A retrospective clinical, multi-center cross-sectional study to assess the severity and sequela of Noma/Cancrum oris in Ethiopia.

INTRODUCTION: Noma is a disfiguring gangrenous disease of the orofacial tissue and predominantly affects malnourished children. The tissue gangrene or necrosis starts in the mouth and eventually spreads intra-orally with the destruction of soft and hard tissues. If not controlled, the natural course of the condition leads to a perforation through the skin of the face, creating a severe cosmetic and functional defect, which often affects the mid-facial structures. Furthermore, the course of the disease is fulminating, and without timely intervention, it is fatal.
MATERIALS AND METHODS: A retrospective clinical cross-sectional study was conducted to assess the sequela and severity of Noma in Ethiopia. Medical records of patients diagnosed with Noma were reviewed. The medical files were obtained from Yekatik 12 Hospital, Facing Africa, and the Harar project,-the three major Noma treatment centers in Ethiopia. The severity of facial tissue damage and the extent of mouth trismus (ankylosis) were examined based on the NOIPTUS score.
RESULTS: A total of 163 medical records were reviewed. Of those, 52% (n = 85) and 48% (n = 78) have reported left-sided and right-sided facial defects, respectively. The facial defects ranged from minor to severe tissue damage. In other words, 42.3% (n = 69), 30.7% (n = 50), 19% (n = 31), and 8% (n = 13) have reported Grade-2 (25-50%), Grade-3 (50-75%), Grade-1 (0-25%), and Grade-4 (75-100%) tissue damages respectively. Cheek, upper lip, lower lip, nose, hard palate, maxilla, oral commissure, zygoma, infra-orbital region, mandible, and chin are oftentimes the major facial anatomic regions affected by the disease in the individuals identified in our review. Complete loss of upper lip, lower lip, and nose were also identified as a sequela of Noma. DISCUSSION: The mortality rate of Noma is reported to vary between 85% and 90%. The few survivors suffer from disfigurement and functional impairment affecting speech, breathing, mastication, and/or even leading to changes in vision. Often, the aesthetic damage becomes a source of stigma, leading to isolation from society, as well as one's family. Similarly, our review found a high level of facial tissue damage and psychiatric morbidity.

Introduction

Noma is a necrotizing and disfiguring condition of the orofacial and para-oral structures [1]. In many cases, the disease begins to develop from acute necrotizing ulcerative gingivitis (ANUG) [2]. ANUG is a non-contagious anaerobic infection associated with the proliferation of borrelia vincentii and fusiform bacteria [3,4]. The condition primarily affects children under the age of 10 years [3]. The major risk factors of ANUG/Noma in children are malnutrition, diarrheal diseases, measles infection, lack of proper sanitation, and poor living conditions. Alternatively, typical predisposing risk factors in young adults, including those who serve in the military, include: poor oral hygiene, smoking, viral respiratory infections, and immune defects, such as HIV/AIDS [5-7]. Characteristic features of ANUG include profuse gingival bleeding, severe soreness from gingival ulceration, halitosis (bad breath), and changes in taste. Malaise, fever, and cervical node enlargement are less commonly reported in those with ANUG. Other characteristics of ANUG include ulceration of the gingival papillae, pain, and sometimes the presence of grey pseudomembranes [8].

If left untreated, Noma often rapidly progresses to gangrenous stomatitis and gingival ulcer [9]. Within days, it spreads to adjacent hard and soft tissues by disrupting anatomical barriers, causing lysis and necrosis of bones and muscles of the orofacial region. Noma disfigures the cheek (maxilla & mandible), the floor of the mouth, head and neck, the infra-orbital region, and the nose [10]. In most instances, the lesion (wound) area is well defined (cone-shaped), with unilateral, yellowish, and necrosis and foul-smelling purulent discharge. Fetid odor, significant pain, fever, malaise, tachycardia, tacyhpnea, anemia, leucocytosis, and regional lymphadenopathy are common clinical findings or frequently occur (as blending symptoms with physical exam findings). Additional lesions also may occur in distant sites, such as the scalp, neck, ear, shoulders, chest, perineum, and vulva [11].

The disease is associated with very high morbidity and mortality [9]. Associated septicemia, intracranial infection, and pneumonia are the leading causes of death. Most survivors present with prominent facial deformities, trismus or ankylosis of the temporomandibular joint, and extensive muscle and skin contracture, which leads to the difficulty of opening and closing of the mouth, thereby, trouble in mastication and swallowing, oral incontinence, and speech difficulties [12]. The problems in mastication and swallowing can also further exacerbate or cause malnutrition and as a result, many young patients experience significant stunting of growth [13]. In those with more advanced Noma, the lesions and contractures often lead to growth disturbance and result in further facial disfigurement and functional impairment [14].

