Royal College of General Practitioners - Online Learning Environment

Written by Dr Toni Hazell

Please note: this document was last updated on April 15 2024

1. There are treatments available for community management of COVID-19

For most of the pandemic, the primary care management of those with COVID-19 was supportive – if the patients weren’t unwell enough to be admitted then we managed them in the same way as patients with other viral respiratory tract infections. This changed in early 2022 with the arrival of new community treatments, which can be divided into two groups – antivirals and neutralising monoclonal antibodies (nMABs).

NICE1 has approved two drugs for use in the community. The first is nirmatrelvir plus ritonavir (an antiviral, given orally) and it is approved for adults who do not need supplemental oxygen for COVID-19 and have an increased risk for progression to severe COVID-19. The second option is sotrovimab (an nMAB, given intravenously), which is approved for adults and children who are at least 12 and weigh at least 40kg, for whom nirmatrelvir plus ritonavir is contraindicated or unsuitable. They also have to have no need for supplemental oxygen and be in the group with an increased risk for progression to severe COVID-19.

2. Only the highest risk patients are eligible for these treatments

Patients who are a member of the ‘highest risk group’ should have all received a letter from NHSEI telling them about these new treatments. They were also initially sent a PCR test kit to keep at home so that they can test promptly if they have symptoms of COVID-19. Advice has now changed and they are advised to take a lateral flow test as soon as possible if they have any symptoms that could be COVID-192. If positive, this should be uploaded online.

The group of patients defined as being in the ‘highest risk group’ is given in the table below – it is not identical to the group who were asked to shield during the pandemic, nor is it the same as the group who are usually invited for flu vaccinations.

The following patient cohorts were determined by an independent advisory group commissioned by the Department of Health and Social Care (DHSC)1.

Down's syndrome and other genetic disorders	All individuals with Down's syndrome or other chromosomal disorders known to affect immune competence.
Solid cancer	Metastatic or locally advanced inoperable cancer. Lung cancer (at any stage). People receiving any chemotherapy (including antibody-drug conjugates), PI3K inhibitors or radiotherapy within 12 months. People who have had cancer resected within 3 months and who received no adjuvant chemotherapy or radiotherapy. People who have had cancer resected within 3 to 12 months and receiving no adjuvant chemotherapy or radiotherapy are expected to be at less risk (and thus less priority) but still at increased risk compared with the non-cancer populations.
Haematological diseases and recipients of haematological stem cell transplant (HSCT)	Allogeneic HSCT recipients in the last 12 months or active graft versus host disease (GVHD) regardless of time from transplant (including HSCT for non-malignant diseases). Autologous HSCT recipients in the last 12 months (including HSCT for non-malignant diseases). Individuals with haematological malignancies who have received CAR-T cell therapy in the last 24 months, or until the lymphocyte count is within the normal range. Individuals with haematological malignancies receiving systemic anti-cancer treatment (SACT) within the last 12 months, or radiotherapy in the last 12 months. All people who do not fit the criteria above, and are diagnosed with: myeloma (excluding monoclonal gammopathy of undetermined significance [MGUS]) AL amyloidosis chronic B-cell lymphoproliferative disorders (chronic lymphocytic leukaemia, follicular lymphoma) myelodysplastic syndrome (MDS) chronic myelomonocytic leukaemia (CMML) myelofibrosis any mature T-cell malignancy. All people with sickle cell disease. People with thalassaemia or rare inherited anaemia with any of the following: severe cardiac iron overload (T2 * less than 10 ms) severe to moderate iron overload (T2 * greater than or equal to 10 ms) plus an additional comorbidity of concern (for example, diabetes, chronic liver disease or severe hepatic iron load on MRI). Individuals with non-malignant haematological disorders (for example, aplastic anaemia or paroxysmal nocturnal haemoglobinuria) receiving B-cell depleting systemic treatment (for example, anti-CD20, anti-thymocyte globulin [ATG] and alemtuzumab) within the last 12 months.
Renal disease	Renal transplant recipients (including those with failed transplants within the past 12 months), particularly those who have: received B-cell depleting therapy within the past 12 months (including alemtuzumab, rituximab [anti-CD20], ATG) an additional substantial risk factor that would in isolation make them eligible for monoclonals or oral antivirals. Non-transplant renal patients who have received a comparable level of immunosuppression. People with chronic kidney disease (CKD) stage 4 or 5 (an estimated glomerular filtration rate [eGFR] less than 30 ml per min per 1.73 m2) without immunosuppression.
Liver diseases	People with cirrhosis Child-Pugh (CP) class A, B and C, whether receiving immune suppressive therapy or not. Those with decompensated liver disease (CP B and C) are at greatest risk. People with a liver transplant. People with liver disease on immune suppressive therapy (including people with and without cirrhosis).
Solid organ transplant recipients	Solid organ transplant recipients not in any of the above categories. Immune-mediated inflammatory disorders (diseases in which autoimmune or autoinflammation-based pathways are implicated in disease, for example, inflammatory arthritis, connective tissue diseases, inflammatory skin diseases, inflammatory gastrointestinal disease). People who have received a B-cell depleting therapy (anti-CD20 drug, for example, rituximab, ocrelizumab, ofatumumab, obinutuzumab) in the last 12 months. People who have been treated with cyclophosphamide (IV or oral) in the 6 months prior to positive PCR or relevant COVID test. People who are on corticosteroids (equivalent to 10 mg or more per day of prednisolone) for at least the 28 days prior to positive PCR or relevant COVID test. People who are on biologics or small molecule JAK inhibitors. People who are on current treatment with mycophenolate mofetil, oral tacrolimus, azathioprine, mercaptopurine, or similar agents (for major organ involvement such as kidney, gastro-intestinal tract, liver, lung, brain), methotrexate (for interstitial lung disease or asthma only) and/or ciclosporin. No minimum dose threshold is suggested. People who are on current treatment (or within the last 6 months) with S1P modulators (fingolimod, ponesimod or siponimod), or alemtuzumab or cladribine within the last 12 months. People who exhibit at least one of: (a) uncontrolled or clinically active disease (that is, required recent increase in dose or initiation of new immunosuppressive drug or IM steroid injection or course of oral steroids within the 3 months prior to positive PCR or relevant COVID test); and/or (b) other high risk comorbidities (for example, body mass index [BMI] greater than 30, diabetes mellitus, hypertension, major organ involvement such as significant kidney, liver, nervous system or lung inflammation or significantly impaired renal, liver, nervous system and/or lung function).
Respiratory	Asthma in people on oral corticosteroids (defined above). Any asthma patient taking immunosuppressants for their asthma including but not exclusively methotrexate, ciclosporin. Frequent exacerbations requiring 4 or more courses of prednisolone per year, usually 40 mg per day for 5 days or more. COPD on long term home non-invasive ventilation (NIV). Patients on long term oxygen therapy. People with moderate or severe disease (FEV1 less than or equal to 50% predicted) who have required 4 or more courses of prednisolone 30 mg for 5 days or greater in last 12 months. Interstitial lung disease (ILD) – all patients with idiopathic pulmonary fibrosis. Sub-types of ILD, for example, connective tissue disease related, sarcoidosis, hypersensitivity pneumonitis, NSIP (non-specific interstitial pneumonia) who have received a B-cell depleting therapy in last 12 months, or IV or oral cyclophosphamide in the 6 months prior to testing positive for COVID-19. Any ILD patient on current treatment with corticosteroids, mycophenolate mofetil, azathioprine, tacrolimus, cyclosporin or methotrexate. No minimum dose criteria. Any people with any type of ILD who may not be on treatment due to intolerance but has severe disease with an FVC predicted less than 60%. NIV and tracheostomy ventilated – all patients requiring this type of support regardless of the underlying disorder (which might include COPD, obesity hypoventilation syndrome, scoliosis, bronchiectasis, neurodisability and genetic muscular diseases [refer to neurology section]). Lung cancer patients, refer to 'Solid cancer' section above. Lung transplant patients (refer to solid organ transplant section). Pulmonary hypertension (PH): groups 1 and 4 from PH classification.
Immune deficiencies	Common variable immunodeficiency (CVID). Undefined primary antibody deficiency on immunoglobulin (or eligible for Ig). Hyper-IgM syndromes. Good's syndrome (thymoma plus B-cell deficiency). Severe combined immunodeficiency (SCID). Autoimmune polyglandular syndromes or autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy (APECED syndrome). Primary immunodeficiency associated with impaired type 1 interferon signalling. X-linked agammaglobulinaemia (and other primary agammaglobulinaemias). Any person with secondary immunodeficiency receiving, or eligible for, immunoglobulin replacement therapy.
HIV/AIDS	People with high levels of immune suppression, have uncontrolled or untreated HIV (high viral load) or present acutely with an AIDS defining diagnosis. People on treatment for HIV with CD4 less than 350 cells per mm3 and stable on HIV treatment or CD4 greater than 350 cells per mm3 and additional risk factors (for example, age, diabetes, obesity, cardiovascular, liver or renal disease, homeless, alcoholic dependency).
Neurological disorders	Conditions associated with neuromuscular respiratory failure requiring chronic ventilatory support: motor neurone disease Duchenne muscular dystrophy. Conditions that require use of specific immunotherapies: multiple sclerosis (MS) myasthenia gravis (MG) other immune-mediated disorders. Dementia, neurodegenerative and neuroimmune disorders when associated with severe frailty (for example, levels 7 or 8 on Clinical Frailty Scale, as part of a personalised care plan): Alzheimer's disease, vascular disease, Lewy body disease, or frontotemporal atrophy Parkinson's disease Huntington's disease progressive supranuclear palsy and multiple system atrophy motor neurone disease multiple sclerosis and other immune-mediated neurological disorders.
Children and young people (CYP) at substantial risk	Complex life-limiting neurodisability with recurrent respiratory infections or compromise.
CYP at significant risk if 2 or more of these risk factors are present	Primary immunodeficiency: common variable immunodeficiency (CVID). primary antibody deficiency on immunoglobulin (or eligible for immunoglobulin replacement). hyper-IgM syndromes. Good's syndrome (thymoma plus B-cell deficiency) severe combined immunodeficiency (SCID). autoimmune polyglandular syndromes or autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy (APECED syndrome). primary immunodeficiency associated with impaired type 1 interferon signalling. X-linked agammaglobulinaemia (and other primary agammaglobulinaemias). Secondary immunodeficiency: HIV CD4 count less than 200 cells per mm3. solid organ transplant. haematological stem cell transplant (HSCT) within 12 months, or with graft versus host disease (GVHD). CAR-T cell therapy in last 24 months. induction chemotherapy for acute lymphoblastic leukaemia (ALL), non-Hodgkin's lymphoma, chemotherapy for acute myeloid leukaemia (AML), relapsed and/or refractory leukaemia or lymphoma. Immunosuppressive treatment: chemotherapy within the last 3 months. cyclophosphamide within the last 3 months. corticosteroids greater than 2 mg per kg per day for 28 days in last 4 weeks. B-cell depleting treatment in the last 12 months. Other conditions: high body mass index (BMI; greater than 95th centile). severe respiratory disease (for example, cystic fibrosis or bronchiectasis with FEV1 less than 60%). tracheostomy or long-term ventilation. severe asthma (paediatric intensive care unit [PICU] admission in 12 months). neurodisability and/or neurodevelopmental disorders. severe cardiac disease. severe chronic kidney disease. severe liver disease. sickle cell disease or other severe haemoglobinopathy. trisomy 21. complex or chromosomal genetic or metabolic conditions associated with significant comorbidity. multiple congenital anomalies associated with significant comorbidity. bronchopulmonary dysplasia – decisions should be made taking into account degree of prematurity at birth and chronological age.

