|Year : 2021 | Volume
| Issue : 4 | Page : 216-225
Ayurveda approach to mucormycosis and other fungal infections: A comprehensive review
Kasimadom P Karthik1, Aparna Dileep1, Shrikrishna Rajagopala1, Arun K Mahapatra1, Prasanth Dharmarajan2
1 Department of Kaumarabhritya, All India Institute of Ayurveda, New Delhi, India
2 Department of Panchakarma, All India Institute of Ayurveda, New Delhi, India
|Date of Submission||30-May-2021|
|Date of Decision||14-Aug-2021|
|Date of Acceptance||01-Nov-2021|
|Date of Web Publication||29-Dec-2021|
Dr. Kasimadom P Karthik
Department of Kaumarabhritya, All India Institute of Ayurveda, New Delhi.
Source of Support: None, Conflict of Interest: None
Introduction: Mucormycosis is an opportunistic angio-fungal infection that has resurfaced during the COVID-19 pandemic period due to multifarious reasons. Due to the limitations of current interventions associated with it, prevention is the recommended strategy. Ayurveda has a significant role to play in prevention, for which prior understanding of the condition in its own parlance is essential. Materials and Methods: Literature and research works from Ayurveda and Western biomedicine relevant to the subject were identified, screened, explored, and interpreted. The data obtained were grouped into three major criteria: etiological factors, disease patterns, and disease targets. These ideas were grouped to obtain a near-total picture of mucormycosis. A set of recommendations, including diet, regimen, single drugs, formulations, therapeutic procedures, and community-level interventions, were made on the basis of research evidence and textual indications. Results and Discussion: Mucormycosis is an exogenous condition that initially follows a common pathogenetic pattern, localizing at various sites to show diverging manifestations. Kapha and Pitta (especially in terms of Snigdha and Uṣṇa properties) play a major role in preventive and curative strategies in terms of food, regimen, medicine, and therapies. Conclusion: The current Ayurveda knowledge should be effectively used in diagnosing, staging, preventing, and rehabilitating the cases of mucormycoses. Their curative role as adjuvant and standalone therapies are to be subjected to further research.
Keywords: Antifungal, Ayurveda, COVID-19, fumigation, mucormycosis
|How to cite this article:|
Karthik KP, Dileep A, Rajagopala S, Mahapatra AK, Dharmarajan P. Ayurveda approach to mucormycosis and other fungal infections: A comprehensive review. J Indian Sys Medicine 2021;9:216-25
|How to cite this URL:|
Karthik KP, Dileep A, Rajagopala S, Mahapatra AK, Dharmarajan P. Ayurveda approach to mucormycosis and other fungal infections: A comprehensive review. J Indian Sys Medicine [serial online] 2021 [cited 2022 Jan 23];9:216-25. Available from: https://www.joinsysmed.com/text.asp?2021/9/4/216/334257
| Introduction|| |
In the background of the COVID-19 pandemic, an invasive fungus, mucormycosis has also set its foot in, worsening the scenario. Mucormycosis is an opportunistic angio-fungal infection predominantly occurring in subjects with low immunity, which can turn fatal. It is a severe but uncommon systemic mycosis caused by Mucor or Rhizopus species of Mucoraceae family. This disease, which is most prevalent in the tropical regions, is more pronounced in Asia, with India leading among them. The sudden rise in cases in the background of COVID-19 due to multitudinous reasons and the high mortality rate, despite appropriate therapies, has created panic among the public as well as the health-care system. Hence, there is currently a need for integrated strategies for identification of populations at risk and execution of effective and evidence-based preventive measures. This is where traditional knowledge systems such as Ayurveda have a significant role to play.