In general, the disease begins as an ulcer of the mucous membrane in the mouth, which causes an edematous face; the condition extends from within out; it rapidly destroys the soft and hard tissues of the face [15]. The acute phase of the disease affects the mouth with denudation of bone, spontaneous exfoliation of teeth, necrotizing fasciitis, and lips and cheeks myonecrosis [16]. The acute phase of the disease has a high mortality, and the evolution is exceptionally rapid, causing the loss of soft and bony facial tissues within days [17,18].

Treatment of acute Noma includes transfusion of blood and intravenous fluids, administration of antibiotics, a high protein diet supplement, and debridement of necrotic areas [19]. The surgical phase is usually initiated 6 to 18 months after a period of quiescence [20]. Even after modern and sophisticated interventions (particularly reconstructive and plastic surgeries), Noma is associated with considerable morbidity and mortality, and, understandably, psychosocial impacts on the patients remain substantial [21]. Often, those patients that survive are not only severely disfigured, but also rejected from family and society [22]. However, these longer-term effects, including psychosocial aspects, are incompletely understood and an area for further study [23].

Ethiopia is one of the countries in the Noma-belt region where people, particularly children, are profoundly affected by the disease. However, attention and resources dedicated to this devastating condition remains inadequate [24]. This study was initiated to assess the sequela and severity of Noma in Ethiopia. The findings of this study can be used as a baseline for further investigation and help to fill the current knowledge gap.

Materials and methods

Ethics statement

The study was approved by the Addis Ababa Health Bureau Institutional Review Board (IRB), Ethical clearance committee. The approval number of the clearance statement is “A/A/H/B/2116/227”. Medical information was kept confidential. Moreover, the researcher used patients’ initials in the MCRFs and excel sheet. However, as the study was retrospective, formal consent was not sought and obtained.

Study design

A descriptive retrospective clinical cross-sectional study was carried out to assess the sequela and severity of Noma/Cancrum oris in Ethiopia. This retrospective descriptive cross-sectional study was undertaken to provide a snapshot of the severity of Noma in Ethiopia. The sequela and severity of the disease were investigated based on written and graphic data retrieved from Yekatit 12 Hospital, Facing Africa Ethiopia, and Harar Project Ethiopia,—the three major Noma care centers in the country.

Study location and population

The study was conducted in Addis Ababa, the capital city of Ethiopia. Patients who were diagnosed with Noma and admitted to these three treatment centers between March 2004 and December 2020 were retrospectively studied.

Data collection and analysis

The medical records of patients with Noma were reviewed to extract relevant clinical information that help to answer the research questions. A modified case report form (MCRF) consisting of demographic and clinical information was used to collect the relevant clinical information (S1 Appendix). The demographic section of the MCRF contains the name, gender, age, physical address, telephone address, and year of admission of the patients. Whereas, the clinical part of the MCRFs primarily subdues the localization of Noma-induced anatomical lesions and associated functional limitations. The localization of lesions was based on the WHO classification, which distinguishes commissure, cheek, lip, and complex lesions. The patient’s data was summarized in the MCRFs. The clinical data obtained from MCRFs was considered for data analysis. The researcher verified the validity of the CRFs. Therefore, the sequela and severity of Noma in Ethiopia were evaluated based on the relevant clinical data recorded on the MCRFs and the NOIPTUS score. The extent of jaw constrictions (ankylosis) was described in terms of NOIPTUS mouth trismus classification. According to NOIPTUS measurement, Grade-0 implies no mouth opening difficulty. Grade-1, Grade-2, Grade-3, Grade-4 imply mouth opening of > 40mm, 20-40mm, 1-20mm, and locked jaw respectively. Furthermore, the severity of the lesions was recorded using the NOIPTUS guideline of classifying facial tissue damage. SPSS software program was used to calculate the numerical values that are used to describe the severity of the disease.

Results

A total of 163 patients’ medical records were selected for data analysis. All the retrospectively studied participants had at least a single Noma-induced facial defect. The severity of the facial defects varies among the retrospectively studied population. The facial anatomical landmarks damaged by the disease, the severity of the tissue damage, and associated functional limitations are presented as follows.

Left-sided facial anatomical defects

Table 1 shows that out of the 163 medical records reviewed to identify the anatomical landmarks affected with the disease, 85 of them have reported left-sided facial defects. In general, the left-sided facial anatomical regions can be grossly classified as combined and non-combined defects. Of these 85 medical records which have reported left-sided facial deformities, 30.6% (n = 26) of them have reported non-combined defects such as cheek, upper lip, lower lip, nose, and oral commissure. Whereas, the remaining 69.4% (n = 59) medical records have reported combined facial defects such as cheek and nose; upper lip, cheek and nose; and upper lip, nose, zygoma, hard palate, and maxilla. The combined defects such as cheek and nose; cheek and oral commissure; cheek, nose and upper lip; and upper lip, nose, zygoma, hard palate, and maxilla are reported only at the left side of the face. The combined defects involved multiple facial anatomical regions.

