What are the causes of mouth sores in patients, including those with compromised immune systems, such as Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS) or undergoing chemotherapy?

Causes of Mouth Sores

Mouth sores arise from infectious agents (viral, fungal, bacterial), immune-mediated conditions, trauma, malignancy, and systemic diseases—with immunocompromised patients experiencing more severe, prolonged, and atypical presentations requiring aggressive diagnostic evaluation.

Infectious Causes

Viral Infections

• Herpes Simplex Virus (HSV-1 and HSV-2) is the most common viral cause, presenting as recurrent herpes labialis (cold sores) or intraoral ulcerations, with 85-90% of adults showing serologic evidence of exposure 1, 2.
• Primary HSV-1 infection causes self-limiting gingivostomatitis in immunocompetent hosts, while reactivation triggers herpes labialis with prodromal symptoms of itching, burning, and paresthesia before lesion appearance 1.
• In immunocompromised patients (HIV/AIDS, chemotherapy recipients), HSV episodes are longer, more severe, and may extend across the face or involve the entire oral cavity 1.
• Reactivation stimuli include ultraviolet light exposure, fever, psychological stress, and menstruation 1.
• HSV can cause severe systemic disease including encephalitis, meningitis, pneumonia, esophagitis, and colitis in immunocompromised hosts 1.

Fungal Infections

• Candida species cause oral candidiasis (thrush) and angular cheilitis, particularly when the immune system is weakened 1, 3.
• Angular cheilitis represents one of three clinical patterns of oropharyngeal candidiasis in HIV-infected patients and may indicate progressive immunodeficiency 4.
• Invasive fungal infections should be investigated with elevated 1-3-β-D-glucan and galactomannan levels, especially in diabetic or immunocompromised patients 5.

Bacterial Infections

• Acute necrotizing ulcerative gingivitis causes rapid-onset oral ulcers 6.
• Secondary bacterial infection (impetiginization) can complicate existing oral lesions 4.

Immune-Mediated Causes

Autoimmune Conditions

• Erosive lichen planus, mucous membrane pemphigoid, and pemphigus vulgaris cause multiple chronic oral ulcers associated with immune system disturbances 6.
• Direct immunofluorescence (DIF) is required for suspected erosive lichen planus, pemphigoid, and pemphigus 5.
• Biopsy is mandatory for ulcers persisting beyond 2 weeks without clear diagnosis to exclude malignancy and serious systemic diseases 5.

Recurrent Aphthous Ulcers

• "Canker sores" are common in young persons and can be distinguished from HSV lesions largely by location 6, 7.
• Major aphthous ulcers represent a more severe variant occurring in otherwise healthy patients 7.

Allergic Reactions

• Erythema multiforme causes rapid-onset oral ulcers 6.

Traumatic Causes

• Mechanical trauma from ill-fitting dentures, loss of vertical dimension, or habits like lip licking creates innocent solitary ulcerations 3, 6.
• Occlusal vertical dimension restoration should be considered in appropriate cases 3.

Neoplastic Causes

• Squamous cell carcinoma typically presents as solitary ulcers and must be distinguished from innocent traumatic ulcerations 6.
• Neoplastic ulcerated lesions mimic benign ulcerative lesions, making biopsy essential for lesions that are not clinically identifiable or do not respond as expected to treatment 8.
• In immunocompromised patients, Kaposi's sarcoma and non-Hodgkin lymphoma can present as oral lesions 1.
• Actinic cheilitis is a premalignant condition requiring different treatment approaches than angular cheilitis 3.

Systemic Disease-Associated Causes

Inflammatory Bowel Disease

• Crohn's disease causes oral ulcers, particularly in patients with abdominal pain; colonoscopy is recommended for investigation 5.

Renal Disease

• Uremic stomatitis is an uncommon lesion associated with advanced renal disease, presenting as erythematous patches, uremic frost, and ulceration when BUN levels exceed 300 mg/mL 1.

Hematologic Disorders

• Anemia, leukemia, neutropenia, and other blood disorders can manifest with oral ulcers; full blood count screening is recommended 5.

Metabolic Conditions

• Hyperglycemia predisposes to fungal infections; fasting blood glucose testing is recommended 5.

Infectious Systemic Diseases

• Tuberculosis should be investigated with history, tuberculin skin test (PPD), interferon gamma release assay (TB-IGRA), and chest CT 5.
• HIV/AIDS increases susceptibility to opportunistic oral infections; HIV antibody testing should be performed to exclude infectious causes 5.
• Syphilis can cause oral ulcers; serology testing is recommended 5.

Medication-Related Causes

• Lichenoid oral lesions occur in dialysis and renal transplant patients due to drug therapy 1.
• Oral hairy leukoplakia can occur after immunosuppressive drug therapy 1.
• Medications should be reviewed as potential contributors to oral lesions 3.

Critical Diagnostic Considerations for Immunocompromised Patients

Immunocompromised patients require heightened vigilance because:

• Infections are caused by diverse organisms, including those not ordinarily pathogenic in healthy hosts 1.
• Infection may occur as part of broader systemic infection 1.
• The degree and type of immune deficiency attenuate clinical findings, making diagnosis challenging 1.
• Laboratory confirmation may be required if clinical presentation is atypical 1.
• Multiple biopsies are needed when ulcers have different morphological characteristics 5.
• Maxillofacial CT should be performed for ulcers near hard tissue to assess bone destruction 5.
• Chest CT should be performed to rule out tuberculosis, invasive fungal infection, and paraneoplastic syndrome 5.