Case Report: Glans penile necrosis in a patient with SARS-CoV-2 and leprosy infection

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was firstly identified in China and has been declared a global pandemic. Several serious extrapulmonary manifestations due to SARS-CoV-2 infection have also been reported and associated with hypercoagulability thrombotic vasculopathy. In addition, cases of Mycobacterium-leprae infection have also been known associated with blood coagulation abnormality. Methods Here, we report a 56-year-old male with coronavirus disease-19 (COVID-19) with concomitant leprosy infection with manifestation of glans penile necrosis, presented to the emergency department with acute penile pain. This case is unique because no occlusion blood flow to the penile was observed in the radiographic imaging. We described the potential pathophysiology in this case through a literature review. Results The patient received treatment according to the COVID-19 protocol and was given low molecular weight heparin (LMWH) therapy for 4 days. During the follow up, the clinical and functional condition of the penis showed significant improvement. Conclusions Microthrombus involvement, platelet abnormalities and impaired hemostasis due to SARS-CoV-2 and leprosy co-infection are the hypothesis in this case report.


Introduction
At the beginning of 2020, the World Health Organization (WHO) declared novel coronavirus disease-2019 (COVID- 19)  infection as a pandemic which caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) that has led to a global health crisis due to acute respiratory distress syndrome (ARDS). 1 The pandemic started in the seafood market of Wuhan, China, and rapidly spreading to Thailand, Japan, south Korea, Singapore, Iran, Italy, Spain, United States, United Emirates Arab, and United Kingdom. 2 SARS-CoV-2 is an enveloped positive single-stranded RNA virus with a 5 0 terminal that encodes proteins necessary for virus replication and a 3 0 terminal that contains five structural proteins: membrane protein (M), envelope protein (E), spike protein (S), nucleocapsid protein (N), and hemagglutinin-esterase protein (HE). 3st cases have mild-to-moderate symptoms, with approximately 15% developing severe pneumonia, while about 5% developing ARDS and organ failure. 4Other serious complications related to SARS-CoV-19 infection include hypercoagulability and thrombotic vasculopathy with clinical manifestations such as coronary syndrome, deep vein thrombosis, ischemic stroke, and pulmonary embolism. 5,6Recently, other serious clinical manifestations associated with genitalia condition were reported in patients with SARS-CoV-2 infection with penile ischemia. 7In patients infected by SARS-CoV-2, penile priapism and erectile function has also been reported, probably as a result of changed immunological and endothelial pathways, as well as the simultaneous production of the ACE and TMPRSS2 proteins.][10] Some authors have speculated that these conditions related to COVID-19 may be due to severe hypercoagulability and thrombotic tendency observed in patients with COVID-19. 7,11 the other hand, penile involvement in leprosy is uncommon. 12Leprosy (also known as Hansen's disease) is an infection caused by Mycobacterium leprae (M.leprae) that can damage the peripheral nerves and bone absorption.Leprosy has two distinct phases: direct infection of macrophages and Schwann cells and reactional episodes.Approximately 50% of patients with leprosy are affected by a reactional episode, 13 which occurs because of endothelial inflammation leading to necrotizing pan-vasculitis.This condition, in severe cases, progresses to necrotic hemorrhagic lesions of the extremities and trunk, as well as Lucio's phenomenon. 14,15nile ischemia or necrosis is rare due to its abundant blood circulations.Usually, penile necrosis is associated with thrombotic phenomena and calcium deposits in patients on dialysis. 16However, no previous cases of penile ischemia in a COVID-19 patient who concomitantly infected with leprosy have ever been reported.Here, we presented a unique case of penile necrosis in acute COVID-19 and leprosy infection following the CARE guidelines. 17To the best of our knowledge, this case is the first case presenting penile glans necrosis in COVID-19 patient concomitant leprosy.We also described the potential pathophysiology of glans penis necrosis in this case through a literature review.

Case report
A 56-year-old Indonesian male patient was admitted to Dr. Zainoel Abidin General Hospital in Aceh, Indonesia.He was referred from a regional hospital with SARS-CoV-2 infection and necrotic penile glans.Complaints of changes in the color of the glans penis occur progressively without any past intervention.In addition, he also complained of pain in the penis, dysuria and difficulty urinating.He worked as a farmer, actively smoked since he was an adolescent, and does not consume any drugs or alcohol.Currently, he is undergoing treatment for leprosy disease.Table 1 summarizes the patient's characteristics.
The patient has been diagnosed with leprosy since April 2021, he complained of a rash and atrophy of the hand muscles.Then the patient received leprosy treatment with a regiment of clofazimine 50 mg and Dapsone 100 mg.This patient had a past medical history of hypertension, which is well-controlled with 10 mg/day oral amlodipine.There was no complaint in micturition, meatal discharge, and other genital problems.
On examination, his condition was stable with blood pressure 134/91 mmHg, pulse 90 bpm, respiratory 22 breaths/ minute, and oxygen saturation at 97% on room temperature.The patient was afebrile and fully alert.His localized status found a discoloration involving the penile glans (Figure A).

