Category Archives: Rheumatology

Familial Mediterranean Fever

General paediatrics, Immunology, Rheumatology

Short attacks of fever, usually lasting 1-3 days, recurring at varying intervals (periodic), cf Behcet’s.

Most children develop severe abdominal pain with the episodes, due to sterile peritonitis.

Pleuritis, leading to chest pain, arthritis, myalgia and skin rashes may also occur.

Most cases are from Arabic Turkish, Armenian or Jewish background. Inheritance is autosomal recessive. The gene has been cloned and four mutations have been identified.

Colchicine is the treatment of choice. Some patients may develop amyloidosis; certain mutations are at higher risk.



Raynauds etc

General paediatrics, Rheumatology

Raynaud’s syndrome is where digits turn cold, white and numb transiently, usually triggered by the cold but more particularly by cold, wet weather. Can be painful and disabling.

Severe with ischaemia (ulcers, atrophy) likely to be part of a broader rheumatological syndrome.

Prevention mostly. Smoking and cocaine likely to worsen. Moisturise dry skin!

Avoid injury while numb!

Differentiate from acrocyanosis (sluggish peripheral circulation, asymptomatic, common in young children), vibration white finger, perniosis (chilblains), cervical rib, subclavian steal.

Investigations are for underlying causes, namely connective tissue disorder (especially scleroderma in adults), vasculitis, malignancy. So if unusually severe and/or atypical:

  • Full blood count
  • ANA, rheumatoid factor, antiphospholipid antibodies
  • Complement levels
  • Protein electrophoresis
  • Cold agglutinins and, in children, cryoglobulins. You don’t expect distal pallor, just blueness.

Nifedipine has most evidence to support use, other calcium channel blockers could be considered. Main side effect is low blood pressure.

Some evidence for diltiazem. Other options losartan, GTN patch, fluoxetine, alpha blockers.

For severe, sildenafil and atorvastatin! No evidence for aspirin but makes sense…

Systemic onset JIA

General paediatrics, Immunology, Rheumatology

Features

  • Prolonged pyrexia (see below)
  • Intermittent characteristic rash (see below)
  • Raised CRP, ESR, ferritin (esp over 1000 – also haemophagocytic syndromes, haemochromatosis, liver disorders, malignancy)
  • Poor response to IVIG (cf Kawasakis)
  • Leucocytosis (neutrophilia, can be leukaemoid)
  • Thrombocytosis
  • Arthritis
  • Hepatosplenomegaly
  • Generalised lymphadenopathy
  • Pericarditis

Can be systemically very unwell and potentially life threatening complications may occur early in the disease course (eg pericarditis, macrophage activation syndrome or HLH, sepsis). See the Big Sick film from Netflix. Start high dose corticosteroids after careful exclusion of other diagnoses, especially infection, Kawasaki disease, and malignancy – difficult when arthritis is absent! But maybe you have to look harder…

Systemic features may predate the arthritis by several weeks and occasionally longer. Typically involves small joints of the hands and wrists, ankles, hips, knees, and cervical spine – about 30% ultimately develop severe polyarthritis.

There are no pathognomic tests or agreed diagnostic criteria for SOJIA! Classic features:

  • quotidian (=daily) evening spiking temperature, that returns to or falls below baseline by the morning.
  • Rash is faint, salmon pink maculopapular, most obvious during pyrexia. Usually not on the face so easily missed – typically on the trunk, inner thigh and axillae, especially on areas of trauma or pressure (Koebner phenomenon).

Treat with IV methylprednisolone pulses (30mg/kg over 4 hours, max 1g, once daily for 3 days) and ibuprofen (seems better than piroxicam for SOJIA!). Oral prednisolone may then be used while methotrexate is introduced.

