Gingival Necrosis Related to Sepsis-Induced Agranulocytosis Due to Pseudomonas aeruginosa Bacteraemia: A Case Report

Background: There have been no reports of sepsis-induced agranulocytosis causing gingival necrosis in otherwise medically healthy patients to the authors’ best knowledge. Even though there are several case reports of gingival necrosis secondary to medication-induced agranulocytosis, they have not systematically described the natural progression of agranulocytosis-related gingival necrosis. Methods: This paper presents a case report of a 29-year-old female Indian patient with generalised gingival necrosis and constitutive signs of intermittent fever, nausea, and vomiting. She also complained of abdominal pains. Blood counts showed agranulocytosis, and the patient was admitted for a workup of the underlying cause. Parenteral broad-spectrum antibiotics were administered, which brought about clinical resolution. Results: Her gingival necrosis was attributed to sepsis-induced agranulocytosis triggered by Pseudomonas aeruginosa bacteraemia, and upon clinical recovery, spontaneous exfoliation left behind exposed bone. Secondary healing over the exposed alveolar bone was noted after a year-long follow-up, albeit with some residual gingival recession. Conclusions: Oral manifestations of gingival necrosis, when present with concomitant constitutive symptoms, could indicate a serious underlying systemic condition that could be potentially life-threatening if left untreated. Dentists should be cognizant of this possibility so that timely intervention is not delayed.


Introduction
Neutrophils are granulocytes that make up 50-70% of the white blood cells in the human body.They mediate inflammatory processes and destroy invading pathogens through phagocytosis, intracellular degradation, granule release, and the formation of neutrophil extracellular traps [1].Agranulocytosis is a severe form of neutropenia, where the counts of granulocytes are commonly below 0.5 × 10 9 /L [2].Patients commonly present with fever, malaise, and non-specific pharyngitis, and they may also develop pneumonia and deep infections [3,4].Common causes of acquired neutropenia or agranulocytosis include malnutrition, infection, bone marrow disorders, autoimmune conditions, hypersplenism, and drugs [3].Leukocytes, and neutrophils in particular, serve as an important contributor to immunity at the gingival margin [5].During a neutropenic state, the marginal gingiva is more susceptible to rapidly progressing bacterial challenges that cause cell and connective tissue destruction, especially if mechanical plaque control is inadequate [6,7].Overgrowth of these commensals can lead to the formation of rampant necrotising gingival lesions and ulcerations in the oral cavity [3,6,7].
Pseudomonas aeruginosa is a gram-negative pathogen that is one of the most common causes of bacteraemia, accounting for up to 5.3% of all bloodstream infections [8], and it has the highest mortality rate of about 26-40% [8][9][10][11].Infection by Pseudomonas aeruginosa usually occurs in immunocompromised patients and frequently causes nosocomial infections [11,12].Such infections can cause necrotic lesions in the oral cavity [13][14][15].However, there have been instances of severe community-acquired Pseudomonas aeruginosa pneumonia resulting in septic shock in immunocompetent patients [16][17][18][19], with resultant neutropenia [20] or even death [16,18,20].However, oral manifestations are not commonly reported for these cases.Community-acquired pneumonia due to Pseudomonas aeruginosa is rare but can be transmitted to medically healthy individuals [20].It occurs five times more commonly in developing countries as compared to developed countries [21], and predisposing factors include prolonged antibiotic intake [22], poor dwelling conditions [19], and environmental pollution [21,23].Transmission may occur through the environment, such as through exposure to contaminated water [16,24], and possibly through person-to-person transmission through droplets and aerosols [25,26].
The aim of this present study is to report a novel case of gingival necrosis associated with sepsis in an otherwise medically healthy patient due to a Pseudomonas aeruginosa infection, in accordance with CARE guidelines (for CAse REports) (https://www.carestatement.org/,accessed on 14 January 2024).