REVISED Amendments from Version 3
In this version, we added references to the introduction section according to the reviewer's suggestions.
Any further responses from the reviewers can be found at the end of the article An urgent radiologic investigation with Doppler ultrasound of the penile and pelvic computerized tomography (CT) angiography revealed no occlusion nor thrombus on the arteria that supplies the penile (Figure B).
The patient was admitted to the COVID ward with therapy as follows; 2 L/min nasal oxygen, 1000 mg ceftriaxone injection twice daily, 10 mg amlodipine daily, 50mg clofazimine daily, 100mg dapsone daily, 5000 U vitamin D daily, 1000 mg vitamin C daily and 300 international unit low molecular weight heparin (LMWH) intravenous drip daily for 4 days.No challenges were found during treatment.After 4 days of LMWH administration without any treatment changes, the clinical condition of the gland penile and laboratory of haemostatic was improved, the necrosis was less extensive and limited to one-third of the superficial of the glans penis (Figure C).The patient then continued to isolate in the COVID-19 ward.On 6 weeks follow-up, the clinical and functional condition of the penis were excellent without any unexpected events.The patient's urinary and erectile functions remained unchanged.The patient was also satisfied with the treatment that he received.

Discussion
We searched four online databases (the Medline EMBASE, Google Scholar, PubMed, and Scopus) for the literature review.Four terms related to the patient's condition were combined in the searching strategy; 1) Penile; 2) Penis; 3) COVID-19 and 4) SARS-CoV-2 to investigate the relationship between COVID-19 and leprosy infection in necrosis of glans penis.In the end, we found only one publication by Sarkis et al. that presented the penile ischemic condition in COVID-19 infection. 7This publication reported glans penile discoloration due to ischemia secondary to COVID-19.However, the patient had several comorbidities such as type 2 diabetes, hypertension, and end-stage kidney disease which could also be risk factors for thrombus vasculopathy.
Penile necrosis is linked to thrombotic events and calcium deposits in dialysis patients. 16Another study also reported penile necrosis secondary to purpura fulminans. 18One study in Japan described fifteen patients with penile necrosis due to calciphylaxis and a long history of diabetes. 19In this condition, it is clearly understood that diabetic vasculopathy and calcium deposits can become a thrombus which causes impaired blood flow to penis.In our patient, he had no comorbid precipitating thrombus vasculopathy.Although the patient is an active smoker, we still cannot conclude that this is the cause of penile necrosis.Uniquely, the CT angiography investigation of our patient did not reveal any occlusion or thrombus.On the basis of the above finding, we hypothesized that the patient's penis glans necrosis is caused by COVID-19 and leprosy co-infection.][22][23] There is a definite link between inflammation, hypercoagulation, and thrombosis, according to previous research.Part of this interaction is likely mediated by a cytokine storm, which increases the risk of developing disseminated intravascular coagulopathy. 24The stimulation of coagulation pathways throughout the body by mediators produced during a cytokine storm can result in a prothrombotic condition marked by the formation of microthrombi, diffuse capillary blockage, tissue ischemia, and organ damage. 21This pathogenesis indicates the possible tendency for physiopathology of glans penile necrosis secondary to SARS-CoV-2 infection.
Similar to SARS-CoV-2 infection, leprosy has long been known to trigger haemostasis disorders due to platelet abnormalities, blood coagulation, and fibrinolysis. 13Several studies have previously reported that patients with tuberculoid leprosy who develop erythema nodosum leprosum (ENL) had a longer activated partial thromboplastin time (aPTT) with elevated fibrinogen and platelet activation. 15,25,26One review of related studies conducted by Nery has described thrombophlebitis and pulmonary embolism in leprosy patients who develop ENL. 27Another study also found that leprosy disease was associated with coronary thrombosis and cerebral vascular accidents. 28,29These findings indicate that the severity of leprosy potentially leads to occlusion of blood flow which eventually causes organ damage.We assume that patients co-infected with SARS-CoV-2 and leprosy have a greater risk of complications, especially haemostasis disorders and thrombus vasculopathy, as in our patient who showed elevated of D-Dimer and fibrinogen levels.This case report and literature review provide preliminary evidence of the association between SARS-CoV-2 and leprosy infection in glans penile necrosis; however, further studies are warranted.
This case report and literature review is limited by its short-term follow-up period, however its strength is that as we directly observed the patient rather than taking his information retrospectively, this reduces any potential bias.
Finally, several highlights should be considered in managing glans penile necrosis in patients with COVID-19 infection.
As previously described, penile necrosis can occur as a result of a vasculopathy thrombus.On the other hand, COVID-19 and leprosy infection can also induce coagulopathy and microvascular thrombus.Therefore, choosing anticoagulant therapy than immediate aggressive amputation of the organ is still a viable option.Administering anti-thrombus therapy is a less-intrusive treatment approach that physicians can consider, which gave a good result in our patient.

