Investigation of Dental Health in Children With Neutrophil Defects: A Clinical Study
Condition: Primary Immune Deficiency Disorder; Periodontitis
MeSH terms: Periodontitis; Primary Immunodeficiency Diseases; Immunologic Deficiency Syndromes
Study type: Interventional

Summary: 
      Title: Investigation of neutrophil defects associated with periodontal disease and tooth loss
      in children. A clinical study.

      Objectives: The primary objective of this study is:

        -  To investigate presence of periodontal disease and response to periodontal treatment in
           children affected by neutrophil defects

      The secondary objectives of this study are:

        -  To investigate presence of other dental diseases in children affected by neutrophil
           defects

        -  To assess oral microbiological and inflammatory parameters in children affected by
           neutrophil defects

      Primary outcomes: The primary outcomes are (a) presence of periodontal disease as assessed by
      clinical factors: probing pocket depth, attachment level, bleeding on probing and
      radiographic bone loss) (b) microbiological and host response factors: detected in
      periodontal pockets and gingival crevicular fluid and (c) response to treatment

      Study sample: Children affected by neutrophil defects and meeting outlined inclusion and
      exclusion criteria

      Number of participants: 50 children

      Study design: This is a longitudinal treatment study. All participants will attend for 4-7
      visits during the study as outlined below:

        -  Screening visit (visit 1): consent procedure, dental examination, saliva and plaque
           sampling

        -  Baseline visit (visit 2):, detailed periodontal examination, dental radiographs,
           sampling of gingival crevicular fluid and, if appropriate scaling, polishing and oral
           hygiene instructions

        -  Non-surgical periodontal treatment (visit 3A to 3D, max 4 sessions): oral hygiene
           instructions and supra- and sub-gingival debridement (under local anaesthesia if
           necessary)

        -  Follow-up Visit (visit 4, 4th to 7th visit) (six months following treatment): detailed
           dental examination, oral hygiene instructions, sampling of saliva, subgingival plaque
           and gingival crevicular fluid, tooth scaling and polishing.
    

Detailed description: 
      1. BACKGROUND Primary immunodeficiency diseases (PIDs) are a group of rare inherited
           disorders that are estimated to affect approximately 1 in 2,000 children. In PIDs there
           is an intrinsic defect in the human immune system, such as a failure to produce enough
           antibodies to fight infection, or a failure in the cellular defences against infection .
           These conditions usually manifest themselves early in life and are often
           life-threatening. Rarer, severe forms of PIDs present in childhood with serious
           infections and are often associated with additional autoimmune and inflammatory
           complications. Periodontal diseases are inflammatory diseases of the gingivae (gums) due
           to an imbalance in the host response to subgingival bacteria and are associated with
           destruction of the supporting tissues of the teeth and early loss of the dentition and
           masticatory function. While periodontitis and its non-destructive partner condition,
           gingivitis (reversible plaque-induced gingival inflammation), are very common, the
           prevalence of periodontitis in the primary dentition and in the second decade of life
           appears very low, ranging from 0.1% to 1%. This prevalence increases dramatically in
           children affected by PIDs, to the point that periodontitis is considered a common
           feature of syndromic genetic conditions due to single gene defects affecting the host
           response, such as leukocyte adhesion deficiency (LAD), severe congenital neutropenia,
           cyclic neutropenia and Chediak-Higashi syndrome. Children with defects in neutrophil
           activity seem particularly susceptible to develop severe periodontitis, due to the
           important defensive role of neutrophils against periodontopathogenic bacteria. In such
           cases, both primary and permanent dentitions are affected, with a devastating effect on
           mastication, aesthetics and quality of life, also owing to the lack of reliable
           restorative solutions. Furthermore, oral diseases (in particular periodontitis) may also
           provide an additional systemic inflammatory burden for these subjects. This could occur
           since periodontal bacteria have been shown to enter the systemic circulation from
           inflamed gum tissues even during normal tooth brushing, have been found in atheromatous
           plaques and in the amniotic fluid of pregnant women.

