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Mycobacterium bovis cervical lymphadenitis: A representative case and review
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PEDOT-7753; No. of Pages 4 International Journal of Pediatric Otorhinolaryngology xxx (2015) xxx–xxx
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International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Review article
Mycobacterium bovis cervical lymphadenitis: A representative case and review Peter S Han a, Pedro Orta a, Daniel I Kwon b,*, Jared C Inman b a b
Loma Linda University School of Medicine, Loma Linda, CA, USA Department of Otolaryngology-Head and Neck Surgery, Loma Linda University Medical Center, Loma Linda, CA, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 25 June 2015 Received in revised form 3 September 2015 Accepted 4 September 2015 Available online xxx
Mycobacterium bovis is a tuberculosis causing bacterium that commonly presents with cervical lymphadenopathy. It is important to differentiate M. bovis from other Mycobacterial pathogens to ensure selection of correct anti-microbial therapy. This may decrease the number of treatment failures, the prevalence of anti-mycobacterial drug resistance patterns, and the need for surgical intervention. M. bovis has universal resistance to pyrazinamide and thus may not respond to typical first line mycobacterial drugs and may require surgical intervention. This case report and review of M. bovis cervical lymphadenitits demonstrates the need for accurate diagnosis as well as combined management with infectious disease and public health specialists. ß 2015 Published by Elsevier Ireland Ltd.
Keywords: Tuberculosis Mycobacterium bovis Cervical lymphadenitis Lymphadenopathy Infectious disease Public health
Contents 1. 2. 3.
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1. Introduction According to the World Health Organization (WHO), tuberculosis bacillus (TB) is the second leading cause of death due to an infectious agent worldwide. Although the incidence of TB has declined by 1.5% every year since 2000 and mortality due to TB has dropped by more than 45% since 1990, the WHO estimates that in 2013, nearly 9 million people were infected with TB and 1.5 million died as a result [1,26]. Mycobacterium bovis is one of three species of Mycobacterium capable of causing TB—M. tuberculosis, bovis, and africanum. Together these three species
* Corresponding author. Tel.: +1 909 558 8558; fax: +1 909 558 4819. E-mail address: [email protected] (D.I. Kwon).
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are referred to as ‘‘typical’’ or ‘‘tuberculous mycobacteria,’’ which are clinically distinct from the more than fifty other species of ‘‘atypical’’ or ‘‘non-tuberculous mycobacteria’’ (NTM) that usually only cause local infections. One of the leading clinical manifestations of head and neck tuberculosis is cervical lymphadenopathy, which is present in up to 95% of patients with TB [2,3]. Among all of the causes of cervical lymphadenitis, approximately 8% is of mycobacterial origin of which more than 90% is caused by NTM [4]. M. bovis lymphadenitis is suspected from history, physical, and PPD testing. Similar to atypical forms, lymphadenopathy presentation predominates in the anterior cervical chains, most likely because the oral cavity is the primary site of inoculation and is preferentially drained by the anterior cervical chains. This is in contrast to the posterior cervical chain lymphadenopathy often seen in M. tuberculosis infections.
http://dx.doi.org/10.1016/j.ijporl.2015.09.007 0165-5876/ß 2015 Published by Elsevier Ireland Ltd.
Please cite this article in press as: P.S. Han, et al., Mycobacterium bovis cervical lymphadenitis: A representative case and review, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.09.007
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2
Of all the mycobacterium that causes tuberculosis, M. bovis is especially concerning due to its multi-drug resistance. It also is frequently associated with HIV infection. As M. bovis is likely under-reported, it is difficult to quantify the actual prevalence of tuberculosis due to M. bovis. According to the National TB Genotyping Service of the CDC, the percentage of all TB infections in the United States attributed to M. bovis is 1–2% [6,41]. However, in regions of the country with greater concentrations of foreignborn individuals, the incidence of TB caused by M. bovis is even greater. In California, the overall occurrence of TB infections as a whole has decreased from 2003 to 2011. But cases of M. bovis in this same time period, have relatively increased from 3.4% to 5.4% of TB infections [6]. From 2001 to 2005, 10% of tuberculosis cases observed in San Diego, California – which, due to its bordering city Tijuana, Mexico, is the largest binational metropolitan region in the country – were caused by M. bovis infection. Almost all of the M. bovis cases reported were in Hispanic individuals [6,7]. M. bovis incidence in endemic, developing countries is often underreported because diagnosis requires specialized laboratory equipment and expertise that is costly and not readily available. Not only do these countries lack the infrastructure to perform routine testing but the implication of positive testing also increases cost due to need for vaccinate and the slaughter of infected animals [8]. Even in the United States, speciation beyond Mycobacterium complex (typical TB) is often not performed. Historically, the epidemiological link between human and bovine TB has been well documented. TB was initially clinically described in the early 1800’s among slaughterhouse workers. In 1882, Koch showed that TB in cattle could directly cause TB in humans. It has been postulated that cattle were the major culprits for the spread of M. bovis to humans from the Victorian Age and World War II. In England where, historically, TB was epidemic, more than 40% of cattle were infected with tuberculosis, pasteurization was not universal, and cattle slaughterhouses were within city limits. In the mid-1900’s, however, control measures virtually eradicated the disease in industrialized countries [9– 11]. Unfortunately, the past several decades have witnessed a resurgence of bovine TB. In countries like the United States and Great Britain, increased transportation of cattle across national borders has been associated with increased incidence of bovine TB, which can then be transmitted to humans [8,12].
