Can the current monkeypox affect the heart? A Comprehensive Systematic Review

doi:10.21203/rs.3.rs-2252998/v1

Background

Till now all symptoms of monkeypox virus aren’t known, and we still discover new symptoms associated with monkeypox. Accordingly, we aimed to summarize evidence about cardiac complications associated with monkeypox virus.

Methods

On Oct. 27, 2022, a systematic search of the literature was done to locate papers that discuss any cardiac complications associated with monkeypox, then data were analyzed qualtitively.

Results

five articles including seven cases that reported cardiovascular complications of the disease were included in the review, it was reported that five were men of which four are bisexual or gays which reveal the importance of the sexual route in the disease transmission. All of seven cases have different forms of cardiac complications such as acute myocarditis, pericarditis, pericardial effusion and myopericarditis. Most of them have evidence of systemic inflammatory response in the form of fever, myalgia, and headache.

Conclusions

The first study summarizes cardiac complications of monkeypox infection. It indicates the possibility of cardiac complications of monkeypox infection which can be managed by supportive treatment and complete rest for a period that may reach 6 months depending on the status of the patient.

Monkeypox

monkeypox

cardiomyopathy

myocarditis

pericarditis

sexual transsmission

Monkeypox is a viral zoonotic disease caused by the monkeypox virus (MPXV) which is a member of the orthopoxviral genus as a part of the Poxviridae family of viruses [1]. The first human case of the disease was firstly detected in 1970 after the eradication of smallpox [2] and from the epidemiological history of the disease, it was mainly endemic to central and western regions of Africa with a few sporadic cases outside Africa due to the traveling to these African countries then the importation of animals such as Squirrels and rodents from Ghana in 2003 leads to an outbreak of the disease in USA [3]

The 1st human case of monkeypox in 2022 was reported to the WHO on 7 May 2022 from a traveler who returned from Nigeria then the cases started to increase in number which promoted the WHO to declare the monkeypox disease as a public health emergency of international concern to raise the awareness about it and promote the countries preparedness [4]. According to the center for disease control and prevention (CDC), the total number of monkeypox cases is 76806 in both the endemic and non-endemic sites of the disease.

The disease manifestation starts with a prodromal phase of fever, headache, myalgia, lymphadenopathy, and other features which last 5 days, it’s a common period that occurs with other Orthpoxviruses followed by the rash development which proceed over different phases starting with macular, papular, vesicular, pustular, and finally, the crustation phase lasting from two to four weeks on common sites on the body such as the face, palm and soles, and oral membranes. The disease also may include certain complications such as cellulitis, Encephalitis, Corneal infection, and Sepsis[5]. This reveals the diversity of the disease manifestations, but other manifestations are unknown till now, so we aim here to summarize the cardiological complications of the monkeypox infection.

We followed the approaches for conducting the current study based on the Cochrane handbook of systematic reviews on interventions [6]. During the drafting of our manuscript, we strictly followed the recommended reporting items for the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines. [7]

Search Strategy

The following electronic databases were systematically searched: Pubmed, Cochrane, Medline, Scopus, and WoS till 27 Oct. 2022. We used the following search strategy in the previously mentioned databases: ((Monkeypox) AND (cardi* OR Heart OR myocarditis or cardiomyopathy)). All the included studies’ references were screened to avoid missing any studies and guarantee high-quality screening.

Eligibility Criteria

We included the studies following the eligibility criteria as follow: any patient has cardiac complications (myocarditis, pericarditis, pericardial effusion or myopericarditis) after monkeypox infection, the study design included any original study design (case reports، case series, cohort, etc.). On the other hand, we excluded non-human studies, conference abstracts, review, and non-English studies.

Screening And Study Selection

Using Endnote software (version X20.4.1), we collected the different records from the different databases and removed duplicates. To determine the relevancy, the retrieved references were examined. The screening was done in two steps; title and abstract screening, followed by full-text screening for final eligibility. Two independent authors conducted the screening, and after comparing their findings, group discussions were used to settle any differences.

Data Extraction

The following data was extracted from the included studies by two independent authors. Study ID, Setting, Study design, Sample, Age, Male gender, Presenting symptoms (Systemic, Non-systemic, and Cardiac), History of vaccinations, History of other infections, Homosexual/bisexual/MSM (Yes/No), Route of transmission, Immunocompromised (Yes/No), Treatment (Monkeypox and Myocarditis), Duration of hospitalization, and Investigation (Monkeypox, Myocarditis, and Follow-up). Arguments were later resolved through group discussion.