           The treatment of periodontitis involves a non-specific reduction of the bacterial load
           below the gingival margin, achieved by oral hygiene instructions and non-surgical
           periodontal therapy (NSPT). More advanced cases need antibiotics, surgical treatment or
           extractions. In children with PID the response to this treatment is highly variable and
           the presence of periodontitis often leads to early tooth loss, adding to the poor
           quality of life of sufferers. Incorporation of periodontal screening has been advocated
           for early diagnosis and treatment of periodontal diseases in all children and especially
           for children with neutrophil defects, in order to prevent disease progression and tooth
           loss. However, most published papers on periodontitis in children with
           immunodeficiencies are case reports or familial observations or reviews. Therefore,
           there's a lack of well-designed studies investigating both the prevalence of
           periodontitis and oral diseases in general in children with neutrophil defects and their
           response to treatment. In particular, it is not clear which factors determine the onset
           of periodontitis in a subset of children with PID. Such factors may range from the
           composition of the subgingival microbiota, the immunological reaction against these
           bacteria, to the inflammatory response in the periodontium. A better understanding of
           the causative factors may help in early diagnosis and treatment, reducing the burden on
           affected children.

        2. AIMS AND OBJECTIVES

           The hypotheses behind this study are that:

           i) Specific microbiological and host response parameters dictate severity of periodontal
           diseases and associated risk of early tooth loss in children suffering from neutrophil
           defects ii) Periodontal treatment in children with neutrophil defects and periodontitis
           can lead to an improvement in their oral health (reduction in periodontal pockets and
           bleeding scores), which would reduce their risk of tooth loss and potentially improve
           their future quality of life.

           Therefore, the aims of this study are to offer specialist periodontal assessment and
           treatment to children with neutrophil defects, to determine the impact of neutrophil
           defects upon gingival health and to assess their response to periodontal therapy. This
           will facilitate the development of novel therapeutic management pathways specific for
           these conditions, and will determine whether there is a need for specific care protocols
           with a consequent improvement in tooth retention, quality of life and systemic health.

             -  The primary objective of this study is:

                - To investigate presence of periodontal disease and response to periodontal
                treatment in children affected by neutrophil defects

             -  The secondary objectives of this study are:

                  -  To investigate presence of other dental diseases in children affected by
                     neutrophil defects

                  -  To assess oral microbiological and host response parameters in children
                     affected by neutrophil defects.

        3. STUDY DESIGN 3.1 Overall study plan This is an exploratory longitudinal study. Fifty
           children affected by neutrophil defects potentially affecting the periodontium will be
           identified from subjects attending the Immunology and Haematology clinics at Great
           Ormond Street Hospital (GOSH), following a medical examination. All children will
           undergo a dental examination by a qualified dentist currently completing specialist
           training in periodontology. Children will also provide samples of gingival crevicular
           fluid (GCF) and subgingival plaque. Following the baseline, non-surgical periodontal
           therapy will be provided as necessary and participants will be followed-up and
           re-examined up to 6 months after treatment.

        4. STUDY POPULATION 4.1 Participant Selection Fifty children affected by neutrophil defects
           and under care at Great Ormond Street Hospital (GOSH) and meeting the inclusion criteria
           will participate in the study. Most children attend GOSH regularly (at least 6-monthly)
           for review/treatment planning appointments (seen by Dr Ancliff or Dr Worth). The
           parents/guardians of potentially suitable children will be initially contacted by letter
           prior to their attendance at GOSH. Every invitation will be followed up by a telephone
           call to discuss any issues and enquiry about willingness to participate. When possible,
           upon parents' agreement about study participation, patients could be enrolled and
           undergo the screening visit on the same day as their routine GOSH visit (this would save
           on extra travel for patients living outside London). Alternatively, they will be offered
           another appointment. All the study visits will take place at GOSH. QMULwill only serves
           as the sponsor and coordinating centre for this study. .

        5. STUDY VISITS Study visits include baseline, non-surgical periodontal therapy and
           follow-ups. All visits will be carried out at Great Ormond Street Hospital.

           5.1 Visit 1 (Screening) o Informed consent

           o Collection of data on clinical and laboratory diagnosis, time of diagnosis, previous
           and current systemic treatment and on any previous dental treatment

           o Basic Periodontal Examination (BPE) and assessment of caries (DMFT) and mucosal
           diseases

           o Saliva and plaque sample

             -  Clinical photographs

             -  Treatment plan All children found to have BPE scores of 1 (gingival bleeding), 2
                (presence of calculus), 3 or 4 (presence of gingival pockets) will be offered the
                possibility to enter the treatment phase of the study (from visit 2 onwards), which
                will be provided at GOSH. Children found not to be affected by periodontal diseases
                will be offered the possibility to be seen at GOSH for visit 2 only, if they wish
                so.