Fig. 1. A 23 month old female with M. bovis presenting as submandibular neck mass.
DOT was not documenting EMB administration—thus the patient was only receiving INH and RMP. M. bovis diagnosis was recognized based on the previously documented PZA resistance. At this point, considering the patient had not had resolution for approximately 4 months, the size of the neck mass, and the recognizance of M. bovis, surgery was offered. The patient was taken to the operating room for excision of 2.5 1.7 1 cm mass and two necrotic nodes deep to the mass. Pathology again showed AFB and caseous necrosis. Post-operatively, the surgical wound healed well. INH, RMP, and EMB were continued for 9 additional months. On last follow up, over 2 years post-treatment, there have been no signs of recurrence. 3. Discussion Before the advent of anti-TB drugs, BCG (bacillus Calmette– Guerin) vaccination and animal control measures were standard techniques to control TB incidence. Since the 1950’s, control measures have virtually eradicated human bovine TB in developed
2. Case report A 23-month old Hispanic female presented with a 3 day history fever and redness overlying a 2 2 cm left submandibular neck mass (Fig. 1). Previously treated with 4 weeks of cephalexin, the mass had been increasing in size. Both parents were PPD converters in the past with a normal CXR. There was no history of travel, animal, or unpasteurized dairy product. There was history of a recent visit from a grandmother from Mexico. Initial work-up revealed a temperature of 37 8C, WBC 11.9, ESR 50, normal CXR, and a strongly positive 20 mm wheal from PPD testing. FNA yielded acid-fast bacilli (Fig. 2). INH, RMP, EMB, PZA, and Azithromycin were started and the public health department was notified for direct observed therapy (DOT). Within 3 weeks, the mass showed improvement. After 5 weeks, final cultures had shown Mycobacterium complex sensitive to INH and RMP but resistant to PZA. Azithromycin and PZA were discontinued and the specimen was sent for PCR identification. Over the next 3 months, the mass slowly enlarged and overlying skin changes worsened with extension into the posterior cervical lymph node chain. CT scan showed a 3 2 cm mass in the posterior chain (Fig. 3). The patient was observed for possible paradoxic upstaging reaction by the primary care physical but she was eventually referred to Otolaryngology for surgical consultation. It was discovered that
Fig. 2. Acid-fast staining bacilli demonstrated in tissue biopsy.
Please cite this article in press as: P.S. Han, et al., Mycobacterium bovis cervical lymphadenitis: A representative case and review, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.09.007
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Fig. 3. Deep cervical lymphadenopathy as a result of inadequately treated Mycobacterium bovis infection.
countries [9–11]. Control measures typically involve BCG vaccination of children, universal cattle TB testing, and destruction of infected cattle. The BCG vaccine for humans is not ideal and causes infection in 0.5–1% of recipients. While it has been useful in preventing TB in endemic areas, vaccination is not recommended in countries with a low prevalence of tuberculosis. In the United States, the vaccine has not been given routinely since the 1950’s [13–15]. Universal cattle testing and destruction is crucial in eradicating bovine TB. Unfortunately, this method is cost-inhibitive in many areas. For example, an estimated 30,000 cattle are slaughtered every year in the United Kingdom alone where bovine TB has made a strong resurgence due to animal vectors [9]. Additionally, there has been research into administering the BCG vaccine to cattle and other disease vectors though this has not become widespread, largely due to cost and regulations [42]. Separate studies have estimated the yearly financial impact of bovine TB in Turkey and Argentina to be 15–60 million USD and 63 million USD, respectively [16,17]. Because of inadequate control measures, M. bovis has had resurgence in industrialized nations due to reservoir animal populations, immigration from endemic areas, and importation of infected foods or animal products. In addition to cattle, the primary carrier of M. bovis, more than 20 other mammals have been shown to harbor the pathogen. A direct correlation exists between the diversity of vector species and the spread of the TB caused by M. bovis [24,25]. In addition, multiple species reservoirs confound M. bovis eradication in cattle populations by allowing disease to pass freely between different species sharing habitats. This has been best documented in Great Britain, where an estimated 40% of badgers carry latent M. bovis inoculums, continuously re-infecting cattle herds. Population studies show a parallel relationship between these two species disease rates over decades [9,18,19]. In the United States, pathogen vectors of particular concern include the white-tailed deer of southern Michigan and the bison of the plain states [20,21].
