Laryngeal Actinomycosis in an Immunocompromised Patient Sheylan Patel, Aaron J. Jaworek, Vatsal Patel, Lizette Vila Duckworth, Raja Sawhney, and Neil N. Chheda, Gainesville, Florida
Summary: Actinomycosis of the larynx represents an unusual presentation for a common bacterium comprising the oral and oropharyngeal florae. There are few cases reported in the literature of laryngeal actinomycosis occurring primarily in the immunocompromised population. Here, we present a case in a 74-year-old man that occurred in the setting of neutropenia as a result of chemotherapy. Once the diagnosis was made with biopsy of the larynx, the infection was resolved after a prolonged course of penicillin-based therapy. Key Words: Neutropenia–Actinomycosis–Immunocompromised–Larynx.
INTRODUCTION Actinomyces are gram-positive, filamentous, anaerobic bacteria that are a normal constituent of the human oral and oropharyngeal florae. It is estimated that nearly 100% of people are colonized by 2 years of age.1 Although the bacteria typically do not cause disease, individuals with a history of radiation therapy to the neck or trauma are at increased risk of progressing to infection, presumably through mucosal damage.2 However, several case reports have been published regarding actinomycosis infections of individuals who were immunocompromised most often because of human immunodeficiency virus (HIV) or from the chronic use of corticosteroids.3 Diagnosis of actinomycosis is particularly challenging as it is frequently mistaken for other infectious pathogens or even malignancy, which may delay diagnosis and appropriate treatment. When the disease occurs, it can affect a variety of tissues; however, more than 50% of the cases are oral-cervical in nature, typically affecting the soft tissues around the mandible.2 Rarely, cases have been reported in which actinomycosis affects the larynx primarily.4–17 Here, we present the case of laryngeal actinomycosis that developed in an immunocompromised patient with chronic lymphocytic leukemia (CLL). CASE REPORT A 74-year-old man was diagnosed with CLL 12 years ago and had been undergoing treatment with bendamustine and rituximab since 2010, with his last treatment ending in November 2012. In January 2013, he was admitted to the hospital for febrile neutropenia and complaints of odynophagia and dysphagia. Computed tomography (CT) of the neck and chest with contrast was ordered but did not demonstrate any findings to explain the patient’s symptoms. Subsequent esophagogastroduodenoscopy was only significant for an erythematous epiglottis. Otolaryngology was consulted, and flexible nasoAccepted for publication February 21, 2014. Poster Presentation at Fall Voice Conference October 18–19, 2013; Atlanta, Georgia. From the Division of Laryngology, Department of Otolaryngology—Head and Neck Surgery, University of Florida Health, Gainesville, Florida. Address correspondence and reprint requests to Neil N. Chheda, Division of Laryngology, Department of Otolaryngology, PO Box 100264, Gainesville, FL 32610. E-mail: Neil. [email protected] Journal of Voice, Vol. 28, No. 6, pp. 838-840 0892-1997/$36.00 Ó 2014 The Voice Foundation http://dx.doi.org/10.1016/j.jvoice.2014.02.011
pharyngolaryngoscopy did not show any mucositis, masses, or structural abnormalities. He was started on a proton-pump inhibitor trial for suspected laryngopharyngeal reflux. Symptoms improved with conservative management, and the patient was discharged home on prophylactic ciprofloxacin and amoxicillin-clavulanate potassium. Two months later, the patient was readmitted for febrile neutropenia. Repeat CT of the neck with contrast showed a rapidly progressive infiltrating process (Figure 1) with associated necrosis within the larynx. Although the location and progression of the radiographic findings were suspicious for tuberculosis, his workup including Tuberculin Skin Test was negative. The patient was subsequently taken to the operating room for direct laryngoscopy with biopsy. Examination under anesthesia showed diffuse supraglottic edema and erythema with exudative lesions along the right true and false vocal folds. Histologic examination revealed markedly inflamed and ulcerated squamous and respiratory-type mucosa (Figure 2) with numerous bacterial colonies including Actinomyces sulfur granules (Figures 3 and 4). Acid-fast stain was negative for mycobacterial