Ayurveda has also identified and described dynamic disease patterns rather than static diseases. Hence, the descriptions regarding these diseases have served as templates into which newer and newer diseases that have troubled science could be incorporated and successfully managed. Moreover, the variables that are considered in the diagnostic and therapeutic decision-making algorithm enable a physician to choose custom, tailor-made interventional strategies for the condition that is encountered. To achieve this, any new disease entity, whether it matches with the textual description or not, has to be critically analyzed in terms of these variables from different perspectives. Till date, there have been no efforts to delineate the nosology of this condition from an Ayurveda perspective, and that is what the article endeavors to do.
| Materials and Methods|| |
As mucormycosis, as a clinical entity, has not been recorded as such in any of the classical scriptures, the inputs regarding the symptomatology and management have to be adopted from Western biomedicine. Hence, the current research literature regarding mucormycosis was searched from the platforms PubMed, Scopus, Embase, Cochrane, Google scholar, and clinicaltrails.gov; the total number of articles identified were screened for duplicate, repetitive, out-of-interest data; languages other than English, and publications out of timeline were excluded. The remaining articles were subjected to qualitative synthesis, and the data obtained were grouped under the categories Etiology (and Risk factors), Pathogenesis, Clinical features, and Diagnosis and Treatment. Parallelly, Ayurveda literature from classic to modern-day literature was referred and corresponding descriptions regarding the earlier mentioned domains were grouped accordingly; assumptions and extrapolations were made based on empirical as well as experimental evidence. The greater trio of texts (Caraka Samhitā,Suśruta Samhitā,Aṣṭāṅga Saṅgrahaḥ,Aṣṭāṅga Hr̥dayaḥ) and their commentaries have been used as the baseline standard for deciphering the etiopathology, symptomatology, prognosis, and prevention and cure. These standards were complemented by inputs from texts such as Mādhava Nidānaṃ (nosology), Siddhānta Nidānaṃ (current perspectives of etiopathology), Bhāvaprakāśaḥ (properties of single drugs), and Bhaiṣajya Ratnāvalī (formulations and dietary recommendations) [Figure 1] and [Figure 2].
|Figure 1: Variables used in diagnostic and therapeutic algorithms in Ayurveda|
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| Results and Discussion|| |
Western Biomedicine’s View
The fungi are commonly found in decomposing organic matter such as spoiled food materials and soil. Mucor reproduces to form broad, aseptate hyphae right angle-branched zygospores. The spores from the fungus gain entry to the host’s body by ingestion, inhalation, or direct inoculation. As the fungi have an affinity for blood vessels, they localize and multiply in the walls of the vasculature, especially of the paranasal sinuses, respiratory system (lungs), and gastrointestinal (GI) tract causing thrombosis followed by infraction with dry gangrene and tissue necrosis.
In a healthy individual, the immune mechanism, particularly neutrophil and macrophage mediated, is responsible for the ingestion and destruction of the spores. Therefore, rapid necrotizing infection progression takes place in an overt immunocompromised host, in whom the phagocytosis is limited (conditions such as neutropenia, diabetic ketoacidosis, cancer, transplant patients, HIV, having steroids for a long period).
Based on the anatomic site of infection, the disease is classified as rhino-orbito-cerebral, pulmonary, cutaneous, GI, renal, and disseminated mucormycosis [Table 1] and [Figure 3].
|Figure 3: A case of ROCM (Original Source: Wikidoc). Available from: https://www.wikidoc.org/index.php/File:Mucormycosis.png.|
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Diabetes mellitus: ROCM is often seen in subjects having uncontrolled diabetes mellitus (DM) or in those with diabetic ketoacidosis (DKA). Hyperglycemia, decreased chemotaxis, and phagocytic efficiency favor the organism to thrive in an acid-rich condition.
Infants and neonates who are of low birth weight, malnourished, or under peritoneal dialysis are prone to GI mucormycosis.
Hematological malignancy and solid organ transplant increase vulnerability toward pulmonary mucormycosis.
Iron overload state and deferoxamine therapy in patients with DKA, renal disorder, or hemodialysis are susceptible for the infection. HIV infection, intravenous drug use, and prolonged and irrational use of broad-spectrum antibiotics enable people to become susceptible for the infection.
Bandage, patches, tape, adhesives, linen, wooden tongue depressors, catheters, dental procedures, and a negative pressure room for patients undergoing transplant surgery are found to be a potential source for health care associated mucormycosis.
COVID-19 associated mucormycosis
India was already one of the nations with the highest incidence of mucormycosis among the uncontrolled DM. The second wave of COVID-19 crisis is witnessing a further rise in cases of mucormycosis among the patients who are COVID infected. As on 22 May 2021, mucormycosis, also known as black fungus, has been found among 8848 COVID cases across India, thus becoming an endemic within the larger COVID-19 pandemic. Most of the cases are of the rhino-orbital-cerebral and pulmonary form, followed by the GI form.