3
Patients that are more prone to becoming infected with M. bovis include the elderly with emergence of latent disease, the immunocompromised (especially those with HIV/AIDS), children with a recent BCG vaccination history, those exposed to infected animals or animal products, and immigrant populations in the United States, particularly Hispanics of Mexican origin [6,7,21,30]. A study of 315 M. bovis infections showed that 49% of patients had consumed unpasteurized dairy products and 37% had direct physical exposure to cattle [36]. The CDC estimates that 20% of Mexican milk is not pasteurized and is readily available in the form of soft cheeses in some US communities [37]. Classically, patients exposed orally to infected material will present with cervical lymphadenitis after M. bovis gains access to the immune system through mucosal breaks. Alimentary exposure to M. bovis is highly infectious, as exemplified in a 1936 case series where young children from a small town ingested milk from an active bovine tuberculous mastitis resulting in over 90% of the exposed children becoming PPD converters [38]. Although unproven, airborne transmission has been perceived as the principal transmission route in cattle populations [24,32,33]. Approximately 94% of M. bovis bacterium can survive for 10 min after aerosolization, with a half-life of 1.5 h [20]. M. bovis has been documented to cause tuberculosis in humans after airborne inoculation from cattle byproducts [9]. With the advancement of TB bacterial genotyping since the late 1990’s, human–human transmission of M. bovis has also been theorized based on identical genotyping from infected families and case series showing statistically similar PPD conversion rates in patients exposed to M. bovis and M. tuberculosis infected patients [39,40]. Diagnosis of M. bovis should be considered when there is a history of TB exposure, travel to endemic areas, ingestion of unpasteurized animal products, or exposure to infected animal products or waste. Because atypical presentations make M. bovis infections difficult to diagnose, awareness of early symptoms is critical to effective diagnosis. The majority of M. bovis infections present in an extra-pulmonary site such as cervical lymphadenitis [41]. Typically, TB cervical adenitis will present as a painless neck mass increasing in size with no fevers, a normal white count, and no systemic symptoms (unless pulmonary disease or dissemination is present). Skin changes typically occur later in the progression of the disease. A CT scan of the neck may show nodal involvement or fluid collections. PPD will be positive in 74–96% of patients and CXR will be negative in 90% of cases. The more strongly reactive the PPD test, the more likely that typical TB is the diagnosis. However, 40% of atypical Mycobacterium will yield a positive PPD [5,22,23]. Histopathology, culture, and genetic testing techniques are required to differentiate typical from atypical forms of TB. FNA or fresh tissue biopsy including complete excision should be obtained in all masses suspicious for TB. FNA or biopsy yield for acid-fast bacilli varies and usually improves with higher tissue bulk. Organism recovery can take 2–8 weeks and only occurs in 30– 80% of cultures [5]. The gold-standard of M. bovis diagnosis is by PCR testing for specific genome domains. The hallmark method of identification is the absence of the gene producing pyrazinamidase, which gives M. bovis its characteristic resistance to PZA. Because the M. tuberculosis genome was not mapped until the late 1990’s, it is likely that the significance M. bovis is grossly underestimated. The new and rapid development of Mycobacterium genome testing now allows differentiation of wild-type strains, indicating transmission patterns, and identification of BCG vaccination types. Practically, resistance to PZA on culture may be used as an alternative to genotype-based definition of M. bovis, which is the gold standard for diagnosis. Treatment of M. bovis is similar to that of M. tuberculosis [27]. Based on PPD reactivity and suspicion, typical 4 drug (INH, PZA,
Please cite this article in press as: P.S. Han, et al., Mycobacterium bovis cervical lymphadenitis: A representative case and review, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.09.007