Juvenile Idiopathic Arthritis

General paediatrics, Immunology, Rheumatology

Seven subtypes – only diagnose when symptoms for at least 3 months:

  • Oligo (persistent or extended) – Arthritis affecting up to four joints during the first six months of disease. If subsequently more than four joints are affected the term extended oligoarthritis is used, otherwise the term persistent oligoarthritis is used. This is the most common pattern (50% of all JIA) and usually involves large joints of the lower limbs, especially knees. These children have the best prognosis but are at high risk of asymptomatic uveitis (30%, and risk highest in monoarthritis!) and therefore must be screened regularly. In aggressive disease, can develop within 3 months of presentation. Girls mostly ankles, knees or wrists, 50% will be ANA positive and particularly associated with chronic (even subclinical) uveitis. Boys tend to get sacroiliitis and are HLA B27 positive, which is associated with acute uveitis…
  • Polyarthritis (rheumatoid factor -ve) – 5+ joints affected during first 6 months. Tends not to be hips! 17% of all JIA. Severity is very variable.
  • Polyarthritis (RF +ve) – 7% of all JIA. Symmetrical polyarthritis, nodules, and Rheumatoid factor IgM +ve at least twice, 3 months apart. Typically adolescent girls of 10yrs+. Prognosis is guarded as early joint damage often occurs.
  • Systemic onset – SOJIA, 11% of all JIA. Can occur at any age, often pre-school but rarely in infancy. Males and females affected equally.
  • Enthesitis related arthritis – inflammation of tendon insertions eg sternum, around knee (at 2,6 and 10 o’clock positions), tibial tubercle, achilles/plantar, tibialis anterior, flexor digitorum insertion in foot. Often dactylitis. Asymmetric, distal lower limbs large joints commonly affected, high risk of developing ankylosing spondylitis in early adulthood – spine rarely affected early on. BASMI score consists of 5 measurements of spinal mobility. The group also includes arthritis or enthesitis with at least two of:
    • tenderness of the sacroiliac joint and/ or inflammatory spinal pain
    • HLA B27 positive (10% of normal population)
    • family history in a first or second degree relative of HLA B27 related disease (ie arthritis, IBD, Reiter’s, uveitis)
    • anterior uveitis (usually symptomatic with redness, pain and blurred vision)
    • arthritis after 8 years of age in a boy (esp large lower limb joints).
  • Psoriatic arthritis – esp umbilicus, behind ear, scalp. The arthritis is usually asymmetrical, mixed large/small joints. Often NOT psoriasis, at least initially, but includes children with arthritis and at least two of:
    • dactylitis (fat, sore fingers!)
    • pitting or onycholysis of nails
    • psoriasis in a first degree relative
  • Other arthritis – This group is for children with idiopathic arthritis that does not fit the other groups (or into more than one! eg Crohns & UC associated arthritis, features overlap). Downs syndrome children can get a resistant polyarthritis.

Presentation

Clinically, history of pain, swelling, stiffness. Pain is usually not severe, and often avoided completely by adapting movement; can occur at night, and occurs in the joint line. Degree of pain does NOT predict severity of synovitis. Swelling may be due to effusion or bony overgrowth. Stiffness not so severe as to cause gelling ie sitting still leads to freezing (cf myasthenia gravis, hypermobility). Bony overgrowth, discrepant leg length (longer with inflammation! Leads to postural scoliosis), wasting show chronicity.

Differentials:

  • Benign hypermobility – typically get pain related to exertion, short lasting although may occur at night.
  • Reactive arthritis – can last up to 3/12.
  • Rubella, chronic meningococcus
  • HSP before rash develops
  • Rheumatic fever
  • Behçets – mouth/genital ulcers, uveitis.
  • SLE (high ESR with normal CRP, low WCC/platelets, autoantibodies) or dermatomyositis (stiffness, rather than true arthritis – proximal muscle weakness, high CK)

Investigations:

  • Mono JIA usually CRP <7 – else beware infection
  • Micro of joint fluid nonspecific
  • XR – to exclude tumour etc. Lucency in metaphysis may be marrow infiltration in leukaemia, Brodie’s abscess or Langerhans’ histiocytosis. Moth eaten appearance and onion skin periosteal reaction suggests tumour or infection.
  • RF v non specific, like autoantibodies, only significant in discriminating teenage girls with adult type Rheumatoid Arthritis.
  • US is good but operator dependent. MRI probably better, predicts extension in mono, 4-11/12 before clinical signs.