COVID-19 predisposes one to pulmonary and alveolo-interstitial pathologies. COVID induced immune response alteration, damaged airway mucosa and blood vessels, and increased serum iron; steroid-induced hyperglycemia, intensive use of broad-spectrum antibiotics and antifungals, and long-term ventilation are other predisposing factors to the invasion of fungi.
Diagnosis and management of mucormycosis
The European Confederation of Medical Mycology (ECMM) has laid down the “One World, One guideline” system for the multidisciplinary approach toward the management of mucormycosis. On suspicion, appropriate sampling, staging, and imaging are recommended to estimate the extent of infection.
In case of suspected pulmonary mucormycosis in hematological malignancy, a pulmonary CT scan is to be done for detecting cavity, air crescent sign, reversed halo sign, or pulmonary angiography to check vessel occlusion. Cranial CT or MRI is advised in case sinusitis with other early symptoms of mucormycosis is found in patients with DM. If diagnosis is potentially mucormycosis, biopsy is strongly recommended. Cranial, thoracic, and abdominal imaging should be done once mucormycosis is proven. The diagnosis is confirmed by tissue culture, and molecular or in situ identification measures. The most recent advance in the diagnosis and staging is the proposal for the staging of ROCM from the Indian Journal of Ophthalmology.
The suspected and confirmed cases are subjected to emergency surgical debridement followed by drug treatment. Treatment involves (1) primary prophylaxis among neutropenic patients with Posaconazole delay release tablets; (2) secondary prophylaxis in immunosuppressed patients who have undergone surgical resection for mucormycosis; (3) fever-based treatment, when the infection is substantiated by fever of an unknown origin; (4) diagnosis-based interventions in suspected mucormycosis; (5) first-line antifungal monotherapy in cases of organ involvement with liposomal amphotericin and Isavuconazole; (6) antifungal (first line) combined therapy; or (7) antifungal salvage therapy. Interventions are continued till there is resolution of disease along with reconstitution of host immunity.
Etiological and other influencing factors
Diseases of fungal origin are considered under exogenous, toxin-induced pathologies in Ayurveda. Contact with the spores of toxic plants has been documented to cause exogenous edema (A. Hr. Ni. 13/41) and lead to ulceration (Su. Ci. 1/3). These edematous lesions are fast spreading, and they develop into ulcerations. The pathogen in this context possesses all the general features of the toxic materials (Viṣa) mentioned in Ayurveda, that is, to impart dryness (Rūkṣatā) and heat (Uṣṇatva) to the body, to be highly sharp (Tīkṣṇa), capable of traversing small passages. Hence, it has access to every site in the body, rapidly acting (Āsukāri), gets homogenous with the body immediately (Vyavāyi), destroys the bodily structures (Vikāṣi), being light (Laghu) and unmetabolizable (Apāki), and becomes difficult to be treated as well as self-eliminated (Su. Ka. 2/19–24). However, these fungal spores, even though omnipresent, do not affect every individual. Most of the times, they are denied invasion by the immune mechanism of the host (Bala). Bala is the optimality of the Kapha Doṣa in the body (Ca. Su. 17/117). It is considered the culmination of a proper metabolism, which is rooted in the digestive fire (Agni) (Su. Su. 15/19, A. S. Ci. 12/31) [Table 2].
Doṣa, dūṣya, bala, agni, prakr̥ti
Individuals who resort to food and regimen that hamper the digestive mechanism, derange the Kapha and Pitta Doṣa, especially in the form of increased moisture (Kl̥eda), exert their impact on fat tissue (Medo Dhātu); they show diminished profiles of Bala in spite of clinical signs of increased Kapha Doṣa (since it is an increase in the form of metabolic waste and not the essence) (Si. Ni. 1/6). In the course of the metabolic process, they also tend to have a prolonged and pathological phase of semi-digested, fermented, and acidic content (Vidāha) (Ca. Ci. 15/9–11). These individuals, in the Ayurveda purview, are more susceptible to infections and infestations (Kr̥mi), dermatological conditions (Kuṣṭha), diabetes (Prameha), inflammation, and edema (Śopha); its complications resemble abscess (Vidradhi) and cellulitis (Visarpa) and several diseases affecting the nose, eyes, and throat.
