Angina Bullosa Haemorrhagica in COVID 19: A Diagnostic Conundrum. Case Report and Review of Literature

Abstract

Oral manifestations of COVID-19 are amongst the most obscure and ill-reported. Of these, angina bullosa haemorrhagica is amongst the rarest. Only 2 cases of angina bullosa haemorrhagica in COVID-19 patients have been reported in literature. Angina bullosa haemorrhagica (ABH) is an enigmatic, abstruse condition represented by sudden onset of painful subepithelial, mucosal blood-filled vesicles and bullae in the oral cavity. It is not attributed to any systemic conditions, blood dyscracias or other well-known dermatological pathologies. The occurrence of these lesions in patients of COVID-19 suggests that the underlying pathology of the latter may predispose to ABH and thus help in shedding some light onto the pathogenesis of this obscure disease. Herein we present 2 cases of ABH in patients of COVID-19 within a few weeks of the resolution of the latter. Both patients reported that they had never had this condition before and that this was the first presentation of the symptom. A review of literature shows that the etiopathogenesis of ABH is ambiguous at best and that the pathology underlying the oral manifestation of COVID-19 may well be applicable to ABH as well. Various mechanisms have been proposed to cause oral manifestations in COVID-19 patients. These include imbalance in the RAS pathway causing mucosal disruption, immune dysregulation, deranged cellular immune mechanism and disruption of local immune mechanisms. Since ABH has been reported in COVID 19, it is plausible that some of the mechanisms underlying the pathogenesis of oral manifestations may explain the pathogenesis of ABH.

Introduction

In recent times, COVID-19 has presented with a myriad of symptoms in different patients. The oral manifestations of COVID-19 are one of the most obscure and ill-reported. The data on the epidemiology and prevalence of oral manifestations in COVID-19 is sparse and heterogenous. Many reasons have been postulated for this occurrence. Firstly it is thought to be due to lack of histopathological evaluation secondary to avoidance of examination and investigation of oral lesions in positive patients, to prevent transmission of the disease. Also these symptoms are generally overshadowed by the more acute and critical symptoms of COVID 19 like pulmonary compromise, breathlessness etc. Lastly oral lesions are not obvious and difficult to access in seriously ill, intubated patients and those on ventilators and may be overlooked.

Various oral pathologies like aphthous stomatitis, herpetiform lesions, candidiasis, vasculitis, Kawasaki-like lesions, EM-like lesions, mucositis, drug eruption, necrotizing periodontal disease, angular cheilitis, atypical Sweet syndrome, and Melkerson-Rosenthal syndrome have been reported sporadically in patients of COVID 19 [1]. Of these, angina bullosa like lesions are amongst the most uncommon.

Angina bullosa haemorrhagica (ABH) is an enigmatic, ill-understood condition represented by sudden onset of painful subepithelial, mucosal blood-filled vesicles and bullae in the oral cavity. The lesion increases in size progressively over hours or days and then bursts releasing the blood. Following this, it resolves spontaneously over a few days without scarring.

It is not attributed to any systemic conditions, blood dyscracias, autoimmune vesiculo-bullous disorder or true vasculitis.

Herein, two cases of ABH are discussed, which presented in patients for the first time after infection by the SARS CoV 2 virus. The occurrence of these lesions in patients of COVID-19 suggests that the underlying pathology of the latter may predispose to ABH and thus help in shedding some light onto the pathogenesis of this obscure disease.

