Co-Infection dynamics between Mpox and COVID-19
Mpox is a zoonotic disease caused by the monkeypox virus [21]. The current outbreak of Mpox in July 2022 was declared a global health emergency as it spread to over 100 non-endemic countries [22]. Co-infection of Mpox with COVID-19 has been reported, with patients showing symptoms of both infections. One of the first reported cases of COVID-19 and Mpox confection was from Florida in the United States of America (USA). The patient was immunosuppressed with a history of intravenous drugs on current HAART (highly active antiretroviral therapy and coinfected with Mpox, COVID-19 and herpes [23]. Another case report, published in Barcelona, Spain, revealed a 56-year-old man to have both Mpox and COVID-19 and syphilis simultaneously [24]. According to a review done in 2022, it was found that 3 patients who had sex with men were found co-infected with Mpox and COVID-19 [25]. A 38-year-old from the USA was found to be COVID-19 and Mpox positive by PCR [25]. One more case was reported from Italy about a 36-year-old male who was coinfected and diagnosed by PCR and tested positive for Mpox and COVID-19 at the same time [25].
Epidemiological characteristics of Mpox and COVID-19 co-infections
Between 2001 and 2021, no significant data were found about the co-infection of Mpox and COVID-19, despite the COVID-19-caused pandemic in 2020. On the contrary, significant cases were found in 2022 co-infection of MpOX and COVID-19 [26].In the post-COVID-19 era around March 2022, most countries removed their travel restrictions and returned to their pre-pandemic policies, which further provided a favourable environment for co-infections [26]. Additionally, three cases of co-infection reported were of men who had engaged in sex with men before their infections. This suggests a potential risk factor for transmission of viral infections and sexual health [25]. However, it is still too early to form any definitive epidemiological trends due to a lack of data.
Outcomes of co-infection
According to one study published, 3 patients with co-infection of Mpox and COVID-19 were diagnosed through PCR and were subsequently admitted to the hospital. Their hospital stays lasted between 4 and 9 days, indicating a need for medical intervention and monitoring during their co-infection [26]. Upon admission, two patients exhibited multiple vesicular lesions on various body sites, along with tonsillar inflammation. The third patient presented with genital ulcers and inguinal lymph node enlargement. These symptoms highlight the diverse clinical manifestations that can arise from co-infection, which may complicate diagnosis and treatment [26]. However one of the reported cases of a patient with HIV co-infected with monkeypox and COVID-19, the clinical course was relatively uncomplicated despite the presence of multiple infections [26].
Shared risk factors
The symptoms of co-infection can overlap, making diagnosis challenging. A patient exhibited symptoms common to both Mpox and COVID-19, such as fever, sore throat, and lymphadenopathy [27]. This overlap can complicate clinical assessments and necessitates thorough anamnestic collection and consideration of sexual habits for accurate diagnosis [27]. Both COVID-19 and Mpox require close contact for transmission. Mpox is primarily spread through direct contact with infected skin lesions or bodily fluids, while COVID-19 spreads through respiratory droplets during close interactions [28]. This overlap in transmission dynamics increases the risk of co-infection in settings where close contact is common, such as households or social gatherings [28].
Immune response interactions
Due to limited research studies on the co-infections of COVID-19 with Mpox, there is currently a significant gap in understanding the immune response interactions each disease has concurrently or sequentially. Comprehending these interactions is crucial, especially since both viruses are known to provoke strong immune responses that may interact in intricate ways. The innate and adaptive immune response systems both play a hand in viral clearance. In the case of orthopoxvirus infections, including Mpox, bypassing the immune system is a major factor in the progression of the disease. Through the generation of proteins, the virus impedes the host’s natural antiviral defenses, including nuclear factor kappa B (NF-kB) signalling and cytokine production [29, 30]. Mpox has also been studied to repress the cytotoxicity and migration of natural killer (NK) cells, as well as the complement system [31]. A powerful type 2 immune response is set off by Mpox infection with high levels of Th2-associated cytokines. Type 1 associated cytokines, however, remain at baseline levels. This displays the complicated immune dysfunction seen in Mpox infections [32,33,34]. Adding to the list of proteins released by the Mpox virus is a protein named orthopoxvirus MHC class I-like protein (OMCP), which helps evade the immune system by avoiding the NK response and also deflecting recognition by T cells [35]. Taking into consideration the role of adaptive immunity, especially the antibody response, the presence of Mpox-specific immunoglobulin G and immunoglobulin M antibodies is generally found in infected patients and is thus also used as a diagnostic markers [31].