Bala is influenced by the robustness of blood in terms of quality and quantity too (Ca. Su. 24/4). There can also be direct insults on Bala, in the form of diseases, medications, and therapies (denoted by the terms Vyādhikṣīna and Bheṣajakṣīṇa).
Improper care of the wound also renders a person susceptible to conditions such as abscesses (A. Hr. Ni. 11/11) and cellulitis (Su. Ni. 9/12, 10/7).
The observations that there is upregulated lipid metabolism in the fungi and findings that the Doṣa genotype (Prakr̥ti) of an individual predisposes him to the diseases predominant in that particular Doṣa (Nānātmaja diseases)hint to the inclination of the condition to Kapha-Pitta Prakr̥ti.
Though there are insufficient data regarding the geographical and seasonal distribution of the condition, there are indications that the disease is more prevalent in the tropical region and climate. As in 2019, Asia (31%) had the highest incidence of mucormycosis, and India leads among the nations. The relationship between the seasonal patterns of the region and incidence has not been established. However, the stronger determinant of mucormycosis incidence is the higher prevalence of diabetes in these regions. The renal variant of mucormycosis, nearly endemic to these regions, substantiates the same, and also the involvement of fat and moisture here. Analyzing the seasonal patterns, in India, the prevalence has been observed to be higher in the post-rainy season and autumn seasons, which are in line with Ayurveda’s observations wherein the former season is mentioned to be the one in which Agni and Bala are diminished, and the sudden cooling of the heated earth makes it acidic (leading to the increase in Pitta and Kapha) (Ca. Su. 6/34); this state is further worsened in the latter when the earth is further heated up, resulting in pronounced Pitta vitiation (Ca. Su. 6/41).
Disease pattern and target
When an individual who has passed through some or all of the earlier mentioned states encounters the pathogen, contrary to the normal, the immune system fails to ward it off, and therefore falls victim to its invasion [Figure 4]. This invasion can be through inhalation (Śvāsa), ingestion (Bhojana), or inoculation (Sparśa) of the infective material (Viṣa of the Kr̥mi). The pathogen then causes a local inflammation, which is not necessarily representative of any Doṣa (A. Hr. Ci. 1/171). This inflammation rapidly develops into a lesion (A. Hr. Ni. 13/49) that is associated with necrosis of the tissue associated with exudation representing the site involved. Association with a particular Doṣa is attained once that Doṣa in circulation gets localized at this site of inflammation due to the defect (Khavaiguṇya) produced therein. This progression, which starts as an inflammation, very rapidly spreads everywhere in the body, resulting in ulceration; necrosis is very much akin to that of the cellulitis-like conditions (A. Hr. Ni. 13/48, 50–55). Depending on the site of inflammation and the sites in the structures in its vicinity, diverse clinical presentations (resembling some local pathologies in Ayurveda) are exhibited. When the disease gets localized at the nose and paranasal sinuses, they resemble the patterns of Duṣṭapratiśyāyaḥ (chronic rhinitis) (A. Hr. U. 19/9–12) and Nāsāpākaḥ (suppuration of the nasal region) (Su. U. 32/8). In the lungs and gut, their localization shows features similar to those of Antarvidradhiḥ (internal abscess) (A. Hr. Ni. 11/12–17). The staging of disease, especially in severity, should be preliminarily judged from the substratum involved (Vraṇavastu). This can be confirmed by the color of the ulcer, the nature of exudate, and clinical symptoms mentioned in the ulcer diagnosis (Su. Su. 22).
In summary, the etiopathology of mucormycosis can be understood in Ayurveda as:
The mortality rate in mucormycosis is high (46.8% in 388 cases reported). Usually, the wounds on the forehead and other regions of the face heal easily (Su. Su. 23/5), but the population that is affected (diabetes, skin diseases, immunocompromised) drags the prognosis down to “difficult-to-treat” or “palliable” (Su. Su. 23/7). Ulcers associated with extensive necrosis, exudation indicative of deeper tissue involvement and that has affected the skull bone are considered to be untreatable as per Ayurveda nosology (Su. Su. 23/12).