organisms, and no fungal organisms were seen on Gomori’s methenamine silver (GMS) stain. The patient was discharged home on a course of ciprofloxacin and Augmentin for 1 month as recommended by infectious disease specialists. A thorough dental evaluation and cleaning was also recommended to reduce Actinomyces colonization. A follow-up flexible laryngoscopy was unable to be performed; however, a telephonic interview revealed near-complete resolution of his dysphonia along with subjective improvement in dysphagia after completing the course of antibiotics. DISCUSSION Actinomycotic colonies can be present in the normal oral/ oropharyngeal flora of healthy individuals; however, certain pathologic states can make an individual much more likely to progress to infection—namely being immunocompromised.4 The primary pathogen is Actinomyces israelii, although other species can also cause infection. Actinomycosis can be difficult to diagnose as it is frequently mistaken for other disease entities including cervicofacial abscesses and benign or malignant neoplasms. Although it is a relatively rare infection, certain ‘‘classic’’ scenarios should prompt the clinician to suspect actinomycosis. Infections of the soft tissues, such as a painless mass at the angle of the
Sheylan Patel, et al
Actinomycosis in an Immunocompromised Patient
FIGURE 1. CT neck with contrast axial cut showing right-sided supraglottic edema and necrosis.
839
FIGURE 3. Classic sulfur granule associated with Actinomyces (hematoxylin and eosin; magnification at 340).
jaw, that respond to a course of empiric antibiotics and subsequently relapses, regardless of location, should prompt the provider to suspect actinomycosis. Also, infections that spread without regard to fascial planes or those that create recurrent ‘‘draining’’ sinus tracts should also raise suspicion for an Actinomyces infection.2 In this particular case report, the patient’s presentation mimicked that of a laryngeal tuberculosis infection in the setting of immunocompromise. Biopsy is the best way to confirm the diagnosis. Histologic examination demonstrates granulation tissue with variable numbers of club-shaped basophilic filamentous organisms arranged in a rosette pattern surrounded by neutrophils (so called sulfur granules), which are best visualized on Gram or GMS stain. Diagnosis can also be made by culturing the sample under anaerobic conditions; however, this is less sensitive and typically takes between 2 and 4 weeks for primary isolation. Because of the presence of overgrowth of other bacteria or lack of anaerobic conditions, recovery rates are often less than 30%. This can potentially delay or miss the diagnosis altogether. Perhaps, the greatest histologic mimicker of Actinomyces is Nocardia, which are also gram-positive slender branching filamentous bacteria. However, a modified acid-fast
stain can be used to differentiate Actinomyces species from Nocardia, which are partially acid fast. The immunocompromised patient may present in a variety of ways increasing the challenge of diagnosis. Involvement of the head and neck region most frequently includes the parotid, submandibular area, and the mandible with the larynx being a rarer site. Infection has been more frequently seen in those with a history of radiotherapy. When there is involvement of the larynx, dysphonia is a frequent symptom, but this may not always be present. Our patient primarily endorsed dysphagia but denied significant voice change and presented without neck mass or draining tract. Chaudhry et al noted that when actinomycosis was detected in immunocompromised patients with HIV, most patients were initially misdiagnosed.18 The severity of the immunosuppression supported a more aggressive and fulminant infection. This is consistent with our patient, and the rapid progression observed on serial imaging. Actinomycosis typically responds well to a penicillin-based therapy. The typical treatment regimen for orocervicofacial actinomycosis is penicillin G 18–24 million units intravenous per day or 2–4 grams by mouth per day for a duration of 2–6
FIGURE 2. Inflamed granulation tissue of the larynx with dense mixed inflammatory infiltrate consisting of lymphocytes, plasma cells, and eosinophils (hematoxylin and eosin; magnification at 320).
FIGURE 4. Filamentous rods within a sulfur granule of Actinomyces (magnification at 340).