Case Presentation
A 29-year-old Indian female presented as an emergency case at the National Dental Centre Singapore in March 2022 complaining of burning pain along her entire gingiva, especially around the upper anterior region.The patient also noticed her gingiva changing colour, and the pain was affecting her sleep for four days.The patient reported no known medical conditions.She was a non-smoker and -drinker and had no history of betel nut consumption or family history of cancer.The patient had not taken any new food or drugs and denied trauma to the area.
The patient reported acute pain along her gingiva around the upper anterior region five days prior and was prescribed Oracort E ® (triamcinolone acetonide 0.1%, lidocaine hydrochloride 3%) and Augmentin ® (500 mg amoxicillin trihydrate, 125 mg potassium clavulanate) 625 mg twice a day by a medical doctor.The patient noticed that her gingiva, predominantly around the region of her upper right canine to upper left central incisor, developed a purplish patchy appearance, with the central part of the lesion becoming white after two days.She consulted a private dental practitioner for persistent gingival pain and was referred to the Emergency Department of Singapore General Hospital, where she was given intramuscular diclofenac for pain control and referred to our centre for urgent consultation.
On presentation, the patient reported malaise, odynophagia, abdominal pain, and intermittent nausea and vomiting.Her symptoms started roughly a month before presentation since her return from a developing country and were progressively worsening.At triage, she was noted to be febrile and tachycardic.On examination, we noted bilateral submandibular lymphadenopathy and necrosis of the buccal attached gingiva of the upper anterior region, predominantly from her upper right canine to her upper left central incisor, extending up the upper midline frenum (Figure 1).
Pseudomonas aeruginosa is a gram-negative pathogen that is one of the most common causes of bacteraemia, accounting for up to 5.3% of all bloodstream infections [8], and it has the highest mortality rate of about 26-40% [8][9][10][11].Infection by Pseudomonas aeruginosa usually occurs in immunocompromised patients and frequently causes nosocomial infections [11,12].Such infections can cause necrotic lesions in the oral cavity [13][14][15].However, there have been instances of severe community-acquired Pseudomonas aeruginosa pneumonia resulting in septic shock in immunocompetent patients [16][17][18][19], with resultant neutropenia [20] or even death [16,18,20].However, oral manifestations are not commonly reported for these cases.Community-acquired pneumonia due to Pseudomonas aeruginosa is rare but can be transmitted to medically healthy individuals [20].It occurs five times more commonly in developing countries as compared to developed countries [21], and predisposing factors include prolonged antibiotic intake [22], poor dwelling conditions [19], and environmental pollution [21,23].Transmission may occur through the environment, such as through exposure to contaminated water [16,24], and possibly through person-to-person transmission through droplets and aerosols [25,26].
The aim of this present study is to report a novel case of gingival necrosis associated with sepsis in an otherwise medically healthy patient due to a Pseudomonas aeruginosa infection, in accordance with CARE guidelines (for CAse REports) (https://www.care-statement.org/,accessed on 14 January 2024).