Prevention and cure
Due to the fast-spreading nature and high mortality despite aggressive interventions, the role in treatment of the cases once occurred is very limited. Hence, efforts need to be concentrated on the preventive aspect. They can be deployed at two broad levels:
- i. Protecting and strengthening the host (individual level)
- ii. Limiting the pathogen (community level)
Among these, protection and strengthening the host is the most important, because it is the method that is more sustainable. Protection is to be ensured by two measures: avoiding the exposure to the pathogen, and also keeping the body hostile (mainly covering the site of entry) to the pathogen. This includes:
- - Covering the face with a mask while at construction sites, gardens, etc.
- - Wearing shoes and a dress that covers the whole body while handling soil, manure, etc.
- - Proper wound care, especially dressing and covering (A. Hr. Ni. 11/11).
To keep the body hostile to the pathogen, prophylaxis needs to be attained, for which Ayurveda prefers a healthy lifestyle over overmedication (B. P. Ma. Jvaraṃ 1/15). Food and regimen are the pillars of lifestyle that have to be systematized (A. Hr. Su. 7/52).
In general, it is observed that the diet and regimen as well as medications mentioned for diabetes, dermatological conditions, infections and infestations, abscesses, and cellulitis-like conditions are very much comparable and analogous to each other (Su. Ci. 10/3, Ca. Ci. 6/46–48). Hence, recommendations that are common to these pathologies have been adopted here.
The use of bitter taste vegetables is strongly recommended, after proper cleaning and washing. Cereals such as wheat and barley; millets such as Jowar, Ragi, and Panicum sumatrense (Śyāmāka), Vigna radiata (Mudga), Lens culinaris (Masūra), Cajanus cajan (Ādhakī) among beans; and fruits such as gooseberry and pomegranate are recommended. Food habits such as consuming only when there is good appetite, and the previously consumed food that is digested are also to be followed. (B. R. 37/237–241)
These food items should be used minimally, especially by the population at risk, for infection by the pathogen: milk and milk products, especially curd, fish, other aquatic animals, jaggery products, sesame-based food articles, fruits and other foods with predominance of sour–sweet taste, fermented foods containing rice-flour (Piṣṭa) and Vigna mungo (Māṣa), Allium sativum (Laśuna), Macrotyloma uniflorum (Kulattha), leafy vegetables (spinach, cauliflower, cabbage, etc.,), alcoholic drinks, junk food, soft drinks, etc. (Su. U. 54/2–5, 40).
Regular scrub bath, steam inhalation, gargling of water boiled in antifungal drugs, usage of Aṇu tailaṃ or other medicated oils such as nasal drops, proper maintaining of oral hygiene and Yoga, Prāṇāyāma, and other exercise that suits the parameters of the individual are to be followed. The seasonal regimen mentioned in Autumn (A. Hr. Su. 13/14) and measures such as fumigation mentioned in rainy season are also to be adopted.
Sleeping during daytime, sedentary lifestyle, suppression of urges, gardening, and excessive outdoor activities, especially for a month after COVID infection, are among the regimens that are to be avoided.
Judicious and physician-supervised internal and external usage of the following common Ayurveda drugs that have been reported to show antifungal activity are advisable [Table 3].
Even while considering the antifungal activities, an account of the general pharmacological properties of the drug must not be overlooked. Drugs chosen for prevention have to be pro-host (protective to the organs and body systems of the host) and anti-pathogen (conducive in inhibiting the infection). Restoration of immunity and health of the tissues are to be ensured in immunocompromised individuals using Rasāyana drugs. The drugs belonging to the following category are recommended in general for prevention: drugs that are bitter, moderately spicy, and astringent in taste, light, dry and not too cold or hot in attributes (Guṇa), and spicy in postdigestive effect (Vipākaḥ). Special pharmacological actions (Prabhāvaḥ) are preferred: skin health promoting (Tvacya), blood-purifying (Raktaśodhana), reducing moisture (Kl̥edahara), antimicrobial (Kr̥mihara), and immune-boosting (Rasāyana).
As the patients with DM and immunocompromised individuals form a major share of the high-risk population, formulations that are hyper-potent such as Paṭolamūlādi and those that are not recommended for diabetics (alcoholic formulations and electuaries) have been omitted, though they should be made use of judiciously.
The following formulations have been either classically recommended in the Prameha-Kuṣṭha-Kapha spectrum, or they have been proven to have broad-spectrum antifungal action:
Gaṇās: Triphalā, Sālasāradi/Asanādi, Nyagrodhādi, Āragvadhādi, (Su. Ci. 10/3) Varuṇādi (Su. Ci. 17/16), Surasādi (A. Hr. Su. 15/31).
Decoctions: The earlier mentioned, Trāyantyādi (A. Hr. Ci. 13/10–12) Pañcanimba.
Tablets: Ārogyavardhinī Vaṭi, Gandhaka Rasāyana, Triphalā guggulu, Kaiśora Guggulu.
Powders: Pañcanimba, Nimbādi.
Electuaries: Māṇibhadraṃ, Madhusnūhī.
These formulations should be extrapolated to the curative aspect, especially in the stages 1a to 2d of the proposed staging of ROCM by the Indian Journal of Ophthalmology and in other variants.
In the phase postsurgical debridement, internal medications such as Triphalā guggulu,Āragwadhādi kaṣāyaṃ,Pañcavalkala,Kaiśora guggulu, and Sañjīvanī vaṭi, and external medications, such as Jātyādi tailaṃ, Daśāṅga lepaṃ, and Ficus racemose, which have been used in various necrotizing and gangrenous conditions, should be considered for accelerating the healing process, especially in cutaneous mucormycosis and early stages of ROCM. Fumigation over ulcer (Vraṇadhūpana) has also been mentioned in classical texts to be effective in healing ulcers.
Various modalities that are available to address the local as well as systemic pathologies, though yet to be proven for the condition, should be practiced on a preventive line.
Nasal medication:Aṇutailaṃ, Ṣaḍbindutailaṃ.
Gargling:Haridrā, Triphalā, Tulasi.
Bio-purificatory procedures: Procedure suiting the constitution and health status of the individual.
Limiting the pathogen (community level interventions)
Measures of limiting the pathogen are to be implemented at the community level, especially in settings where there are higher chances of interaction between the fungus and immunocompromised individuals. One of the most effective strategy in this respect is fumigation. Herbal and chemical fumigations are widely used in practice. Aparājita Dhūma was found to effectively reduce the microbial load of Aspergillus species and several other bacterial and fungal species when fumigated for half an hour daily.Yavasarṣapādi dhūma cūrṇa, when used for fumigation along with ghee for the sterilization of operation theatre, was found to be significant and more effective compared with formalin gas in reducing the load of Candida albicans and other microbes such as Staphylococcus aureus. In another in vitro study against Staphylococcus aureus, 20 min of fumigation with Nimbādi Dhūpah, Kumārāgāra Dhūpaḥ, Daśāṅga Dhūpaḥ, and Gaṇa Dhūpaḥ brought about a reduction in the total colony count by 76.61%, 84.13%, 80.51%, and 98.94%, respectively. Another patent fumigation powder “Dhup,” when burned in the medium of cow dung cakes, reduced the bacterial and fungal load after fumigation for one week. Other Ayurveda drugs containing volatile oils and other antifungal principles need to be subjected to further research for their effectiveness.
| Scope|| |
This review attempts to make an integrative Ayurveda profiling of the fungal infection that encompasses the aspects right from etiology to management. It gives inputs on the diagnostic and therapeutic considerations to be taken care of while managing them and also identifies the scope of Ayurveda interventions. The prognostic knowledge in Ayurveda basis and comparison with the current staging method of the disease may guide the decision of which category of patients are fit for Ayurveda curative therapies. The repurposing of Ayurvedic interventions mentioned in Viperine poisoning (Maṇḍalī viṣa, hemotoxin) such as Pārantyāditaila, paste of Datura metel, Azadirachta indica, etc. should also be considered.
| Conclusion|| |
This review provides an understanding of mucormycosis from both the Ayurveda and Western biomedical perspectives. It also gives leads or directions in which future research works, both observational and experimental, may be oriented. Ayurveda has been proactive in the public health scenario of India for centuries and is still continuing to be. Mucormycosis, even when surgically treated, leaves severe sequelae that are incapacitating and disfiguring. There are an umpteen number of Ayurveda herbs and formulations that have preliminary evidence to back their antifungal action. The role in early phases (such as in stages “1–2” or “probable ROCM”) as standalone and adjuvant therapies and possibilities of them avoiding the need for surgical interventions would be of substantial service to humanity.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published, and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]