Conclusions
In our perspective, microthrombus formation, diffuse capillary occlusion and tissue necrosis are the basis of the aetiology penile glans necrosis in our patient.It is likely associated with SARS-CoV-2 and leprosy co-infection.This hypothesis makes this case an interesting report.In addition, from what we know at the time of writing this manuscript, this is the first case report of glans penile necrosis in a patient with SARS-CoV-2 and leprosy co-infection.

Introduction
Correct South Korea in the sentence: "The pandemic started in the seafood market of Wuhan, China, and rapidly spreading to Thailand, Japan, south Korea, Singapore, Iran, Italy, Spain, United States, United Emirates Arab, and United Kingdom." Correct SARS-CoV-2 in the sentence:"Other serious complications related to SARS-CoV-19 infection include hypercoagulability and thrombotic vasculopathy with clinical manifestations such as coronary syndrome, deep vein thrombosis, ischemic stroke, and pulmonary embolism." The term phase is wrong for leprosy.Please rephrase it:"Leprosy has two distinct phases: direct infection of macrophages and Schwann cells and reactional episodes."

Results:
Did the patient had any signs of eritema nodosum?
I recommend that the authors consider making grammatical adjustments to enhance the text's scientific accuracy.

Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes
Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?Partly

Is the case presented with sufficient detail to be useful for other practitioners? Yes
Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Leprosy diagnosis
I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes
Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?Yes

Is the case presented with sufficient detail to be useful for other practitioners? Yes
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Microscopy, Anatomy, Morphology, Histology, Pathology We confirm that have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Version 3
Reviewer

Diana Torge
Department of Clinical Medicine, Public Health, Life and Environmental Sciences, University of L'Aquila, L'Aquila, Italy The aim of this manuscript is to present a unique case of penile necrosis in acute COVID-19 and leprosy infection following the CARE guidelines.Overall, a significant effort was made to prepare this manuscript, which is quite interesting and unique.This article is impressive for the reviewer and audience of the scientific community as well as the study of SARS-CoV-2 infection.This manuscript in fact would show a significant impact, rich content, providing a deep insight for some works: the study is within the journal's scope, and I found it to be well-written, providing sufficient information.Even if the manuscript provides an organic overview, with a densely organized structure and based on well-synthetized evidence, there are several recommendations that can be implemented to improve the clarity and organization of the content.In fact, there are areas that could benefit from improvement to enhance the overall quality of the article.For these reasons, the manuscript requires major changes.
Please find below an enumerated list of comments on my review of the manuscript: MINOR POINTS: The authors should provide a list of the abbreviations, mentioned in this manuscript.World Health Organization (WHO): in this introductive sentence, please, add the related abbreviation.