840 weeks.19 If the patient is allergic to penicillin, then clindamycin or doxycycline is suitable alternatives for mild cases. For more severe infections, rocephin or imipenem can be used. With the appropriate duration of treatment, a complete resolution of the infection is expected. Resolution of immunosuppression will also prevent relapse. CONCLUSION When a laryngeal lesion is detected, particularly with radiographic signs of infiltration, the presence of malignancy must be evaluated. However, in the immunocompromised host, opportunistic infections, such as Actinomyces, may also be present in the larynx. Unless there is a high index of suspicion, diagnosis can be delayed because of the nonspecific nature of symptomatology and imaging findings. In such patients, biopsy should be considered for both histology and microbiology analyses. Full recovery may be expected with the appropriate targeted microbial therapy. REFERENCES 1. Sarkonen N, Kononen E, Summanen P, Kanervo A, Takala A, JousimiesSomer H. Oral colonization with Actinomyces species in infants by two years of age. J Dental Res. 2000;79:864–867. 2. Mandell GL, Bennett JE, Dolin R. Agents of actinomycosis. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 7th ed. Edinburgh: Churchill Livingstone; 2010:3209–3219. 3. Hagan ME, Klotz SA, Bartholomew W, Cherian R, McGregor D. Actinomycosis of the trachea with acute tracheal obstruction. Clin Infect Dis. 1996;6:1126–1127. 4. Sari M, Yazici M, Baglam T, Inanli S, Eren F. Actinomycosis of the larynx. Acta Otolaryngol. 2007;5:550–552.
Journal of Voice, Vol. 28, No. 6, 2014 5. Artesi L, Gorini E, Lecce S, Mullace M, Sbrocca M, Mevio E. Laryngeal actinomycosis. Otolaryngol Head Neck Surg. 2006;135: 161–162. 6. Batur CA, Ozbal AE, Basak T, Turgut S. Laryngeal actinomycosis accompanying laryngeal carcinoma: report of two cases. Eur Arch Otorhinolaryngol. 2006;263:783–785. 7. Brandenburg JH, Finch WW, Kirkham WR. Actinomycosis of the larynx and pharynx. Otolaryngology. 1978;86:739–742. 8. Nelson EG, Tybor AG. Actinomycosis of the larynx. Ear_Nose_Throat_J. 1992;71:356–358. 9. Tsuji DH, Fukuda H, Kawasaki Y, Kawaida M, Ohira T. Actinomycosis of the larynx. Auris Nasus Larynx. 1991;18:79–85. 10. Melgarejo MPJ, Hellin MD, Gil VM, Ruiz MJA. Primary laryngeal actinomycosis. Acta Otorrinolaringol Esp. 1997;48:237–238. 11. Fernandez SH. Actinomycosis of the vocal cord: a case report. Malays J Pathol. 1999;21:111–115. 12. Koegel L Jr, Tucker HM. Postoperative actinomycotic infection of the larynx. Otolaryngol Head Neck Surg. 1983;91:213–216. 13. Wierzbicka M, Bartochowska A, Nowak K, Szyfter W. Laryngeal actinomycosis— a case report and the review of the literature. Otolaryngol Pol. 2013;67:308–311. 14. Abed T, Ahmed J, O’shea N, Payne S, Watters GW. Primary laryngeal actinomycosis in an immunosuppressed woman: a case report. Ear Nose Throat J. 2013;92:301–303. 15. Shaheen SO, Ellis FG. Actinomycosis of the larynx. J R Soc Med. 1983;76: 226–228. 16. Sims HS, Heywood BB. Post-transplant actinomycosis of the posterior glottis involving both vocal processes. Otolaryngol Head Neck Surg. 2007;137:967–968. 17. Thomas R, Kameswaran M, Ahmed S, Khurana P, Morad N. Actinomycosis of the vallecula: report of a case and review of the literature. J Laryngol Otol. 1995;109:154–156. 18. Chaudhry SI, Greenspan JS. Actinomycosis in HIV infection: a review of a rare complication. Int J STD AIDS. 2000;11:349–355. 19. Wong VK, Turmezei TD, Weston VC. Actinomycosis. BMJ. 2011;343: d6099.