Table 1

Noma induced facial tissue damages and frequency of the defects.

Affected facial anatomical region/s	Frequency of the defects
	Left-sided	Right-sided	Neither right nor left-sided (complete loss)	Total
Cheek	19	5	-	23
Lower lip	10	9	-	19
Upper lip	10	6	-	16
Cheek, lower & upper lips	4	6	-	10
Cheek, oral commissure, lower & upper lips	5	6	-	11
Cheek & lower lip	4	6	-	10
Cheek, nose, lower & upper lips	5	4	-	9
Cheek & upper lip	5	4	-	9
Lower & upper lips	3	2	-	5
Oral commissure, lower & upper lips	4	2	-	6
Nose	3	3	-	6
Nose & upper lip	3	3	-	6
Cheek, nose & upper lip	1	3	-	4
Oral commissure & upper lip	2	2	-	4
Nose & upper lip	1	3	-	4
Cheek & oral commissure	-	3	-	3
Oral commissure	2	1	-	3
Maxilla & upper lip	1	2	-	3
Lower lip	-	-	2	2
Nose	-	-	2	2
Central lower lip	-	-	1	1
Central upper lip & nose	-	-	1	1
Chin & upper lip	1	-	-	1
Cheek & nose	-	1	-	1
Cheek, lower lip, nose & mandible	1	-	-	1
Infra-orbital region, oral commissure, nose and zygoma	1	-	-	1
Hard palate, maxilla, nose, upper lip & zygoma	-	1	-	1
Total	85	72	6	163

Left-sided lower lip defects with n = 9 was reported most commonly followed by upper lip with n = 7. Cheek; cheek, both lips, and oral commissure; cheek and lower lip; cheek and both lips; each with n = 6 was reported to be the other most common left-sided Noma induced defects. On the other hand, upper lip, cheek, and nose; upper lip, nose, hard palate and maxilla; upper lip and maxilla; and cheek and nose, each with n = 1 were less frequently reported left-sided anatomical defects.

Right-sided facial anatomical defects

Table 1 reveals that out of the 163 medical records reviewed to identify the anatomical landmarks affected with the condition, 72 of them have reported right-sided facial deformities. In general, the left-sided facial anatomical regions can be grossly classified as combined and non-combined defects. Out of the total 72 medical records which have reported left-sided facial deformities, 61.1% (n = 44) of them have reported non-combined defects such as cheek, upper lip, lower lip, nose, and oral commissure. Whereas, the remaining 38.9% (n = 28) medical records have reported combined facial defects such as cheek and nose; upper lip, cheek and nose; and nose, zygoma, oral commissure, maxilla, and infra-orbital region. The combined defects, such as the nose, zygoma, oral commissure, and infra-orbital, lower lip, cheek, mandible, and nose, and lower lip and chin are reported only on the right side of the face. The combined defects involved multiple facial anatomical regions.

Righted sided cheek defects with n = 19 was reported most commonly followed by the upper lip and lower lip each with n = 10. Cheek and both lips with n = 9; cheek and upper lip with n = 7; both lips, cheek, and nose with n = 5, and both lips, cheek, and oral commissure with n = 5 were reported to be the other most common right-sided Noma induced defects. On the other hand, lower lip and chin; upper lip and nose; lower lip, cheek, mandible and nose; and nose, zygoma, oral commissure, maxilla, and infra-orbital region each with n = 1 were less frequently reported right-sided anatomical defects.

Neither left nor right-sided facial anatomical defects

Table 1 demonstrates that out of the 163 medical records reviewed to identify the anatomical landmarks affected with Noma, 6 of them have reported complete loss of facial tissues. A single entire nose and central upper lip loss, two total nose losses, two complete lower lip loss, and one complete upper lip loss. Out of the 6, only one defect was combined (nose and upper lip). The remaining five defects were non-combined. Only one of the medical records with complete nose loss has reported grade-II mouth opening. No missing teeth or limited mouth opening were reported in the remaining five medical records.

Overall facial anatomical defects

A total of 163 medical records have been reviewed to assess the epidemiology of Noma in Ethiopia. The socio-demographic data of the cases admitted in the three Noma treatment facilities were reviewed from the medical records. All the relevant clinical information obtained from the medical records has been organized and synthesized to come up with the following findings. The sequela of the disease reported in the medical records is classified into combined and non-combined. The combined sequela involved two or more anatomical region defects. The cheek, upper lip, lower lip, nose, and oral commissure are the non-combined anatomical defects reported in the overall medical records. The non-combined anatomical abnormalities consisted of 44.2% (n = 72) of the total defects reported in the whole medical records. The cheek, the lower lip, and the upper lip are the most frequently reported non-combined defects with n = 23, n = 19, and n = 16, respectively.