Table 1: Patient cohorts considered at highest risk from COVID-19 and to be prioritised for treatment with nMABs. Nirmatrelvir plus ritonavir, sotrovimab and tocilizumab for treating COVID-19. National Institute for Health and Care Excellence (NICE) Technology Appraisal (TA), 878, March 2023, last updated: 13 March 2024.

3. Commissioning of these treatments in England has changed.

When these treatments were first offered they were centrally commissioned - a high-risk patient in England who uploaded a positive COVID-19 test would be contacted directly by a COVID-19 medicine delivery unit (CMDU). Commissioning is now done locally4 and patients need to make contact themselves. Depending on local arrangements, they may do this via the GP, via their hospital consultant, via 111 or by contacting the CMDU directly. As time passes, it may be that some areas choose to use a mechanism other than a CMDU to deliver care. It would be sensible to find out how care is offered in your area, before you need to signpost a patient to it. The provision of these medications is arranged differently in Scotland5, Wales6, and Northern Ireland7.

In April 2024, the BMA issued guidance in this area, in response to suggestions from some ICBs that COVID-19 therapeutics should routinely be given by GPs. The BMAs position is that provision of therapeutics for COVID-19 should not be done by primary care, unless this is part of an appropriately commissioned service9.

4. Some patients may not realise that they are at high risk.

COVID-19 and the shielding programme revealed some of the limitations of coding and it is likely that there will be patients in the highest risk group who are unaware of their risk, particularly if they have only recently acquired the condition which makes them high risk. If you speak to such a patient then you can let them know that they are at high risk and should have some COVID-19 tests at home, and how to access treatment in your area.

5. Referring to a CMDU should be easy

If you have a patient who you think needs to be seen at a CMDU then you can refer directly, via e-RS. Your local CMDU should be found within the infectious diseases menu. At the moment, none of these drugs can be prescribed by a GP or by any doctor outside of a CMDU and they are not stocked by community pharmacies. Some of them have significant drug interactions, so if referring from primary care it is important to provide a list of current medication.

6. The PANORAMIC trial8 is now closed

The Platform Adaptive trial of NOvel antiviRals for eArly treatMent of Covid-19 in the Community (PANORAMIC) was open to those with COVID-19 who did not fit the criteria for treatment from a CMDU but had a wider range of co-morbidities or were aged over 50. It offered usual care or usual care plus a COVID-19 therapeutic. The group eligible for this trial were more similar to the group who are routinely offered flu vaccination, than to the shielding group. The trial is now closed to recruitment but will continue to collect data until September 2024. It is hoped that the date from PANORAMIC will inform our understanding about longer-term COVID-19 symptoms, as well as the use of antivirals, as participants will be contacted for six months after their enrolment in the trial.

References

1. NICE Technology Appraisal. Nirmatrelvir plus ritonavir, sotrovimab and tocilizumab for treating COVID-19. March 2023, last updated March 2024.
2. Department of Health and Social Care and UK Health Security Agency. COVID-19: guidance for people whose immune system means they are at higher risk. Last updated May 2024.
3. Department of Health and Social Care. Independent report. Defining the highest risk clinical subgroups upon community infection with SARS-CoV-2 when considering the use of neutralising monoclonal antibodies (nMABs) and antiviral drugs. Last updated March 2023.
4. Powis S. Access to COVID treatments. NHS England, June 2023.
5. NHS Inform. Coronavirus (COVID-19): Treatments. May 2023.
6. Antiviral services across Wales – information for members of the public. July 2023.
7. Nidirect Government Services. Treatments for coronavirus (COVID-19).
8. PANORAMIC trial.
9. BMA. Guidance on Covid Therapeutics for GPs.

