Common variable immunodeficiency (CVID) is an inherited disease characterized by hypogammaglobulinaemia and impaired humoural immunoresponse and is mainly associated with recurrent infections of the airway and the digestive tract. An 18-year old female with a diagnosis of CVID associated with a devastating necrotizing periodontitis, ultimately resulting in complete destruction of the periodontium and loss of all teeth, is reported. Clinical, biochemical, microbiological and radiographic examinations are presented. The report highlights the likely importance of immunoglobulin replacement and intensive dental hygiene in CVID patients, and the devastating effect of non-compliance in such patients.
Necrotizing periodontal diseases include necrotizing ulcerative gingivitis (NUG) and necrotizing ulcerative periodontitis (NUP). The clinical findings are similar and characterized by gingival necrosis and ulceration, gingival bleeding, pain and halitosis. NUP is determined by the destruction of periodontal tissue and loss of bone. The development and progression of periodontal diseases is influenced by the individual immune response. Inherited and acquired immune disorders predispose to severe periodontal disorders. In the case of acquired immune-deficiency syndrome, NUG and NUP are two of the seven cardinal oral lesions. The pathogenesis of NUG/NUP associated with HIV is unclear. Some researchers hypothesize a hyperresponsiveness of neutrophils in local lesions and exacerbation of the physiological acute inflammatory response due to dysregulation and suppression of the systemic and local immune response. The absence of appropriate T-helper lymphocyte-based regulatory mechanisms in the periodontal tissues may lead to progression of periodontal disease in HIV-infected individuals.
Although the correlation between immune dysregulation and periodontal diseases is indisputable, and in the case of HIV still an issue of investigation, there is little evidence regarding the combination of NUP and inherent immunodeficiencies such as common variable immunodeficiency (CVID), a rare combined immunodeficiency with recurrent bacterial and viral infections of the aerodigestive tract, hypogammaglobulinaemia and impaired humoural immunoresponse. The biochemical or genetic pathomechanism is unknown. Laboratory findings include low serum IgG and often low IgA and IgM. The remaining immunological markers can be heterogeneous, from physiological levels to high pathological values.
Additional criteria include a proven lack of specific IgG antibody production, which is usually demonstrated by lack of IgG responses (not attaining laboratory-defined protective levels) to two or more protein vaccines, such as tetanus or diphtheria toxoids. A summary of diagnostic criteria is given in Table 1 .
|Decreased level of IgG|
|Decreased level of IgA|
|Decreased level of IgM|
|Exclusion of other causes of hypogammaglobulinaemia (hyper-IgM syndromes, HIV, agammaglobulinaemia, use of medications, malignancy)|
|Lack of specific IgG antibody production, usually demonstrated by lack of IgG responses (not attaining laboratory-defined protective levels) to two or more protein vaccines|
Given the nonspecific nature of the clinical presentation and fundamental laboratory definition of CVID, the diagnosis remains predominantly one of exclusion. Secondary immunodeficiencies, especially HIV, have to be excluded.
In an European epidemiological study of CVID, the mean age at onset of symptoms was 26.3 years. The average at diagnosis was 35.3 years. The mean delay between the onset of symptoms and diagnosis was 7.5 years (range 0–61 years). In most cases, patients suffer from symptoms for many years before CVID is diagnosed and treatment given.
This case report illustrates the correlation between CVID and the complete destruction of the periodontium. It highlights the importance of the augmentation of immunoglobulins and intensive dental hygiene, and the possible devastating effect of non-compliance with therapy in such a patient.
An 18 year-old Caucasian female was referred to the authors’ department in October 2009 with a complaint of ‘oral pain’ for about 3 years, a burning sensation intraorally and in poor general condition. In the previous 10 days her food intake had been restricted to liquid food due to pain. She suffered from strong halitosis and reduced mouth opening (15 mm). The gingivae of the upper and lower jaw revealed necrosis and ‘punched out’ ulcerations of the interdental papillae. Her upper and lower front teeth showed grade 3 mobility, and her posterior teeth had grade 2 mobility. Mandibular bone was exposed in the incisor area. Owing to the pain and poor condition of the patient, a detailed periodontal investigation and recording pocket depth was not possible.
Detailed history revealed treatment by her dentist for rapidly progressive periodontal disease since 2006. In December 2007 a dramatic worsening of the disease required admission to hospital with suspected oral candidosis. Tonsillitis, disseminated oral mucositis, candidosis and pharyngeal glossitis were diagnosed. Antimycotic therapy with miconazole did not improve the situation, requiring the patient to have parenteral nutrition. After laboratory tests ( Table 2 ) a diagnosis of CVID was made. Following antibiotic and antimycotic therapy, complemented by a single infusion of human immunoglobulin (0.4 mg/kg), the patient’s condition improved. She was discharged after 10 days.
|IgG (549–1584 mg/dl)||<51.1||354||62||368|
|IgA (61–348 mg/dl)||<20||<20||<20||<20|
|IgM (23–259 mg/dl)||<13||<13||<13||<13|
|White blood cells (3.7–10 G/l)||8.9||6.8||5.5||6.2|
During the following 12 months the patient was free of complaints. Intravenous administration of immunoglobulins occurred every 4–6 weeks. Over the course of the year, the patient became non-compliant with treatment, she did not attend recall visits and hence did not receive immunoglobulin injections. Due to her non-compliance the intravenous injections were replaced by a weekly subcutaneous self-injection of 50 ml Subcuvia ® (solvent/detergent-treated immunoglobulin preparation (160 mg/ml), Baxter AG, Vienna, Austria). Following the onset of new intraoral afflictions the patient was referred to the authors’ department again in October 2009.
In December 2007, the patient had a reduced number of CD4 lymphocytes (25.4%, 609 cells/μl; normal range 35–65%, 840–1600 cells/μl) and a reduced ratio of CD4/CD8 lymphocytes (0.7; normal range 1–3). Her white blood cell count showed normal values (8.9 G/l; normal range 3.7–10 G/l). Her neutrophils reached a level of 65% with normal levels of lymphocytes (27%), monocytes (6.4%), basophils (0.3%) and eosinophils (1.3%). An HIV test was negative. Antibody electrophoresis showed a reduced IgG level (<51.1 mg/dl) and non-detectable IgA and IgM levels. A lymphocyte transformation test showed reduced proliferation of T-lymphocytes of 10% after stimulation. Hyper-IgM syndromes and gammaglobulinaemia were excluded by flow-cytometric analysis correlated with differential blood counts. Specific antibody testing revealed that antibody titres did not reach protective levels for diphtheria, tetanus, Haemophilus influenzae, measles, mumps, rubella, varicella and pneumococcus after vaccination.
After immunoglobulin injection, the laboratory parameters improved. Testing in January 2009 showed an IgG level of 354 mg/dl. At the last testing in June 2009, 2 months before the onset of new oral symptoms, the IgG levels showed a dramatic decrease to 62 mg/dl. A second HIV test was negative. Her parents were also tested and no pathological change of biochemical immune markers could be found.
A panoramic radiograph performed by the family dentist in June 2006 did not show any severe pathologies, in particular no bone loss could be detected ( Fig. 1 ). Almost 3 years later, in March 2009, a new radiograph showed massive bone loss in the upper and lower jaw ( Fig. 2 ). A panoramic radiograph taken in the authors’ department in October 2009 demonstrates a severe progression of the bone loss ( Figs. 3 and 4 ).