Quality Assessment

The quality of included studies was assessed using the National Institute of Health (NIH) quality assessment tool for case reports and case series. The tool assesses the quality of each study at the level of nine domains. Each domain, as well as the overall quality, is given a rating of good, fair, or poor [8]. Two independent authors assessed the quality of the included studies and arguments were later resolved through group discussion.

Data Synthesis

Qualitative analysis was done by collecting and summarizing non-numerical data to understand symptoms, criteria and how to manage the cases of mankeypox associated with cardiac complications.

Search results

The search strategy over the different medical databases (PubMed, Scopus, Web of Science, Medline, Cochrane) has yielded 144 studies, which became 106 studies after removing duplication. Screening the title and the abstract yield twenty studies after excluding eighty-six papers because of being animal studies, out of the study criteria, and/or not primary studies. Twenty articles were screened for their full-text testing for eligibility. Five articles[3,4,9-11] met the study question and were further included in the quality assessment (Figure 1). A summary of the included papers can be found in (Table 1).

Baseline characteristics and data analysis

The data presented in the form of case reports were collected and analyzed descriptively. Almost all study participants were males. Most of the patients who eventually developed pericarditis or myocarditis have evidence of systemic inflammatory response in the form of fever, myalgia, and headache. Additionally, four patients developed maculopapular eruption that is sometimes umbilicated. The location of the rash was related to the site of sexual contact including genital, anal, or oral regions. The presentation of myocarditis in the afflicted patients was usually manifested with chest pain that sometimes radiate to the left arm. The history of poxvirus vaccination was either unamenable or negative in all selected patients. Despite the absence of clear vaccination history, two of the patients have a syphilis history with one patient having a history of well-controlled HIV.

Three of the patients have a history of promiscuous and dangerous sexual behavior including (gay, bisexual, or homosexual). When Monkeypox and myocarditis have encountered the aim of treatment is usually supportive. However, one patient was prescribed doses of aspirin aiming to relieve the pericarditis. Real-time PCR targeting the virus nucleic material from the skin lesion was the only method used to surely diagnose the current infection with Monkeypox. To verify the diagnosis of pericarditis and myocarditis various methods are used. Serum troponin was used to diagnose associated myocarditis in most of the patients. In addition, a serial electrocardiogram was usually used to aid the diagnosis of pericarditis. One patient has required cardiac magnetic resonance imaging to confirm the myocarditis. Besides. 2 patients have utilized echocardiography either (transthoracic, transesophageal) to have a proper visualization of the cardiac function and pericardial fluid collection.

Quality Assessment

We have used the NIH quality assessment tool for case series to assess the quality of the included studies as previously described[8]. Two of the included studies have a good quality assessment (>6)[3,10], two studies have a fair assessment (from 3 points to 6 points)[11,12], and one study has a poor assessment (<3)[9]. (Table 2)

The declaration of monkeypox as a public health emergency by the WHO on 23 July 2022 has raised the awareness and the alertness about the disease's manifestation and complications[13]. Our objective in this study is to identify the cardiovascular complications associated with monkeypox infection which is an important aspect of the disease to know how to diagnose and predict the patient status based on the presenting symptoms.

We included five studies that reported cardiovascular complications of the disease in which a total of seven patients were included, it was reported that five were men of which four are men who have sex with men which reveal the importance of the sexual route in the disease transmission as it was reported by the CDC, the sexual contact with an infected patient with monkeypox is considered the main route of the disease transmission during the current outbreak and from the different reported monkeypox cases to the CDC, the male gender is considered the most reported group of patients to CDC.

The patients were diagnosed and confirmed to have monkeypox by using the polymerase chain reaction (PCR) in a specimen from the presenting lesions and based on the presenting symptoms as having chest pain, they undergo certain investigations such as cardiac troponins, chest radiograph, electrocardiogram, Echocardiography, and other laboratory tests and then followed during the hospital stay with other investigations such as Echocardiography, cardiac enzymes, and CMR study to monitor the progression of the case.

From these reported cases, monkeypox becomes a member within a group of viruses causing Viral myocarditis such as Coxsackie (A, B), Adenovirus, Cytomegalovirus, Varicella-zoster virus, Mumps, HIV, Vaccinia besides other viruses by different mechanisms upon which the management is dependent[14]. Cardiomyopathy was reported among the complication associated with Covid-19 as cardiomyopathy, myocarditis, cardiac arrhythmias, and endotheliitis[15], Wichmann et al reported the presence of the virus in five out of 12 patients with a confirmed Covid-19 infection[16].