Written by Dr Emma Nash

Phosphate homeostasis

Phosphate is routinely reported as part of a bone profile blood test. Bone profiles are commonly used to assess calcium and alkaline phosphatase levels, but abnormal phosphate – usually low – is a frequent incidental finding.

Inorganic phosphate is measured as serum phosphate. It has many functions in the body, including calcium homeostasis, cell membrane structure (as phospholipids), DNA and RNA structure, bone growth and mineralisation, intracellular energy control, neuromuscular function, and extracellular pH maintenance.¹

85% of phosphate stores are in bone, mainly as hydroxyapatite. Absorbed phosphorous is converted into its inorganic form by alkaline phosphatase and enters the extracellular fluid pool. From here it moves into bones and tissues as needed. Homeostatic control of phosphate is complex, and occurs through the intestine-bone-kidney-parathyroid axis. A summary of key components, and their effects, are shown in table 1. Some of the mechanisms work to both increase and decrease phosphate levels, depending on the site of action. Intestinal absorption, renal calcitriol (1,25-dihydroxycholecalciferol - the active form of vitamin D) and parathyroid hormone (PTH) are the greatest regulators of serum phosphate levels, although oestrogens, glucocorticoids, metabolic acidosis and various growth factors (particularly fibroblast growth factor 23 – FGF23) are also involved.²

Table 1: Control of phosphate homeostasis1,2,3
Substance	Action	Net effect on phosphate levels
Calcitriol.	Increases phosphate (and calcium) absorption from   gut.  Stimulates FGF23 production.  Increases phosphate (and calcium) reabsorption in   renal tubules.  Inhibits PTH production.	↑
PTH.	Increases renal phosphate excretion (increases   calcium reabsorption).  Stimulates calcitriol synthesis.  Stimulates FGF23 production, promoting bone   turnover and calcium and phosphate release.	↓
FGF23	Promotes bone turnover leading to phosphate   release.  Inhibits PTH secretion.  Reduces renal phosphate reabsorption.  Reduces calcitriol secretion.	↓

Intestinal absorption

Phosphorous is present in a wide variety of foods, in both organic and inorganic forms, with the latter more easily absorbed. Intestinal absorption predominantly takes place in the duodenum and jejunum, with around 60-70% of intake being absorbed. Dietary intake from animal sources is greater than from plants. Dairy and bakery products make up the majority of our dietary intake. Phosphate additives are also commonly found in processed foods as preservatives and stabilisers. The widespread presence of phosphate in dietary sources means that a healthy adult with an ‘average’ diet should not develop dietary deficiency.⁴

Normal phosphate levels 

Local laboratory reference ranges may vary, but normal levels in children aged 1-16 are usually 1.3-2.4 mmol/L, and 0.8-1.5mmol/L in adults. It is important to note that serum levels may naturally be reduced by having had a recent meal (due to insulin production), in the winter due to lower vitamin D, in elderly men, and first thing in the morning. Paraproteinaemia can also cause a spurious low phosphate.⁵ Phosphate levels do not change significantly in pregnancy, but are higher in lactating women, infants and children. It is worth considering these factors when receiving an abnormal result, and some areas prefer a fasting phosphate test.⁶ 

Causes of hypophosphataemia

Medication

• Chronic use of antacids: these antacids form a complex with dietary phosphate, preventing its absorption. This is more prominent with those containing aluminium hydroxide, but those containing calcium carbonate can also decrease intestinal absorption of dietary phosphorous. Regular use of three months or more would normally be required to result in an intestinal deficiency, although this may be sooner in those on a low-phosphate diet (e.g. with advanced chronic kidney disease). Persistent use of magnesium-containing salts can also reduce phosphate absorption.²
• Thiazide diuretics: studies have found that hypophosphataemia is more common in patients taking thiazide (but not loop) diuretics, particularly in patients with hypokalaemia and/or a raised BMI.⁸
• Glucocorticoids and mineralocorticoids.

Intestinal causes

• Alcohol excess: reduced dietary intake, impaired absorption, increased urinary excretion.
• Severe malnutrition and refeeding syndrome: the shift from a catabolic state to an anabolic state can unmask a whole-body phosphate deficiency, even if the serum phosphate is normal prior to refeeding. This can produce a marked reduction in phosphate levels. This is most common in anorexia nervosa, but can also occur where malnutrition has arisen through medical problems such as cancer, alcohol excess and conditions where chewing/swallowing are severely impaired.⁴
• Chronic diarrhoea.

Intra/extracellular shift

• Following treated diabetic ketoacidosis (DKA): the shift in glucose following DKA treatment can result in hypophosphataemia.
• Rapid uptake of phosphate: this can occur in acute leukaemia, but more often is seen following parathyroidectomy for primary hyperparathyroidism. The sudden drop in PTH results in an influx of calcium and phosphate into bones. It can persist for several months following surgery, and is informally known as ‘hungry bone syndrome’.⁷
• Hyperinsulinaemia.

Other metabolic causes

• Hypothyroidism.
• Hypokalaemia.
• Hyperparathyroidism (primary and secondary).
• Vitamin D deficiency.
• Hypercalcaemia.

Consequences and management

Mild hypophosphataemia (0.6-0.8 mmol/L) is usually asymptomatic. Chronic hypophosphataemia below 0.6 mmol/L may still be asymptomatic, but muscle weakness, myalgia, bone pain and changes to mental status (e.g. confusion) can be seen. At this level, phosphate replacement is warranted, ensuring that the person also has adequate calcium and vitamin D stores. The dose is 4-6 effervescent tablets per day, although a lower dosage may be needed if diarrhoea occurs.⁹ _­Replacement should usually be adequate after 7-10 days.^10­­ Alongside replacement, assess for potential causes, recognising that phosphate replacement can affect the PTH-calcium-vitamin D axis, so investigative bloods may need to be done early.

Symptomatic hypophosphataemia usually occurs when phosphate levels are below 0.32 mmol/L,¹¹ and if this occurs acutely, intravenous replacement may be indicated. Severe hypophosphataemia can cause multi-organ cellular dysfunction and impaired energy metabolism. Examples of life-threatening consequences include acute respiratory failure, acute heart failure, arrhythmias, rhabdomyolysis, encephalopathy and seizures.

Mild to moderately low levels do not need urgent input, and time can be taken to ascertain whether they are pathologically low or confounded by any of the factors already mentioned. Repeating the test fasting may be useful, along with considering any recent hospital admissions (severe illness, diabetic ketoacidosis and parathyroidectomy can all result in hypophosphataemia), and reviewing any regular medications to see if they may be contributing to the findings. If not already available, consider checking calcium, urea and electrolytes, vitamin D, PTH and thyroid function tests.

If otherwise asymptomatic and not severe, simple monitoring is all that is needed.⁵

References

1. RL Wadsworth, S Siddiqui, Phosphate homeostasis in critical care, BJA Education, Volume 16, Issue 9, September 2016, Pages 305–309.

2. Goretti Penido M, Alon US. Phosphate homeostasis and its role in bone health. Pediatr Nephrol. 2012 Nov;27(11):2039-2048.

3. Ureña Torres PA, De Brauwere DP. Three feedback loops precisely regulating serum phosphate concentration. Kidney International. 2011; Volume 80, Issue 5, 443 – 445.

4. National Institutes of Health. Phosphorous: Fact Sheet for Health Professionals. 2023. [accessed 29 November 2024].

5. Glendenning P, Bell D, Clifton-Bligh R. Investigating hypophosphataemia. BMJ 2014;348:g3172.

6. Exeter Clinical Laboratory International. Phosphate. 2019. [accessed 29 November 2024].

7. Witteveen JE, van Thiel S, Romijn JA et al. THERAPY OF ENDOCRINE DISEASE: Hungry bone syndrome: still a challenge in the post-operative management of primary hyperparathyroidism: a systematic review of the literature. European Journal of Endocrinology. 2013; Volume 168, Issue 3 Pages R45–R53.

8. Bosman A, Campos-Obando N, de Keyser C et al. Diuretic Use and Serum Phosphate: Rotterdam Study and UK Biobank. Journal of the Endocrine Society. 2024; Volume 8, Issue 5, bvae057.

9. British National Formulary. Phosphate. 2024. [accessed 29 November 2024].

10. Pappoe LK, Singh A. Hypophosphatemia. Editor(s): Stuart B. Mushlin, Harry L. Greene. Decision Making in Medicine (Third Edition). Mosby. 2010. Pages 392-393.

11. Gaasbeek A, Meinders AE. Hypophosphatemia: an update on its etiology and treatment. Am J Med 2005; 118: 1094–101.

Written by Dr Dirk Pilat

Introduction

Mpox (previously known as monkeypox) is a viral, infectious disease caused by a strain of the monkeypox virus (MPXV). The first human cases were identified in 1970 in the rainforest areas of Central and West Africa. Until 2022, outbreaks were usually limited to this geographical area, with occasional imported cases into non-epidemic countries and human to human transmission only present in a limited number of cases. 

MPXV has two distinct genetic lineages, called clade 1 and 2, both split into types a and b. The 2022-2023 global outbreak of mpox that continues to this day is due to clade 2b and caused 3,822 cases in the UK over the last two years. 

Number of confirmed and highly probable mpox cases by UK nation of residence, 6 May 2022 to 31 July. UKHSA. Contains public sector information licensed under the Open Government Licence v3.0.

The 2022-23 outbreak was driven by human to human MPXV transmission via close contact with infected individuals and continues to this day, albeit in lower levels and particularly among men who have sex with men. In 2024, clade 1b mpox cases were starting to spread outside its traditional geographical location in West Africa with the Democratic Republic of the Congo, Republic of the Congo, Central African Republic, Burundi, Rwanda, Uganda, Kenya, Cameroon and Gabon all affected and around 20,000 cases and potentially 1000 deaths reported in the Democratic Republic of the Congo alone. On 14th August 2024 the World Health Organization declared a public health emergency over mpox and since then two imported cases have been identified in Sweden and Thailand. 

Transmission

Mpox is transmitted through skin to skin contact, inhalation or contact with mucous membranes, through direct contact with skin lesions, coughing and sneezing and contact with clothing or linen used by person with mpox. Sexual contact, kissing, cuddling or other skin-to-skin contact can all cause transmission. 

Signs and symptoms

While short incubation periods have been reported, a contact tracing study from the United Kingdom showed that 95% of people with a potential infection had symptoms within 16-23 days. There have been reports that clade 1b might have a shorter incubation record, but there remains a significant degree of uncertainty. Typical prodrome of the illness are fever, headache, myalgia and joint pain and lymphadenopathy, but proctitis and sore throats have also been reported. In the 2022-23 outbreak the subsequent rash was usually limited to fewer than 20 lesions, but there is anecdotal evidence that the rash associated with clade 1b is more severe with up to several thousand pustules. Similarly, mortality seems to be increased in the new outbreak, though this might be due to the affected population being more vulnerable. The rash initially presents with macules, before developing into papules, vesicles, pseudo-pustules containing solid debris, crusts, and finally scabs, before falling off within 7–14 days. These can be painful and are often located orally or in the genital or anorectal areas.

Mpox lesions in various stages of progression. UKHSA. Contains public sector information licensed under the Open Government Licence v3.0.

Management

Making a diagnosis of mpox can be difficult, as there is a broad range of differential diagnoses for pyrexial maculopapular viral rashes such as chickenpox, measles, bacterial skin infections, scabies and herpes. A travel, contact and sexual history is important to narrow the possible diagnosis down. 

If triaging a patient with suspected mpox or if a patient presents with suspected mpox in general practice, the UK Health Security Agency (UKHSA) suggests isolating the patient in a single room and contacting the local infection service for advice, including appropriate arrangements for transfer into secondary care and immediate precautions in the setting (and who will manage contract tracing and advise on vaccination). When examining a suspected patient, clinical staff should wear face fit tested FFP3 masks, eye protection, long-sleeved splash resistant gowns and gloves to provide care if immediately required. 

Treatment is usually symptomatic, but there are antivirals available in secondary care for those with severe disease or immunocompromised patients. The UKHSA has released guidance for pre- and post-exposure vaccination with the smallpox vaccine for patients, contacts and healthcare workers (see references). 

References

Africa Centres for Disease Control and Prevention (Africa CDC). Africa CDC Epidemic Intelligence Weekly Report, August 2024. [accessed 2 September 2024].

Branda F, Romano C, Ciccozzi M, et al. Mpox: An Overview of Pathogenesis, Diagnosis, and Public Health Implications. J Clin Med. 2024 Apr 12;13(8):2234.

Centers for Disease Control and Prevention (CDC). Clinical Recognition: Key Characteristics for Identifying Mpox. Aug 2023. [accessed 2 September 2024].

Center for Health Security Johns Hopkins University. Situation Update Mpox Virus: Clade I and Clade IIb. 2024. [accessed 2 September 2024].

European Centre for Disease Prevention and Control (ECDC). Factsheet for health professionals on mpox. Aug 2024. [accessed 2 September 2024].

Reardon S. Mpox is spreading rapidly. Here are the questions researchers are racing to answer. Nature. 2024 Sep;633(8028):16-17.

UK Health Security Agency (UKHSA). Clade I mpox virus infection. Aug 2024. [accessed 2 September 2024].

UK Health Security Agency (UKHSA). Mpox: background information. Aug 2024. [accessed 2 September 2024].

UK Health Security Agency (UKHSA). Recommendations for the use of pre-and post-exposure vaccination during a monkeypox incident. Aug 2022. [accessed 2 September 2024].

World Health Organization (WHO). Mpox. Aug 2024. [accessed 2 September 2024].

Written by Dr Dirk Pilat

Topiramate is a sulfamate-substituted monosaccharide discovered in 1979 and first sold in 1996 as an anticonvulsant. In the United Kingdom it is licensed as monotherapy of generalised tonic-clonic seizures or focal seizures with or without secondary generalisation, adjunctive treatment of generalised tonic-clonic seizures or focal seizures with or without secondary generalisation, adjunctive treatment for seizures associated with Lennox-Gastaut syndrome and for migraine prophylaxis (British National Formulary, 2024). In other countries it is used off-label for alcohol use disorders and in combination with phentermine it is licensed as an aid to weight loss in the United States (Fariba & Saadabadi, 2024).  It is well absorbed from the gastrointestinal tract with peak plasma levels usually achieved in 2—3 hours. It interacts with other anticonvulsants and decreases the efficacy of hormonal contraceptives and doses should be reduced in patients with severely impaired renal function, as it is predominately cleared through the kidneys (Spritzer, 2016).

Written by Dr Toni Hazell

Public health authorities have noted a recent rise in both measles and pertussis cases. The first three months of 2024 saw 2,793 laboratory-confirmed cases of pertussis in England (compared to 858 in the whole of 2023), with so far five known deaths, all in infants¹. There have been fewer cases of measles (826 over the same time frame²), but again this is a significant increase when compared to the 212 cases seen in the last quarter of 2023².

Prior to the introduction of vaccination, both of these infections were endemic. There were 800,000 cases of measles per year in the UK³, with 120,000 cases of pertussis per year in England and Wales⁴. Infections and deaths fell when vaccination was introduced, but the success of vaccinations for both infections has been hindered by reduced uptake⁵, with pertussis also affected by immunity that wanes over time. This was illustrated by an increase in cases in 2011/12, despite sustained levels of vaccine coverage over 95%⁶.

Laboratory confirmed cases of pertussis in England in 2024, compared to previous years¹.

Image used under the Open Government v3.0 licence.

Laboratory confirmed cases of measles by month of onset of rash or symptoms reported⁷. 

Image used under the Open Government v3.0 licence.

GPs working at the moment will not have been in clinical practice when these infections were endemic, and so may need a reminder of how to spot them – clinical features are outlined below. Both infections present with a prodrome which is similar to a usual viral upper respiratory infection; diagnosis at this point is probably less likely than when specific features develop later on in the evolution of the illness.

Both illnesses have the potential for unpleasant complications. Patients who have had measles are more susceptible to opportunistic infection for around three years after their recovery, because the measles virus suppresses the immune response. Common complications include otitis media, diarrhoea and pneumonia. Rarer, but potentially more severe, are convulsions, encephalitis and subacute sclerosing panencephalitis. This last condition occurs on average seven years after the measles infection (but has been known up to 30 years later) – it presents with neurological symptoms and is always fatal³. Complications of pertussis include pneumonia, apnoea, seizures and encephalopathy. The strength of the cough can cause pneumothorax, abdominal hernia, rib fracture and subconjunctival haemorrhage. It is particularly risky in newborns – anyone aged under six months with suspected pertussis should be referred to paediatrics and is likely to be admitted⁴.

Key features of measles^3,8:

• Prodrome of upper respiratory tract symptoms and conjunctivitis, which starts 10-12 days after contracting the infection and lasts for 2-4 days, at which point a rash appears.
• Children generally feel unwell, with many references describing them as ‘miserable’.
• Fever, which peaks at around 39°C, coinciding with appearance of the rash.
• Rash with the following features:
  • Starts on the face and behind the ears, before spreading down the body and finally to the extremities.
  • Becomes confluent as it spreads.
  • Erythematous and maculopapular.
  • Lasts in total around one week, fading in any given area around five days after first appearance.
  • May be less prominent (or not appear at all) in those who are immunosuppressed. 
• Koplik spots on the buccal mucosa:
  • 2-3mm across. 
  • Red, with white centres.
  • Pathognomic for measles, but their absence does not exclude the condition.  

• Prodrome of upper respiratory tract symptoms which starts 4-21 days after exposure (usually 7-10 days) and lasts for 1-2 weeks.
• Paroxysmal cough with the following features:
  • Is worse at night and may be associated with a short expiratory burst followed by an inspiratory gasp (the ‘whoop’). 
  • Is violent and uncontrolled, due to attempts to bring up thick mucus. This is not always successful, so the cough may appear dry as mucus remains in the bronchial tree.
  • May be triggered by cold or noise.
  • Associated with post-cough vomiting, with a risk of cyanosis in children and syncope in adults.
• Cough gets worse for 1-2 weeks, stays at the same frequency for another 2-3 weeks and then gradually gets less often. Although pertussis is colloquially known as the ‘100 day cough’, the paroxysmal phase of the cough usually lasts for no longer than 10 weeks, more commonly for six weeks. There is then a convalescent phase lasting 2-3 weeks, in which the cough gradually improves. If another respiratory tract infection is contracted in the few months after pertussis, paroxysm of coughing may recur.
• There is usually no fever. 

Written by Dr Emma Nash

Cough is one of the most frequent reasons for presentation to primary care, particularly in children. Acute cough is most  commonly caused by upper respiratory tract infections; chronic cough (over four weeks) is typically attributed to recurrent respiratory tract infection, asthma or pertussis. However, a wet cough lasting more than four weeks should prompt consideration of protracted bacterial bronchitis, also known as persistent bacterial bronchitis (PBB). First described in a study in 2006, the condition is being increasingly recognised clinically. However, there is no clarity on the underlying mechanisms, making definitive diagnostic and therapeutic guidance elusive. Proposed pathophysiological contributory factors include impaired mucociliary clearance, systemic immune function defects (raised NK-cell levels, altered expression of neutrophil-related mediators), and airway anomalies (tracheobronchomalacia). It is also thought that bacteria may produce a biofilm in the airways. This is a secreted matrix that enhances bacterial attachment to cells and facilitates access to nutrients. It also decreases antibiotic penetration, thus protecting the bacteria and making them harder to eradicate with standard length courses of treatment. 

PBB is initially difficult to distinguish from a viral upper respiratory tract infection. The cough is productive, but the child is systemically well. Although wheeze is variably reported, the evidence is that there is a limited response to bronchodilator therapy, if any. Chest examination is typically normal, but if a wheeze is heard, it is monophonic rather than the polyphonic wheeze found in asthma. Sinus and ear disease is absent.

PBB is a clinical diagnosis. It may be suspected when the first two of the European Respiratory Society criteria are met, and confirmed when all three are met:

1. Presence of continuous chronic wet or productive cough (>four weeks’ duration).

2. Absence of symptoms or signs suggestive of other causes of wet or productive cough (see box 1).

3. Cough resolved following a two-to-four-week course of an appropriate oral antibiotic.

Box 1: Pointers suggestive of causes other than PBB. Symptoms: chest pain, history suggestive of inhaled foreign body, dyspnoea, exertional dyspnoea, haemoptysis, failure to thrive, feeding difficulties, cardiac or neurodevelopmental abnormalities, recurrent sinopulmonary infections, immunodeficiency, or epidemiological risk factors for exposure to tuberculosis. Signs: respiratory distress, digital clubbing, chest wall deformity or auscultatory crackles. Tests (if done): chest radiographic changes (other than perihilar changes/bronchial wall thickening) or lung function abnormalities.

The median age of development is 10 months – 4.8 years and it affects more males than females. PBB is no more common in children with an atopic history, but one study has shown that children who attend childcare are significantly more likely to develop PBB than those who do not. Children with an airway malacia are at increased risk of developing the condition as it is harder to clear mucus when the airways tend to collapse. If this is an underlying factor for a particular child, giving a bronchodilator may exacerbate the symptoms as the airways relax even further. PBB is frequently misdiagnosed, or inadequately treated, resulting in a persistence of symptoms and potential structural damage in the form of bronchiectasis.

Most children who have PBB are not able to expectorate sputum for culture due to their age, so treatment is based on  the sensitivity profiles of the typical pathogens. Haemophilus influenzae is the most common causative organism, followed by Streptococcus pneumoniae and Moraxella catarrhalis. However, sputum culture should be sent, if feasible.

Previously, antibiotic treatment courses have been longer, and there has been much debate over optimal drug choice  and  duration. More recent evidence has shown that two weeks may be adequate in many cases. A further two weeks should be prescribed if the child has improved significantly but is not completely cough free. A minority will need longer courses, but if this is the case, there should be a high index of suspicion for more severe disease such as chronic suppurative lung disease (e.g. cystic fibrosis) or bronchiectasis. Therefore, failure of the cough to respond to four weeks of antibiotics should prompt discussion with a paediatrician for consideration of next steps and whether investigation is needed for underlying causes. A reasonable pathway in primary care would therefore be that a GP suspects PBB because the first two criteria are met, treats with two weeks of antibiotics (and a further two if there is no improvement) and then seek specialist advice if the cough persists after four weeks of antibiotics. Chest x-ray is generally only needed if there is a specific reason, such as focal chest signs of concern. 

Unfortunately, no nationally accepted guidelines exist on treatment choice. The most commonly used antibiotic is oral co-amoxiclav but alternatives such as oral second or third generation cephalosporins, trimethoprim-sulfamethoxazole or a macrolide may be used when there is a history of an IgE-mediated reaction to penicillin. 

It is worth noting that recurrent episodes are common, occurring in up to 76% of cases. Antibiotic prophylaxis may be helpful in children who have more than three recurrences in twelve months. Common choices for prophylaxis are azithromycin three days a week, or co-trimoxazole daily, but this would be on specialist advice.    

References

American Thoracic Society. Protracted Bacterial Bronchitis (PBB) in Children. Am J Respir Crit Care Med. 2018; 198, P11-P12. View patient education sheet on Protracted Bacterial Bronchitis (PBB) in Children. [accessed 20 March 2024]

Bergmann M, Haasenritter J, Beidatsch D, et al. Coughing children in family practice and primary care: a systematic review of prevalence, aetiology and prognosis. BMC Pediatr. 2021 Jun 4;21(1):260. 

Di Filippo P, Scaparrotta A, Petrosino Mi et al. An underestimated cause of chronic cough: The Protracted Bacterial Bronchitis. Ann Thorac Med. 2018 Jan-Mar;13(1):7-13.  

Kansra S. Diagnosis and Management of Children with Protracted Bacterial Bronchitis PBB. Sheffield Children’s Hospital NHS Trust. 2017. Download guideline on Diagnosis and Management of Children with Protracted Bacterial Bronchitis PBB. [accessed 20 March 2024]

Kantar A, Chang A, Shields MD, et al. ERS statement on protracted bacterial bronchitis in children. European Respiratory Journal 2017 Aug; 50(2):1602139.  

Dr Dirk Pilat                                                                                                    

Rabies (from latin ‘to rage’) is a zoonotic, mostly fatal disease caused by a neurotropic virus of the lyssavirus genus.

The disease was first described in Egypt around 2300 BCE and is currently endemic in over 150 countries, with the highest risk of exposure in Africa and Asia. Dogs are the principal host in Africa, Asia and America, but the virus can be present in other wild animals, such as bats, cats, skunks or racoons. The most common way of transmission is the bite of an infected dog or cat, though handling of infected carcasses can cause infection too.

Figure 1. 3D still showing rabies virus by www.scientificanimations.com/is licenced under CC BY-SA 4.0 DEED

Worldwide, around 59,000 people die of rabies each year, mainly in Africa and Asia. In the UK there have been reportedly 26 fatalities since 1946, with the most recent in 2018. There is recent qualitative and quantitative evidence that the perceived risk of exposure to rabies for travellers is low, with vaccination often avoided due to cost implications.

Before the SARS-CoV-2 pandemic, circa 2000 people required post-exposure treatment in England per year, of which 12% were potentially exposed to the two bat species in the UK who harbour the virus. The disease remains prevalent in some countries in Eastern Europe.  

After an incubation time of typically three to 12 weeks, infection with the virus can cause a slow but progressive encephalitis with early symptoms being headache, fever, and malaise. The patient may then develop the characteristic symptoms of hydrophobia, hallucinations, and features of mania before progressing to paralysis and coma. Rabies is almost always fatal, and there is currently no specific treatment other than symptom control.

Pre-exposure prophylaxis via vaccination before travelling (or for those with occupational hazards) into endemic areas is a safe and effective method of protecting people from rabies, with the Green Book recommending an individual risk assessment of potential exposure prior to travelling.

Post-exposure management should consist of wound treatment (running tap water over the wound for several minutes, washing with soap or detergent and application of a dressing with disinfectants (such as 40 to 70% alcohol, tincture, or aqueous solution of povidone-iodine) and treatment with either an accelerated course of rabies vaccine or administration of human rabies immunoglobulin. The decision about which course of post-exposure treatment to administer depends on the categories of exposure, which animal was involved and in which country the incident occurred. Advice on who to contact in a suspected case of rabies can be obtained in this table from the Green Book.

Guidance Rabies: the green book, chapter 27, p11. Contains public sector information licensed under the Open Government Licence v3.0.

Tetanus is a disease caused by the neurotoxin produced by the bacterium Clostridium tetani. The spores of the bacterium are ubiquitous in soil throughout the world and enter contaminated wounds or minor abrasions. In low- and middle-income countries, both maternal (tetanus during pregnancy or within 6 weeks of the end of pregnancy via birth, miscarriage, or abortion) and neonatal tetanus (infection occurs via the umbilical stump) are likely significantly under-reported, but it is estimated that in 2015 about 35,000 deaths were due to neonatal tetanus and 57,000 adults were reported to have died. In high income countries, older people and people who inject drugs are the most likely to contract the disease. Migrants from countries with poor vaccination programmes can be particularly susceptible. Between 2001 and 2022, 147 cases of tetanus were reported to the UK Health Security Agency.

Figure 2.Opisthotonus in a patient suffering from tetanus - Painting by Sir Charles Bell - 1809. In public domain.

Under anaerobic conditions the spores germinate, and the newly formed bacteria produce a highly toxic neurotoxin that is transported retrogradely along the axonal pathways, reducing motor nerve inhibition. After an incubation time of up to 21 days, localised or general spasms (such as back arching, known as opisthotonos) can occur, with trismus and ‘risus sardonicus’ being early signs. This can be associated with dysphagia due to laryngeal and pharyngeal spasms. Testing is available via wound samples or serology but should not delay treatment. The UK Health Security Agency defines a probable case as “In the absence of a more likely diagnosis, an acute illness with muscle spasms or hypertonia, and diagnosis of tetanus by a health care provider”.

Treatment requires thorough cleaning and debridement of the wound, antibiotics and in severe cases mechanical ventilation under neuromuscular blocking agents.

Fortunately, a safe and efficient vaccine exists and has been in regular use since 1961. By the 1970s the disease had almost disappeared in children under 15. These days, it is part of the United Kingdom’s routine immunisation schedule.

Patients with tetanus prone wounds might, depending on their vaccination status, receive a reinforcing dose of tetanus vaccine and – if indicated – a dose of human tetanus immunoglobulin after their wound has been thoroughly cleaned. The Green Book categorises tetanus prone wounds as:

• puncture-type injuries acquired in a contaminated environment and likely therefore to contain tetanus spores e.g. gardening injuries and wounds containing foreign bodies
• compound fractures
• wounds or burns with systemic sepsis
• certain animal bites and scratches - although smaller bites from domestic pets are generally puncture injuries, animal saliva should not contain tetanus spores unless the animal has been routing in soil or lives in an agricultural setting.

High-risk tetanus wounds include any of the above with either:

• heavy contamination with material likely to contain tetanus spores e.g. soil, manure
• wounds or burns that show extensive devitalised tissue
• wounds or burns that require surgical intervention that is delayed for more than six hours are high risk even if the contamination was not initially heavy.

 

Guidance Tetanus: the green book, chapter 30, Table 30.1, p.10. Contains public sector information licensed under the Open Government Licence v3.0.
 

References

Marano, C et al. (2019). Perceptions of rabies risk: a survey of travellers and travel clinics from Canada, Germany, Sweden and the UK. Journal of Travel Medicine, Vol 26, Suppl 1, S3–S9, DOI: 10.1093/jtm/tay062

Singh,R et al.(2017). Rabies – epidemiology, pathogenesis, public health concerns and advances in diagnosis and control: a comprehensive review, Veterinary Quarterly, 37:1, 212-251, DOI: 10.1080/01652176.2017.1343516

United Kingdom Health Security Agency (2023). Guidance on the management of suspected tetanus cases and the assessment and management of tetanus-prone wounds. https://www.gov.uk/government/publications/tetanus-advice-for-health-professionals/guidance-on-the-management-of-suspected-tetanus-cases-and-the-assessment-and-management-of-tetanus-prone-wounds (Accessed 14.11.2023)

United Kingdom Health Security Agency (2023). Rabies: the green book, chapter 27. https://www.gov.uk/government/publications/rabies-the-green-book-chapter-27 (Accessed 13.11.2023)

United Kingdom Health Security Agency (2022). Tetanus: the green book, chapter 30. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1080599/Green_Book_on_immunisation_chapter_30_tetanus.pdf  (Accessed 14.11.2023)

Yen, LM; Thwaites, CL (2019). Tetanus. Lancet 2019; 393: 1657–68 http://dx.doi.org/10.1016/S0140-6736(18)33131-3

Written by Dr Dirk Pilat

The Hepatitis E virus (HEV) is the most common cause for acute viral hepatitis worldwide, a fact that is not widely known in the United Kingdom. It is a small RNA virus that has various genotypes, though the most important are HEV 1&2 – the most common types in low-income countries – and HEV 3, which occurs in Europe, the Americas and Australia.

HEV is responsible for about 20 million infections worldwide each year, of which 3 million will be symptomatic and 56,000 lethal. In the United Kingdom, the UK Health Security Agency (UKHSA) follows up confirmed Hepatitis E infections to investigate non-travel related cases of HEV in England and Wales while Public Health Scotland (PHS) monitors HEV infections within their territory.

HEV 1&2 are obligate human pathogens and usually transmitted faecal – orally by contaminated drinking water, while HEV 3 is usually transmitted via inadequately cooked pork, molluscs, or seafood. 90% of pigs in the UK have antibodies to HEV, and around 20% have been known to have an active infection at the time of slaughter. Within Europe the prevalence varies, though there are geographic hotspots with human seroprevalence of >50%. In 2019, UKHSA reported 1202 confirmed HEV infections, PHS reported 158 (>100 cases more than Hepatis A) though due to its often asymptomatic nature, it is reported to be significantly underdiagnosed.

The presentation of acute HEV infections depends on the location of the patient and the genome responsible: In resource poor countries it usually affects young people 15-35 years of age who experience  an acute, self-limiting hepatitis due to HEV1 (Asia) or 2 (Central America). Preterm women are particularly affected, with papers quoting mortality rates of up to 25% and preterm deliveries in 66%. 

This transmission electron micrograph depicts numerous, spheroid-shaped, hepatitis-E viruses (HEV), also known as Orthohepevirus A. Image used with permission from Centers for Disease Control and Prevention (CDC).

During the first 2 weeks of hepatitis E illness:

• avoid preparing food for others
• limit contact with others if possible, especially pregnant women, or people with chronic liver disease

Close contacts should:

• wash hands thoroughly with soap and warm water and then dry properly after contact with an infected person
• wash hands after going to the toilet, before preparing, serving and eating food

Immunosuppressed patients such as transplant recipients, HIV-positive patients or people receiving chemotherapy for haematological malignancies can develop chronic HEV infections and might get treated with ribavirin.

Pregnant women should contact their obstetric team for advice.

As there is currently no licensed vaccine for Hepatitis E in the United Kingdom, prevention is key. UKHSA suggests:

• cooking meat and meat products thoroughly
• avoid eating raw or undercooked meat and shellfish
• washing hands thoroughly before preparing, serving and eating food.

When travelling to countries with poor sanitation:

• boil all drinking water, including water for brushing teeth
• avoid eating raw or undercooked meat and shellfish.

In primary care, a good travel history can be key to diagnose a patient with an unexplained rise in liver function tests and prodromal symptoms.

References:

Aslan, TA; Balaban, HY (2020). Hepatitis E virus: Epidemiology, diagnosis, clinical manifestations, and treatment. World Journal of Gastroenterology. October 7; 26(37): 5543-5560

Horvatits, T; Schulze zur Wisch, J et al. (2019). The clinical perspective on Hepatitis E. Viruses 11, 617

Public Health Scotland: Ten-year gastrointestinal and zoonoses data tables (2023). https://publichealthscotland.scot/publications/ten-year-gastrointestinal-and-zoonoses-data-tables/ten-year-gastrointestinal-and-zoonoses-data-tables-march-2023/ (Accessed 15.08.2023)

UKHSA: Hepatitis E: symptoms, transmission, treatment and prevention (2020). https://www.gov.uk/government/publications/hepatitis-e-symptoms-transmission-prevention-treatment/hepatitis-e-symptoms-transmission-treatment-and-prevention (Accessed 15.08.2023)

Webb, GW; Dalton, HR (2019). Hepatitis E: an underestimated emerging threat. Therapeutic Advances in Infectious Disease Vol. 6: 1–18

Written by Dr Toni Hazell 

Menopause is defined as a biological stage in a woman’s life when menstruation stops permanently, due to the loss of ovarian follicular activity. It is a retrospective diagnosis, made 12 months after the last period, which often follows several years of perimenopause in which periods can be irregular and menopausal symptoms may be felt. The average age of the menopause in the UK is 51. An early menopause is one that happens before 45. Premature ovarian insufficiency (POI) is defined as the transient or permanent loss of ovarian function below the age of 40¹. Care for women with POI should be holistic – as well as the risks to physical health, POI can be very distressing, particularly for those women who do not feel that they have completed their family.

A woman with POI may have an absolutely reduced number of ovarian follicles, or there may be remaining follicles which are not functioning properly. 90% of POI is idiopathic, but the following causes of a reduction or poor function of the follicles may be found in up to 10% of women²:

• Chromosomal disorders (e.g. Fragile X and Turner syndrome)
• Autoimmune disease (e.g. thyroiditis and Addison’s)
• Iatrogenic (e.g. due to the use of chemotherapy or pelvic radiotherapy or surgical after oophorectomy)
• Metabolic disorders (e.g. galactosaemia)
• Toxins such as cigarette smoke and some chemicals and pesticides can speed up follicle depletion
• Infection (e.g. mumps, TB and malaria – this is rare).

POI should be suspected in women who are under than 40 who have at least four months of amenorrhoea, with an estimated FSH level of more than 30 IU/L on two blood samples taken 4 – 6 weeks apart^1,2,3. If the diagnosis is in doubt, then a referral should be done⁴. Referral might be to a specialist menopause clinic, to endocrinology or to gynaecology, depending on your specific concerns and what pathways you have available locally. A full history should be taken, including:

• a review of menopausal symptoms
• other possible causes (including pregnancy)
• lifestyle factors (smoking, alcohol, exercise, nutrition)
• the need for contraception (women with POI still have a small risk of ovulation)
• smear status
• family history of POI, venous thromboembolism or breast cancer
• the woman’s thoughts about HRT use
• any co-morbidities which might be relevant when considering HRT use
• osteoporosis risk – consider a baseline assessment of bone mineral density, with a repeat 2-3 years after diagnosis³.

Those who have worked in primary care for decades will be aware of the changing demand for hormone replacement therapy (HRT) over the years, with a significant decline in the early 2000s⁵, associated with concerns about cardiovascular risk and breast cancer, often based on studies looking at different populations from those who are prescribed HRT in the UK. This has been reversed in the last few years, with a 35% increase in HRT items prescribed from 2020/21 to 2021/22⁶. It is vital that healthcare professionals understand the key difference between prescribing HRT for women who go through their menopause at a normal age, and those with POI, as the risk/benefit analysis is completely different. For women with POI, HRT is merely replacing the hormones that an average woman would have had naturally and reducing the excess risk of osteoporosis that comes with POI. For the vast majority there appears to be no excess risk of breast cancer arising from the use of HRT up to the age of 50³. Both NICE⁴ and the British Menopause Society³ (BMS) are clear that this cohort of women should be offered HRT unless there is a clear absolute or relative contraindication, the main one being a history of a hormone sensitive cancer such as breast cancer. All the data that we have suggests that transdermal oestrogen does not increase the risk of venous thromboembolism (VTE) in women who have their menopause at a normal age^3,4 – the BMS acknowledges the limited data in women with POI but says that the transdermal route should be considered in women with POI who are at an increased risk of VTE, for example due to obesity. Transdermal oestrogen, when used with micronised progesterone, is also ‘unlikely to significantly increase VTE risk above the individual’s intrinsic risk’⁷ for those who have a personal or family history of VTE.

The decision as to whether to refer a woman with POI to a specialist menopause clinic will depend on several factors. These may include the level of suspicion of an underlying cause, the confidence of the GP to manage POI, the woman’s desire for ongoing fertility, a need for specialist psychological input and any individual risk factors for HRT. For women with a history of a hormone sensitive cancer, a referral to discuss the risks and benefits of HRT would be sensible, and this discussion might usefully include her oncologist.

Women who go through their menopause at a normal age are advised to use contraception for one year after their last period (if that happens over the age of 50), or two years if their last period is under the age of 50. Women with POI have a higher risk of spontaneous ovulation and conception and have around a 5 – 10% change of spontaneous natural conception³. Contraception is therefore advised if they do not want to become pregnant and some will prefer to use combined hormonal contraception (CHC) instead of HRT – either are suitable options for oestrogen replacement (assuming no contraindications to combined hormonal contraception), although HRT may be more beneficial for bone health and cardiovascular risk³. They should continue to have smear tests at the normal frequency for their age. If a woman has no need for contraception (e.g. post sterilisation) and has no other licensed indications (e.g. menstrual symptoms) and is using CHC because she prefers it to HRT, then this will be unlicensed.

A diagnosis of POI can have physical, social, and psychological impacts on a woman and her family so holistic care is important. Signposting to a charity such as The Daisy Network⁸ and to reliable sources of information such as the Women’s Health Concern⁹, Rock My Menopause¹⁰, the RCOG menopause hub¹¹, and articles on the website Patient¹² may help her to feel more in control. GPs who wish to learn more about menopause might want to start with the RCGP course on the subject, consisting of a half-hour eLearning module, a short screencast and a podcast¹³. Access Menopause eLearning course via the following link https://elearning.rcgp.org.uk/course/info.php?id=663

Declaration of interests – Dr. Hazell does both paid and unpaid work for the PCWHF, who host Rock My Menopause, and also works for the website Patient.

References (all viewed 26.5.23)

1)     NICE CKS. Menopause. Last updated September 2022. https://cks.nice.org.uk/topics/menopause/

2)     Daisy network. What is POI. https://www.daisynetwork.org/about-poi/what-is-poi/

3)     British Menopause Society. Premature Ovarian Insufficiency. April 2020. https://thebms.org.uk/publications/consensus-statements/premature-ovarian-insufficiency/

4)     NICE. NG23. Menopause: diagnosis and management. Last updated December 2019. https://www.nice.org.uk/guidance/ng23

5)     Cagnacci A, Venier M. The Controversial History of Hormone Replacement Therapy. Medicina (Kaunas). 2019 Sep 18;55(9):602

6)     NHSBSA Statistics and Data Science. Hormone replacement therapy – England. October 2022. https://www.nhsbsa.nhs.uk/statistical-collections/hormone-replacement-therapy-england/hormone-replacement-therapy-england-april-2015-june-2022

7)     Hamoda H, Panay N, Pedder H et al. The British Menopause Society & Women's Health Concern 2020 recommendations on hormone replacement therapy in menopausal women. Post Reprod Health. 2020 Dec;26(4):181-209

8)     The Daisy Network. https://www.daisynetwork.org/

9)     Women’s Health Concern. https://www.womens-health-concern.org/

10)  Rock My Menopause. Premature ovarian insufficiency factsheet. https://rockmymenopause.com/portfolio-item/premature-ovarian-insufficiency

11)  RCOG. Menopause and later life. https://www.rcog.org.uk/for-the-public/menopause-and-later-life/

12)  Patient. What it’s like to go through early menopause. Last updated June 2019. https://patient.info/news-and-features/what-its-like-to-go-through-early-menopause

13)  RCGP eLearning. Menopause. September 2022.  https://elearning.rcgp.org.uk/course/view.php?id=663

14) Eunice Kennedy Shriver National Institute of Child Health and Human Development. What causes POI? https://www.nichd.nih.gov/health/topics/poi/conditioninfo/causes

You might have read recently in the daily and medical press that there has been an outbreak of diphtheria among asylum seekers in England. Even though refugees are often young, physically fit males, they can have complex health needs after their long journeys, such as untreated communicable diseases. Since June 2022 there has been an increase in diphtheria cases, and as of December 2022 62 cases of diphtheria had been confirmed, with half of the cases being cutaneous. Before mass vaccination, diphtheria was once one of the most feared childhood diseases in the UK, with more than 61,000 cases and 3,283 deaths in 1940.

Figure 1 Corynebacteriæ diphtheriæ 
Source: CDC
This image is in the public domain and thus free of any copyright restrictions. Use of this image does not constitute this blog’s endorsement or recommendation by the U.S. Government, Department of Health and Human Services, or Centers for Disease Control and Prevention.

Diphtheria is caused by the non-sporing, non-encapsulated, and non-motile Gram positive bacillus Corynebacteriæ diphtheriæ and Corynebacteriæ ulcerans. Respiratory diphtheria presents with a pharyngitis that often will be associated with a visible greyish membrane and enlarged anterior cervical lymph nodes with perinodal swelling, causing the classic bullneck appearance. Laryngeal diphtheria can be associated with progressive hoarseness and stridor, while nasal diphtheria can present with uni- or bilateral discharge and crustiness. As diphtheria has become increasingly rare in the United Kingdom, thanks to a successful immunisation campaign, it’s not always instantly recognisable for clinicians.

Figure 2 Bullneck appearance

Source: CDC
This image is in the public domain and thus free of any copyright restrictions. Use of this image does not constitute this blog’s endorsement or recommendation by the U.S. Government, Department of Health and Human Services, or Centers for Disease Control and Prevention.

The incubation period for diphtheria is usually 2 to 5 days but may be longer. The commonest mode of transmission of C. diphtheriæ is via droplet spread from a person with respiratory diphtheria; prolonged close contact is usually required for spread.

Cutaneous diphtheria usually starts as a vesicular rash and then forms one or more clearly demarcated ulcer that can be covered in a blueish-grey membrane. Patients may have both cutaneous and respiratory disease.

Figure 4 cutaneous diphtheria 
Source: CDC
This image is in the public domain and thus free of any copyright restrictions. Use of this image does not constitute this blog’s endorsement or recommendation by the U.S. Government, Department of Health and Human Services, or Centers for Disease Control and Prevention.

 

Figure 3 respiratory diphtheria by User: Dileepunnikri is licenced under CC BY-SA 3.0 via Wikimedia Commons.

 

Swabs should be collected from patients and sent to a local diagnostic laboratory with appropriate clinical details.

All suspected cases have to be notified to the UK Health Security Agency. Patients might be referred to the local specialist infectious disease team for face-to-face assessment and review. Treatment options include diphtheria anti-toxin intravenously and macrolide antibiotics.

 

References

Knights, F; Munir, S (2022). Initial health assessments for newly arrived migrants, refugees, and asylum seekers. BMJ 2022;377:e068821 https://doi.org/10.1136/bmj-2021-068821 

British Medical Association (2022). Unique health challenges for refugees and asylum seekers. https://www.bma.org.uk/advice-and-support/ethics/refugees-overseas-visitors-and-vulnerable-migrants/refugee-and-asylum-seeker-patient-health-toolkit/unique-health-challenges-for-refugees-and-asylum-seekers (Accessed 19.01.2023)

UK Health Security Agency (2022): Infectious diseases in asylum seekers: actions for health professionals. https://www.gov.uk/guidance/infectious-diseases-in-asylum-seekers-actions-for-health-professionals (Accessed 19.01.2023)

UK Health Security Agency (2022): Public health control and management of diphtheria in England. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1117027/diphtheria-guidelines-2022_v17_111122.pdf (Accessed 19.01.2023)