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EMB, RMP) therapy is begun as with M. tuberculosis therapy. Most authors recommend treatment with multi-drug therapy excluding PZA [28,29]. Some authors have suggested that 2-drug therapy is sufficient for M. bovis infections. However, the largest case study on M. bovis versus M. tuberculosis does not recommend a ‘‘short’’ therapy course for M. bovis due to increased mortality and an average three month longer treatment course [30]. Post-BCG vaccination lymphadenopathy, monotherapy with INH has been shown to be effective. In M. tuberculosis, surgery is often reserved for medical failures or used in conjunction with medical therapy in select cases. Though in cases where M. bovis is suspected, early implementation of surgical excision may be beneficial as it can be both diagnostic and therapeutic. Typical Mycobacteria are notoriously resistant to less than optimal therapy, developing in-vivo resistance quickly. Although initial failure to improve should raise suspicion of resistance, up to 25% of TB lymphadenitis has been shown to clinically worsen for up to two months [31,32]. When M. bovis is not recognized and treated as M. tuberculosis, PZA will not be effective because of innate resistance and may lead to a higher incidence of medical therapy failure. In the United States, TB resurged in the 1980’s because of the evolving AIDS epidemic and multi-drug resistant TB strains were seen. Worldwide resistance patterns continue to emerge, including documented cases of M. bovis resistant to more than 20 antibiotics, leaving TB therapy focused around long-term multi-drug treatment. In recent years, new drugs such as bedaquiline have been developed as cost-saving therapies to be used in conjunction with the standard regimen in multi-drug resistant strains of TB [33,34]. This case demonstrates M. bovis infection with failure of twodrug therapy for 4 months. Eventually, the mass required complete excision, followed by 9 additional months of three drug therapy. Because of innate PZA resistance, M. bovis should be treated as aggressively, if not more aggressively, as M. tuberculosis. To ensure proper treatment and aid in M. bovis surveillance, it is critical to involve TB specialists and the public health department in active infections. The direction of M. bovis research continues toward development of an optimal TB vaccine. It is estimated that more than 94% of the world’s population live in countries where the control of bovine tuberculosis is limited or absent, leading to inadequate understanding and questionable control of this disease [35]. Continued global monitoring, definitive diagnosis, and reporting is needed to understanding the progression of this disease. Disclosures None. References [1] World Health Organization, Global Health Observatory Data: Tuberculosis, World Health Organization, 2015 hhttp://www.who.int/gho/tb/en/i. [2] Z.B. Khuzwayo, T.K. Naidu, Head and neck tuberculosis in KwaZulu-Natal, South Africa, J. Laryngol. Otol. 128 (2014) 86–90. [3] C.M. Chiesa, F.A. Betances, T. Rivera, C.C. Ossa, M.J. Gonzalez, H.C. Santidrian, Head and neck tuberculosis: 6-year retrospective study, Acta Otorrinolaringol. Esp. (2015). [4] R. Bartralot, R.M. Pujol, V. Garcia-Patos, D. Sitjas, N. Martin-Casabona, P. Coll, et al., Cutaneous infections due to nontuberculous mycobacteria: histopathological review of 28 cases. Comparative study between lesions observed in immunosuppressed patients and normal hosts, J. Cutan. Pathol. 27 (3) (2000) 124–129. [5] K. Munck, A.H. Mandpe, Mycobacterial infections of the head and neck, Otolaryngol. Clin. N. Am. 36 (2003) 569–576. [6] M. Gallivan, N. Shah, J. Flood, Epidemiology of human Mycobacterium bovis disease, California, USA, 2003–2011, Emerg. Infect. Dis. 21 (3) (2015) 435–443. [7] T.C. Rodwell, M. Moore, K.S. Moser, S.K. Brodine, S.A. Strathdee, Mycobacterium bovis tuberculosis in binational communities, Emerg. Infect. Dis. (2008), hhttp:// wwwnc.cdc.gov/eid/article/14/6/07-1485i. [8] C.J. McDaniel, D.M. Cardwell, R.B. Moeller, G.C. Gray, Humans and cattle: a review of bovine zoonoses, Vector Borne Zoonotic Dis. 14 (1) (2014) 1–19. [9] P.D. Davies, Tuberculosis in humans and animals: are we a threat to each other? J. R. Soc. Med. 99 (2006) 539–540. [10] C.H. Collins, The bovine tubercle bacillus, Br. J. Biomed. Sci. 57 (2000) 234–240.