Treatment

NSAIDs and intra-articular steroids work quickly. Ibuprofen can be given at high dose (10mg/kg qds), else Diclofenac 3-5mg/kg in 3-4 divided doses, max 150mg. Piroxicam is once daily, which is convenient but it probably has more GI/cutaneous side effects. No longer considered appropriate for acute pain.

Routine NSAIDs are probably pointless; if you need regular anti-inflammatories, you should probably be on a disease modifying agent eg methotrexate.

Joint injections are given under general anaesthetic in young children or with entonox in older children. Lederspan (triamcinolone) 1mg/kg max 40mg used for big joint, 0.5mg/kg for wrist, TMJ. Knuckles will only take 0.1-0.2ml before they start to leak (which leads to subcut atrophy). Injecting multiple (eg >6) sites can result in Cushings for 3-6/12. Better to pulse methylpred? (Kennilog is another formulation, but seems to give more Cushings). Most patients tolerate injections well and have no loss of function immediately after; physio is usually started after 24hr. How often? Balance of steroid effects and uncontrolled joint disease…

Methotrexate Side effects: GI (nause, ulceration, diarrhoea), hepatotoxicity (reversible elevations of serum liver enzymes eg 3x upper limit normal common), Pulmonary (oedema, pleuritic pain, pulmonary fibrosis, interstitial pneumonitis), mood changes, Renal (haematuria, dysuria, renal failure) – plus usual chemo stuff ie bone marrow suppression.

BNFc

Methotrexate is the disease modifying drug of choice – early use helps to reduce joint damage and minimise the exposure to, and side effects of, corticosteroids. Well tolerated in most children but often causes nausea the day after administration (so usually given on Friday to avoid affecting school). Avoid alcohol, as potentiates risk of cirrhosis. Takes 6-8 weeks to become effective so cover interval with intravenous methylprednisolone. The theoretical risk of malignancy and infertility has not so far been borne out in long term outcome studies. Folic acid improves tolerability but not clear what regimen to use – BNF suggests 5mg once weekly or 1mg daily, theoretically it should not be given within 24 hours of the MTX [so once weekly sounds easier]. Methotrexate is given once a week at 10-25mg/m2 – can be oral but subcut route improves bioavailability at doses beyond 10mg/m2. Metojet has better shelf life (10 months). Regular blood tests to monitor inflammatory markers and side effects eg monthly for 6 months then 3 monthly thereafter. Not great for axial disease ie HLA B27.

Steroids are useful for treating acute flares. Methylprednisolone can be given once daily for 3/7 to control severe exacerbations, then once weekly thereafter (30mg/kg, max 1g). Don’t work well for axial disease though ie HLA B27 (although may be good for peripheral joints) – TNF blockade (ie etanercept or infliximab) effective.

Patients who are refractory to high dose parenteral methotrexate are considered for monoclonal antibodies such as Etanercept/infliximab (TNF antibody), autologous stem cell transplantation, or very high dose immunosuppression.

  • Etanercept (Embrel) used to be twice weekly subcut injection but most now do once weekly 0.8mg/kg. £10 000pa.
  • Infliximab is an infusion, given at 0, 2, 6 weeks then 8 weekly thereafter. Children usually start at 5mg/kg. If control not achieved, a higher dose could be used else the interval reduced. Patients should get a CXR and Mantoux before starting in view of the particular risk of mycobacterial disease.
  • IV immunoglobulin has been used eg 2 doses on consecutive days monthly. Very expensive.
  • Mycophenolate – related to azathioprine. Used for connective tissue disease. SE gastrointestinal, liver, bone marrow. 600mg/m2 BD

Calcium and vitamin D supplements are often given for bone health.