Summary: Actinomycosis of the larynx represents an unusual presentation for a common bacterium comprising the oral and oropharyngeal florae. There are few cases reported in the literature of laryngeal actinomycosis occurring primarily in the immunocompromised population. Here, we present a case in a 74-year-old man that occurred in the setting of neutropenia as a result of chemotherapy. Once the diagnosis was made with biopsy of the larynx, the infection was resolved after a prolonged course of penicillin-based therapy. Key Words: Neutropenia–Actinomycosis–Immunocompromised–Larynx.
INTRODUCTION Actinomyces are gram-positive, filamentous, anaerobic bacteria that are a normal constituent of the human oral and oropharyngeal florae. It is estimated that nearly 100% of people are colonized by 2 years of age.1 Although the bacteria typically do not cause disease, individuals with a history of radiation therapy to the neck or trauma are at increased risk of progressing to infection, presumably through mucosal damage.2 However, several case reports have been published regarding actinomycosis infections of individuals who were immunocompromised most often because of human immunodeficiency virus (HIV) or from the chronic use of corticosteroids.3 Diagnosis of actinomycosis is particularly challenging as it is frequently mistaken for other infectious pathogens or even malignancy, which may delay diagnosis and appropriate treatment. When the disease occurs, it can affect a variety of tissues; however, more than 50% of the cases are oral-cervical in nature, typically affecting the soft tissues around the mandible.2 Rarely, cases have been reported in which actinomycosis affects the larynx primarily.4–17 Here, we present the case of laryngeal actinomycosis that developed in an immunocompromised patient with chronic lymphocytic leukemia (CLL). CASE REPORT A 74-year-old man was diagnosed with CLL 12 years ago and had been undergoing treatment with bendamustine and rituximab since 2010, with his last treatment ending in November 2012. In January 2013, he was admitted to the hospital for febrile neutropenia and complaints of odynophagia and dysphagia. Computed tomography (CT) of the neck and chest with contrast was ordered but did not demonstrate any findings to explain the patient’s symptoms. Subsequent esophagogastroduodenoscopy was only significant for an erythematous epiglottis. Otolaryngology was consulted, and flexible nasoAccepted for publication February 21, 2014. Poster Presentation at Fall Voice Conference October 18–19, 2013; Atlanta, Georgia. From the Division of Laryngology, Department of Otolaryngology—Head and Neck Surgery, University of Florida Health, Gainesville, Florida. Address correspondence and reprint requests to Neil N. Chheda, Division of Laryngology, Department of Otolaryngology, PO Box 100264, Gainesville, FL 32610. E-mail: Neil. [email protected] Journal of Voice, Vol. 28, No. 6, pp. 838-840 0892-1997/$36.00 Ó 2014 The Voice Foundation http://dx.doi.org/10.1016/j.jvoice.2014.02.011
pharyngolaryngoscopy did not show any mucositis, masses, or structural abnormalities. He was started on a proton-pump inhibitor trial for suspected laryngopharyngeal reflux. Symptoms improved with conservative management, and the patient was discharged home on prophylactic ciprofloxacin and amoxicillin-clavulanate potassium. Two months later, the patient was readmitted for febrile neutropenia. Repeat CT of the neck with contrast showed a rapidly progressive infiltrating process (Figure 1) with associated necrosis within the larynx. Although the location and progression of the radiographic findings were suspicious for tuberculosis, his workup including Tuberculin Skin Test was negative. The patient was subsequently taken to the operating room for direct laryngoscopy with biopsy. Examination under anesthesia showed diffuse supraglottic edema and erythema with exudative lesions along the right true and false vocal folds. Histologic examination revealed markedly inflamed and ulcerated squamous and respiratory-type mucosa (Figure 2) with numerous bacterial colonies including Actinomyces sulfur granules (Figures 3 and 4). Acid-fast stain was negative for mycobacterial organisms, and no fungal organisms were seen on Gomori’s methenamine silver (GMS) stain. The