Case Presentation
A 29-year-old Indian female presented as an emergency case at the National Dental Centre Singapore in March 2022 complaining of burning pain along her entire gingiva, especially around the upper anterior region.The patient also noticed her gingiva changing colour, and the pain was affecting her sleep for four days.The patient reported no known medical conditions.She was a non-smoker and -drinker and had no history of betel nut consumption or family history of cancer.The patient had not taken any new food or drugs and denied trauma to the area.
The patient reported acute pain along her gingiva around the upper anterior region five days prior and was prescribed Oracort E ® (triamcinolone acetonide 0.1%, lidocaine hydrochloride 3%) and Augmentin ® (500 mg amoxicillin trihydrate, 125 mg potassium clavulanate) 625 mg twice a day by a medical doctor.The patient noticed that her gingiva, predominantly around the region of her upper right canine to upper left central incisor, developed a purplish patchy appearance, with the central part of the lesion becoming white after two days.She consulted a private dental practitioner for persistent gingival pain and was referred to the Emergency Department of Singapore General Hospital, where she was given intramuscular diclofenac for pain control and referred to our centre for urgent consultation.
On presentation, the patient reported malaise, odynophagia, abdominal pain, and intermittent nausea and vomiting.Her symptoms started roughly a month before presentation since her return from a developing country and were progressively worsening.At triage, she was noted to be febrile and tachycardic.On examination, we noted bilateral submandibular lymphadenopathy and necrosis of the buccal attached gingiva of the upper anterior region, predominantly from her upper right canine to her upper left central incisor, extending up the upper midline frenum (Figure 1).Mixed purple and white necrotic lesions with sloughing were noted around the buccal gingival margins and attached gingiva of all premolars and molars and palatal/lingual gingival margins of all teeth.More photographs are included in the Supplementary Materials (Figure S1).Probing depths were within normal limits, and no mobility or fetid odour was noted.Radiographic examination revealed normal bone levels and no obvious pathology (Figure 2).Mixed purple and white necrotic lesions with sloughing were noted around the buccal gingival margins and attached gingiva of all premolars and molars and palatal/lingual gingival margins of all teeth.More photographs are included in the Supplementary Materials (Figure S1).Probing depths were within normal limits, and no mobility or fetid odour was noted.Radiographic examination revealed normal bone levels and no obvious pathology (Figure 2).Suspecting an underlying systemic aetiology, the patient was sent for a full blood count, renal panel, liver function test, and human immunodeficiency virus screen, which showed severe leukopenia with 0.19 × 10⁹/L.The numbers for individual types of Suspecting an underlying systemic aetiology, the patient was sent for a full blood count, renal panel, liver function test, and human immunodeficiency virus screen, which showed severe leukopenia with 0.19 × 10 9 /L.The numbers for individual types of leukocytes (i.e., neutrophils, lymphocytes, monocytes, eosinophils, basophils) were so low that they could not be quantified (Table 1).An emergency referral to the Department of Haematology was made, and the patient started to decompensate when she presented at the Haematology clinic, entering a state of shock, with marked hypotension at 64/45 mmHg and tachycardia at 148 beats/min.Fluid resuscitation was initiated, and a transfer to the medical intensive care unit was carried out.Her blood pressure was fluid responsive, and she was weaned off vasopressor support after a day.Blood cultures were taken, and she was empirically started on intravenous piperacillin/tazobactam 4.5 g six hourly and vancomycin 750 mg 12 hourly.Erect chest radiography and computed tomography of the thoracic/abdomen/pelvis regions showed air-space consolidation in the lower lobes of the lungs, which was suggestive of pneumonia (Supplementary Materials Figures S2 and S3).In addition, the blood cultures reported pansensitive Pseudomonas aeruginosa bacteraemia, and her human immunodeficiency virus screen was negative.This allowed for a diagnosis of community-acquired Pseudomonas aeruginosa pneumonia that led to sepsis and septic shock, resulting in agranulocytosis.No other systemic health conditions such as autoimmune, cardiovascular, or endocrine disease were detected.Vancomycin administration was paused, and the patient improved clinically, consistent with an up-trending white blood cell count over the course of her stay, eventually completing seven days of intravenous piperacillin/tazobactam.She was discharged after a week of inpatient stay and prescribed another week of oral ciprofloxacin, ascorbic acid, and 0.2% chlorhexidine mouthwash and advised for soft diet only.