[11] P.J. Atkins, The pasteurization of milk in England: the science, culture and health implications of milk processing, 1900–1950, in: Food, Science, Policy and Regulation In 20th Century, Routledge, London, 2000, pp. 37–51, Print. [12] M. Gilbert, A. Mitchell, D. Bourn, J. Mawdsley, R. Clifton-Hadley, W. Wint, Cattle movements and bovine tuberculosis in Great Britain, Nature 435 (2005) 491–496. [13] M.K. Felten, M. Leichsenring, Use of BCG in high prevalence areas for HIV, Trop. Med. Parasitol. 46 (1995) 69–71. [14] P. Azzopardi, C. Bennett, S. Graham, T. Duke, Bacille Calmette–Gue´rin vaccinerelated disease in HIV-infected children: a systematic review, Int. J. Tuberc. Lung Dis. 13 (11) (2009) 1331–1344 (14). [15] A.C. Hesseling, B.J. Marais, R.O. Gie, H.S. Schaaf, P.E.M. Fine, P. Godfrey-Faussett, et al., The risk of disseminated Bacille Calmette–Guerin (BCG) disease in HIVinfected children, Vaccine 25 (1) (2007) 14–18. [16] F. Barwinek, N.M. 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Please cite this article in press as: P.S. Han, et al., Mycobacterium bovis cervical lymphadenitis: A representative case and review, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.09.007
PEDOT-7753; No. of Pages 4 International Journal of Pediatric Otorhinolaryngology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Review article
Mycobacterium bovis cervical lymphadenitis: A representative case and review Peter S Han a, Pedro Orta a, Daniel I Kwon b,*, Jared C Inman b a b
Loma Linda University School of Medicine, Loma Linda, CA, USA Department of Otolaryngology-Head and Neck Surgery, Loma Linda University Medical Center, Loma Linda, CA, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 25 June 2015 Received in revised form 3 September 2015 Accepted 4 September 2015 Available online xxx
Mycobacterium bovis is a tuberculosis causing bacterium that commonly presents with cervical lymphadenopathy. It is important to differentiate M. bovis from other Mycobacterial pathogens to ensure selection of correct anti-microbial therapy. This may decrease the number of treatment failures, the prevalence of anti-mycobacterial drug resistance patterns, and the need for surgical intervention. M. bovis has universal resistance to pyrazinamide and thus may not respond to typical first line mycobacterial drugs and may require surgical intervention. This case report and review of M. bovis cervical lymphadenitits demonstrates the need for accurate diagnosis as well as combined management with infectious disease and public health specialists. ß 2015 Published by Elsevier Ireland Ltd.
Keywords: Tuberculosis Mycobacterium bovis Cervical lymphadenitis Lymphadenopathy Infectious disease Public health
Contents 1. 2. 3.
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1. Introduction According to the World Health Organization (WHO), tuberculosis bacillus (TB) is the second leading cause of death due to an infectious agent worldwide. Although the incidence of TB has declined by 1.5% every year since 2000 and mortality due to TB has dropped by more than 45% since 1990, the WHO estimates that in 2013, nearly 9 million people were infected with TB and 1.5 million died as a result [1,26]. Mycobacterium bovis is one of three species of Mycobacterium capable of causing TB—M. tuberculosis, bovis, and africanum. Together these three species
* Corresponding author. Tel.: +1 909 558 8558; fax: +1 909 558 4819. E-mail address: [email protected] (D.I. Kwon).
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are referred to as ‘‘typical’’ or ‘‘tuberculous mycobacteria,’’ which are clinically distinct from the more than fifty other species of ‘‘atypical’’ or ‘‘non-tuberculous mycobacteria’’ (NTM) that usually only cause local infections. One of the leading clinical manifestations of head and neck tuberculosis is cervical lymphadenopathy, which is present in up to 95% of patients with TB [2,3]. Among all of the causes of cervical lymphadenitis, approximately 8% is of mycobacterial origin of which more than 90% is caused by NTM [4]. M. bovis lymphadenitis is suspected from history, physical, and PPD testing. Similar to atypical forms, lymphadenopathy presentation predominates in the anterior cervical chains, most likely because the oral cavity is the primary site of inoculation and is preferentially drained by the anterior cervical chains. This is in contrast to the posterior cervical chain lymphadenopathy often seen in M. tuberculosis infections.
http://dx.doi.org/10.1016/j.ijporl.2015.09.007 0165-5876/ß 2015 Published by Elsevier Ireland Ltd.
