Summary
Background
The scale of the 2022 global mpox (formerly known as monkeypox) outbreak has been unprecedented. In less than 6 months, non-endemic countries have reported more than 67 000 cases of a disease that had previously been rare outside of Africa. Mortality has been reported as rare but hospital admission has been relatively common. We aimed to describe the clinical and laboratory characteristics and outcomes of individuals admitted to hospital with mpox and associated complications, including tecovirimat recipients.
Methods
In this cohort study, we undertook retrospective review of electronic clinical records and pathology data for all individuals admitted between May 6, and Aug 3, 2022, to 16 hospitals from the Specialist and High Consequence Infectious Diseases Network for Monkeypox. The hospitals were located in ten cities in England and Northern Ireland. Inclusion criteria were clinical signs consistent with mpox and MPXV DNA detected from at least one clinical sample by PCR testing. Patients admitted solely for isolation purposes were excluded from the study. Key outcomes included admission indication, complications (including pain, secondary infection, and mortality) and use of antibiotic and anti-viral treatments. Routine biochemistry, haematology, microbiology, and virology data were also collected. Outcomes were assessed in all patients with available data.
Findings
156 individuals were admitted to hospital with complicated mpox during the study period. 153 (98%) were male and three (2%) were female, with a median age of 35 years (IQR 30–44). Gender data were collected from electronic patient records, which encompassed full formal review of clincian notes. The prespecified options for data collection for gender were male, female, trans, non-binary, or unknown. 105 (71%) of 148 participants with available ethnicity data were of White ethnicity and 47 (30%) of 155 were living with HIV with a median CD4 count of 510 cells per mm3 (IQR 349–828). Rectal or perianal pain (including proctitis) was the most common indication for hospital admission (44 [28%] of 156). Severe pain was reported in 89 (57%) of 156, and secondary bacterial infection in 82 (58%) of 142 individuals with available data. Median admission duration was 5 days (IQR 2–9). Ten individuals required surgery and two cases of encephalitis were reported. 38 (24%) of the 156 individuals received tecovirimat with early cessation in four cases (two owing to hepatic transaminitis, one to rapid treatment response, and one to patient choice). No deaths occurred during the study period.
Interpretation
Although life-threatening mpox appears rare in hospitalised populations during the current outbreak, severe mpox and associated complications can occur in immunocompetent individuals. Analgesia and management of superimposed bacterial infection are priorities for patients admitted to hospital.
Funding
None.
Introduction
The disease is caused by infection with an orthopox DNA virus, monkeypox virus (MPXV). Two different strains of MPXV are endemic in Africa, with clade I predominant in central African regions and clade II predominant in western African regions.
Until the 1990s, both clades caused mostly sporadic cases and outbreaks of disease, with zoonotic transmission.
After discontinuation of smallpox vaccination, which also protects against mpox, mpox incidence increased in Africa.
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Outbreaks of human mpox emerged in the Democratic Republic of the Congo in 1996 and in Nigeria in 2017, with evidence of human-to-human transmission, including in urban areas.
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Research in contextEvidence before this studyWe searched PubMed from Jan 1, 2017, to Oct 31, 2022, for studies published in English on patients admitted to hospital with monkeypox (mpox), severe mpox, and mpox complications using the following keywords: “(monkeypox) AND (hospitalised OR hospitalisation OR complication OR severe)”. Since March, 2022, more than 67 000 cases have been reported worldwide. Monkeypox virus (MPXV) clade IIb has emerged as the likely dominant driver of the current outbreak transmitted predominantly through sexual contact and disproportionately affecting gay and bisexual men who have sex with men. There are no dedicated representative studies of individuals admitted to hospital with mpox or associated complications during the current outbreak. A single national report of hospitalised cases referred to the USA Centre for Disease Control and Prevention Severe Monkeypox Investigations Team and described high mortality (21%) in a highly selected population with high prevalence of advanced HIV infection. Two national retrospective studies in Nigeria during the largest MPXV clade II outbreak reported case fatality rates between 6% and 12·5%, with most deaths occurring in neonates and people living with HIV. Epidemiological and virological factors make the findings of these studies difficult to extrapolate to the populations most affected by the current outbreak. There are no therapies of proven efficacy for human mpox infection. Tecovirimat is an orthopoxvirus envelope protein inhibitor developed for the treatment of smallpox in the context of a deliberate release incident. It is approved for the treatment of mpox in several countries, but studies reporting effectiveness or safety and tolerability in acutely unwell individuals with mpox are unavailable.Added value of this studyWe report the first representative, national-level analysis of individuals admitted to hospital with severe mpox and associated complications in a high-income country. Our retrospective analysis reports cases managed by the UK Specialist and High Consequence Infectious Diseases Network for Monkeypox across 16 centres in ten cities. We describe clinical and laboratory features, including virological data, representing the first such report for a hospitalised cohort, some of whom received treatment with tecovirimat. We report no deaths, but severe pain and secondary bacterial infection were experienced by more than half of the analysis population. We report two cases of encephalitis, five cases of severe ocular complications, and ten cases that required surgical intervention, predominantly for debridement or drainage of secondary bacterial skin and soft tissue infections. More than a third of the analysis population experienced deranged liver function tests during hospital admission. 38 individuals received tecovirimat with early cessation in four individuals, including in two individuals with hepatic transaminitis.Implications of all the available evidenceAlthough we report no deaths, we highlight the substantial burden of complex morbidity in immunocompetent individuals admitted to hospital with mpox. Based on few data in selected populations, advanced HIV infection and other causes of severe immunocompromise might significantly increase morbidity and case fatality. Further prospective studies are required to identify risk factors associated with severe mpox and specific complications. Our data suggest that secondary bacterial infection is common, and that studies of anti-microbial prophylaxis and treatment are required in individuals diagnosed with mpox. Tecovirimat appears to be well tolerated, although randomised controlled trials are required to establish effectiveness in preventing and treating severe disease and complications. Further studies are also needed to identify causes of hepatic dysfunction in patients with mpox.
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In May, 2022, several countries in multiple geographic regions reported cases of MPXV infection, primarily in individuals without history of travel to African countries. By September, 2022, more than 67 000 laboratory-confirmed mpox cases had been reported in 106 countries, including more than 3600 cases in the UK.
Unlike previous outbreaks in countries with zoonotic reservoirs in Africa, close contact during sexual activities was identified as the dominant route of transmission in the 2022 global outbreak caused by Clade IIb MPXV.
Men who are gay or bisexual and other men who have sex with men (GBMSM) have been disproportionately affected, with locally acquired community transmission (particularly sex-associated transmission) predominant in all affected countries.
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Clinical manifestations seen in the 2022 global outbreak have been linked to sexual transmission routes, with most patients experiencing lesions that are focused, more abundant or more severe in genital, ano-rectal and oropharyngeal regions, possibly reflecting exposure of these areas to high levels of the virus during sexual intercourse.
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In previous outbreaks, hospital admission and increased mortality have been linked to patients’ immune status, infection in infancy, and infection with clade I MPXV.
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Secondary bacterial infection at sites of skin or mucosal lesions and extra-cutaneous disease, including ocular disease, pneumonitis, and encephalitis have been described in case series.
Globally, 7·8% of cases in the current outbreak have required hospital admission for medical care and sometimes infection control purposes. Crude estimates suggest an overall mortality rate below 0·05%
for clade IIb disease, although 21% mortality was reported in a highly selected population with high prevalence of advanced HIV infection in the single available national-level study of individuals admitted to hospital with mpox in 2022. Tecovirimat, an orthopoxvirus envelope protein inhibitor developed for treatment of smallpox in the context of a deliberate release incident, is approved for the treatment of mpox in several countries and regions.
Tecovirimat appears to be well tolerated in humans and is efficacious in animal models of mpox,
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but data on effectiveness in treating human mpox is unavailable.
Monkeypox is an emerging infection and cases were rare in the UK and other countries outside Africa before 2022; therefore, there is a need to share experiences of managing more severe disease. This multi-centre, retrospective analysis aims to report the clinical, laboratory, and virological features of the majority of patients who required in-hospital care for mpox in England and Northern Ireland and describes clinical management including tecovirimat use in a proportion of cases.
Methods
Study design and participants
In this retrospective cohort study, all national clinical network hospitals that managed patients admitted to hospital with mpox were invited to perform local service evaluations of their inpatient mpox care. 16 centres across ten cities in England and Northern Ireland submitted data between May 6, and Aug 3, 2022. These data were collated and form the basis of this analysis. All individuals had clinical signs consistent with mpox and MPXV DNA detected from at least one clinical sample by PCR testing done at the UK Health Security Agency Rare and Imported Pathogens Laboratory (RIPL) or at local laboratories using RIPL-validated testing from July, 2022. Hospital admission was defined as admission to any ward bed for an indication related to management of mpox or associated complications, or a period of more than 24 h spent in an emergency department bed space with review by an infection specialist. Patients admitted solely for isolation purposes were excluded. If a patient was admitted for isolation initially but developed complications during their stay, they were included in the analysis. Each contributing centre followed its local policy for reviewing a proposed service evaluation and a request to submit deidentified data, extracted from inpatient records, for the purposes of a network analysis, without obtaining specific consent from individual patients. Local records were accessed only by clinicians involved in care of patients admitted to hospital at each centre. For cases in which local policy required written approval or registration of a service evaluation, this was obtained by the respective centre. Deidentified data were securely transferred by each centre to the coordinating site (Royal Free Hospital, London, UK) for collation and analysis.
Procedures
Deranged liver function was defined by any abnormal liver function test including bilirubin, alkaline phosphatase (ALP) and alanine transaminase (ALT). High ALT was defined as greater than 50 IU/L for men and greater than 35 IU/L for women, high ALP as greater than 130 IU/L, and high bilirubin as greater than 21 μmol/L. A completed course of tecovirimat was defined as having received 600 mg tecovirimat twice daily for 14 days.
Statistical analysis
The primary outcome of the study was mortality. Secondary outcomes were admission to intensive care, any surgical procedure, duration of hospital admission, secondary bacterial infection, severe pain, and deranged liver function. Pre-specified exploratory analyses were undertaken between orthopox PCR Ct values and duration of symptoms and key blood tests (C-reactive protein, white cell count, and ALT). All outcomes were assessed in all patients with available data. Categorical variables were expressed as frequency and percentage. Continuous variables were summarised as median values and IQR if non-normally distributed and as mean with SD if normally distributed, as indicated. Wilcoxon Rank-Sum test was used for analyses of non-normally distributed qualitative data. Tests of significance were done for median lowest orthopox Ct value between anatomical sites. Correlation analyses were done for each anatomical site between orthopox Ct value and duration of symptoms and named blood tests. For correlation analyses, Pearson correlation coefficient with 95% CI for normally distributed data and Spearman correlation with 95% CI for non-normally distributed data were used. All tests had a significance threshold of 0·05. Data were analysed in Stata software (version 14) and Prism Graphpad software (version 8).
Role of the funding source
No funding.
Results
Figure 1Number of individuals admitted to collaborative group hospitals compared with total number of cases in the UK by week during the analysis period
Bars indicate hospital admissions and the line graph indicates the total number of cases.
Table 1Demographic and clinical background of individuals admitted to hospital with monkeypox virus infection
Data are n (%), n/N (%), or median (IQR), unless otherwise indicated. Differing denominators reported are due to missing data.
Table 2Indications and characteristics for admission to hospital
Data are n (%), n/N (%), median (IQR), or mean (SD). Differing denominators reported are due to missing data.
Table 3Clinical and laboratory features in individuals admitted to hospital with monkeypox virus infection, by secondary bacterial infection status
Data are n (%), n/N (%), or median (IQR), unless otherwise indicated. Differing denominators reported are due to missing data. NEWS=National Early Warning Score (an aggregate score of respiratory rate, oxygen saturation, systolic blood pressure, level of consciousness, and temperature). ALT=alanine transaminase. ALP=alkaline phosphatase.
Figure 2Orthopox PCR cycle threshold values by anatomical site
Median and IQR shown in line and box plots. Minimum and maximum values shown by whisker plots. Lesion values were used as the reference for comparisons. NS=not significant (p=0·15). *p<0·0001.
Table 4Clinical characteristics in individuals admitted to hospital with monkeypox, by tecovirimat treatment status
Data are n (%), n/N (%), or median (IQR), unless otherwise indicated. Differing denominators reported are due to missing data.
Discussion
Comparison of our findings with those from other countries is challenging for many reasons, including differences in study designs, virus clades, available health-care resources, and background health at the population level. By contrast to available studies of clade II outbreaks in Nigeria and USA, we did not identify fatal outcomes in our cohort which might, in part, be due to higher rates of severe immunosuppression (particularly advanced HIV infection) in these cohorts.
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Almost a third of our study population had intercurrent sexually transmitted infections, which is higher than that reported for outpatient populations. Pain control is a key clinical management priority for individuals diagnosed with mpox and pain requiring strong opioid analgesia at some point during admission was common amongst patients. We report two cases of MPXV encephalitis; both cases were treated with tecovirimat and had recovered to their normal baseline by the time of hospital discharge. One individual experienced necrotising conjunctivitis and has persistent visual impairment. More detailed descriptions of these cases will be submitted for publication separately by network members. One individual was admitted with dyspnoea but had normal chest radiography, and no episodes of pneumonitis or myocarditis were reported in our analysis, despite these having been described in other studies of mpox.
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Reported secondary bacterial infection was common; no individuals required organ support although surgical management was indicated for skin, soft tissue, or ocular complications in ten individuals. Antibiotic use exceeded 76% for patients and might have been associated with abnormal liver function tests. Prospective studies of antimicrobial therapy in MPXV-infected individuals are warranted to assess outcomes and complications, along with studies to determine whether clinically diagnosed superinfection in this setting is caused by bacteria, MPXV, or both, particularly given that orthopox infections can disrupt skin microbiota and immune homoeostasis.
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Transaminitis was common in our patients; antibiotic and analgesic use was common and might account for some of the liver function test abnormalities recorded, and mpox itself might cause hepatitis.
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Unfortunately, we were unable to obtain liver biochemistry results before diagnosis of mpox. Our report emphasises the challenge of determining whether deranged liver function is due to the infectious process or anti-infective drugs administered, including novel antivirals. Further prospective studies with biochemistry outcomes are required to better characterise any relationship between mpox and hepatitis in addition to randomised control trials of tecovirimat. Our analysis was not designed to measure the clinical or virological effectiveness of tecovirimat, and most individuals did not receive sufficient longitudinal sampling to support a descriptive analysis of orthopox PCR results before, during, and following tecovirimat treatment. Further studies are required to establish the efficacy and role of tecovirimat for treatment of severe mpox.
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Similar to populations in other reported studies, most people living with HIV in our study population had well-controlled HIV infection with normal CD4+ T-cell counts. Limited to available parameters and small patient numbers, there were no clear differences in disease phenotype between people living with HIV and HIV-negative individuals, including for people living with uncontrolled HIV. Further prospective studies are required to better understand MPXV acquisition risk and the natural history of mpox in people living with HIV, and in individuals with different immunosuppression conditions.
We did not collect data to report the timing of microbiology sampling and antibiotic use, which might have confounded rates of bacteraemia in our analysis. Throat swab sampling in our population was biased by oropharyngeal symptoms, so the clinical significance of identified organisms is also difficult to interpret. We did not record the use of specialist bacteriology procedures for laboratory processing of throat swabs at different centres, therefore the relevance of a single isolate of non-toxigenic C diphtheriae is uncertain in an individual without clinical diphtheria. The limited number of individuals with longitudinal virology samples, and the challenge of re-sampling single lesion sites in individuals with high lesion counts, mean that we can infer little about the value of MPXV DNA quantification in disease stratification or prognostication.
Our analysis of a large population of individuals admitted to hospital with mpox and associated complications in the UK serves as salutary reminder that although mild in the majority of those infected, clade IIb mpox can cause a variety of complications in immunocompetent adults that often require multi-disciplinary inpatient management. We believe our specialist clinical network approach helped optimise inpatient care and knowledge-sharing for this emerging infectious disease in the UK. Our observations support the need for prospective studies of individuals with severe disease, including longitudinal sampling for virology and biochemistry analyses, and the need for trials of anti-MPXV therapies and antimicrobials aimed at treating or preventing severe disease.