The least frequently reported non-combined Noma-induced facial defects are oral commissure with n = 3 and nose with n = 6. Furthermore, there are five non-combined complete loss defects.

Nearly 56% (n = 91) of the total facial defects reported in the overall medical records are combined in form. Upper lip, lower lip, and cheek with n = 10; cheek and upper lip with n = 9; cheek and lower lip with n = 10; upper lip, lower lip, cheek and nose with n = 9; and upper and lower lip with n = 10 was the most frequently reported combined sequela of the Noma in the overall medical records.

The least commonly reported combined defects with n = 1 are cheek and nose; lower lip and chin; lower lip, cheek, mandible, and nose; nose, zygoma, oral commissure, maxilla, and infra-orbital region; and upper lip, nose, zygoma, hard palate, and maxilla. Furthermore, there is a single non-combined complete loss defect.

The severity of the facial defects

The extent of the disease sequela was reported in the medical records based on the NOIPTUS guide of classifying facial tissue damage. As Table 2 describes, the NOIPTUS classifies facial anatomical tissue damage into four classes. The classes are graded from 1 to 4, depending on the severity of facial tissue damage. Grade-1, Grade-2, Grade-3 and Grade-4 imply 0–25%, 25–50%, 50–75%, and 75–100% facial anatomical damages respectively. All the anatomical landmarks reported in the reviewed medical records have shown minor to severe tissue damage. Cheek, upper lip, lower lip, nose, hard palate, maxilla, oral commissure, zygoma, infra-orbital region, mandible, and chin are the anatomical landmarks reported to be damaged in the medical records. Accordingly, 42.3% (n = 69) of the total medical records reviewed have reported Grade-2 facial anatomical damages. Furthermore, 30.7% (n = 50), 19% (n = 31), and 8% (n = 13) have reported Grade-3, Grade-1, and Grade-4 tissue damages respectively.

Table 2

Noma cases with different levels of facial tissue damages (NOITULP Grade).

Number of Noma cases	Tissue damage by a percent	NOITULP Grade
69	25–50%	Grade 2
50	50–75%	Grade 3
31	0–25%	Grade 1
13	75–100%	Grade 4
163	Total number of Noma cases with facial tissue damages

Impaired activity of the mouth

Out of the six neither left nor right-sided anatomical defects, only one of the medical records with complete nose loss has reported grade-II mouth opening. The remaining medical records have reported no difficulties with mouth opening. The impaired mouth activities that are reported in the medical records are explained in terms of NOITULP’s mouth opening classification. Table 3 shows the NOITULP’s mouth opening measurement scales. Grade-0 implies no mouth opening difficulty. Grade-1, Grade-2, Grade-3, Grade-4 imply mouth opening of > 40mm, 20-40mm, 1-20mm, and locked jaw respectively. Accordingly, except 23.3% (n = 38) and 4.9% (n = 8) medical records, which have reported intact mouth opening (Grade 0) and with no mouth opening information, respectively, the remaining 71.8% (n = 117) have reported grade-2 to grade-4 mouth opening limitations that related with the disease. Of these, 32.5% (n = 53), 25.2% (n = 41), and 13.5% (n = 22) have reported grade-1, grade-2, and grade-3 mouth opening limitations, respectively. Furthermore, a single locked jaw (grade-4) case has been reported.

Table 3

Noma cases with different levels of mouth opening limitations (NOITULP Grade).

Number of Noma cases	Mouth opening by millimeter	NOITULP Grade
53	> 40mm	Grade 1
41	20-40mm	Grade 2
22	1-20mm	Grade 3
1	Locked jaw	Grade 4
117	Total number of Noma cases with ankylosis

Dental involvement

Dental involvement has been reported in the majority of the patients in this study. Out of the total 163 patients reviewed, 7.4% (n = 12) had no dental 266 information. On the other hand, 25.8% (n = 42) are reported to have healthy teeth, while the remaining 66.9% (n = 109) have reported a varying number of missing teeth. The number of missing teeth ranges from 1 to 19 in patients affected by the disease. The reported missing teeth have been classified into four groups for the sake of understanding. Group-1, Group-2, Group-3, and Group-4 consisted of medical records that reported 1–5, 6–10, 11–15, and 16–20 missing teeth, respectively. Accordingly, 43 medical records have reported 1–5 missing teeth each in group-1. Another 43 medical records have reported 6–10 missing teeth each in group 2. On the other hand, 15 medical records have reported 11–15 missing teeth each in group-3. Similarly, another eight medical records have reported 16–20 missing teeth each in group-4. Furthermore, out of the 109 medical records, 14 have reported different levels of disoriented teeth.