Grumbach et al reported from a study involving 31 patients with myocarditis and dilated cardiomyopathy, an enteroviral genome was detected in 27.3% of the total number which indicates the involvement of enteroviruses in cardiomyopathy[17], Kytö et al. reported that viral nucleic acid was detected in a group of patients out of forty patients with cardiomyopathy by the means of PCR as follow 15 patients for cytomegalovirus, 4 patients with parvovirus B19, one patient with enterovirus and one with human herpesvirus 6[18], which means history of myocarditis with viral infection has existed since previous viral infections, and this is what makes us anticipate the presence of viral myocarditis as a complication of monkeypox viral infection.

The management of Viral myocarditis is dependent on the presenting symptoms and the patient must be initially diagnosed appropriately by using different differential diagnostic techniques to roll out any other causes of the presenting symptoms[19]. Regarding our scope here of the cardiovascular complications that were reported in the cases, we aim to study myocarditis, pericarditis, and myopericarditis. Pericarditis that involves chest pain and neither prominent damage to the heart tissues nor an elevation in the cardiac troponins can be managed by using Colchicine 1–2 mg as an initial dose that will be decreased gradually, and a lower dose of non-steroidal anti-inflammatory drugs can be used as symptomatic treatment[20].

As it was reported in the cases, they were advised to stop any physical activity for a period that may reach 6 months depending on the status of the patient. Other forms of cardiovascular complication include heart failure with its different grades and arrhythmias associated with myocarditis and both of them should be managed according to reasonable guidelines[19]. This is a recommendation on how to deal with the myocarditis-associated monkeypox infection and this review highlights the cardiovascular aspect of the disease to make the healthcare professionals aware of this aspect to be taken into consideration during the assessment of the cases.

Strengths and Limitations

Among the limitations is the small number of cases from the case reports and case series reported cardiovascular complications which necessitate the need for more studies to identify the pathogenesis behind this effect. Among the strengths, our systematic review complies with JBI and PRISMA-ScR guidelines, and most of included studies were evaluated with fair and good quality.

This is the first study to provide a summarized review about cardiac complications of monkeypox infection. Our findings indicate the possibility of cardiac complications of monkeypox infection such as myocarditis, pericarditis, pericardial effusion and myopericarditis, which can be managed by supportive treatment and complete rest for a period that may reach 6 months depending on the status of the patient.

Data availability statement

Data will be provided upon request from Reem Sayad ([email protected])

Funding

This study received no funding

Conflict of interest

No conflict of interest declared

Author contribution statement

Study concept and design: ASE and RS, Acquisition of data: RS, AS, and AH, analysis and interpretation of data: AS and AH, Manuscript writing: RS, AS, ASE, AND AH, Supervision: ASE, revision and approval: all members.

Consent for publication

This review doesn’t have any presentations of case reports that needed consent for publication.

Acknowledgements

None.

