Monkeypox 2022: What clinicians in the dialysis community should do

In 2022, monkeypox outbreaks were reported in non-endemic countries affecting thousands of individuals. With majority of cases in Europe, the majority of those were related to men who have sex with men (MSM) without travel history to endemic areas.1 In the United States (US), cases are rapidly increasing, and most cases are found in major metropolitan areas.1 Though there have not been any reports of outbreaks in hemodialysis centers, it is important for clinicians caring for dialysis patients to be aware of the virology, transmission, management, and prevention of the infection as an outbreak could be swift. Similar to Europe most of the reported cases in the US also lack travel to endemic areas and involve in MSM patients, raising concerns for the possibility of sexual transmission even though traditionally monkeypox has not been considered a sexual transmitted disease.2 Transmission occurs from direct contact with skin lesions or from respiratory droplets during kissing or face to face contact, which can occur during intimate or sexual activity. Indirect transmission through fomites such as bed linens, towels, and sex toys has been also reported.2 It should be noted that unlike SARS-CoV-2 which is a respiratory virus, monkeypox is not, therefore it does not cause air-borne transmission. While monkeypox can be transmitted via respiratory secretions, it primarily spreads from prolonged direct contact with bodily fluids from patients who are infected.2 To reduce the possibility of spread in dialysis centers, patients with suspected monkeypox infection should receive dialysis in a separate room in a similar fashion to the management of coronavirus disease 2019 (COVID-19). Symptoms of monkeypox usually appear within 6–13 days of exposure; however, it can be as high as 21 days, often begin with 1–3 days of non-specific prodromal symptoms that include myalgias, chills, and malaise or even an asymptomatic presentation.2 Following the development of fever, the rash begins on the face and moves centrifugally to concentrate on the arms, legs, and face within 1 day. The painful rash moves and evolves uniformly through four stages over a week: macular, papular, vesicular, pustular developing the characteristic umbilication. The rash then crusts over becomes itchy and last between 14 and 21 days.2 In contrast to this current outbreak, the rash occurred near the anus or genitalia without affecting the whole body and progressing through the four stages at different rates. With the initial lesions surrounding the anus or genitalia, other disease processes such as herpesvirus, syphilis, or other poxviruses should be ruled out. It is important to note that a person is considered infectious starting 5 days prior to the onset of lesions and is infectious until lesions have healed and a new layer of skin has appeared. Severe complications include encephalitis, pneumonia, and retropharyngeal abscess. The mortality rate has been less than 1% in this current outbreak outside of Africa.3 Clinically suspected monkeypox virus is confirmed with a polymerase chain reaction (PCR) test by swabbing samples from skin lesions. The positive tests should be reported to the Center for Disease Control (CDC) for further characterization. Overall, monkeypox is a self-limiting disease; however, severe cases or immunocompromised patients may qualify for antiviral therapy in consultation with the local department of health or CDC. Currently, there is no treatment approved for monkeypox infection in human. However, there are three antivirals that may be used for monkeypox infection and are available from the Strategic National Stockpile (SNS) (Table 1). Tecovirimat is effective in nonhuman primates against monkeypox virus and is efficacious in humans.2, 4 Tecovirimat is available in both oral and intravenous (IV) formulations. Oral formulation must be taken 30 min before or after meal as with food with at least ~600 kcal or ~25 g fat to improve absorption. For intravenous formulation, similar to remdesivir, tecovirimat has poor water solubility; therefore, it has to be compounded with a solubilizing agent. Each 200 mg of tecovirimat is compounded with 8 g of hydroxypropyl-B-cyclodextrin. Although the medication labeling suggests caution in patients with impaired kidney function due to the concerns of toxicity from cyclodextrin accumulation, in a healthy human study, no side effects were observed after parenteral administration of up to 24 g of hydroxypropyl-B-cyclodextrin daily for 15 days.5 Further, cyclodextrin is effectively removed by hemodialysis, suggesting that tecovirimat may be safe and effective in dialysis population.6 No dosage adjustment necessary in hemodialysis Dose: 600 mg twice daily for 14 days Not dialyzable due to extensive volume of distribution (Vd 383–1030 L, 77%–82% protein bound) IV formulation contains cyclodextrin. If IV route is selected, hemodialysis will clear a clinically significant amount of cyclodextrin. Caution in predialysis patients and patients with GFR < 30 ml/min/1.73 m2 In anuric hemodialysis patients: Dose: 2.5 mg/kg once weekly for 2 weeks, followed by 2.5 mg/kg IV once every other week, given without pre-hydration and probenecid Dialyzable: Give medication after completion of hemodialysis (Vd 0.4–0.5 L/kg, <6% protein bound) Nephrotoxic may not be significant in patients without residual renal function. For patients with significant residual renal function, the use should be avoided. If the use is warranted, pre-hydration and probenecid may be recommended. Caution with excessive fluid from pre-hydration. Probenecid is contraindicated in sulfa allergy patients. No dosage adjustment necessary in hemodialysis Dose: Adults weighing ≥48 kg: 200 mg once weekly for two doses. For adults weighing ≥10 kg to less than 48 kg: 4 mg/kg of the oral suspension once weekly for two doses Not dialyzable due to extensive volume of distribution (Vd 1230 L, >99.9% protein bound) During COVID-19 pandemic, remdesivir was initially cautioned to use in patients with renal impairment due to the risk of cyclodextrin accumulation (each 200 mg of remdesivir contains 12 g of cyclodextrin). However, several observational studies show no reported clinical significance of adverse reactions during COVID-19 pandemic.7 While remdesivir has shown to be safe in renally impaired patients, it is important to note that treatment for COVID-19 is only 5 days where in monkeypox it ranges from 14 days and up to 90 days.4 For this reason, it is prudent to avoid using tecovirimat in patients who are predialysis or have GFR < 30 ml/min/1.73 m2.8 Cidofovir received FDA approved indication for the treatment of cytomegalovirus infection and has long known to cause severe nephrotoxicity. For patients with normal renal function, cidofovir is given 5 mg/kg once weekly for induction and 2.5 mg/kg every other week for maintenance.8 Currently, there is no data regarding dosing, monitoring, and effectiveness of cidofovir in monkeypox treatment. However, in the in vitro and animal models, cidofovir has shown to be effective against orthopoxviruses.8 Given the lack of data, 5 mg/kg of cidofovir could possibly be utilized for monkeypox treatment. For anuric hemodialysis patients, where the risk of nephrotoxicity is negligible, administrating 50% of standard dose before hemodialysis without probenecid has been recommended (2.5 mg/kg induction weekly for 2 weeks and 2.5 mg/kg every other week).9 Cidofovir should not be used in patients with significant residual renal function. Brincidofovir, an analog of cidofovir, was approved in 2021 for smallpox and is a weight-based medication supplied in 100 mg tablets and 10 mg/ml oral suspension formulations. A significant increase in transaminase enzymes has been observed.8 Vaccinia immune globulin intravenous (Human, VIGIV) could also be utilized when other options have failed. Even though the mechanism of action of VIGIV is not fully understood, it is recognized that achieving passive immunity through the pooled human plasma of immunized individuals is a major factor. When using VIGIV among patients with preexisting renal insufficiency, the lowest possible infusion rate should be used to avoid renal function deterioration.8 In Table 1, we suggested adult dosing recommendations based on the available pharmacokinetic and pharmacodynamic data. So far, there are no clinical trials or reports that report the use of any medication utilized in the treatment of monkeypox in hemodialysis patients. For the prevention of monkeypox, the Advisory Committee on Immunization Practices (ACIP) suggests either ACAM2000 or JYNNEOS for pre-exposure prophylaxis (PrEP) vaccination. JYNNEOS is a live non-replicating vaccine and can be used in immunocompromised patients. ACAM2000 should be avoided in immunocompromised patients including hemodialysis patients since it is a live replicating vaccine and is associated with more adverse events.8 To prevent the spread of monkeypox virus in hemodialysis center, appropriate cleaning measures need to be implemented. Similar to SAR-CoV-2, monkeypox was classified as Tier 1 by the United States Environmental Protection Agency (EPA).10 Disinfecting measures that are currently used to prevent the spread of COVID-19 in hemodialysis center should be utilized for patients with or suspected of having monkeypox. Disinfectants used should have the ability to damage the lipid envelope, thereby rendering the infectivity of the virus. Tier 1 viruses can be inactivated by hypochlorous acid, chlorine dioxide, and sodium chlorite with the contact time ranging from 5 to 10 min on hard, nonporous surfaces. Contact transmission within the center can be limited by appropriate hand hygiene (i.e., hand washing or use of a waterless hand rub), and glove use.10 In conclusion, the increasing prevalence of monkeypox could be a new potential threat to dialysis communities. Currently, monkeypox may not be a major concern but it is imperative that we remain vigilant. End-stage renal disease patients are considered immunocompromised and are at risk. Understanding the nature of the disease will ensure clinicians better handle affected individuals and coordinate their care. I would like to thank Dr. Eunice Han for her feedback and comments. No conflict of interest.

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