           5.2 Visit 2 (Baseline and first treatment session- ± 28 days) o Recording of any adverse
           events (AE or concomitant medication)

             -  Full periodontal examination including collection of periodontal measurements (and
                dental radiographs if appropriate)

             -  Gingival crevicular fluid (GCF) sample

             -  Session of tooth scaling, oral hygiene and polishing

           All children found to require further treatment will need to attend an additional 1 to 4
           treatment sessions at GOSH as detailed below:

           5.3 Visit 3A to 3D (treatment, within 2 months of visit 1, from 1 to 4 visits) Update
           medical history, check adverse events, non-surgical periodontal therapy (maximum 4
           sessions): oral hygiene instructions and supra- and sub-gingival debridement.

           5.4 Visit 4 (last follow-up, 6 months after last treatment visit ± 21 days) Update
           medical history, check adverse events, dental examination and collection of periodontal
           measurements, perform oral hygiene instructions, sampling of saliva, subgingival plaque
           and gingival crevicular fluid, tooth scaling and polishing (if needed).

           5.5 Medical and dental history A complete medical and dental history will be obtained
           during screening and confirmed during the baseline visit. Information on previous
           medical tests and status of current treatment will be obtained by the treating GOSH
           physician. The histories will include demographic background information, ethnicity,
           systemic and dental status information.

           5.6 Concomitant medications All concomitant medications will be recorded throughout the
           study.

           5.7 Periodontal examination At the screening visit, a Basic Periodontal Examination
           (BPE) will be performed, consisting of gentle probing between teeth and gums on index
           teeth (UR6, UR1, UL6, LL6, LL1 and LR6 or URd,URc,ULd,LLD,LLc,LRd) to identify presence
           of gum disease. A number between 0 (health) and 4 (gingival pocket>5mm) will be recorded
           for each quadrant. The dmft/ DMFT (decayed missing filled teeth) index will be used for
           recording caries experience. Mucosal status will be investigated by recording presence
           of ulcers, blisters, white patches, speckled areas and masses. Saliva samples and plaque
           samples will be collected. At the baseline visit, a calibrated dental examiner will
           perform a more detailed assessment, consisting of collection of full-mouth measurements
           of probing pocket depth (PPD), clinical attachment level (CAL), gingival bleeding on
           probing gingival crevicular fluid sampling and assessment of plaque levels (simplified
           visible biofilm index).

           5.8 Dental sampling A series of samples will be collected from the patients' oral cavity
           (sample of saliva, GCF and subgingival plaque biofilm). GCF will be taken by gentle
           insertion of 4 paper-strips in the gingival crevice of the mesio-buccal aspect of 4
           teeth (3 first molars and 1 incisor). Subgingival plaque will be collected by the
           examiners following gentle insertion of a curette at the base of 3 first molars and 1
           first incisor sites (one in each quadrant). In case of absence of permanent molars, the
           samples will be collected from the second deciduous molars. The 4 subgingival samples
           will be pooled together.

           5.9 Definition of periodontal disease

           Following the periodontal examination, children will be diagnosed as:

           - Healthy: no attachment loss (measured as no CAL>3mm or CAL>3mm in <2 non-adjacent
           teeth) and no/minimal gingival inflammation (measured as <15 sites bleeding on probing)

           - Gingivitis: no attachment loss (measured as no CAL>3mm or CAL>3mm in <2 non-adjacent
           teeth) and presence of gingival inflammation (≥15 sites bleeding on probing)

           - Periodontitis: attachment loss (measured as CAL>3mm in ≥2 non-adjacent teeth)

           5.10 Dental radiographs If a BPE code 3 or more is detected, bite-wings or long cone
           parallel periapical radiographs (more indicated for a BPE of 4) using Rinn holders will
           be taken to detect marginal bone levels, according to clinical needs. The distance
           between coronal and apical bone levels and cemento-enamel junction will be analysed as
           described previously, also taking into account age of the patient, tooth eruption stage
           and presence of primary, mixed or permanent dentition. Radiographs will then be
           digitized for future analysis using an image-analysis software.