Case 1

A 41-year-old female presented with history of a dark, reddish brown vesicle over the right lateral border of tongue, 4 weeks after being diagnosed with COVID 19. The COVID 19 infection had resolved without any sequelae within 10 days of being confirmed. The bulla appeared suddenly and started as mild itching over the tongue [Fig. 1]. It grew in size over 24 h, finally bursting and releasing frank blood and few clots. During the first episode she did not report to the hospital. She presented again with a bulla one month after the first episode, in the same region. She presented to the hospital with the burst lesion. There was no history of trauma, any association with meals, eating hard/hot foodstuff or dental complaints. She had no history of any systemic disorders, co-morbidities or use of medications such as intranasal corticosteroids. All her biochemical and inflammatory (IL6, CRP, ANCA, ESR) markers were within normal limits and she had no clinical features of connective tissue disorders. On examination, a shallow ulcer, 1 cm × 1 cm was observed on the right lateral border of the tongue. It was mildly tender, non-indurated and soft with sharp margins. There was mild surrounding oedema and congestion.

Fig. 1.

Photograph showing the initial bulla on the right lateral border of tongue within an hour of its appearance

A biopsy was taken from the lesion and sent for histopathological analysis. Histopathological examination showed foci of viable tissue with both intra and subepidermal clefts filled with blood and acute inflammatory exudate confirming the diagnosis of Angina bullosa haemorrhagica [Figs. 2 and 3].

Fig. 2.

Histopathological picture showing foci of viable tissue with both intra and subepidermal clefts filled with blood

Fig. 3.

Histopathological picture showing capillaries with minimal connective tissue and red cell extravasation

She was managed conservatively with a local steroid ointment, chlorhexidine mouthwash and multivitamin supplement.

It resolved completely without scarring within 7 days. She reported 3 more such episodes over a 6 month period but did not present for evaluation and reported that each time it resolved spontaneously within 10 days of its appearance.

Case 2

A 35-year-old female presented with history of a soft, bullous, dark brown lesion over the soft palate on the left side, 6 weeks after being diagnosed with COVID-19. As in the previous case the COVID 19 symptoms were mild and resolved within 2 weeks of being diagnosed.

The bullous lesion appeared suddenly 6 weeks post her initial COVID diagnosis. It grew rapidly in size and burst releasing frank blood within 18 h of its appearance. She had no history of trauma, exposure to hot/hard foodstuff, any systemic disorders, connective tissue disorders or any other co-morbidities. The patient also had no history of intake of medications including oral or intra-nasal corticosteroids. All her biochemical parameters and serum inflammatory markers were within normal limits. On examination there was a shallow, well-defined mucosal ulcer of 1 × 0.5 cm over the soft palate on the left side [Fig. 4]. It was soft, non-tender with no features of inflammation except slight congestion around the ulcer.

Fig. 4.

Photograph showing the shallow ulcer with the surrounding congestion after the rupture of the bulla

A biopsy was taken after a negative RTPCR for COVID-19 and send for histopathological examination which confirmed the diagnosis of ABH.

The patient was prescribed oral anti-inflammatory medication and chlorhexidine mouth wash. The lesion resolved without scarring within 10 days. The patient has not reported any further episodes till date.

Discussion

Various oral manifestations have been commonly observed and reported in patients of COVID-19. Besides the nasal cavity and pharynx, oral mucosa and salivary glands have also been established as potential sites for harbouring and active replication SARS-CoV-2 virus [2, 3].

There is still no consensus as to whether the oral manifestations in COVID-19 are a result of direct viral infection or a result of its systemic effects on immunity resulting in opportunistic infections or the immune-mediated damage to the mucosa.

The theory of direct viral replication has gained traction due to the fact that ACE2 (Angiotensin Converting Enzyme) receptors, which mediate the entry of the virus into the host cells are abundantly expressed on the oral epithelium and salivary glands. It has been well established that cell entry of coronaviridae (both non-novel and novel) depend on binding of the viral spike (S) proteins to cellular receptors followed by priming by host cell proteases. It has been postulated that SARS-CoV-2 uses the ACE2 receptor for entry and the serine protease TMPRSS2 (Transmembrane Serine Protease) for S protein priming [4, 5].

Some researchers have proposed however that some of the oral manifestations may even be due to adverse reactions to drugs administered to counter this disease or iatrogenic trauma due to prolonged intubation. [4].