Patients on immunosuppressants should avoid live vaccines and beware of infection. If unwell enough to need antibiotics they should probably stop treatment temporarily. Varicella is a particular concern – if contact with chickenpox and non-immune, consider VZIG or oral aciclovir for prophylaxis, and early IV aciclovir treatment. See Greenbook.

Not clear when to wean… Many patients do well for a year or so before their condition begins to worsen, swapping to another agent often works, and swapping back is also a useful option.

Outcome

JIA is a not a benign disease and outcome is variable. At least a third of patients have ongoing active disease into adulthood and many have sequelae eg:

  • joint damage requiring joint replacement
  • short stature from chronic disease compounded by steroid toxicity
  • localised growth problems (micrognathia or leg length inequality)
  • visual loss from uveitis
  • osteoporosis: one off DEXA scan not predictive of # (maybe better if serial scans?) so clinical. Minimize steroids; optimize exercise, nutrition, growth/puberty, calc/vitD/bisphosph

Bisphosphonates seem to be effective for increasing bone mass in JIA. Flu-like symptoms with first IV dose can be treated with paracetamol and tend not to recur.

Uveitis

Clinical, General paediatrics, Immunology, Infectious disease, Rheumatology

The Uvea is the term for the whole eye (uvea=peeled grape). Whereas conjunctivitis looks like a red eye, it’s only really the surface that is inflamed. With uveitis, all the different tissues of the eye are inflamed. Acutely, might not look that different to conjunctivitis but painful, whereas latter usually just itchy. Anterior chamber starts to fill up with inflammatory cells so vision starts to deteriorate. An irregular pupil due to synechiae can eventually be seen, with hypopyon. Cataracts and scarring can follow.

Chronic on the other hand can be subclinical but potential for visual loss so screening important in associated conditions.

Usually idiopathic, otherwise:

  • Juvenile idiopathic arthritis – about 10% of patients with non-oligoarthritis, and 30% of ANA positive oligo so pretty common
  • HLA-B27 – with or without other B27 conditions such as Ankylosing spondylitis
  • Behcet’s disease (so do HLA B51)
  • Crohns disease and other IBD
  • Granulomatosis with polyangitis (ex-Wegeners)
  • Sarcoidosis (so do chitotriosidase)
  • Tubulointerstitial nephritis and uveitis (TINU) syndrome

Some infections can cause it:

COVID19 treatment

General paediatrics, Infectious disease, Rheumatology

Death from COVID19 usually from cytokine storm and multi-organ failure (often resulting in secondary haemophagocytic lymphohistiocytosis).

NICE has risk factors for young people 12-16yrs:

  • Complex life limiting neurodisability

Otherwise you need 2 of the following to justify treatment in ill (hospitalised) patient:

  • Primary immunodeficiency:
  • Secondary immunodeficiency viz:
    • HIV with CD4 count less than 200 cells per mm3
    • solid organ transplant
    • 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 ALL etc
  • 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/chronic kidney/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
    • infants less than 1 year with cyanotic CHD, or haemodynamically significant acyanotic CHD with history of prematurity, or those due for corrective surgery (to avoid complications or delay)

Steroids

WHO recommends dexamethasone 150mcg/kg once daily for 10 days for severe/critical COVID19 disease, on basis of REACT metanalysis.

Severe defined as any of:

  • Sats <90%
  • Tachypnoea (>30 in over 5s, >40 over 2 etc)
  • Severe respiratory distress

Critical defined as ARDS, septic shock or anything else that would require critical care.

Remdesivir

For Patients at ‘high risk’ of complications (as above, in particular immunocompromise) plus:

  • >4 weeks of age and at least 3kg 
  • Within 10 days of symptoms onset

NOT for patients requiring ventilatory support unless high risk, and not for ALT > 5x upper limit of normal .

5mg/kg loading dose on day 1, followed by 2.5mg/kg once a day for 4 days. May be extended to 10 days in immunocompromised.

Toculizimab is an option for pneumonitis.