The patient returned for a dental review a week after discharge on 6 April 2022, with severe pain at her periodontium.Exposed bone was present at the attached gingiva of previously necrotic areas (Figure 3A).J. Clin.Med.2024, 13, x FOR PEER REVIEW 4 of 21 leukocytes (i.e., neutrophils, lymphocytes, monocytes, eosinophils, basophils) were so low that they could not be quantified (Table 1).An emergency referral to the Department of Haematology was made, and the patient started to decompensate when she presented at the Haematology clinic, entering a state of shock, with marked hypotension at 64/45 mmHg and tachycardia at 148 beats/min.Fluid resuscitation was initiated, and a transfer to the medical intensive care unit was carried out.Her blood pressure was fluid responsive, and she was weaned off vasopressor support after a day.Blood cultures were taken, and she was empirically started on intravenous piperacillin/tazobactam 4.5 g six hourly and vancomycin 750 mg 12 hourly.Erect chest radiography and computed tomography of the thoracic/abdomen/pelvis regions showed air-space consolidation in the lower lobes of the lungs, which was suggestive of pneumonia (Supplementary Materials Figures S2 and S3).In addition, the blood cultures reported pansensitive Pseudomonas aeruginosa bacteraemia, and her human immunodeficiency virus screen was negative.This allowed for a diagnosis of community-acquired Pseudomonas aeruginosa pneumonia that led to sepsis and septic shock, resulting in agranulocytosis.No other systemic health conditions such as autoimmune, cardiovascular, or endocrine disease were detected.Vancomycin administration was paused, and the patient improved clinically, consistent with an up-trending white blood cell count over the course of her stay, eventually completing seven days of intravenous piperacillin/tazobactam.She was discharged after a week of inpatient stay and prescribed another week of oral ciprofloxacin, ascorbic acid, and 0.2% chlorhexidine mouthwash and advised for soft diet only.
The patient returned for a dental review a week after discharge on 6 April 2022, with severe pain at her periodontium.Exposed bone was present at the attached gingiva of previously necrotic areas (Figure 3A).The mucosa around the exposed bone was friable and bled on palpation.No discernible bone loss was noted on radiographic examination.
The patient was advised to avoid brushing her teeth or consuming hard, spicy, or hot food and to continue chlorhexidine mouthwash and analgesics when needed.A week later, the patient no longer had pain but experienced sensitivity due to recession.She was The mucosa around the exposed bone was friable and bled on palpation.No discernible bone loss was noted on radiographic examination.
The patient was advised to avoid brushing her teeth or consuming hard, spicy, or hot food and to continue chlorhexidine mouthwash and analgesics when needed.A week later, the patient no longer had pain but experienced sensitivity due to recession.She was advised to resume toothbrushing and was prescribed vitamin B supplements, iron, and folic acid.Her teeth exhibited normal results on sensibility tests during all reviews, and the sensitivity improved over time.Her oral mucosa continued to heal over the exposed bone over the next eleven months.Professional mechanical plaque control was carried out in July and September 2022 while the patient continued to be on chlorhexidine mouthwash.A localised abscess around the exposed bone around #12 developed at the end of September 2022, which resolved with drainage and saline irrigation.Superficial mobile bony sequestra were noted at the buccal of the upper right lateral incisor and upper right second molar measuring 6 × 8 mm and 7 × 3 mm, respectively (Figure 3B), in December 2022, and they spontaneously exfoliated in February 2023.
By March 2023, all previously affected areas had fully mucosalised, although the buccal attached gingiva of her upper right first premolar to upper left central incisor remained erythematous and spongy, with no associated deep-probing depths (Figure 4A).Buccal recession around her upper central incisors was observed.Oracort E ® (triamcinolone acetonide 0.1%, lidocaine hydrochloride 0.3%) was prescribed, but the patient discontinued use after two days, as she found the texture uncomfortable.The spongy erythematous lesion at the buccal of the upper right canine to upper left central incisor was still present at the 18-month review but had decreased in size (Fig- ure 4B).
Creeping attachment of the previously receded buccal gingiva of the upper right lateral and central incisors was observed despite the remaining presence of black triangles at the area.The lesion was tender to palpation but otherwise asymptomatic.The lesion will be monitored closely at regular reviews.A detailed timeline can be found in Figure 5. Oracort E ® (triamcinolone acetonide 0.1%, lidocaine hydrochloride 0.3%) was prescribed, but the patient discontinued use after two days, as she found the texture uncomfortable.The spongy erythematous lesion at the buccal of the upper right canine to upper left central incisor was still present at the 18-month review but had decreased in size (Figure 4B).
Creeping attachment of the previously receded buccal gingiva of the upper right lateral and central incisors was observed despite the remaining presence of black triangles at the area.The lesion was tender to palpation but otherwise asymptomatic.The lesion will be monitored closely at regular reviews.A detailed timeline can be found in Figure 5.

Discussion
Sepsis is a dysregulated host response to infection that results in life-threatening organ dysfunction.Septic shock occurs when a patient with sepsis also has hypotension that persists despite adequate volume resuscitation, and it requires treatment with vasopressors [27].Leukopenia can also occur during the immunosuppressive phase of sepsis due

Discussion
Sepsis is a dysregulated host response to infection that results in life-threatening organ dysfunction.Septic shock occurs when a patient with sepsis also has hypotension that persists despite adequate volume resuscitation, and it requires treatment with vasopressors [27].Leukopenia can also occur during the immunosuppressive phase of sepsis due to reduction in bone marrow production or increased destruction of granulocytes [28,29].In this report, the patient experienced agranulocytosis due to septic shock induced by Pseudomonas aeruginosa bacteraemic pneumonia and required ionotropic and fluid support.Though extremely rare, we hypothesise that this patient was exposed to contaminated water containing Pseudomonas aeruginosa, which resulted in her developing community-acquired pneumonia and subsequent septic shock [20].As the oral cavity provides a favourable environment for microorganisms to flourish [30], and as local intra-oral bacterial challenges could not be contained due to her neutropenia, this resulted in rapid cell and connective tissue destruction of her marginal gingiva and alveolar bone exposure [6,7].Bacteria colonisation on the exposed bone may have stimulated bone necrosis [31][32][33] and, combined with possible low-grade trauma to her upper right anterior region, resulted in a localised abscess and bone sequestrum six months later.
The patient presented with purple and white necrotic gingiva that exfoliated, leading to bone exposure with eventual localised sequestrum formation.She did not present with any other cutaneous lesions except for the lips.Patients with agranulocytosis may present with pale white necrotic lesions, as a late-stage presentation where the gingiva has already exfoliated [41], or where the necrotic lesions are black or violaceous in colour [43,45].Oral lesions may also include ulcers or extension of necrosis to the tongue [6,41,48], retromolar pad [48], palate [36,39,40,43,44], floor of the mouth [47,49], lip [39,44], or vestibule [49].
The spongy appearance of the patient's anterior maxillary buccal-attached gingiva at the 18-month review is reminiscent of localised spongy gingival hyperplasia, which presents as erythematous, raised areas of attached gingiva [52][53][54][55].An inflammatory response resulting in hyperplasia has been postulated to be a possible mechanism of pathogenesis [53,56].The persistent spongy gingival lesion could have been triggered by inflammation due to the extensive necrosis and presence of sequestrum in the area for a prolonged time span.Some cases in the tables above similarly described an irregular granulomatous [36] or a shiny band of erythematous tissue [6,37] that replaced the necrotic gingiva at different time points between 11 days and eight months.Limitations of this report include the unknown source of the patient's Pseudomonas aeruginosa pneumonia.However, the strength of this report is in the novelty of the presentation of gingival necrosis as an early sign of sepsis related to a Pseudomonas aeruginosa infection in an otherwise medically healthy patient.Regular reviews are planned for this patient.

Figure 3 .
Figure 3. (A) Two weeks after initial presentation.Exposed bone at the upper anteriors after the necrotic gingiva sloughed off.(B) At nine-month follow-up.Slightly mobile sequestrum (white arrow) at the upper right lateral incisor, which spontaneously exfoliated.

Figure 3 .
Figure 3. (A) Two weeks after initial presentation.Exposed bone at the upper anteriors after the necrotic gingiva sloughed off.(B) At nine-month follow-up.Slightly mobile sequestrum (white arrow) at the upper right lateral incisor, which spontaneously exfoliated.

Table 1 .
Haematological laboratory values taken at initial presentation.

Table 2 .
Features of agranulocytosis-related gingival necrosis and their presentation.

Table 3 .
Management and outcomes of agranulocytosis-related gingival necrosis.