Angina bullosa like lesions are amongst the most uncommon oral manifestations of COVID 19. Angina bullosa haemorrhagica is an idiopathic condition for which the exact prevalence is not known. It was first described in the late 1900s as ‘traumatic oral hemophlyctenosis’. It was renamed angina bullosa haemorrhagica by Badham [6], and is called such to date. In 2010, Mehrotra et al., assessed the prevalence of oral pathologies in 3030 Indian adults and reported a prevalence of ABH of only 0.03% [7]. Retrospective studies by Grinspan et at and Rosa et al. show a prevalence of 0.5% of ABH amongst patients presenting with oral pathology [8, 9]. However, clinicians and researchers estimate the prevalence to be much higher. They have posited that the non-specific, vague character of the presentation, quick resolution and lack of residual morbidities leads to a disinterest on the patients’ part to seek medical consultation.

Majority of the patients present with solitary lesions, however multiple lesions have been described in about 30% of the patients [10]. Most of the lesions described in literature are over 1 cm. In contrast, Rosa et al., observed that most of the lesions in their study were sub-centimetric.

The treatment in all reported cases of ABH, both during normal and COVID times, has been conservative. Most physicians believe that a specific treatment for ABH is unnecessary. In cases where patients had pain or discomfort, different medications have been used including benzydamine hydrochloride mouthwash [11], anti-inflammatory drugs and topical corticosteroids [12]. Hopkins and Walker [10] in their article have recommended chlortetracycline rinse in cases of ABH to prevent superinfection of the ulcer. Most authors [13, 14] recommend the use of chlorhexidine mouthwashes for symptomatic management of ABH. Use of ascorbic acid and citro-flavonoids have been suggested in some studies to prevent recurrences. However there is no consensus regarding its efficacy [12].

The most affected site has been observed to be the soft palate. Other areas generally affected include the lateral border of tongue and buccal mucosa. Rarely, it may occur on the ventral surface of the tongue, lip, the floor of the mouth, pharynx or esophagus. It has been posited that these regions are more prone to occurrence of these bullous lesions are they are non-keratinized [15, 16]. It has been suggested that the soft, loosely adherent mucosa of the soft palate is more prone to decreased cohesion between the epithelium and the underlying connective tissue. This is thought to provide weak attachment to the subepithelial capillaries, predisposing to rupture of the vasculature with or without obvious trauma leading to the emergence of blood-containing bullae [12, 17].

Despite the strong suspicion of a triggering traumatic event (exposure to hard/crunchy food, dental trauma etc.) a substantial proportion of the patients usually give no such history. In the cases mentioned above, both patients did not give a history of any such event. Nor did they have any systemic diseases or bleeding diathesis, either on presentation or history. Various factors have been hypothesized to play a role in the pathogenesis of ABH. These include diabetes mellitus, hypertension rheumatoid arthritis, asthma, chronic kidney disease, gastro-intestinal disorders and autoimmune conditions like systemic lupus erythromatosus. These conditions are thought to Beguerie and Gonzalez reported that 64% of the patients in their study had underlying systemic disease (either hypertension or diabetes) [17]. COVID-19 is well known to cause systemic immune alterations. This includes a propensity to cause extensive alveolo-interstitial damage, immune dysregulation and cytokine storms. Despite the fact that immune dysregulation has not been proven to play a role in occurrence of ABH, the immune dysfunction in COVID-19 may be responsible for this presentation in otherwise healthy individuals.

There are various mechanisms that are thought to contribute to the pathogenesis of oral, especially vesiculobullous or vascular, lesions in COVID 19. Some or all of these may have a role to play in the pathogenesis of ABH as well [Fig. 5].

Fig. 5.

Proposed pathogenesis of oral lesions in COVID-19

1. The local RAS (Renin Angiotensin System) system is considered one of the mechanisms responsible for the maintenance of mucosal integrity. Angiotensin (1–7) acts through the Mas 1p (mitochondrial assembly protein) receptor to induce epidermal proliferation, vasodilation and angiogenesis thus promoting mucosal protection and wound healing [18].