           5.11 Non-surgical periodontal treatment All children will be offered an oral hygiene and
           tooth scaling and polishing session. For children affected by periodontal disease,
           subgingival debridement will also be performed according to needs, with the aim to
           disrupt the subgingival biofilm responsible for the onset and progression of the
           periodontal pathology. This can be accompanied, when appropriate, by the use of local
           anaesthesia and adjunctive antimicrobials (systemic or locally applied subgingivally),
           according to the clinical presentation and the child's medical conditions. In addition,
           when required, nitrous oxide sedation (NOS) could be used before treatment. NOS is a
           safe and widely-used technique in paediatric dentistry. It is administered by inhalation
           via a nasal mask and is used to reduce dental anxiety along with behaviour management
           techniques. There are very few contra-indications. It is not suitable for patients who
           have nasal congestion or severe dental anxiety. NOS will be conducted following the
           guidelines by Standards for Conscious Sedation in the Provision of Dental Care and
           appropriate clinical consent forms will be obtained before its use.

           Accurate supra- and sub-gingival removal of calculus and dental plaque will be performed
           both with ultrasonic and/or manual instruments. The necessary sub-gingival debridement
           will be performed in 1 to 4 visits (either full mouth treatment, half-mouth treatment or
           quadrant-wise treatment) depending on patient preference and practical considerations,
           using manual (Gracey curettes, Hu-Friedy) and ultrasonic devices (EMS). Caries will be
           treated as necessary (shared care with the general dental practitioners / community
           dental services). Children with mucosal lesions requiring treatment will be given a
           letter for their GDP suggesting referral to a collaborating expert in Oral Medicine
           (Prof. Stephen Porter).

        6. Missing data The inclusion of very young subjects in the present study introduces the
           risk of missing data, owing to the difficulty in data and sample collection in some
           children (due to their unwillingness to be examined or sampled). The Investigators will
           endeavor to complete data and sample collection with minimal discomfort to each subject.
           However, should dental and periodontal examination not be achievable, the subjects will
           be exited from the study. Once the main variable outcome of the study (presence of
           periodontal disease by means of collection of BPE) is recorded, the subject will not be
           excluded from analysis, even if some of the other data are not collected. For example,
           if a child tolerated periodontal probing (hence collection of BPE) but refuses to
           provide a plaque sample, he/she will still be included in the study until the last
           visit. The final study analyses and report/publications will take into account possible
           missing data and reasons why they were not collected.

      5.7 Repeatability Prior to initiation of the study, the designated examiner will participate
      in a training and repeatability exercise. For the repeatability exercise, the examiner will
      score 5 subjects for PPD and REC and then perform repeated examinations of the same subjects
      on the same day after at least 15 minutes separation. Upon completion of all measurements,
      intra-examiner repeatability for PPD measurements will be assessed. The reproducibility of
      the examiner will be tested using the Bland-Altman approach and by calculating Lin's
      concordance correlation coefficient. A co-efficient of repeatability less than ± 2 mm in 95%
      of the cases is considered acceptable.

      5.8 Laboratory analyses Samples will initially be stored at -70° to -80° for analysis.
      Microbiological analysis will involve next generation sequencing of the 16S rRNA metagenome
      at QMUL. GCF samples will be eluted and will undergo analysis of inflammatory markers as
      described before.

      9. PARTICIPANTS' COMPLETION AND WITHDRAWAL 9.1Reasons for withdrawal

      Participants will be informed that they have the right to withdraw from the study at any time
      for any reason, without prejudice to their medical care. The investigator also has the right
      to withdraw participants from the study for any of the following reasons:

        -  Occurrence of an unacceptable adverse event/illness

        -  Participant/parent/guardian request

        -  Protocol violations

        -  Administrative reasons

        -  Failure to return for follow-up

        -  General or specific changes in the Participant's condition unacceptable for further
           treatment in the judgment of the investigator

      9.2 Completion/Withdrawal Procedures At the time of withdrawal, all study procedures outlined
      for the end of study visit should be concluded. The primary reason for a participant's
      withdrawal from the study is to be recorded on the CRF.

      10. ADVERSE EVENT REPORTING 7.1 Adverse Events (AEs) An adverse event includes any noxious,
      pathological or unintended change in anatomical, physiological or metabolic functions as
      indicated by physical signs, symptoms and/or laboratory changes occurring in any phase of the
      clinical study, whether associated with the study or not. This includes exacerbation of
      pre-existing conditions or events, inter-current illnesses, drug interaction or the
      significant worsening of the disease under study. For all adverse events, the investigator
      must pursue and obtain information adequate both to determine the outcome of the adverse
      event and to assess whether it meets the criteria for classification as a serious adverse
      event requiring immediate notification to the sponsor or its designated representative. For
      all adverse events, sufficient information should be obtained by the investigator to
      determine the causality of the adverse event.