Discussion

Noma is a disfiguring necrotizing condition of the orofacial tissues. The condition may be an extension of ANUG (acute necrotizing ulcerative gingivitis) [4]. In Africa, there is a high prevalence of ANUG in children that ranges from 15% to 60%, depending on the region and the degree of poverty [15,25]. Accordingly, most cases of Noma are reported from the so-called Noma belt in Africa, which is located south of the Sahara and runs across Africa from Senegal to Ethiopia [12,21,26]. Recently, isolated cases of Noma have been reported from developed countries. The burden of the disease can be explained through its high mortality rate and psychosocial morbidity [14,27]. Noma survivals are often left with devastating orofacial defects [23]. All cases reviewed in this study have reported minor to severe orofacial tissue damages. According to the NOITULP tissue damage classification system, 73% of the total cases with Noma have reported 25–75% facial tissue damage. Nearly 8% have reported 75–100% facial anatomical landmarks damage. Furthermore, a complete absence of facial tissues such as the nose, upper lip, and lower lip has been reported.

Most defects resulting from Noma involve the lateral and anterolateral aspects of the face and are often combined with severe functional deficits [19]. A subgroup, commonly called “central Noma,” is composed of defects of the upper lip, maxillary soft tissues, premaxilla, nasal cartilaginous infrastructure, and soft tissues. In contrast to unilateral involvement of the face, central Noma does not affect the opening of the jaw; however, it results in severe mutilation, with disfiguring three-dimensional defects erasing any individual traits from a face [28]. Various forms of post-Noma defects were reported among 84.6% of the retrospectively studied population in Nigeria [29]. Furthermore, the estimated incidence of Noma in the north-central zone was found to be 8.3 per 100000 with a range of 4.1–17.9 per 100000 across various states. Period prevalence of Noma–which incorporated all cases seen within the study period–was also reported to be 1.6 per 100000 population at risk [30]. Among the Noma cases involved in a hospital-based retrospective study in north-western Nigeria, 84.3% had manifest outer and inner cheek layer lesions. The study examined 1923 patients admitted to the hospital from January 1999 to December 2011 [31]. Another study, which assessed the outcomes at 18 months of 37 surgically treated Noma cases at the Noma Children’s Hospital, Sokoto, Nigeria revealed 36.0% of outer cheek involvement among the studied population [32]. Similarly, another research reported 26% to 50% outer cheek tissue loss [33].

Oral incompetence, speech difficulties, post-wound healing ankylosis, and dental or malalignment are reported as a sequela of Noma [34]. In this study, 74.9% (n = 122) have reported grade 1 to grade 4 levels of trismus, and 66.9% (n = 109) have reported a different number of missing teeth. Furthermore, a significant number of the cases have reported dental anarchy.

Oral incompetence, speech difficulties, airway challenges, chemotherapy-induced neutropenia, post wound healing ankylosis, and dental anarchy are reported as a sequela of Noma [35] [36] [37] [24]. Depending on the degree of inner and outer cheek lining deficit, trismus can result simply from soft tissue contracture that the cheek undergoes with resultant scarring [38]. Bony trismus can also result from the fusion of the coronoid process to the zygoma and may require surgical intervention [39] [40]. A retrospective study that investigated the long-term results of trismus release among Noma patients reported a poor prognosis. This study showed that trismus is one of the most disabling sequelae among Noma survivals [41]. Out of the 163 medical records reviewed, 74.9% (n = 122) have reported grade 1 to grade 4 levels of trismus according to the NOITULP classification system for Noma-induced ankylosis. On the other hand, 66.9% (n = 109) have reported a different number of missing teeth. Furthermore, of these, 14 have reported varying levels of dental anarchy.

Conclusion

Noma can only be described as a terrifying disease considered ‘too disturbing’ to feature in developed countries’ mass media. As a result, there is little awareness of the dire need to eradicate this disease, notably in East Africa. Noma oftentimes occurs in impoverished individuals, particularly in malnourished individuals. The condition is associated with significant morbidity and mortality. The findings of this study shed light on the severity of Noma in Ethiopia. Most of the surveyed patients suffered from extensive Noma-induced facial disfigurements, which exposed them to eminent functional limitations, social discrimination, and negative psycho-social effects. This work provides baseline data for calculation of the disease burden which can explain better the disease’s ill-outcomes. Whereas other health challenges such as cleft palate have received global attention and funding, Noma remains tragically unknown and neglected. While prevention and eradication of Noma should be specifically considered among the Sustainable Development Goals, the urgency of psychological and physical rehabilitation for patients with Noma should be treated as an international humanitarian emergency.

A modified case report form (MCRF) consisting of demographic and clinical information.