On the other hand, in COVID-19, which is brought about by the novel coronavirus SARS-CoV2, the innate system can occasionally produce inadvertent effects. In particular, an inflated surge in cytokine output, which is also known as a “cytokine storm”, often leads to the unfavourable aggravation of immune-mediated tissue damage [36, 37]. Monocytes especially play a vital role in cytokine storm formation because they release pro-inflammatory cytokines such as IL-6 and TNF-⍺ [38]. Eosinophils have also been studied to be involved in the immune response by releasing cytokines associated with homeostasis and type 2 immune responses [39]. Following infection with SARS-CoV-2, there have been reports of low blood eosinophil levels, which were strongly associated with poor disease prognosis and mortality [40,41,42,43,44,45]. In a study done by Ranjbar et al., they reported an increase in levels of type 2 cytokines in their patients with COVID-19. On the other hand, no notable elevations were seen in type 1 cytokine levels [38]. This coincides with the pattern of cytokines observed in Mpox infections, however, there is reliable research yet to be done on an official link in the pattern between the two.
A common factor linking the two diseases was recently studied and involves the endoglycosidase named Heparanase (HPSE). HPSE, which cleaves heparan sulfate (HS), is produced by both SARS-CoV-2 and Mpox, and the interplay between the two molecules leads to the release of pro-inflammatory cytokines and thus the evolution of a cytokine storm, endothelial dysfunction and thrombotic events [46]. Furthermore, activated HPSE increases the polarization of macrophages, T cells and NK cells through the expression of TLR4 [47]. HPSE can initiate NK cells through natural cytotoxic receptors and simultaneously can get rid of HS, which antagonizes NK cell activation [48]. As a result of these findings, treatments targeting HPSE with specific inhibitors like low molecular weight heparin (LMWH) could lower the risk of complications in coinfection with Mpox and Covid 19 [46]. Additionally, HS mimetic compounds like pixatimod may serve as important therapeutic tools by inhibiting HPSE and reducing its induced inflammation and blood clotting issues [49] (Table 1 shows a summary of all studies).
Disease severity and complications
Mpox, previously endemic to the African region, commonly presents with a prodromal stage manifesting as fever, body ache, back pain, sore throat, chills, cough, and fatigue. Following that, is the emergence of the characteristic Mpox rash, starting typically on the face. As the infection progresses, the rash becomes generalized and typically spreads centrally. It starts with the involvement of the oral mucosa, eyes, and then prominently in the genital area. The vesiculopapular skin lesions can range from a few to thousands and are typically elevated and filled with clear/yellowish fluid [50,51,52]. The lesions undergo gradual desquamation and completely resolve 4 weeks after initial symptoms [52].
In contrast, the current global outbreak of Mpox since 2022 has been labelled as atypical as it has proved to be mostly a mild version of its previous type. The clinical presentation varies occasionally, manifesting with the absence of the classic prodromal symptoms before the rash, while the observed skin lesions are most commonly found and primarily limited to the genital and perianal region. Nonetheless, lymphadenopathy presenting as painful and enlarged lymph nodes in the maxillary, cervical, or inguinal region continues to be a distinctive sign even in the current atypical presentation [52, 53]. The interleukin-1 receptor antagonist-like protein pathway is a shared link, leading to a sustained immune response in Mpox while causing a rapid remission of COVID-19 [14, 54]. This indicates that while both these infections may co-exist, it is unlikely to find any severe instances of COVID-19 cases in monkeypox infections, and any co-infection will most likely follow the pattern of decreased clinical severity [14]. The re-emergence of Mpox is still relatively new, and the reported cases in the literature of its co-infection with COVID-19 are rare, with a small sample size to conclude from. A systematic review summarized the effects of co-infection of Mpox and COVID-19 as reported in three different case reports. It is to be noted that all patients also had multiple co-morbid illnesses (such as HIV, herpes, syphilis, type 2 diabetes mellitus, depression, and bipolar disorder) before co-infection and in some cases tri-infection with other viruses [25].
It is to be considered that all 3 patients observed in a study25 were male and most often presented with minor systemic symptoms of fever, lymphadenopathy, headache, sore throat, and fatigue, which are common overlapping symptoms of both Mpox and COVID-19. However, due to these non-specific symptoms mostly being attributed to COVID-19, the presence of vesicular and ulcerative lesions, especially in the genital area, is what confirmed the Mpox diagnosis [25]. The systematic review outlined that all 3 of the cases were hospitalized for the provision of proper care and further monitoring. The hospital stay was uncomplicated, lasting for around 4–9 days, and no severe outcomes were observed [25]. Another reported case of co-infection had an asymptomatic presentation of COVID-19, further confirming that concurrent infection does not mean more severe symptoms or complications [55]. Complications of Mpox vary in intensity and include, but are not limited to, keratitis, bronchopneumonia, altered levels of consciousness, secondary bacterial infections of the skin lesions, and eye infection with corneal scarring so severe that it leads to vision loss [56, 57]. Previously reported co-morbidities that exacerbated COVID-19 outcomes now had no such severe effect during the co-infection [58]. The current atypical Mpox outbreak has followed a mild clinical course, with estimated mortality in non-endemic regions being 0.01% [25].