McCollum AM, Damon IK. Human monkeypox. Clin Infect Dis. 2014;58:260–7.
Ladnyj I, Ziegler P, Kima E. A human infection caused by monkeypox virus in Basankusu Territory, Democratic Republic of the Congo. Bull World Health Organ. 1972;46:593.
Thornhill JP, Barkati S, Walmsley S, Rockstroh J, Antinori A, Harrison LB, Palich R, Nori A, Reeves I, Habibi MS. Monkeypox virus infection in humans across 16 countries—April–June 2022. N Engl J Med. 2022;387:679–91.
Tan WYT, Wong CS, Ho MZJ, Said Z, Cui L, Lin RTP, Chan M, Vasoo S, Lee VJM, Leo YS. The first imported case of monkeypox in Singapore during the 2022 outbreak–Reflections and lessons. Travel Med Infect Dis. 2022;50:102431.
Webb E, Rigby I, Michelen M, Dagens A, Cheng V, Rojek AM, Dahmash D, Khader S, Gedela K, Norton A. Availability, scope and quality of monkeypox clinical management guidelines globally: a systematic review. BMJ global health. 2022;7:e009838.
Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA. Cochrane handbook for systematic reviews of interventions. John Wiley & Sons; 2019.
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst reviews. 2021;10:1–11.
National Heart L, Institute B. Study quality assessment tools. National Institutes of Health. Edited by.
Pinho AI, Braga M, Vasconcelos M, Oliveira C, Santos LD, Guimarães AR, Martins A, Chen-Xu J, Silva S, Macedo F. Acute Myocarditis–a new manifestation of Monkeypox infection? JACC: Case Reports 2022.
Rodriguez-Nava G, Kadlecik P, Filardo TD, Ain DL, Cooper JD, McCormick DW, Webber BJ, O'Laughlin K, Petersen BW, Narasimhan S. Myocarditis Attributable to Monkeypox Virus Infection in 2 Patients, United States, 2022. Emerging Infectious Diseases 2022, 28.
Shaik TA, Voloshyna D, Nasr TH, Makki A, Kosuru SH, Khan MH, Ghobriel NG, Sandhu QI, Saleem F. Monkeypox-Associated Pericarditis: A Maiden Case. Cureus 2022, 14.
Tan DH, Jaeranny S, Li M, Sukhdeo SS, Monge JC, Callejas MF, Hasso M, Fattouh R, Lalonde SD, Lam J. Atypical clinical presentation of monkeypox complicated by myopericarditis. In: Open Forum Infectious Diseases. Oxford University Press; 2022. ofac394.
Sah R, Padhi BK, Siddiq A, Abdelaal A, Reda A, Ismail Lashin B, Mohanty A, Alshahrani Z, Rodriguez-Morales N AJ: Public Health Emergency of International Concern declared by the World Health Organization for Monkeypox. Global Security: Health, Science and Policy 2022, 7:51–56.
Kearney M, Cotton J, Richardson P, Shah A. Viral myocarditis and dilated cardiomyopathy: mechanisms, manifestations, and management. Postgrad Med J. 2001;77:4–10.
Kang Y, Chen T, Mui D, Ferrari V, Jagasia D, Scherrer-Crosbie M, Chen Y, Han Y. Cardiovascular manifestations and treatment considerations in COVID-19. Heart. 2020;106:1132–41.
Wichmann D, Sperhake J. P., Lütgehetmann M. Autopsy findings and venous thromboembolism in patients with COVID-19. Ann Intern Med. 2020;173:268–77.
Grumbach IM, Heim A, Pring-Akerblom P, Vonhof S, Hein W, Müller G, Figulla H. Adenoviruses and enteroviruses as pathogens in myocarditis and dilated cardiomyopathy. Acta Cardiol. 1999;54:83–8.
Kytö V, Vuorinen T, Saukko P, Lautenschlager I, Lignitz E, Saraste A, Voipio-Pulkki L-M. Cytomegalovirus infection of the heart is common in patients with fatal myocarditis. Clin Infect Dis. 2005;40:683–8.
Olejniczak M, Schwartz M, Webber E, Shaffer A, Perry TE. Viral myocarditis—Incidence, diagnosis and management. J Cardiothorac Vasc Anesth. 2020;34:1591–601.
Sarda L, Colin P, Boccara F, Daou D, Lebtahi R, Faraggi M, Nguyen C, Cohen A, Slama MS, Steg PG. Myocarditis in patients with clinical presentation of myocardial infarction and normal coronary angiograms. J Am Coll Cardiol. 2001;37:786–92.