(DOCX)

Click here for additional data file.

15 May 2022

Dear Dr Gebretsadik,

Thank you very much for submitting your manuscript "A retrospective clinical, multi-center cross-sectional study to assess the severity and sequela of Noma/Cancrum oris in Ethiopia" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Joseph M. Vinetz

Deputy Editor

PLOS Neglected Tropical Diseases

Joseph Vinetz

Deputy Editor

PLOS Neglected Tropical Diseases

***********************

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: 2. Methodology : Fair but no words on the software employed for analysis

Reviewer #2: (No Response)

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: 3. RESULTS

Some Observation:

“All the retrospectively 138 studied study participants” a sentence like this affected the flow of the write up. There is a need to appreciate that once the study method has been mentioned, generated data should be used freely example “138 participants were studied”

I am of the opinion that a table summarizing left sided and right sided deformities will be easier to follow.

Also when using a table, its important to mention it at the beginning of the sentence rather than the end. EG Table 1 shows the distribution of facial defects on the right side of the face observed from the study population

Ethics is always a controversial issue. However blocking the face in these subjects has substancially affected the true extent and appreciation and hence limiting how much the public need to be educated. So I am of the opinion that the face should be presented following informed consent. I appreciate the fact that it is a retrospective study but all surgeons are married to our patients and I am sure some of them will still be around.

Reviewer #2: yes - most images are good quality - 1 noticeably blurry - on the cut-off for what I would consider acceptable for an image

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: 5. Conclusion

What was presented was not a summary. Conclusion should be the opinion arrived from discussion. The write up looks like another view. A revision is needed.

“Noma is a debilitating disease primarily affecting the poor and has been called the “face of poverty.” It occurs among the underprivileged society where patients do not have access to proper medical care. Those who do develop Noma are doomed to suffer the tragic consequences of disfigurement and functional impairment, or death.” These are established facts from past studies, so cant be a conclusion of this study

Reviewer #2: yes - writing needs to be improved - I have made the majority of required grammatical changes. This manuscript will require another proofread to make sure no errors remain.

--------------------

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: Substantial revision important

Reviewer #2: (No Response)

--------------------

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: Overall: The work of the authors is commendable. Despite the debilitating nature of cancrum oris, information about the disease is sparse and hence the study is very relevant to the advancement of knowledge on the subject. However substantial revision is needed to be acceptable as a scientific publication.

Reviewer #2: Thank you for your submission.

Detailed review.

Would make changes to the manuscript as follows:

In the abstract

Would reword:

The facial defects depicted minor to severe tissue damages

to:

The facial defects ranged from minor to severe tissue damage.

In the abstract

The precise meaning of this sentence was unclear to me:

In general, 73% (n=119) of medical records have reported 25-75% of facial tissue damages.

in abstract would change 'chewing' to 'mastication'

in abstract would change ...or even vision to ...and/or even lead to changes in vision.

in abstract

Cheek, upper lip, lower lip, nose, hard palate, maxilla, oral commissure, zygoma, infra-orbital region, mandible, and chin are the major facial anatomic regions affected by the disease

would change to:

Cheek, upper lip, lower lip, nose, hard palate, maxilla, oral commissure, zygoma, infra-orbital region, mandible, were the major facial anatomic regions affected by the disease in the individuals identified in our review.

in abstract

would reword

Often, the aesthetic damage becomes a source of stigma leading to isolation from society and the family

to:

Often, the aesthetic damage becomes a source of stigma, leading to isolation from society, as well as one's family.

would reword closing few sentences of abstract (currently below)

Furthermore, patients reported high psychiatric morbidity. These facts can well describe the severity of the disease. Thus, the findings of this study also support these assertions. Three fourth of the retrospectively studied Noma cases were presented with 25-75% of facial tissue damages.

to:

Similarly, our review found a high level of psychiatric morbidity. Would then remove "

These facts can well describe the severity of the disease. Thus, the findings of this study also support these assertions"

then

this last sentence of the abstract - below - was also unclear to me (and also grammatically incorrect as written).

this needs to be better explained

Three fourth of the retrospectively studied Noma cases were presented with 25-75% of facial tissue damages.

line 18- would not capitalize oro-facial

line 19 - consider removing :debilitated" from the sentence - it's meaning is vague in this context

lines 20 to 22:

If not controlled the condition perforates the facial skin and causes severe damage, particularly to the mid-facial structures.

would reword sentence to:

If not controlled, the natural course of the condition leads to a perforation through the skin of the face, creating a severe cosmetic and functional defect, which often affects the mid-facial structures.

line 33-34

The facial defects depicted minor to severe tissue damages.

again,

would change to below (important to remove 'depicted' as that is not the best word choice for what you are trying to describe - and the below rewording is one way to accomplish this.

to:

The facial defects ranged from minor to severe tissue damage.

line 35-36

reword - and chin are the major facial anatomic regions affected by the disease.

to:

and chin are oftentimes the major facial anatomic regions affected by Noma in general.

then - the next line allows you to describe your findings.

line 36-37

This sentence needs to be reworded (I mentioned this earlier - but the precise meaning of the sentence is unclear). I would remove in general, as it is apparent that you are talking about your study individuals.

line 41 - again change 'chewing' to mastication and

change

...or even vision to ...and/or even lead to changes in vision.

line 49

oro-facial should not be capitalized

line 49 - would remove the word - apparatus

would change to:

line 49

would chnage Noma is a necrotizing and disfiguring disease of the Oro-facial apparatus (1)

to:

Noma is a necrotizing and disfiguring condition of the oro-facial and para-oral structures (1).

line 54- measle should be measles

line 54 - would remove

debilitating disease from the sentence - as this term is vague

line 54 would change phrase

bad living conditions to:

poor living conditions

line 54 would change

On

55 the other hand, the typical predisposing factors in young adults, especially in armed forces,

56 are poor oral hygiene, smoking, viral respiratory infections, and immune defects such as in

57 HIV/AIDS (5) (6) (7).

to:

Alternatively, typical predisposing risk factors in young adults, including those who serve in the military include: poor oral hygiene, smoking, viral respiratory infections, and immune defects, such as HIV/AIDS.

line 57 'characteristics' should be 'characteristic' - that is making it singular rather than plural

line 58 would change

'and bad taste'

to:

changes in taste

line 58 would change

Malaise, fever, and cervical lymph node enlargements are rare but possible disease symptoms

to:

Malaise, fever, and cervical node enlargement are less commonly reported in those with ANUG.

line 60

and sometimes, greyish pseudomembranes (8).

would change to:

and sometimes the presence of grey pseudomembranes (8)

line 62 - replace 'the disease' with 'Noma'

line 67

would change:

and blackish necrosis

to:

necrosis

line 68

would change

increased respiratory rate

to:

tacyhpnea

line 69

and regional lymphdenopathy are typical.would changeto:

...and regional lymphadenopathy are common clinical findings or frequently occur (as blending symptoms with physical exam findings)

line 76 would replacechewing with mastificaton

line 77

evidence would be changed to:

experience.

line 77 to 78 - would change the beginning of the sentence to: In those with more advanced Noma, ...

line 80 - it appearsas though are you describing the initial stages of Noma - however, this order can be improved - as I would talk above the early stages of Noma - and then go through a discussion of the progression - to allow for readersto understand the natural history of Noma, with regardsto it's temporal progression

lines 89-90

the outcome is reported to be less than complete recovery

would change to:

Noma is associated with considerable morbidity and mortality

line 91

Often, survival patients

change to:

Often, those patients that survive...

line 92 to 93

However, these longer-term effects and particularly

93 the psychosocial aspects have been studied rarely.

would reword to:

However, these longer-term effects, including psychosocial aspects, are incompletely understood and an area for further study.

would change:

However, the attention given to this ruinous condition is remained to be very low

to:

However, attention and resources dedicated to this devastating condition remains inadequate.

line 96-97 - would remove this sentence

So far, there are no considerable systematized studies conducted

97 in Ethiopia regarding Noma

line 98 - would change

the country

to:

Ethiopia

line 99 would change

scientific knowledge gap

to:

current knowledge gap

line 104 change

considered

to:

undertaken

subdues

perhaps you mean:

describes?

line 127 - put an "and" in before the word 'locked"

All the patients’

134 information was treated secretly

would rephrase to:

Medical information was kept confidential

line 234 - would change damages to damage

line 276 - would change

Noma is a disfiguring necrotizing disease of the Oro-facial tissue

to:

Noma is a disfiguring necrotizing condition of the oro-facial tissues.

It is the descendant of ANUG

277 (4)

would change to:

Noma may be an extension of ANUG (acute necrotizing ulcerative gingivitis).

line 283 - I would remove this phrase phrase from the sentence

"which resembles a dramatic amalgamation of

oncologic, congenital, and traumatic deformities "

line 296

disclosed 84.3%

would reword- I believe you mean 84.3% of the cases had involvement of the cheeks

line 301 to 306 would remove the discussion of the below case report

A case report presented a 20-year-old Laotian woman

302 presented with a large facial defect and bilateral trismus. The report revealed a major soft-

303 tissue defect involving the right cheek, nasal ala, upper lip and oral commissure, and severe

304 trismus. The defect was reported to be the precursor of foul-smelling and fulminating ulcers

305 developed over the patient’s right cheek and evolved into a black eschar that eventually

line 306 orofacial should not be capitalized

line 311 - would better define "dental anarachy" the word anarachy in this context is unclear

line 319 - would remove "tenacious" from the sentence

line 320 would replace

need

with require

line 329 - would change

among the underprivileged society where patients do not have access to

330 proper medical care.

to:

Noma oftentimes occur in impoverished individuals, particularly in malnourished individuals.