MAJOR POINTS: INTRODUCTION:
In the introductive section of this manuscript, there is a lack of evidence regarding the temporal background and context of SARS-CoV-2 infection: in fact, the pandemic started in the seafood market of Wuhan, China, in December 2019, rapidly spreading to Thailand, Japan, South Korea, Singapore, Iran, Italy, Spain, the USA, the UAE, and the U.K.Moreover, on 11 March 2020 the World Health Organization (WHO) declared the outbreak of COVID-19 disease a pandemic (Umakanthan S. et al., (2020) 1 ).This will provide a clear background and context, ensuring that readers understand the temporal dynamics of SARS-CoV-2 infection.Another major point of this manuscript is the lack of evidence about the molecular features of SARS-CoV-2 infection: in fact, the causative agent COVID-19, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is an enveloped positive single-stranded RNA virus, whose viral genome includes a 5' terminal, which encodes proteins essential for virus replication, and a 3' terminal, that includes five structural proteins, Spike protein (S), membrane protein (M), nucleocapsid protein (N), envelope protein (E), and hemagglutinin-esterase protein (HE) (Lu R. et al., (2020) 2 ).Furthermore, endothelial damage, associated to COVID-19, is likely to compromise the penile vascular flow, also determining a significant impairment in the erectile function, as suggested by recent structural and ultrastructural studies.SARS-CoV-2 infection exerts its histopathological and clinical effects also on male reproductive tissues, probably due to the simultaneous expression of ACE and TMPRSS2 proteins, altered immunological and endothelial pathways.Specifically, the endothelial integrity is essential for erectile function, so impairment in the erectile function can be considered an extra-pulmonary manifestation of SARS-CoV-2 infection (Torge D., et al., (2022) 3 ).
Exploring morphological evidence associated to SARS-CoV-2 infection in the introduction, referencing recent articles, will enrich the manuscript's quality and captivate reader interest.It is advisable to incorporate pertinent literature quotes to strengthen the manuscript's credibility and relevance.This is the major concern of this manuscript.For these reasons, the authors should improve the references section, by including recent evidence on this topic.The main topic is interesting, and certainly of great clinical impact.As regards the originality and strengths of this manuscript, this is a significant contribute to the ongoing research on this topic, as it extends the research field on a unique case of penile necrosis in acute COVID-19 and leprosy infection.Overall, the contents are rich, and the authors also give their deep insight for some works.
As regards the section of methods, there is a specific and detailed explanation for the methods used in this study: this is particularly significant, since the manuscript relies on a multitude of methodological and statistical analysis, to derive its conclusions.The methodology applied is overall correct, the results are reliable and adequately discussed.The conclusion of this manuscript is perfectly in line with the main purpose of the paper: the authors have designed and conducted the study properly.As regards the conclusions, they are well written and present an adequate balance between the description of previous findings and the results presented by the authors.The authors in fact provided a focused conclusion, which summarizes the key points and challenges discussed in the paper and offers insights into future research directions.Finally, this manuscript also shows a basic structure, properly divided and looks like very informative on this topic.Furthermore, figures and tables are complete, organized in an organic manner and easy to read.In conclusion, this manuscript is densely presented and well organized, based on well-synthetized evidence.The authors were lucid in their style of writing, making it easy to read and understand the message, portrayed in the manuscript.Besides, the methodology design was appropriately implemented within the study.However, many of the topics are very concisely covered.This manuscript provided a comprehensive analysis of current knowledge in this field.Moreover, this research has futuristic importance and could be potential for future research.However, major concerns of this manuscript are with the introductive section: for these reasons, I have major comments for this section, for improvement.

Harrina Erlianti Rahardjo
Department of Urology, Cipto Mangunkusumo Hospital-Faculty of Medicine, University of Indonesia, Jakarta, Indonesia This is a very interesting case report of penile necrosis in a patient with both a Covid and leprosy infection, perhaps this is the first case reported.
However several details need to be provided.
In the case report the author has included the baseline data of the patient, however during treatment and follow up there was only a clinical picture after 4 days of treatment.The authors should also add the penile clinical condition on the 6th week follow up.The data is also lacking on the status of the patient's leprosy infection in terms of clinical history and medication.It would also add substantial information if the authors would include the changes in laboratory parameters throughout the course of treatment.Was it inline with the improvement seen clinically?Changes of the hemostasis lab parameters, clinical progress during treatment and perhaps cytokine data (if it was measured) would add up to a nice discussion.

Is the background of the case's history and progression described in sufficient detail? Yes
Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?Partly Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?
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Figure A .
Figure A. Color change at the glans penile, suggesting clinical signs of penile glans necrosis.

Figure B .
Figure B. Pelvic Computerized Tomography Angiography showed no occlusion that obstructed blood flow in the right and left internal pudendal arteries was observed.

Figure C .
Figure C.The clinical condition at 2-week follow-up after administration of low molecular weight heparin, the necrosis was less extensive and limited to one-third of the superficial of the glans penis.

Reviewer Report 03
September 2024 https://doi.org/10.5256/f1000research.162133.r243966© 2024 Bianchi S et al.This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Serena Bianchi University of L'Aquila, L'Aquila, Italy Diana Torge Department of Clinical Medicine, Public Health, Life and Environmental Sciences, University of L'Aquila, L'Aquila, Italy I have no further comments.Well done.

Table 1 .
Baseline characteristics of the patient.
Report 24 January 2024 https://doi.org/10.5256/f1000research.132446.r224136© 2024 Bianchi S et al.This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The article is accurate and provides relevant Laboratory data of homeostatic parameters after LWMH therapy was improved, we added the data of parameters laboratory after administration of LWMH in table 1.At 6 of follow-up at the polyclinic, we did not check the laboratory haemostatic parameters again.
© 2022 Rahardjo H.This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.