Head and Neck Manifestations of Immunocompromised Patient

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Head and Neck Manifestations of Immunocompromised Patient

Head and Neck Surgery
Author Credentials 

Brian Boyce, MD, FACS
Assistant Professor 
Otolaryngology – Head and Neck Surgery
Emory University
Atlanta, GA

Module Summary

Immunocompromised patients may present with diverse pathologies of the head and neck that range from benign to life-threatening. A complete evaluation including a detailed history and physical examination is important in arriving at the correct diagnosis. Malignancies and atypical infections are more common in immunosuppressed individuals, so a broad differential should be maintained during an evaluation. These patients are managed in a multidisciplinary fashion and significant weight should be placed on correcting the underlying etiology of the immune dysfunction. Imaging, biopsies, and microbiology are important diagnostic modalities in the evaluation of immunodeficient patients. Arriving at the correct diagnosis promptly is paramount and treatment should be guided by the disease process.

Module Learning Objectives 
  1. Review fundamental components of normal immune system function.
  2. Describe most common etiologies of immune dysfunction.
  3. Explain appropriate diagnostic approach to immune compromised patient.
  4. List the common diseases that affect the salivary glands in immunocompromised patients.
  5. Recognize the increased risk of malignancies in immunocompromised patients and be familiar with treatment guidelines.
  6. Explain the increased risk of atypical and unusual infections in immunodeficient patients.
  7. Describe the appropriate evaluation and management of hearing loss in an immunocompromised patient.

Pathogenesis

Learning Objectives 
  1. Objectives
    1. Understand common causes of congenital (primary) immunodeficiency
      1. Severe combined immunodeficiency
      2. Congenital agammaglobulinemia (Bruton’s disease)
        1. All isotypes of antibodies decreased
        2. X-linked version with mutation in BTK
      3. Selective IgA deficiency
        1. Most common primary immunodeficiency
        2. Decreased IgA antibodies with normal IgG and IgM
        3. Maturation defect in B cells to produce IgA
      4. Ataxia-telangiectasia
        1. Reduced, defective T cell response, ataxia, telangiectasia
        2. Autosomal recessive, mutation in ATM
      5. Chronic granulomatous disease
        1. Defect in respiratory burst of
        2. X-linked and autosomal recessive versions, mutations in CYB or NCF (proteins in electron transport)
      6. DiGeorge syndrome
        1. Decreased T cells, hypoparathyroid, VPI, cardiac malformation
        2. De novo mutations and autosomal dominant, mutation in 22q11.2
      7. Wiskott-Aldrich syndrome
        1. Progressive T cell decrease, decreased IgM, thrombocytopenia
        2. X-linked, mutation in WAS
    2. Understand common causes of acquired (secondary) immunodeficiency
      1. Human immunodeficiency virus (HIV)
        1. Profound depletion and impairment of CD4 T-cells
        2. Spread through blood, semen, vaginal fluid, rectal fluid, breast milk
          1. Most common methods of transmission are unprotected sex and sharing contaminated syringes
        3. Multiple stages of infection
          1. Acute – flu like symptoms, 2-3 weeks after infection
          2. Latent – asymptomatic stages, lasts 10years on average
          3. Acquired Immune Deficiency Syndrome (AIDS) – CD4 levels below 200 cells/mm3 or AIDS defining illness
      2. Systemic disease
        1. Diabetes mellitus
        2. Nutritional deficiencies
        3. Obesity
        4. Rheumatologic disease
        5. Renal disease, nephrotic syndrome
      3. Medication related
        1. Immunosuppressants
          1. Autoimmune diseases
          2. Organ transplant
        2. Chemotherapy
      4. Malignancies
        1. Leukemia and lymphoma
        2. Bone marrow transplant
References 
  1. Picard C, et al. Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J Clin Immunol. 2015 Nov;35(8):696-726.
  2. “What Are HIV and AIDS?” HIV.gov. U. S. Department of Health and Human Services.