Prophylaxis for high risk patients is available:

  • Remdesivir 3 days once daily infusions
  • Paxlovid (Nirmatrelvir +Ritonavir) 300/150mg BD for 5 days

Neutralising antibodies have also been tried but not in guidance.

Sotrovimab [NO LONGER AVAILABLE] – for 12-16yrs, pre-hospitalisation, PCR positive and onset of symptoms within previous 5 days. Not if new oxygen requirement or weight under 40kg. 1% vs 7% placebo hospitalisation or death (85% reduction).

Rheumatic fever

Cardiology, Clinical, General paediatrics, Immunology, Infectious disease, Microbiology, Rheumatology

Rare in developed world now, still common in underdeveloped world, or at least in underdeveloped communities eg Aboriginal Australians.  Prob also genetic susceptibility.

Caused by Group A streptococcus.  Important cause of acquired heart valve disease.  Can recur.

Probably cross reactivity between specific Group A strep M proteins and human tissues.

Erythema marginatum
Erythema marginatum

Diagnosis

Jones criteria:

  • Major
    • Carditis eg new murmur.  Mitral most commonly, classically apical blowing pan-systolic.  Aortic next most common.
    • Arthritis esp large joints.  Migratory.
    • Subcutaneous nodules – these are the most uncommon major criterium (in Turkish study of over 1000 cases there were none with nodules).  Typically over extensor surfaces of joints, 0.5-2cm, symmetrical.
    • Sydenhams chorea
    • Erythema marginatum – not specific to rheumatic fever. Seen in 0.4% of Turkish study patients. Serpiginous or annual eruption, can look similar to erythema multiforme. Provoked by warmth eg bath.  Non pruritic.
  • Minor
    • Fever
    • Arthralgia
    • Prolonged PR interval on ECG
    • Elevated CRP/ESR
  • 2 major or 1 major plus 2 minor, plus confirmation of group A streptococcal infection eg positive culture, high ASO titre sufficient for diagnosis. Modified Jones takes into account background incidence.

Note that initial infection may be subclinical eg pharyngitis, erysipelas. Symptoms of rheumatic fever develop 10 days to several weeks later. Chorea can appear months later.  Low threshold for echo as carditis can also be subclinical.

Established criteria for rheumatic valvulitis – Gewitz 2015

Treatment

Antibiotics – Treat with penicillin,  this does not however affect clinical course but hopefully prevents further spread of that particular bug. Traditionally single dose intramuscular Penicillin G Benzathine.

NSAIDs for joint pain.  Usually dramatic response, if not then reconsider diagnosis!

Valproate for chorea, possibly steroids – see Sydenham’s.

Aspirin and/or Steroids for carditis, but not much evidence.  Diuretics, ACE inhibitors for cardiac failure.

Long term treatment

Recurrence with progression of valve damage is the main concern, and well recognized. Subclinical carditis improves in about 50% but definite risk of progression (mild definite and borderline RHD showed 26% and 9.8% echocardiographic progression respectively).

Regular intramuscular penicillin (benzathine pencillin G) every 2-3 weeks has the lowest recurrence rates but oral penicillin V more acceptable.  Erythromycin or cephalexin if allergic.

WHO recommendations:

  • Rheumatic fever without carditis: 5 years after last attack or until age 18 (whichever is longer)
  • Rheumatic fever with carditis but without residual disease: 10 years after last attack or until age 25 (whichever is longer)
  • Residual valve disease or valve replacement: lifelong

American and Australian heart association guidelines vary slightly:

Penicillin prophylaxis guidelines comparison

Henoch Schonlein Purpura

Common, Dermatology, General paediatrics, Immunology, OPD, Renal, Rheumatology

or HSP. Usually preschool but any age! Boys more than girls. Vasculitis, leucocytoclastic with IgA predominance. EULAR criteria 2010.

Features:

  • Urticarial rash becoming purpuric but still raised (pathognomic), predominantly on lower limbs, especially extensor surfaces incl buttocks, but sometimes trunk, rarely face (infant).  Accompanying soft tissue swelling, as seen in photo in feet.
  • Arthralgia (not migratory, cf acute rheumatic fever)
  • Abdo pain, diffuse, colicky, often severe – possible intussusception, melaena
  • Proteinuria (30+ mmol/mg albumin:creatinine ratio), 2+ red cells on dip or 5+ on microscopy (or casts) indicating glomerulonephritis, usually asymptomatic cf streptococcal, but a few develop diffuse proliferative lesions with irreversible renal damage.
  • Scrotal rash/bruising common, rarely torsion
  • Rarely encephalitis, seizures, pulmonary haemorrhage

Pathology

Leukocytoclastic vasculitis with glomerular mesangial IgA deposits.  Biopsy of patients with IgA nephropathy identical, and indeed both groups have defective IgA1 glycosylation, which may explain why they may aggregate and precipitate IgA in small vessel walls as well as in the glomerular mesangium.

Complications

Complications and relapse associated with age esp over 6yr. 50% relapse, usually within 6 weeks but can be up to a year later; 50% of those will relapse more than once. Treat with NSAIDs (unless renal involvement!) for joint pain, analgesics for abdo pain. Small study from Turkey found that Ranitidine reduced symptoms.

Steroids (prednisolone 1-2 mg/kg/day for 1-2 weeks) are suggested (grade 2 recommendation) within 3 days of onset of severe abdominal pain (defined as pain requiring hospital admission) or acute GI bleeding – after exclusion of intussusception, of course.

Steroids are also suggested for orchitis, after excluding torsion.

Reviewing 101 children with abdo involvement those who did not receive steroids had an average of 5 days of abdominal pain, whereas all those treated recovered within 24 to 48 hours of starting steroids (letter, J Pediatr Gastroenterol Nutr. 31(3):323-4, 2000).

Abdominal pain is a predictor of renal involvement, so maybe that’s the best reason for giving steroids… (Kidney Int 1998; 53:1755-9).

Renal disease

20 to 90% risk of renal disease, but generally mild (mostly just mild proteinuria and/or haematuria)! Normal urinalysis at day 7 has 97% negative predictive value for chronic renal disease [PLoS One 2012;7:e29512].

About 56% of those children with renal disease develop signs and symptoms of renal disease a week or more after presentation, although generally in first month.  Can be up to 6 months later.  Incidence of renal failure in HSP nephritis is just 2 to 5%.  Risk factors are severe abdominal pain (OR=2.1), age >8yrs (OR=2.7), and relapsed HSP (OR=3).[Arch Dis Child. 2010 Nov;95(11):877-82. doi: 10.1136/adc.2009.182394]

A normal urinalysisNB Children who appear to recover may have significant renal disease many years later. (Lancet. 339:280282, 1992).

If more than 50% crescents on biopsy, then poor prognosis.  Only 1% get that far.

Archimedes in 2012 found 3 RCTs of steroids, treatment courses 2-4 weeks, seemed to shorten duration of abdominal pain, with most obvious effect when used early.

Dudley trial of early steroids (day 7) failed to find any benefit at 12 months (n=352).  Quite a high proportion of drop outs unfortunately, but prob not enough to influence results.  Doesn’t answer question of what to do if severe disease at onset eg nephrotic range.  [Arch Dis Child. 2013 Oct;98(10):756-63.]

Non-randomized prospective clinical trial of 223 kids showed that steroids were effective in reducing the severity of abdominal and joint pain and in treating renal disease – steroids did not prevent the development of nephritis [Archives of disease in childhood. 2010;95:877–82, doi: 10.1136/adc.2009.182394 ].  Previous systematic review suggested that steroid treatment at diagnosis did not reduce the median time to resolution of abdominal pain but did significantly reduce the mean resolution time, and increased the odds of resolution within 24 hours.

There is no proven benefit of corticosteroids in the treatment of established HSP nephritis (2009 Zaffanello systematic review, evidence is poor), but used anyway.

The major risks of corticosteroid treatment in children with HSP are masking an acute abdomen or intussuception, and GI bleeding.