Those who do develop Noma are doomed to suffer the tragic

331 consequences of disfigurement and functional impairment, or death

change to:

Noma is associated with significant morbidity and mortality.

line 334

change

psycho-social crisis

to: negative pyscho-social effects

The overall burden of the disease should be

335 better explained by calculating the disability-adjusted life year (DALY). As DALY is a measure

336 of the number of years lost due to ill-health (physical, mental and social), disability, or early

337 death.

This work can also provide the basis for burden of diseases calculations that can explain

338 better the disease ill-outcomes and generally a gateway to gradually more complex, yet also

339 increasingly improved descriptions of the reality.

would remove these above three sentences - did you provide DALYs/estimate?

--------------------

PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Dr Seidu Adebayo Bello

Reviewer #2: No

Figure Files:

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org.

Data Requirements:

Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Submitted filename: Cancrum Oris review.docx

Click here for additional data file.

17 Jun 2022

Submitted filename: Response to reviewers_PLOS_HGG_LC.docx

Click here for additional data file.

26 Jul 2022

Dear Dr. Gebretsadik,

Thank you very much for submitting your manuscript "A retrospective clinical, multi-center cross-sectional study to assess the severity and sequela of Noma/Cancrum oris in Ethiopia" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations.

Editorial comments:

1. Table……………………………Line tables are not acceptable in scientific writing. PLs employ no line designs to eliminate the lines

2. Dental involvement has been reported in the majority of medical records reviewed in this study. Out of the total 163 medical records reviewed, 7.4% (n=12) had no dental 266 information………….In scientific reseach , source of information could be medical records also known as case file or a proforma. But once inforemation are retrieved, these sources are dropped and we focus on the subjects. The above statement should be repframed as follows:

Dental involvement has been reported in the majority of the patients in this study. Out of the

total 163 patients reviewed, 7.4% (n=12) had no dental 266 information

3. Discussion: The authors have shown that they understand how to employ result for discussion, however it takes the reader 26 lines before the mention of the study results. Just a brief introduction is needed before bringing your result. Maximum within 5 to 10 lines.

Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to all review comments, and a description of the changes you have made in the manuscript.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Thank you again for your submission to our journal. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Joseph M. Vinetz

Section Editor

PLOS Neglected Tropical Diseases

Joseph Vinetz

Section Editor

PLOS Neglected Tropical Diseases

***********************

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: Methodology is in order

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: Analysis and figures well presented. The tables should be change dfrom Line design to non line design

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: Appropriate

--------------------

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: Its ok

--------------------

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: Substaantial revision done

--------------------

PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Dr Seidu Bello

Figure Files:

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org.

Data Requirements:

Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

References

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article's retracted status in the References list and also include a citation and full reference for the retraction notice.

Submitted filename: REvision Review PNTD 22.docx

Click here for additional data file.

12 Aug 2022

Submitted filename: Response to reviewers_PLOS_HGG_LC.docx

Click here for additional data file.

1 Sep 2022

Dear Dr. Gebretsadik,

We are pleased to inform you that your manuscript 'A retrospective clinical, multi-center cross-sectional study to assess the severity and sequela of Noma/Cancrum oris in Ethiopia' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Joseph M. Vinetz

Section Editor

PLOS Neglected Tropical Diseases

Joseph Vinetz

Section Editor

PLOS Neglected Tropical Diseases

***********************************************************

8 Sep 2022

Dear Dr. Gebretsadik,

We are delighted to inform you that your manuscript, "A retrospective clinical, multi-center cross-sectional study to assess the severity and sequela of Noma/Cancrum oris in Ethiopia," has been formally accepted for publication in PLOS Neglected Tropical Diseases.

We have now passed your article onto the PLOS Production Department who will complete the rest of the publication process. All authors will receive a confirmation email upon publication.

The corresponding author will soon be receiving a typeset proof for review, to ensure errors have not been introduced during production. Please review the PDF proof of your manuscript carefully, as this is the last chance to correct any scientific or type-setting errors. Please note that major changes, or those which affect the scientific understanding of the work, will likely cause delays to the publication date of your manuscript. Note: Proofs for Front Matter articles (Editorial, Viewpoint, Symposium, Review, etc...) are generated on a different schedule and may not be made available as quickly.

Soon after your final files are uploaded, the early version of your manuscript will be published online unless you opted out of this process. The date of the early version will be your article's publication date. The final article will be published to the same URL, and all versions of the paper will be accessible to readers.

Thank you again for supporting open-access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases