Mumps caused by a viral infection can cause sterility in males - Piril Erel

ABSTRACTAs trainee pharmacists, it is important to understand why there are sudden upsurges of diseases in the world what can be done to help the population. As a result I would like to discuss what mumps virus is, how it can be treated and has decreased in prevalence due to vaccination programmes along with why, in recent years, there has been an escalation in the number of cases of mumps. Furthermore I analyse complications that resulted from mumps and how, on a molecular level, infection can lead to mumps orchitis and then sterility in post pubertal boys. Possible treatment methods, apart from vaccinations, can assist in helping prevent these further complications from arising. Vaccinations methods have not been consistent and when a drop in herd immunity occurs in any population worldwide complications follow, many years later, affecting individuals and increasing cases of impaired fertility in men.

Mumps caused by a viral infection can cause sterility in males

1 Piril Erel – UoB 12004723

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ccination programmes worldwide has vastly improved the reduction of Mumps virus in all gender, this also led to further complications such as acute meningitis, encephalitis and orchitis which occur as a result from mumps to also decrease in prevalence. However, not all individuals have been vaccinated and therefore mumps has not been eradicated totally in a worldwide setting and can be spread via population movement. In the UK there has been a recent sharp increase in Mumps and consequently also in Mumps Orchitis (Masarani et al., 2006).

For a vaccination programme to be affective herd immunity is required, the threshold of that which is 75-86%. Once a community falls below this threshold, unvaccinated people become at much greater risk of catching the infection. The MMR vaccine (the triple mumps, measles and rubella vaccine) was introduced in 1968 and effected a dramatic fall in orchitis and consequently sterility for example in the USA reporting a fall of 99%. However, about 15 years ago due to a global shortage of vaccine and together with (now discredited) papers that linked MMR to Crohn’s disease and autism (Thompson et al., 1995, Wakefield et al., 1998) meant that vaccine uptake fell.

In some areas of the UK uptake fell to only 58% (Davis et al., 2010). This has lead to a sharp increase in mumps cases reported Figure 1 (Davis et al., 2010) (and by inference, orchitis). This meant that the threshold for herd immunity was not reached in 1999 and after 2000. Thus from these data it is possible to extrapolate that children aged 16 in 2018 may be at risk of orchitis due to the lack of uptake of the vaccine in 2002. Problems could be more far reaching since there are reports of males up to the age of 24 becoming ill and suffering sterility due to mumps orchitis (Davis et al., 2010).

In England, 274 cases out of 1,365 in 2013 have been reported to affect children between the ages of 10-16 at secondary school due to a none or incomplete MMR vaccination (Public Health England, 2013).



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Figure 1 - Graph showing % uptake of the MMR vaccine in the UK population against the year. Highlights the public response to the vaccine after publication of two papers that suggested a poor health outcome connected to the vaccine. (Davis et al., 2010)

Mumps virus starts to exhibit symptoms in the host when they experience headaches, joint pain, nausea, dry mouth, mild abdominal pain, fatigue, loss of appetite and a high temperature (Nhs.uk, 2014). Orchitis may occur four or five days after the start of parotitis in 30% of postpubertal boys and appears with chills, sweats and severe local testicular pain and tenderness making the scrotum area swollen and oedematous so that the testes are impalpable. 13% of individuals affected with orchitis lead to infertility in males (Patient.co.uk, 2014, Domino et al, 2007).

Since orchitis occurs four or five days after initial symptoms are reported the earlier the disease is correctly diagnosed, the less likely testicular damage is to have taken place. In clinical settings antibodies against mumps can be detected early on in the course of infection from peripheral blood samples. Tests also include analysis of T cell subtypes and presence of specific cytokines; cytokines being key mediators in the inflammatory response during viral infections are particularly elevated in patients affected with orchitis (Wang and Zhu et al., 2014).

CRP is an acute phase protein, which rises in proportion to inflammation and cell death. As orchitis presents itself as inflammation of the testes this is a good indicator whether mumps orchitis is present. As 13% of individuals who are present with orchitis are more prone it gives us a good idea, which patients could be at risk of sterility. Normal CRP should be around 10mg/L however in individuals with Orchitis this level rises to 140mg/L. (Casella et al., 1997, Webmd.com, 2014). Ultrasonography will also



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analyse whether testicular involvement is apparent in the specific case of mumps. Urine analysis is taken to eliminate the involvement of bacterial infections along with mumps (Figure 2).

Figure 2. Flow diagram indicates approaches to determine the markers, agent of infection and affects.

Perhaps the most significant outcome is that mumps in children can result in irreversible infertility in males due to orchitis (Wang et al., 2013). The cause of this long-term damage is not fully understood. What is known is that the seminiferous epithelium is damaged and undergoes progressive degeneration. Sometimes, only Sertoli cells are involved and this indicates that they are essential in sperm formation (Wang et al., 2013) (Fig 3a and 3b).



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Figure 3 a) Testis (Rabbit) low magnification, seminiferous epithelium (Slomianka, 2014).

Figure 3 b) Tesis (Rabbit) high magnification with Sertoli cells indicated(Slomianka, 2014).

In normal male testes seminiferous tubules contain diploid spermatogonium that mature into sperm cells. During spermatogenesis each of the diploid spermatogonium becomes four haploid sperm cells. This process is accomplished through the meiotic cell division. Males, at puberty will begin to produce millions of sperm each day for the rest of their lives. Thus in normal spermatogenesis it is crucial to regulate cell proliferation. Research has demonstrated, highly regulated and coordinated mechanisms that work between the mitotically inactive Sertoli cells and the cells that divide mitotically and meiotically known as germ cells. How efficient spermatogenesis is depends on both the proliferative activity of spermatogonia balanced with the loss of germ cells during meiosis and spermiogenesis (Steger et al., 1998).

Researchers have described posttranslational modifications of protein called farnesylation (the addition of hydrophobic molecules to a protein) and geranylgeranylation (addition of 20-carbon lipophilic geranylgeranyl isoprene molecules to cysteine residues at the C-terminus of the protein) and have suggested that the balance between the two is important for patients’ fertility (Wang et al., 2013). Scientists have implicated an enzyme, geranylgeranyl diphosphate synthase 1 (GGPPS) in the development of orchitis. Expression has been shown to be decreased in infertile patients. The molecular mechanism appears to be through the methylation of the promoter at the DNA level (Wang et al., 2013).



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In mice when this gene is knocked out, Sertoli cells were unaffected but nearby spermatogonia significantly decreased days five after birth. Proinflammatory markers MAPK and NF-κB were activated because of increased farnesylation of the oncogene H-Ras. In the knockout mice, their Sertoli cells secreted a number of cytokines whose purpose was to increase stimulation of spermatogonia programmed cell death (apoptosis), and chemokine’s that increase macrophage invasion into the seminiferous tubules. These macrophages then blocked spermatogonia development and this resulted in detrimental effects through to adulthood. The researchers reversed this effect by administering the enzyme GGPP in the mouse model. These results suggest a new mechanism by which childhood mumps infection causes adult sterility (Wang et al., 2013). These data fit in well with earlier results from other researchers that indicated that mumps virus damaged the testes via parenchyma oedema that leads to congestion of seminiferous tubules and perivascular infiltration of lymphocytes leading to necrosis of the seminiferous tubules due to reduced blood supply and atrophy of the testis. (Davis et al., 2010)

Prevention is better than cure in the case of mumps. Patients are advised to stay at home to prevent spread of the virus, to wash hands regularly and to prevent droplet spread of the virus by using a tissue. Treatment options are limited to bed rest, over the counter drugs for pain and inflammation (paracetamol and ibuprofen), increased fluid intake, cold or warm compress on the swollen testes and a light soft diet (Nhs.co.uk, 2014).

Due to the fact that mumps can lead to serious complications including aseptic meningitis, orchitis, infertility and the problems with the vaccination program outlined in this essay, a lack of treatment methods for mumps is of serious concern. It has attracted research, which looks for a suitable pharmacological treatment. Recently, researchers looked at the anti-mumps virus activity of Mimosa pudica (Figure 4).



MPharm Year 2 SSAFigure 4. Mimosa pudica

Mumps virus was isolated and verified using antibody assays, reverse transcriptase PCR and phylogenetic analysis. Viral titre was quantified and extract was applied. The research demonstrated that 150 μg/ml of M. pudica totally inhibited the mumps virus. In addition, the drug was found to be non-toxic up to 2 mg/ml. Thus M. pudica has been shown to be a potent inhibitor of the mumps virus and possibly a new treatment for human infection (Malayan et al., 2013).

In summary: mumps can cause sterility in males following mumps induced orchitis. This essay has discussed the prevalence of mumps in a worldwide context and specifically in the UK. Vaccination has been successful to prevent many millions of cases of mumps since 1968 when it was introduced. However, uptake of the MMR vaccination varies according to popular conception of safety. Publication of papers linking MMR to autism and Crohn’s has meant a lowering of uptake, coupled with a scarcity of vaccine in the 1990s. In addition, the increase in population movement enabling more rapid spread of the virus thus, cases of the serious complications following mumps infection, including orchitis and sterility, have increased. Understanding the aetiology of the damage to the testes will help improve the existing, minimal, possible clinical interventions. In addition, recent work looks to investigate possible antiviral drugs with some promising results.



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Mumps caused by a viral infection can cause sterility in males - Piril Erel

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