patient was discharged home on a course of ciprofloxacin and Augmentin for 1 month as recommended by infectious disease specialists. A thorough dental evaluation and cleaning was also recommended to reduce Actinomyces colonization. A follow-up flexible laryngoscopy was unable to be performed; however, a telephonic interview revealed near-complete resolution of his dysphonia along with subjective improvement in dysphagia after completing the course of antibiotics. DISCUSSION Actinomycotic colonies can be present in the normal oral/ oropharyngeal flora of healthy individuals; however, certain pathologic states can make an individual much more likely to progress to infection—namely being immunocompromised.4 The primary pathogen is Actinomyces israelii, although other species can also cause infection. Actinomycosis can be difficult to diagnose as it is frequently mistaken for other disease entities including cervicofacial abscesses and benign or malignant neoplasms. Although it is a relatively rare infection, certain ‘‘classic’’ scenarios should prompt the clinician to suspect actinomycosis. Infections of the soft tissues, such as a painless mass at the angle of the
Sheylan Patel, et al
Actinomycosis in an Immunocompromised Patient
FIGURE 1. CT neck with contrast axial cut showing right-sided supraglottic edema and necrosis.
839
FIGURE 3. Classic sulfur granule associated with Actinomyces (hematoxylin and eosin; magnification at 340).
jaw, that respond to a course of empiric antibiotics and subsequently relapses, regardless of location, should prompt the provider to suspect actinomycosis. Also, infections that spread without regard to fascial planes or those that create recurrent ‘‘draining’’ sinus tracts should also raise suspicion for an Actinomyces infection.2 In this particular case report, the patient’s presentation mimicked that of a laryngeal tuberculosis infection in the setting of immunocompromise. Biopsy is the best way to confirm the diagnosis. Histologic examination demonstrates granulation tissue with variable numbers of club-shaped basophilic filamentous organisms arranged in a rosette pattern surrounded by neutrophils (so called sulfur granules), which are best visualized on Gram or GMS stain. Diagnosis can also be made by culturing the sample under anaerobic conditions; however, this is less sensitive and typically takes between 2 and 4 weeks for primary isolation. Because of the presence of overgrowth of other bacteria or lack of anaerobic conditions, recovery rates are often less than 30%. This can potentially delay or miss the diagnosis altogether. Perhaps, the greatest histologic mimicker of Actinomyces is Nocardia, which are also gram-positive slender branching filamentous bacteria. However, a modified acid-fast
stain can be used to differentiate Actinomyces species from Nocardia, which are partially acid fast. The immunocompromised patient may present in a variety of ways increasing the challenge of diagnosis. Involvement of the head and neck region most frequently includes the parotid, submandibular area, and the mandible with the larynx being a rarer site. Infection has been more frequently seen in those with a history of radiotherapy. When there is involvement of the larynx, dysphonia is a frequent symptom, but this may not always be present. Our patient primarily endorsed dysphagia but denied significant voice change and presented without neck mass or draining tract. Chaudhry et al noted that when actinomycosis was detected in immunocompromised patients with HIV, most patients were initially misdiagnosed.18 The severity of the immunosuppression supported a more aggressive and fulminant infection. This is consistent with our patient, and the rapid progression observed on serial imaging. Actinomycosis typically responds well to a penicillin-based therapy. The typical treatment regimen for orocervicofacial actinomycosis is penicillin G 18–24 million units intravenous per day or 2–4 grams by mouth per day for a duration of 2–6
FIGURE 2. Inflamed granulation tissue of the larynx with dense mixed inflammatory infiltrate consisting of lymphocytes, plasma cells, and eosinophils (hematoxylin and eosin; magnification at 320).
FIGURE 4. Filamentous rods within a sulfur granule of Actinomyces (magnification at 340).
840 weeks.19 If the patient is allergic to penicillin, then clindamycin or doxycycline is suitable alternatives for mild cases. For more severe infections, rocephin or imipenem can be used. With the appropriate duration of treatment, a complete resolution of the infection is expected. Resolution of immunosuppression will also prevent relapse. CONCLUSION When a laryngeal lesion is detected, particularly with radiographic signs of infiltration, the presence of malignancy must be evaluated. However, in the immunocompromised host, opportunistic infections, such as Actinomyces, may also be present in the larynx. Unless there is a high index of suspicion, diagnosis can be delayed because of the nonspecific nature of symptomatology and imaging findings. In such patients, biopsy should be considered for both histology and microbiology analyses. Full recovery may be expected with the appropriate targeted microbial therapy. REFERENCES 1. Sarkonen N, Kononen E, Summanen P, Kanervo A, Takala A, JousimiesSomer H. Oral colonization with Actinomyces species in infants by two years of age. J Dental Res. 2000;79:864–867. 2. Mandell GL, Bennett JE, Dolin R. Agents of actinomycosis. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 7th ed. Edinburgh: Churchill Livingstone; 2010:3209–3219. 3. Hagan ME, Klotz SA, Bartholomew W, Cherian R, McGregor D. Actinomycosis of the trachea with acute tracheal obstruction. Clin Infect Dis. 1996;6:1126–1127. 4. Sari M, Yazici M, Baglam T, Inanli S, Eren F. Actinomycosis of the larynx. Acta Otolaryngol. 2007;5:550–552.
Journal of Voice, Vol. 28, No. 6, 2014 5. Artesi L, Gorini E, Lecce S, Mullace M, Sbrocca M, Mevio E. Laryngeal actinomycosis. Otolaryngol Head Neck Surg. 2006;135: 161–162. 6. Batur CA, Ozbal AE, Basak T, Turgut S. Laryngeal actinomycosis accompanying laryngeal carcinoma: report of two cases. Eur Arch Otorhinolaryngol. 2006;263:783–785. 7. Brandenburg JH, Finch WW, Kirkham WR. Actinomycosis of the larynx and pharynx. Otolaryngology. 1978;86:739–742. 8. Nelson EG, Tybor AG. Actinomycosis of the larynx. Ear_Nose_Throat_J. 1992;71:356–358. 9. Tsuji DH, Fukuda H, Kawasaki Y, Kawaida M, Ohira T. Actinomycosis of the larynx. Auris Nasus Larynx. 1991;18:79–85. 10. Melgarejo MPJ, Hellin MD, Gil VM, Ruiz MJA. Primary laryngeal actinomycosis. Acta Otorrinolaringol Esp. 1997;48:237–238. 11. Fernandez SH. Actinomycosis of the vocal cord: a case report. Malays J Pathol. 1999;21:111–115. 12. Koegel L Jr, Tucker HM. Postoperative actinomycotic infection of the larynx. Otolaryngol Head Neck Surg. 1983;91:213–216. 13. Wierzbicka M, Bartochowska A, Nowak K, Szyfter W. Laryngeal actinomycosis— a case report and the review of the literature. Otolaryngol Pol. 2013;67:308–311. 14. Abed T, Ahmed J, O’shea N, Payne S, Watters GW. Primary laryngeal actinomycosis in an immunosuppressed woman: a case report. Ear Nose Throat J. 2013;92:301–303. 15. Shaheen SO, Ellis FG. Actinomycosis of the larynx. J R Soc Med. 1983;76: 226–228. 16. Sims HS, Heywood BB. Post-transplant actinomycosis of the posterior glottis involving both vocal processes. Otolaryngol Head Neck Surg. 2007;137:967–968. 17. Thomas R, Kameswaran M, Ahmed S, Khurana P, Morad N. Actinomycosis of the vallecula: report of a case and review of the literature. J Laryngol Otol. 1995;109:154–156. 18. Chaudhry SI, Greenspan JS. Actinomycosis in HIV infection: a review of a rare complication. Int J STD AIDS. 2000;11:349–355. 19. Wong VK, Turmezei TD, Weston VC. Actinomycosis. BMJ. 2011;343: d6099.