Please cite this article in press as: P.S. Han, et al., Mycobacterium bovis cervical lymphadenitis: A representative case and review, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.09.007
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Of all the mycobacterium that causes tuberculosis, M. bovis is especially concerning due to its multi-drug resistance. It also is frequently associated with HIV infection. As M. bovis is likely under-reported, it is difficult to quantify the actual prevalence of tuberculosis due to M. bovis. According to the National TB Genotyping Service of the CDC, the percentage of all TB infections in the United States attributed to M. bovis is 1–2% [6,41]. However, in regions of the country with greater concentrations of foreignborn individuals, the incidence of TB caused by M. bovis is even greater. In California, the overall occurrence of TB infections as a whole has decreased from 2003 to 2011. But cases of M. bovis in this same time period, have relatively increased from 3.4% to 5.4% of TB infections [6]. From 2001 to 2005, 10% of tuberculosis cases observed in San Diego, California – which, due to its bordering city Tijuana, Mexico, is the largest binational metropolitan region in the country – were caused by M. bovis infection. Almost all of the M. bovis cases reported were in Hispanic individuals [6,7]. M. bovis incidence in endemic, developing countries is often underreported because diagnosis requires specialized laboratory equipment and expertise that is costly and not readily available. Not only do these countries lack the infrastructure to perform routine testing but the implication of positive testing also increases cost due to need for vaccinate and the slaughter of infected animals [8]. Even in the United States, speciation beyond Mycobacterium complex (typical TB) is often not performed. Historically, the epidemiological link between human and bovine TB has been well documented. TB was initially clinically described in the early 1800’s among slaughterhouse workers. In 1882, Koch showed that TB in cattle could directly cause TB in humans. It has been postulated that cattle were the major culprits for the spread of M. bovis to humans from the Victorian Age and World War II. In England where, historically, TB was epidemic, more than 40% of cattle were infected with tuberculosis, pasteurization was not universal, and cattle slaughterhouses were within city limits. In the mid-1900’s, however, control measures virtually eradicated the disease in industrialized countries [9– 11]. Unfortunately, the past several decades have witnessed a resurgence of bovine TB. In countries like the United States and Great Britain, increased transportation of cattle across national borders has been associated with increased incidence of bovine TB, which can then be transmitted to humans [8,12].
Fig. 1. A 23 month old female with M. bovis presenting as submandibular neck mass.
DOT was not documenting EMB administration—thus the patient was only receiving INH and RMP. M. bovis diagnosis was recognized based on the previously documented PZA resistance. At this point, considering the patient had not had resolution for approximately 4 months, the size of the neck mass, and the recognizance of M. bovis, surgery was offered. The patient was taken to the operating room for excision of 2.5 1.7 1 cm mass and two necrotic nodes deep to the mass. Pathology again showed AFB and caseous necrosis. Post-operatively, the surgical wound healed well. INH, RMP, and EMB were continued for 9 additional months. On last follow up, over 2 years post-treatment, there have been no signs of recurrence. 3. Discussion Before the advent of anti-TB drugs, BCG (bacillus Calmette– Guerin) vaccination and animal control measures were standard techniques to control TB incidence. Since the 1950’s, control measures have virtually eradicated human bovine TB in developed
2. Case report A 23-month old Hispanic female presented with a 3 day history fever and redness overlying a 2 2 cm left submandibular neck mass (Fig. 1). Previously treated with 4 weeks of cephalexin, the mass had been increasing in size. Both parents were PPD converters in the past with a normal CXR. There was no history of travel, animal, or unpasteurized dairy product. There was history of a recent visit from a grandmother from Mexico. Initial work-up revealed a temperature of 37 8C, WBC 11.9, ESR 50, normal CXR, and a strongly positive 20 mm wheal from PPD testing. FNA yielded acid-fast bacilli (Fig. 2). INH, RMP, EMB, PZA, and Azithromycin were started and the public health department was notified for direct observed therapy (DOT). Within 3 weeks, the mass showed improvement. After 5 weeks, final cultures had shown Mycobacterium complex sensitive to INH and RMP but resistant to PZA. Azithromycin and PZA were discontinued and the specimen was sent for PCR identification. Over the next 3 months, the mass slowly enlarged and overlying skin changes worsened with extension into the posterior cervical lymph node chain. CT scan showed a 3 2 cm mass in the posterior chain (Fig. 3). The patient was observed for possible paradoxic upstaging reaction by the primary care physical but she was eventually referred to Otolaryngology for surgical consultation. It was discovered that
Fig. 2. Acid-fast staining bacilli demonstrated in tissue biopsy.
Please cite this article in press as: P.S. Han, et al., Mycobacterium bovis cervical lymphadenitis: A representative case and review, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.09.007
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Fig. 3. Deep cervical lymphadenopathy as a result of inadequately treated Mycobacterium bovis infection.
countries [9–11]. Control measures typically involve BCG vaccination of children, universal cattle TB testing, and destruction of infected cattle. The BCG vaccine for humans is not ideal and causes infection in 0.5–1% of recipients. While it has been useful in preventing TB in endemic areas, vaccination is not recommended in countries with a low prevalence of tuberculosis. In the United States, the vaccine has not been given routinely since the 1950’s [13–15]. Universal cattle testing and destruction is crucial in eradicating bovine TB. Unfortunately, this method is cost-inhibitive in many areas. For example, an estimated 30,000 cattle are slaughtered every year in the United Kingdom alone where bovine TB has made a strong resurgence due to animal vectors [9]. Additionally, there has been research into administering the BCG vaccine to cattle and other disease vectors though this has not become widespread, largely due to cost and regulations [42]. Separate studies have estimated the yearly financial impact of bovine TB in Turkey and Argentina to be 15–60 million USD and 63 million USD, respectively [16,17]. Because of inadequate control measures, M. bovis has had resurgence in industrialized nations due to reservoir animal populations, immigration from endemic areas, and importation of infected foods or animal products. In addition to cattle, the primary carrier of M. bovis, more than 20 other mammals have been shown to harbor the pathogen. A direct correlation exists between the diversity of vector species and the spread of the TB caused by M. bovis [24,25]. In addition, multiple species reservoirs confound M. bovis eradication in cattle populations by allowing disease to pass freely between different species sharing habitats. This has been best documented in Great Britain, where an estimated 40% of badgers carry latent M. bovis inoculums, continuously re-infecting cattle herds. Population studies show a parallel relationship between these two species disease rates over decades [9,18,19]. In the United States, pathogen vectors of particular concern include the white-tailed deer of southern Michigan and the bison of the plain states [20,21].
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Patients that are more prone to becoming infected with M. bovis include the elderly with emergence of latent disease, the immunocompromised (especially those with HIV/AIDS), children with a recent BCG vaccination history, those exposed to infected animals or animal products, and immigrant populations in the United States, particularly Hispanics of Mexican origin [6,7,21,30]. A study of 315 M. bovis infections showed that 49% of patients had consumed unpasteurized dairy products and 37% had direct physical exposure to cattle [36]. The CDC estimates that 20% of Mexican milk is not pasteurized and is readily available in the form of soft cheeses in some US communities [37]. Classically, patients exposed orally to infected material will present with cervical lymphadenitis after M. bovis gains access to the immune system through mucosal breaks. Alimentary exposure to M. bovis is highly infectious, as exemplified in a 1936 case series where young children from a small town ingested milk from an active bovine tuberculous mastitis resulting in over 90% of the exposed children becoming PPD converters [38]. Although unproven, airborne transmission has been perceived as the principal transmission route in cattle populations [24,32,33]. Approximately 94% of M. bovis bacterium can survive for 10 min after aerosolization, with a half-life of 1.5 h [20]. M. bovis has been documented to cause tuberculosis in humans after airborne inoculation from cattle byproducts [9]. With the advancement of TB bacterial genotyping since the late 1990’s, human–human transmission of M. bovis has also been theorized based on identical genotyping from infected families and case series showing statistically similar PPD conversion rates in patients exposed to M. bovis and M. tuberculosis infected patients [39,40]. Diagnosis of M. bovis should be considered when there is a history of TB exposure, travel to endemic areas, ingestion of unpasteurized animal products, or exposure to infected animal products or waste. Because atypical presentations make M. bovis infections difficult to diagnose, awareness of early symptoms is critical to effective diagnosis. The majority of M. bovis infections present in an extra-pulmonary site such as cervical lymphadenitis [41]. Typically, TB cervical adenitis will present as a painless neck mass increasing in size with no fevers, a normal white count, and no systemic symptoms (unless pulmonary disease or dissemination is present). Skin changes typically occur later in the progression of the disease. A CT scan of the neck may show nodal involvement or fluid collections. PPD will be positive in 74–96% of patients and CXR will be negative in 90% of cases. The more strongly reactive the PPD test, the more likely that typical TB is the diagnosis. However, 40% of atypical Mycobacterium will yield a positive PPD [5,22,23]. Histopathology, culture, and genetic testing techniques are required to differentiate typical from atypical forms of TB. FNA or fresh tissue biopsy including complete excision should be obtained in all masses suspicious for TB. FNA or biopsy yield for acid-fast bacilli varies and usually improves with higher tissue bulk. Organism recovery can take 2–8 weeks and only occurs in 30– 80% of cultures [5]. The gold-standard of M. bovis diagnosis is by PCR testing for specific genome domains. The hallmark method of identification is the absence of the gene producing pyrazinamidase, which gives M. bovis its characteristic resistance to PZA. Because the M. tuberculosis genome was not mapped until the late 1990’s, it is likely that the significance M. bovis is grossly underestimated. The new and rapid development of Mycobacterium genome testing now allows differentiation of wild-type strains, indicating transmission patterns, and identification of BCG vaccination types. Practically, resistance to PZA on culture may be used as an alternative to genotype-based definition of M. bovis, which is the gold standard for diagnosis. Treatment of M. bovis is similar to that of M. tuberculosis [27]. Based on PPD reactivity and suspicion, typical 4 drug (INH, PZA,
Please cite this article in press as: P.S. Han, et al., Mycobacterium bovis cervical lymphadenitis: A representative case and review, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.09.007
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EMB, RMP) therapy is begun as with M. tuberculosis therapy. Most authors recommend treatment with multi-drug therapy excluding PZA [28,29]. Some authors have suggested that 2-drug therapy is sufficient for M. bovis infections. However, the largest case study on M. bovis versus M. tuberculosis does not recommend a ‘‘short’’ therapy course for M. bovis due to increased mortality and an average three month longer treatment course [30]. Post-BCG vaccination lymphadenopathy, monotherapy with INH has been shown to be effective. In M. tuberculosis, surgery is often reserved for medical failures or used in conjunction with medical therapy in select cases. Though in cases where M. bovis is suspected, early implementation of surgical excision may be beneficial as it can be both diagnostic and therapeutic. Typical Mycobacteria are notoriously resistant to less than optimal therapy, developing in-vivo resistance quickly. Although initial failure to improve should raise suspicion of resistance, up to 25% of TB lymphadenitis has been shown to clinically worsen for up to two months [31,32]. When M. bovis is not recognized and treated as M. tuberculosis, PZA will not be effective because of innate resistance and may lead to a higher incidence of medical therapy failure. In the United States, TB resurged in the 1980’s because of the evolving AIDS epidemic and multi-drug resistant TB strains were seen. Worldwide resistance patterns continue to emerge, including documented cases of M. bovis resistant to more than 20 antibiotics, leaving TB therapy focused around long-term multi-drug treatment. In recent years, new drugs such as bedaquiline have been developed as cost-saving therapies to be used in conjunction with the standard regimen in multi-drug resistant strains of TB [33,34]. This case demonstrates M. bovis infection with failure of twodrug therapy for 4 months. Eventually, the mass required complete excision, followed by 9 additional months of three drug therapy. Because of innate PZA resistance, M. bovis should be treated as aggressively, if not more aggressively, as M. tuberculosis. To ensure proper treatment and aid in M. bovis surveillance, it is critical to involve TB specialists and the public health department in active infections. The direction of M. bovis research continues toward development of an optimal TB vaccine. It is estimated that more than 94% of the world’s population live in countries where the control of bovine tuberculosis is limited or absent, leading to inadequate understanding and questionable control of this disease [35]. Continued global monitoring, definitive diagnosis, and reporting is needed to understanding the progression of this disease. Disclosures None. References [1] World Health Organization, Global Health Observatory Data: Tuberculosis, World Health Organization, 2015 hhttp://www.who.int/gho/tb/en/i. [2] Z.B. Khuzwayo, T.K. Naidu, Head and neck tuberculosis in KwaZulu-Natal, South Africa, J. Laryngol. Otol. 128 (2014) 86–90. [3] C.M. Chiesa, F.A. Betances, T. Rivera, C.C. Ossa, M.J. Gonzalez, H.C. Santidrian, Head and neck tuberculosis: 6-year retrospective study, Acta Otorrinolaringol. Esp. (2015). [4] R. Bartralot, R.M. Pujol, V. Garcia-Patos, D. Sitjas, N. Martin-Casabona, P. Coll, et al., Cutaneous infections due to nontuberculous mycobacteria: histopathological review of 28 cases. Comparative study between lesions observed in immunosuppressed patients and normal hosts, J. Cutan. Pathol. 27 (3) (2000) 124–129. [5] K. Munck, A.H. Mandpe, Mycobacterial infections of the head and neck, Otolaryngol. Clin. N. Am. 36 (2003) 569–576. [6] M. Gallivan, N. Shah, J. Flood, Epidemiology of human Mycobacterium bovis disease, California, USA, 2003–2011, Emerg. Infect. Dis. 21 (3) (2015) 435–443. [7] T.C. Rodwell, M. Moore, K.S. Moser, S.K. Brodine, S.A. Strathdee, Mycobacterium bovis tuberculosis in binational communities, Emerg. Infect. Dis. (2008), hhttp:// wwwnc.cdc.gov/eid/article/14/6/07-1485i. [8] C.J. McDaniel, D.M. Cardwell, R.B. Moeller, G.C. Gray, Humans and cattle: a review of bovine zoonoses, Vector Borne Zoonotic Dis. 14 (1) (2014) 1–19. [9] P.D. Davies, Tuberculosis in humans and animals: are we a threat to each other? J. R. Soc. Med. 99 (2006) 539–540. [10] C.H. Collins, The bovine tubercle bacillus, Br. J. Biomed. Sci. 57 (2000) 234–240.
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Please cite this article in press as: P.S. Han, et al., Mycobacterium bovis cervical lymphadenitis: A representative case and review, Int. J. Pediatr. Otorhinolaryngol. (2015), http://dx.doi.org/10.1016/j.ijporl.2015.09.007