      Clinically significant symptoms following NSPT include those that are outside a normally
      accepted range (as judged by the clinician). This would include:

        -  Excessive or progressively increasing pain or discomfort

        -  Excessive swelling

        -  Signs of infection (e.g. suppuration)

        -  Excessive bleeding

      Moreover we shall record if the participants take any drugs as a result of these adverse
      events.

      7.2 Serious Adverse Events definition

      A serious adverse event or serious adverse drug reaction is any untoward medical occurrence
      at any dose which:

        -  results in death

        -  is life-threatening (immediate risk of death)

        -  requires participant hospitalization or prolongation of existing hospitalization

        -  results in persistent or significant disability/incapacity

        -  results in congenital anomaly/birth defect.

      Medical and scientific judgment should be exercised in determining whether an event is an
      important medical event. An important medical event may not be immediately life-threatening
      and/or result in death or hospitalization. However, if it is determined that the event may
      jeopardize the participant and may require intervention to prevent one of the other outcomes
      listed in the definition above, the important medical event should be reported as serious.

      7.3 Reporting of Serious Adverse Events Because of the need to report to health authorities
      all suspected unexpected serious adverse reactions (SUSARs) in a timely manner, it is vitally
      important that the investigator reports immediately any adverse events which would be
      considered serious. Any serious adverse event (including death) due to any cause, which
      occurs during the course of this clinical study, whether or not related to the study, must be
      reported immediately to the Principal Investigator or its designee.

      7.4 Reporting period The nature of each individual adverse event, date and time of onset,
      duration, severity and relationship to treatment and corrective treatment must be established
      by the investigator and recorded in the CRF. Adverse events will be recorded following
      signing of the first consent form up to the last study visit. Any serious adverse event
      occurring any time after the reporting period must be promptly reported if a causal
      relationship to the investigational product is suspected and all SUSARs will be followed up
      until resolution.

      8 STATISTICAL PROCEDURES 6.1 Sample size estimation A convenience sample of 50 children
      (based on current estimation of numbers of children with neutrophil defects seen yearly at
      GOSH) is proposed for this study, since no formal power calculation could be performed owing
      to the lack of similar studies in the literature. However, hypothesising that subgingival
      presence of bacterium A.actinomycetemcomitans at baseline could discriminate between
      responders and non-responders to periodontal treatment (difference 0.5mm ± 0.5 mm mean
      clinical attachment gain), 41 children (including 20% drop-outs) who undergo periodontal
      therapy would give 80% power to prove or disprove this hypothesis.

      6.2 Statistical analysis All data derived from the study will be anonymised and entered in a
      dedicated database. The initial plan of analysis will describe the prevalence of periodontal
      diseases in the study cohort (divided by medical diagnosis). Appropriate summary statistics
      will be determined separately for affected and non-affected subjects. Differences in
      demographic and systemic parameters (diagnosis, current treatment) between affected and
      non-affected subjects will be assessed by the two-sample t-test or Mann-Whitney test as
      appropriate. Explorative logistic regression analyses will be performed to detect the effect
      of microbiological and inflammatory parameters (e.g. presence of periodontopathogenic
      bacterium A.actinomycetemcomitans or cytokine concentrations in the GCF) on groups, taking
      into account that many children may be on long-term antimicrobial therapy. Response to
      therapy will be assessed by comparing clinical periodontal parameters at baseline and
      follow-ups by random effects analysis taking time points as repeated measures. This will be
      then associated to patients' demographics, compliance and microbiological and inflammatory
      factors.

      7 ADMINISTRATIVE REQUIREMENTS 9.1 Good clinical practice The study will be conducted in
      accordance with the International Conference on Harmonisation (ICH) for Good Clinical
      Practice (GCP) and the appropriate regulatory requirement(s). Essential clinical documents
      will be maintained to demonstrate the validity of the study and the integrity of the data
      collected. Master files should be established at the beginning of the study, maintained for
      the duration of the study, and retained according to the appropriate regulations.