   SARS CoV 2 downregulates ACE2 expression, which results in increase in angiotensin II, and a decrease in angiotensin. ACE2 also converts angiotensin I into angiotensin-(1–9), which is then converted to angiotensin-(1–7) by ACE1. [Fig. 6] Angiotensin II is known to have pro-inflammatory properties. An imbalance between angiotensin II and angiotensin therefore increases the inflammatory response in tissues expressing ACE2, due to its diminished action [18].

2. Immune Dysregulation – As with other cytopathic viruses, viral endocytosis occurs followed by active replication of the virus which promotes cell injury and death by pyroptosis. This leads to release of damage-associated molecular patterns (DAMPs) like ATP and nucleic acids etc. triggering the generation of pro-inflammatory cytokines (IL-6, IP-10, macrophage inflammatory protein 1α (MIP1α), MIP1β and MCP 1(monocyte chemoattractant protein). These mediators lead to the migration of monocytes, macrophages and T cells to the site of infection, causing further inflammation establishing a positive feedback loop. In normal individuals, this immune reaction recedes once the infection subsides, but in some patients immune dysfunction occurs due to mechanisms like interferon antagonism by the virus. This causes an exaggerated and ineffective immune response causing a cytokine storm which causes widespread and deleterious local and systemic effects. Interferon antagonism is thought to be one of the mechanisms by which SARS CoV 2 causes immune dysregulation in patients of COVID 19 [19, 20].

3. There is strong evidence of large scale recruitment and upregulation of T-cell following Th1 response in COVID 19 infection. This contributes to cellular immunity with increased expression of NK (Natural Killer) cells and cytotoxicity. Genetic mapping has also revealed similarities between viral proteins and mitochondrial protein, F-actin and TPO protein. Therefore, it is probable that SARS-specific T cell may target oral mucosal antigens as well. [20].

4. Local immunity in conjunction with the commensal microorganisms play a major role in homeostatic immune responses. Systemic disorders such as diabetes, hypertension alter the oral immune barriers and lead to oral mucosal atrophy [17, 21, 22]. This is further aggravated by increased inflammatory mediators and oxidative stress observed in these conditions and may cause increased susceptibility to cross-reactions with pathogenic organisms manifesting as oral lesions [22]. This also supports the pathogenesis of ABH, as arterial hypertension, diabetes mellitus and long-term use of inhalational corticosteroids have often been associated with this condition [23–26].

Fig. 6.

RAS Pathway with downregulation of ACE2 by SARS CoV 2

All these theories may well be applicable to the pathogenesis of ABH as well and need to be further investigated. Weakening of the epithelial membrane due to loss of mucosal integrity and increased predisposition to vasculitis and thrombotic vasculopathy may explain the occurrence of ABH in patients of COVID 19. Cruz Tapia et al. reported two COVID-19 patients with angina bullosa haemorrhagic-like (ABH-like) lesions located on the tongue and hard palate, respectively [27]. Till date these are the only cases of ABH reported in patients of COVID-19.

There is no consensus regarding the aetiology, pathogenesis or the course of this disease. However its relation to other diseases, when present, may help to understand the underlying mechanism of ABH.

Conclusion

Various theories have been put forward to explain the pathogenesis of oral lesions in COVID 19. The pathogenesis of ABH in general, is still obscure. Since ABH has been reported in COVID 19, it is plausible that some of the mechanisms underlying the pathogenesis of oral manifestations may explain the pathogenesis of ABH. However, more in depth biochemical and molecular research is essential to explore this possibility.

Funding

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Data availability

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Declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethics approval

Ethical approval was waived by the Institutional Ethics Committee of Sharda University in view of the retrospective narration of the case study and as all the procedures performed were part of routine care.

Consent to participate

Written informed consent was obtained from the patients.

Consent for publication

The patient signed an informed consent regarding publishing their data and photographs.