Mpox cases have not had any intensive care unit admissions, and co-infection with COVID-19 did not alter the favourable outcome [23]. So far, no documented cases of co-infection have reported any complications, and all patients made a recovery and were swiftly discharged [25]. It can be inferred, from all the evidence provided in the limited research available, that Mpox does not lead to drastic patient outcomes whether it manifests alone or in concurrence witCOVID-1919. However, further research and documentation of cases are required to fully understand co-infection, as it can vary from person to person [25].
Impact on transmission dynamics
A study done to correlate cell culture infectivity with viral load in an Mpox clinical sample showed that viral load was increased in skin lesions in comparison to those in throat or nasopharyngeal samples [59]. Additionally, samples from the anal region showed a high viral load in comparison to the throat or nasopharyngeal samples [59]. Similarly, another study done to evaluate the relationship between viral load and the course of COVID-19 showed that 5 days after the symptom onset, the viral load was significantly higher in the fatal cases in comparison to those cases which were symptomatic or asymptomatic [60]. Additionally, people who had a worse prognosis were older in comparison to those in the symptomatic or asymptomatic groups [60]. A cohort study done to see pre-symptomatic viral shedding in high-risk Mpox individuals [61] showed that presymptomatic Mpox DNA was seen as early as 4 days before the symptom onset [61]. Another study done to understand temporal dynamics in viral shedding and transmissibility of COVID-19 showed that viral shedding might begin 5–6 days before the appearance of first symptoms [62].
Another study on the estimation of Mpox spread in non-endemic countries with contact tracing showed delay in contact tracing led to a higher number of cases [63]. When the primary affected individual self-reports, the number of infections only rises by 11%; however, if the primary affected individual does not self-report, the average number of infections would rise by 40%. Similarly, an increase in the number of cases was seen if an unreported individual had contact with more people [63]. Another study showed the impact of delay on effective contact tracing strategies for COVID-19 [64]. With a 0-day tracing delay, prevention can reach up to 79.9%, but if a 3-day tracing delay occurs, the figure drops to 41.8 and similarly decreases to 4.9% with a 7-day treatment delay [64]. A study showed that all 20 patients who tested positive for SARS-COV2 had positive respiratory samples; similarly, among 20 stool samples, the SARS-COV-2 genome was found to be positive in 10 stool samples. In most patients, the ability to diagnose SARS-COV2 in the respiratory tract disappears after 2–3 weeks, but it can still be detected in stool samples for more than 4 weeks, thereby showing that stool can be used as an additional source of diagnosis [65].
Increased compliance with facemask usage can reduce the transmission of both COVID-19 and Mpox by limiting the spread of respiratory droplets. Vaccination provides immunity against both diseases, thereby reducing the number of susceptible individuals in the population. Similarly, practicing social distancing among infected individuals can prevent the incidence of coinfection. The use of personal protective equipment (PPE) can reduce the occurrence of healthcare-associated transmissions and the incidence of Mpox cases. Additionally, the use of rodenticides which target the vector of Mpox can help in reducing the overall reservoir population of the vectors, thereby decreasing the likelihood of spillover events [66].
There is no data available which shows whether infection with one virus affects the transmissibility of the other hence, further research should be done on this to understand the dynamics between these two viruses. (Table 2 shows the summary of all the studies).
Vaccine efficacy and cross-reactivity
The rising co-infection of COVID-19 and increased Mpox infection rate has led to the development of only the approved third-generation smallpox/monkeypox vaccine JYNNEOS, which is based on the highly attenuated modified vaccinia Ankara (MVA) vector [67]. COH04S1 is a clinically evaluated, multiantigen COVID-19 vaccine candidate built on a fully synthetic platform of the highly attenuated modified vaccinia Ankara (MVA) vector, representing the only FDA-approved smallpox/mpox vaccine, JYNNEOS [68]. The immune responses elicited by COH04S1 were compared to those from individuals vaccinated with JYNNEOS, the only FDA-approved smallpox/mpox vaccine. The results showed that the MPXV cross-reactive humoral responses from COH04S1 were comparable to those from JYNNEOS-vaccinated subjects. This indicates that COH04S1 could serve as an effective alternative or complement to existing mpox vaccines [68].
In a Phase 1 clinical trial, healthy adults who received COH04S1 exhibited substantial humoral and cellular immune responses. Notably, 45% of these subjects developed MPXV cross-neutralizing antibodies, indicating a significant level of cross-reactivity. This suggests that vaccination with COH04S1 not only protects against COVID-19 but may also confer some level of immunity against MPXV [68]. (Table 3 shows all the listed vaccines). While the above studies primarily focus on the immune response to MPXV and COVID-19 vaccines, the findings imply that vaccination against one virus may influence the immune response to the other. The presence of cross-reactive antibodies could potentially alter disease outcomes in individuals co-infected with both viruses. Dual-purpose vaccines like COH04S1 could streamline vaccination efforts by reducing the number of vaccines needed, thus conserving resources and simplifying logistics. The ability to provide immunity against multiple pathogens could be particularly beneficial in endemic regions or during concurrent outbreaks, enhancing public health responses [67].
However, further research is needed to fully understand the implications of such co-infections and the role of vaccination in modulating immune responses.