Basic Science

Learning Objectives 
  1. Objectives
    1. Explain the differences in innate versus adaptive immunity
    2. Describe innate immunity and explain how it functions
      1. Barrier system (skin, mucous, sweat, saliva, etc)
      2. Complement
      3. Cytokines
      4. Macrophages, dendritic cells, neutrophils, natural killer cells
    3. Describe acquired immunity and explain how it functions
      1. Function of B-cells
        1. Antibody-mediated response
      2. Function of T-cells
        1. Cell-mediated response
      3. Explain the differences in primary and secondary responses
References 
  1. Lane, A.P. Curr Allergy Asthma Rep (2009) 9: 205. 

Incidence

Learning Objectives 
  1. Objectives
    1. Identify risk factors for HIV infection
    2. Understand the changing incidence of HIV in United States
    3. Understand that the rates of organ transplant and stem cell transplants continue to increase each year
References 
  1. “HIV Surveillance Report.” Centers for Disease Control. U. S. Department of Health and Human Services.
  2. D'Souza A, Lee S, Zhu X, Pasquini M. Current Use and Trends in Hematopoietic Cell Transplantation in the United States. Biol Blood Marrow Transplant. 2017 Sep;23(9):1417-1421. 
  3. “OPTN/SRTR 2016 Annual Data Report.” Organ Procurement and Transplant Network. U.S. Department of Health and Human Services.

Patient Evaluation

Learning Objectives 
  1. Objectives
    1. Describe the components of full head and neck history with attention to infectious possibilities and immune status
      1. Immune status
        1. Viral load
        2. Taking HARRT
        3. Medication history
        4. Medical history
      2. Travel history
      3. Exposure to tuberculosis
      4. Exposure to animals
      5. Other risk factors for malignancy including tobacco, alcohol, occupation, etc
      6. B symptoms (fever, malaise, fatigue, etc)
    2. Understand the importance of complete head and neck exam in immunocompromised patients
    3. Understand the symptoms might be masked due to immunocompromised state
      1.  Important to rule out life-threatening etiologies of symptoms
        1. Evaluate for signs of meningitis
    4. Understand the broad differential for neck masses in immunocompromised patients
      1. Infectious
        1. Viral
        2. Bacterial
        3. Atypical
        4. Fungal
      2. Malignancy
    5. Choose the appropriate patients to further evaluate with endoscopy
      1. Nasal endoscopy
      2. Laryngeal endoscopy
    6. Describe useful adjunctive testing in evaluating immunocompromised patients and understand when to obtain testing
      1. Imaging
        1. Ultrasound
        2. CT scan
        3. MRI
      2. Laboratory
        1. Culture
          1. Order all studies given the increased risk of unusual infection
          2. Anaerobic, aerobic, mycobacterial, fungal, etc
        2. White blood cell count
        3. HIV test with viral load and CD4 count
        4. Biopsy
          1. Fine needle
          2. Core needle
    7. Explain the importance of collaboration with appropriate multidisciplinary team
      1. Medical oncology
      2. Infectious disease
      3. Transplant medicine
      4. Rheumatology

Imaging

Learning Objectives 
  1. Objectives
    1. Understand when to obtain imaging and the differences in various imaging modalities
      1. CT scan
        1. Evaluation of osseous landmarks
        2. Evaluation of neck masses
      2. MRI
        1. Evaluation of soft tissue
        2. Expensive
      3. Ultrasound
        1. Low cost and operator dependent
        2. Evaluation of neck masses or salivary gland enlargement
      4. Nuclear imaging
        1. PET-CT and PET-MRI
          1. Staging malignancies
          2. Usually utilize
        2. Technetium-99
          1.  Correlates with increased osteoblastic activity
        3. Gallium-67
          1. Binds to dividing leukocytes at site of infection
          2. Can be used to monitor treatment
References 
  1. van Kroonenburgh AMJL, et al. Advanced Imaging Techniques in Skull Base Osteomyelitis Due to Malignant Otitis Externa. Curr Radiol Rep. 2018;6(1):3.
  2. Juliano A, Moonis G. Computed Tomography Versus Magnetic Resonance in Head and Neck Cancer: When to Use What and Image Optimization Strategies. Magn Reson Imaging Clin N Am. 2018 Feb;26(1):63-84. 
  3. Gupta A, et al. Sonographic assessment of cervical lymphadenopathy: role of high-resolution and color Doppler imaging. Head Neck. 2011 Mar;33(3):297-302.

Pathology

Learning Objectives 
  1. Objectives
    1. Understand the common malignancies and their presentations seen in immunocompromised patients
      1. Malignancy is the leading cause of death in solid organ transplant patients
      2. Immunosuppressed patients have increased mortality rates for malignancy
      3. Skin cancer
        1. Squamous cell carcinoma
        2. Basal cell carcinoma
        3. Merkel cell carcinoma
      4. Kaposi sarcoma
        1. Human herpes virus 8
      5. Lymphoma
        1. Non-Hodgkin’s lymphoma is most common lymphoproliferative malignancy in HIV patients and is an AIDS-defining illness
          1. Most commonly diffuse large B-cell lymphoma (DLBCL)
    2. Be familiar with the broad differential for lymphadenopathy in immunocompromised patients
      1. Malignant
        1. Lymphoproliferative malignancies
        2. Metastatic disease
      2. Infectious
        1. Bacterial
          1. Syphilis
        2. Mycobacterial
          1. Risk of tuberculosis co-infection is 30 times higher in HIV patients
        3. Viral
          1. Cytomegalovirus
          2. Epstein-Barr virus
          3. Herpes virus
        4. Fungal
          1. Candida
          2. Aspergillus
          3. Histoplasmosis
          4. Cryptococcus
          5. Mucor
    3. List common oral cavity lesions seen in immunocompromised patients
      1. Non-infectious
        1. Aphthous
          1. Biopsy sometimes required for severe or large lesions
        2. Hairy tongue
          1. Typically due to systemic disease and poor oral hygiene
      2. Infectious
        1. Herpes virus
          1. Painful vesicular eruptions
        2. Candida
          1. Three types: angular chelitis, erythematous, pseudomembranous
        3. Oral hairy leukoplakia
          1. Due to EBV
          2. Leukoplakia on lateral border of tongue
        4. Oral condyloma
          1. Human papilloma virus
      3. Malignant
        1. Kaposi sarcoma
        2. Oral squamous cell carcinoma
    4. Understand the increased risk of sinonasal and ear infections in patients with compromised immune systems
      1. Acute and chronic rhinosinusitis
      2. Acute invasive fungal infection
        1. Life-threatening infection
      3. Acute and chronic otitis media and externa
      4. Malignant otitis externa/skull base osteomyelitis
        1. Life-threatening infection
    5. Understand the variety of salivary gland pathology common in immunocompromised patients
      1. Xerostomia
        1. Direct viral damage in HIV
        2. Medication induced
      2. Lymphoepithelial cysts
      3. Diffuse infiltrative lymphocytosis
    6. Describe the differential and appropriate work-up for hearing loss in immunosuppressed patients
      1. Otitis media and externa
      2. Eustachian tube dysfunction
      3. Direct viral labyrinth damage
      4. Medication induced hearing loss
      5. Otosyphilis
      6. Meningitis
References 
  1. Meister A, Hentrich M, Wyen C, Hübel K. Malignant lymphoma in the HIV-positive patient. Eur J Haematol. 2018 Jul;101(1):119-126. 
  2. Barrionuevo-Cornejo C, Dueñas-Hancco D. Lymphadenopathies in human immunodeficiency virus infection. Semin Diagn Pathol. 2018 Jan;35(1):84-91. 
  3. Reznik DA. Oral manifestations of HIV disease. Top HIV Med. 2005 Dec-2006 Jan;13(5):143-8.
  4. Brin L, Zubair AS, Brewer JD. Optimal management of skin cancer in immunosuppressed patients. Am J Clin Dermatol. 2014 Aug;15(4):339-56.
  5. Goldberg, AN, Pletcher SD, Kim T. “Head and Neck Manifestations in the Immunocompromised Host.” Cummings Otolaryngology, 6th Edition. Ed Paul Flint, Bruce Haughey, Valerie Lund, John Niparko, K. Thomas Robbins, J. Regan Thomas, and Marci Lesperance. Philadelphia: Mosby Elsevier, 2016, pages 193-96