      9.2 Ethical considerations The study will be conducted in accordance with ethical principles
      founded in the Declaration of Helsinki. The Research Ethics Committee will review all
      appropriate study documentation in order to safeguard the rights, safety, and well-being of
      the participants. The study will be conducted only at sites where Research Ethics Committee
      approval has been obtained. The protocol, informed consent, advertisements (if applicable),
      written information given to the participants, safety updates, progress reports, and any
      revisions to these documents will be provided to the Research Ethics Committee by the
      investigator.

      9.3 Participant Information and Informed Consent During the first screening session and the
      enrolment visit, written informed consent will be obtained from all
      participants/guardians/parents. The method of obtaining and documenting the informed consent
      and the contents of the consent will comply with ICH-GCP and all applicable regulatory
      requirement(s).

      9.4 Participant confidentiality In order to maintain participant privacy, all CRFs, study
      reports and communications will identify the participant by initials and the assigned
      participant number. The participant's confidentiality will be maintained and will not be made
      publicly available to the extent permitted by the applicable laws and regulations.

      9.5 Protocol compliance The investigator will conduct the study in compliance with the
      protocol and given approval/favorable opinion by the Research Ethics Committee and the
      appropriate regulatory authority(ies). Changes to the protocol will require written Research
      Ethics Committee approval/favourable opinion prior to implementation, except when the
      modification is needed to eliminate an immediate hazard(s) to participants.

      9.6 Study monitoring Monitoring and auditing procedures developed by the investigator will be
      followed, in order to comply with GCP guidelines. On-site checking of the CRFs for
      completeness and clarity, cross-checking with source documents, and clarification of
      administrative matters will be performed. The study will be monitored by a clinical trial
      coordinator or its designee.

      9.7 Case report form completion Case report forms will be completed for each study
      participant. It is the investigator's responsibility to ensure the accuracy, completeness,
      and timeliness of the data reported in the participant's CRF. Source documentation supporting
      the CRF data should indicate the participant's participation in the study and should document
      the dates and details of study procedures, adverse events and participant status.

      The investigator, or designated representative, should complete the CRF pages as soon as
      possible after information is collected, preferably on the same day that a study participant
      is seen for an examination, treatment, or any other study procedure. Any outstanding entries
      must be completed immediately after the final examination. An explanation should be given for
      all missing data. The investigator must sign and date the Investigator's Statement at the end
      of the CRF to endorse the recorded data.

      9.8 Premature closure of the study This study may be prematurely terminated, if in the
      opinion of the investigator there is sufficient reasonable cause. Written notification,
      documenting the reason for study termination, will be provided to the investigator by the
      terminating party.

      Circumstances which may warrant termination include, but are not limited to:

        -  Determination of unexpected, significant, or unacceptable risk to participants

        -  Failure to enter participants at an acceptable rate

        -  Insufficient adherence to protocol requirements

        -  Insufficient data

      9.9 Complaints and indemnity

        -  Complaints. In the event of complaint about the conduct of the study, the hosting NHS-
           Great Ormond Street Hospital for Children NHS Foundation - complaints policy should
           apply as the research subject is recruited through an NHS Trust.

        -  Indemnity QMUL holds insurance against claims from participants for harm caused by their
           participation in this clinical study. Participants may be able to claim compensation if
           they can prove that QMUL has been negligent. However, if this clinical study is being
           carried out in a hospital, the hospital continues to have a duty of care to the
           participant of the clinical study. QMUL does not accept liability for any breach in the
           hospital's duty of care, or any negligence on the part of hospital employees. This
           applies whether the hospital is an NHS Trust or otherwise.
    

Intervention name(s): Oral hygiene advice, non surgical periodontal treatment
Intervention type(s): Procedure
Intervention description(s): For children affected by periodontal disease, oral hygiene advice, non surgical periodontal treatment will also be performed according to needs. This can be accompanied, when appropriate, by the use of local anaesthesia and adjunctive antimicrobials (systemic or locally applied subgingivally), according to the clinical presentation and the child's medical conditions. Accurate supra- and sub-gingival removal of calculus and dental plaque will be performed both with ultrasonic and/or manual instruments. The necessary sub-gingival debridement will be performed in 1 to 4 visits (either full mouth treatment, half-mouth treatment or quadrant-wise treatment) depending on patient preference and practical considerations, using manual (Gracey curettes, Hu-Friedy) and ultrasonic devices (EMS). .
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: primary immunodeficiency; dental health; neutrophil defect; periodontitis