N		1		2		3	4	5
Study ID		Pinho et al. 2022		Rodriguez-Nava et al. 2022		Shaik et al. 2022	Tan et al. 2022	Thornhill et al.2022
Study ID				Case 1	Case 2			Case 1	Case 2
Setting		Portugal		USA		USA	Canada	16 Countries
Study design		Case-Report		Case-Report		Case-Report	Case-Report	Case-series
Sample		1		2		1	1	2
Age		31 years		32 years	37 years	51	40	NA	NA
Male gender		Yes		Yes	Yes	Yes	Yes	NA	NA
Presenting symptoms	Systemic	Malaise, myalgias and fever		Viral illness with cervical lymphadenopathy	Fever, dyspnea, bilateral inguinal lymphadenopathy and decreased exercise tolerance.	Fatigued with a gradual progression of fever, flu-like symptoms and malaise.	Fever, chills, myalgias, and headache	NA	NA
	Non-systemic	Eruption of multiple swollen and umbilicated cutaneous lesions on his face, hands, and genitalia		Disseminated rash and a painful penile lesion	Multiple skin lesions in both arms and a lesion at the base of the penis	Developed several vesiculopustular lesions on his face and extremities.	Umbilicated maculopapular and vesicular skin lesions over his chest and arms, lips, and genital regions.	NA	NA
	Cardiac	chest tightness radiating to the left upper extremity that awoke him during the night		Chest pain and dyspnea for 1 day	Difficulty breathing and decreased exercise tolerance without chest pain breathing and decreased exercise tolerance without chest pain	Retrosternal chest pain radiating to the left arm.	Central, nongraduating, pressure-like chest pain but denied cough, palpitations, or shortness of breath.	NA	NA
History of vaccinations		NA*		No	No	NA	NO	NA	NA
History of other infections		Paucisymptomatic, and SARS-CoV-2 infection		Syphilis	Syphilis	NA	HIV	NA	NA
Homosexual/bisexual/MSM (Yes/No)		Yes		Yes	Yes	NA	Yes	NA	NA
Route of transmission		NA		Sexual transmission	Sexual transmission	NA	Sexual transmission	NA	NA
Immunocompromised (Yes/No)		NA		No	No	No	No	NA	NA
Treatment	Monkeypox	NA		Oral tecovirimat	Supportive care	Supportive care	Valacyclovir	NA	NA
Treatment	Myocarditis	Supportive care and exercise restriction		No specific treatment	Supportive care	Nitroglycerin, and aspirin	NA	NA	NA
Duration of hospitalization		7 days		10 days	4 days	7 days	NA	NA	NA
Investigation	Monkeypox	PCR assay of a swab sample from a skin lesion.		PCR test on a skin lesion specimen.	Non-variola orthopoxvirus PCR from skin lesion specimens.	PCR	Real-time PCR in skin lesions	NA	NA
	Myocarditis	ECG, Chest X-ray, TTE, and laboratory tests ( C-reactive	protein - creatine phosphokinase - troponin I - brain natriuretic peptide)	Troponin T and N-terminal prohormone B-type natriuretic peptide, Electrocardiogram, chest radiograph, C-reactive protein, and erythrocyte sedimentation rate	Serum troponin I, B-type natriuretic peptide, electrocardiogram, and Echocardiography	Hb (g/dL), MCV (fl), WBC (X109/l), Platelets (X103/ul), ALT (IU/L) ,AST (IU/L) ,BUN (mg/dL) ,Cr (mg/dL) ,CRP (mg/L) ,ESR (mm/hr.), Troponin I (ng/mL) , Troponin T (ng/mL) , HbA1c% ECG, and TEE	Routine chemistries and complete blood count, troponin Serial electrocardiograms Creatine kinase, Cardiac catheterization, Cardiac magnetic resonance imaging	NA	NA
	Follow-up	CMR study		Echocardiography and high-sensitivity troponin	Cardiac enzymes testing	High-dose aspirin, and a planned cardiac follow-up	NA	NA	NA

Table 1: summary of included studies.

NA*: not applicable

Author (YOP)*	Q1	Q2	Q3	Q4	Q5	Q6	Q7	Q8	Q9	Overall rating
Pinho et al. 2022	N	N	NA	NA*	N	N	NA	NA	N	Poor
Rodriguez-Nava et al. 2022	Y	Y	Y	Y	Y	Y	Y	NA	Y	Good
Shaik et al. 2022	Y	Y	NA	NA	Y	NA	Y	NA	Y	Fair
Tan et al. 2022	Y	Y	NA	NA	Y	Y	Y	NA	Y	Fair
Thornhill et al.2022	Y	Y	Y	NA	Y	Y	Y	Y	Y	Good

Table 2: The quality of included studies using the NIH tool for case series.

YOP: Year of publication; Y: Yes: N: No; NA: not applicable; NIH: national institute of health

Q1: Was the study question or objective clearly stated? Yes/No/Unclear

Q2: Was the study population clearly and fully described, including a case definition?

Q3: Were the cases consecutive?

Q4: Were the subjects comparable?

Q5: Was the intervention clearly described?

Q6: Were the outcome measures clearly defined, valid, reliable, and implemented consistently across all study participants?

Q7: Was the length of follow-up adequate?

Q8: Were the statistical methods well-described?

Q9: Were the results well-described?

No competing interests reported.

Can the current monkeypox affect the heart? A Comprehensive Systematic Review

Status:

Version 1

Abstract

Background

Methods

Results

Conclusions

Figures

Introduction

Materials And Methods

Search Strategy

Eligibility Criteria

Screening And Study Selection

Data Extraction

Quality Assessment

Data Synthesis

Results

Discussion

Strengths and Limitations

Conclusion

Declarations

References

Tables

Additional Declarations

Status:

Version 1