Treatment

Learning Objectives 
  1. Objectives
    1. Understand the importance of multidisciplinary care to manage medications to maximize immune function or reverse causes of immune dysfunction
      1. Start highly active antiretroviral therapy (HAART)
      2. Minimizing or modifying immunosuppressive regimen
    2. Understand that the treatment should be directed at the underlying pathology
      1. Malignancies
        1. Treatment should be directed by established guidelines
      2. Infectious
        1. Includes all upper aerodigestive tract infections
          1. Otitis
          2. Sinusitis
          3. Lymphadenitis
          4. Stomatitis
        2. Appropriate antimicrobial, antifungal, or antiviral treatment
          1. Culture-directed if needed
          2. Recognize the importance of prompt diagnosis
          3. Occasional need for longer duration of antibiotic treatment or need for prophylactic antibiotics
        3. Appreciate the need for consultation with Infectious Disease specialists in unusual or atypical infections
        4. Functional endoscopic sinus surgery is beneficial in immunosuppressed patients that fail maximal medical treatment
      3. Lymphoepithelial cysts
        1. Usually improve with implementation of HAART
        2. Radiotherapy
        3. Surgery not typically used
        4. Sclerotherapy
      4. Xerostomia
        1. Medical management
      5. Acute invasive fungal sinusitis
        1. Aggressive debridement
        2. Aggressive antifungal therapy with Infectious Disease support
        3. Typically high mortality rate despite treatment
      6. Malignant otitis externa
        1. Antipseudomonal antibiotics (intravenous, oral, ototopical)
        2. Radical surgery rarely indicated
      7. Aphthous ulcers
        1. Topical steroids, oral steroids in severe cases
References 
  1. Chiarella SE, Grammer LC. Immune deficiency in chronic rhinosinusitis: screening and treatment. Expert Rev Clin Immunol. 2017 Feb;13(2):117-123. 
  2. Naik AN, et al. Nonsurgical management of human immunodeficiency virus-associated parotid cysts: A systematic review and meta-analysis. Head Neck. 2018 May;40(5):1073-1081. 

Medical Therapies

Learning Objectives 
  1. Objectives
    1. Understand the role of culture-directed antimicrobial treatment
    2. Be familiar with the chemotherapy regimens for treatment of lymphoproliferative malignancies
    3. Understand the variety of treatments for HIV associated xerostomia
      1. Oral lubricants, gels, mouthwashes, gum
      2. Pilocarpine
      3. Cevelimine
References 
  1. Chai, RL, Tassler AB, Kim S. “Lymphomas of the Head and Neck.” Bailey’s Head and Neck Surgery: Otolaryngology. Ed. Jonas T. Johnson and Clark A. Rosen. Philadelphia: Lipincott Williams, and Wilkins; 2006 pages 2007-2010.
  2. Nizamuddin I, Koulen P, McArthur CP. Contribution of HIV Infection, AIDS, and Antiretroviral Therapy to Exocrine Pathogenesis in Salivary and Lacrimal Glands. Int J Mol Sci. 2018 Sep 13;19(9). pii: E2747. 

