazid, pyridoxine, pyrazinamide, and ethambutol. Tentative plans included a 26-week treatment course, repeat AFB cultures to be collected a few weeks after initiation of therapy, and to undergo complete HIV screening. Her rheumatoid arthritis therapy, certolizumab pegol (400mg subcutaneous injection every 4 weeks), was held.
Outcome and follow-up. She tolerated the first 4 weeks of therapy well before she transferred her care to another medical center so that she could have all her subspecialists in a single health care network.
Discussion. Despite its low prevalence in the United States, MTB infection is a leading cause of mortality worldwide.1 The organism is latent in the human host and spread via the inhalation of aerosolized droplets. Inhalation of these droplets by a human host can result in various outcomes, including acute MTB infection, latent MTB infection, reactivation of previously latent MTB, or clearance of MTB from the host without causing infection.
The likelihood of developing an MTB infection depends on both host and MTB organism factors. Host factors of particular interest are the genetic and acquired predisposition to infections.2 Acquired risk of MTB infection has been demonstrated in individuals with immunocompromising disorders such as HIV. In addition to HIV confection, increased incidence of MTB infection is present in patients with inflammatory disease processes that require treatment with TNF-a inhibitors, such as RA.3
Our patient was appropriately screened for TB infection by her rheumatologist and documentation was provided of a negative Interferon gamma release assay prior to initiating therapy with certolizumab pegol, a TNF-a inhibitor. Certolizumab pegol is one of the newer TNF-a inhibitors available and, to date, there have been a lack of trials to evaluate the incidence of MTB infection in patients taking certolizumab pegol. Based on safety and efficacy data released during drug development, it is thought that the incidence of MTB infection with certolizumab pegol is similar to other TNF-a inhibitors.4 Our patient had continued her certolizumab pegol therapy until she and her family noticed the left supraclavicular lymphadenopathy, night sweats, and unexplained weight loss, which prompted her to seek medical attention. She had been on certolizumab pegol for approximately 6 months prior to her hospital presentation, including initiation and 2-week interval maintenance dosing. This increased the likelihood that this eventual diagnosis of MTB infection represented an acute, acquired infection given her previously negative interferon-gamma release assay, rather than reactivation of a latent infection that would be more likely to occur immediately following initiation of TNF-a inhibitor therapy. There has been much debate surrounding whether it is necessary to rescreen patients undergoing therapy with TNF-a inhibitors.
This case highlights another important area of debate in the literature that a diagnosis of RA itself, not solely treatment with TNF-a inhibitors, may increase the risk of developing tuberculosis. This phenomenon was demonstrated by Carmona and colleagues in a 2003 study that included patients from 34 centers throughout Spain and found the risk ratio of developing TB to be 3.68 times higher in patients with RA compared with the general population.5 Further data from registries in China revealed a dramatically increased risk of developing TB in patients with RA who were receiving TNF alpha therapy when compared with the general population.6 However, in a 2004 review study Wolfe and colleagues demonstrated that RA alone did not significantly increase the risk of developing TB.7 While not clearcut, attributing all of our patient’s risk of developing a MTB infection to the certolizumab pegol therapy may unfairly place blame on her therapeutic regimen as the sole cause of her infection.
Of further interest is the presence of the patient’s tuberculous lymphadenitis as a presenting symptom of her acute illness. The general differential diagnosis for lymphadenopathy is broad. However, MTB is a common cause of lymphadenopathy and most typically occurs in resource-depleted areas.8 Our patient presented with left-sided supraclavicular lymphadenopathy. While her imaging-guided biopsy with interventional radiology specialists was negative for evidence of tuberculous disease, her AFB sputum culture turned positive for MTB 4 weeks after collection and confirmed her diagnosis. Lymphadenitis is a well-documented extra-pulmonary manifestation mycobacterial infection.9 Interestingly, lymphadenopathy had previously been thought to be a childhood disease. However, previously published literature has suggested that lymphadenopathy associated with MTB infection commonly presents in adulthood.10
Immunosuppression, both innate and iatrogenic, is a well-known risk factor for contracting otherwise rare communicable diseases. The physical examination findings in this case highlight the importance of maintaining a broad differential for lymphadenopathy, particularly in resource depleted urban centers, and the risks that come along with iatrogenic immunosuppression. This patient is an example of lymphadenopathy as a presenting symptom of MTB infection occurring during adulthood in a developed nation. Overall, this case highlights the importance of screening for MTB infection prior to the start of and during TNF-a inhibitor therapy use, as well as the high index of suspicion for MTB infection that must be maintained by clinicians when evaluating lymphadenopathy in patients with known MTB risk factors.
- Global tuberculosis report 2022. World Health Organization. October 27, 2022. Accessed January 25, 3023. https://www.who.int/tb/publications/global_report/en/
- Fordham von Reyn. Tuberculosis: natural History, microbiology, and pathogenesis. Uptodate. Updated September 15, 2021. Accessed January 25, 2023. https://www.uptodate.com/contents/tuberculosis-natural-history-microbiology-and-pathogenesis
- Gómez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD; BIOBADASER Group. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum. 2003;48(8):2122. doi:10.1002/art.11137.
- Bykerk VP, Cush J, Winthrop K, et al. Update on the safety profile of certolizumab pegol in rheumatoid arthritis: an integrated analysis from clinical trials. Ann Rheum Dis. 2015;74(1):96-103. doi:10.1136/annrheumdis-2013-203660.
- Carmona L, Hernández-García C, Vadillo C, et al; EMECAR Study Group. Increased risk of tuberculosis in patients with rheumatoid arthritis. J Rheumatol. 2003;30(7):1436. https://www.jrheum.org/content/jrheum/30/7/1436.full.pdf
- Wang X, Wong SH, Wang XS, et al. Risk of tuberculosis in patients with immune-mediated diseases on biological therapies: a population-based study in a tuberculosis endemic region. Rheumatology. 2019;58:803–810. doi:10.1093/rheumatology/key364.
- Wolfe F, Michaud K, Anderson J, Urbansky K. Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy. Arthritis Rheum. 2004;50(2):372. doi:10.1002/art.20009.
- Dandapat MC, Mishra BM, Dash SP, Kar PK. Peripheral lymph node tuberculosis: a review of 80 cases. Br J Surg. 1990;77(8):911. doi:10.1002/bjs.1800770823.
- Fontanilla JM, Barnes A, von Reyn CF. Current diagnosis and management of peripheral tuberculous lymphadenitis. Clin Infect Dis. 2011;53(6):555. doi:10.1093/cid/cir454.
- Gopalaswamy R, Dusthackeer VNA, Kannayan S, Subbian S. Extrapulmonary tuberculosis—an update on the diagnosis, treatment and drug resistance. J. Respir. 2021;1(2):141-164. doi: 10.3390/jor1020015