Pharmacology

Learning Objectives 
  1. Objectives
    1. Describe the basic mechanisms of immunosuppressant medication
      1. Glucocorticosteroids: Downregulates proinflammatory cytokines and inhibits NF-kB
      2. Azathioprine: Inhibits purine synthesis and CD28 signaling
      3. Calcineurin inhibitors
      4. Cyclosporin: Inhibits calcineurin
      5. Tacrolimus: Binds FK-binding protein and inhibits calcineurin
      6. Mycophenolate mofetil: Inhibits purine synthesis
      7. Sirolimus: Bonds FK-binding protein and inhibits mTOR
        1. Antitumor in addition to immunosuppressive effects
      8. Everolimus: Derivative of rapamycin, similar mechanism as sirolimus
      9. Monoclonal antibodies
      10. Belatacept: modified CTLA-4-Ig to block B7/CD28
      11. Polyclonal antibodies
References 
  1. Hartono C, et al. Immunosuppressive Drug Therapy. Cold Spring Harb Perspect Med. 2013 Sep; 3(9): a015487.
  2. Klintmalm GB, Saab S, Hong JC, Nashan B. The role of mammalian target of rapamycin inhibitors in the management of post-transplant malignancy. Clin Transplant. 2014 Jun;28(6):635-48. 

Case Studies

  1. Case Study 1
    1. A 53-year-old man presents with a past medical history significant for HIV infection presents with an enlarging neck mass that has been present for 4 months. Physical exam reveals a mobile, nontender, firm 3 x 3 cm mass in level 3 of the right neck. A CT scan obtained 1 week prior shows diffuse lymphadenopathy in the neck bilaterally without necrosis.
      1. What other pertinent history should be obtained?
      2. You obtain an FNA biopsy that showed atypical lymphocytes and cultures of the biopsy were negative. What is your next step?
      3. Core-needle biopsy revealed non-Hodgkin’s lymphoma, but further tissue is needed for analysis. What is your next step?

 

  1. Case Study 2
    1. A 62-year-old man who is 9 days status-post bone marrow transplant presents with fevers that have persisted despite antibiotic and antifungal medications given by the Medical Oncology team. A maxillofacial CT reveals pansinusitis with retroantral soft tissue infiltration. Physical exam with nasal endoscopy shows fungal debris on the right middle turbinate that is insensate.
      1. What is your differential diagnosis?
      2. What are your next steps in the evaluation and management of the patient?
      3. What other treatment besides aggressive surgical debridement is needed?
      4. What is the patient’s overall prognosis?

 

  1. Case Study 3
    1. A 68 year old man with a history of a kidney transplant presents with a rapidly enlarging left preauricular mass over the past 4 weeks. Physical exam reveals a 2 cm mobile preauricular mass that is fleshy in appearance and otherwise asymptomatic.
      1. What is your differential diagnosis?
      2. What is the next step?
      3. Biopsy reveals Merkel cell carcinoma. What are the next steps in management?
      4. Imaging demonstrates a hypermetabolic primary in the left preauricular area with multiple hypermetabolic nodes in the left parotid and upper neck. How is this staged? What is next step?
      5. What adjuvant treatment would you expect?
References 
  1. Barzan, L., Tavio, M., Tirelli, U., & Comoretto, R. (1993). Head and neck manifestations during HIV infection. The Journal of Laryngology & Otology, 107(2), 133-136. 
  2. Ergun O, et al. Acute Invasive Fungal Rhinosinusitis: Presentation of 19 Cases, Review of the Literature, and a New Classification System. J Oral Maxillofac Surg. 2017 Apr;75(4):767.e1-767.e9. 
  3. Silverman CS, Mancuso AA. Periantral soft-tissue infiltration and its relevance to the early detection of invasive fungal sinusitis: CT and MR findings. AJNR Am J Neuroradiol. 1998 Feb;19(2):321-5.
  4. Bichakjian CK, et al. “Merkel Cell Carcinoma.” NCCN Guidelines Version 1.2019. National Comprehensive Care Network.

Complications

Learning Objectives 
  1. Objectives
    1. Understand that delays in diagnosis and misdiagnosis of atypical infections can lead to decreased survival and increased morbidity

Review

Review Questions 
  1. What is the most common malignancy in immunocompromised individuals?
  2. What are the differences between primary and secondary immunodeficiencies?
  3. What is the most common type of lymphoma in immunocompromised patients?
  4. What is the optimal management of acute invasive fungal sinusitis?
  5. What is the appropriate work-up for hearing loss in immunocompromised patients?
  6. What is the differential for an immunocompromised patient with a neck mass?
Resources 

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