Follow up

UK Kidney association guideline 2022 – for uncomplicated presentation, do frequent dipstick checks, for example weekly for first 4-6 weeks then monthly. BP check at presentation and then if evidence of nephritis. No need for parents to check at home otherwise. 6 months minimum (audit criteria, rather than recommendation).

If hypertensive or urinalysis pos, then do proper urine protein:creatinine ratio, U&Es, MC&S. Isolated haematuria is benign. As soon as urinalysis becomes normal, child can have routine follow up.

Scottish guideline was that persisting proteinuria of + or more needs more frequent follow up eg 2 weekly, 2 monthly then 3 monthly with the second line investigations.

Refer urgently for confirmed hypertension, or nephrotic range proteinuria (P:CR over 200mg/mmol).

Refer for biopsy if persisting severe proteinuria (UP: UC >250 mg/mmol for up to 4
weeks), persisting moderate proteinuria (UP: UC 100–250 mg/mmol for 3 months),
AKI stage 1 or greater (creatinine >1.5 × previous baseline or >1.5 × upper limit of normal for age). Treatment depends on histology and severity of clinical features.

ACE inhibitor is suggested (grade 2 recommendation) for persisting mild/moderate proteinuria.

A systematic review found no risk of long-term renal impairment in children with Henoch-Schonlein purpura with normal or minimal urinary findings without nephritic or nephrotic syndrome or renal failure (Arch Dis Child 2005;90:916-20). If urine analysis is normal at presentation, then test for 6 months after the last symptoms. If there is renal disease at presentation, then the risk for progression seems to be more associated with rising proteinuria during follow-up rather than presentation features. (Am J Kidney Dis 2006;47:993-1003)

Chronic fatigue syndrome

General paediatrics, Mental health, Neurology, OPD, Psychology, Rheumatology

NICE update 2021 a bit depressing:

  • Therapy based on physical exercise should NOT be offered “as a cure”, nor should graded exercise programmes (which by definition use fixed increments in exercise) be used!
  • Instead, self management, flexible and tailored
  • CBT should only be offered to manage symptoms, improve functioning and reduce distress.
  • Talks about “energy management” – includes emotional, social, cognitive.
  • “Care and support plan” – physical activity including mobility but also activities of daily living.  Plan periods of rest and activity, and incorporate the need for pre-emptive rest.  Management of relapses and flares.

Main thrust of update is that CFS/ME is a complex, chronic medical condition affecting multiple body systems and its pathophysiology is still being investigated. It affects everyone differently and its impact varies widely – for some people symptoms still allow them to carry out some activities, whereas for others they cause substantial incapacity.  It is a fluctuating condition in which a person’s symptoms can change unpredictably in nature and severity over a day, week or longer.

Often it profoundly affects different aspects of the lives of both people with ME/CFS and their families/carers including social life, emotional wellbeing and education.

Another big theme is prejudice, disbelief and stigma experienced by patients.

US IOM expert panel have rejected the name “chronic fatigue syndrome”, as patients hate it!  Myalgic encephalitis (ME) also rejected on basis of insufficient evidence that this is the pathological process.  They suggest “Systemic exertion intolerance”, which is probably even more rubbish, in my opinion.

Diagnostic criteria: all of the following 3 [BMJ 2015; 350]

  1. Substantial reduction/impairment in pre-illness levels of activity, that persists for more than six months [NICE 2007 says 3/12 for children], and accompanied by fatigue (often profound, new or definite onset, not the result of ongoing excessive exertion and not substantially alleviated by rest)

  2. Worsening of symptoms after any type of exertion (including cognitive and emotional stress) – “post-exertional malaise“

  3. Unrefreshing sleep, and/or sleep disturbance.

In addition, should have at least one of:

  • Cognitive impairment

  • Orthostatic intolerance.

Doesn’t mention chronic pain?! NICE says reconsider diagnosis in absence of cognitive difficulties or chronic pain.

Causes

Evidence (reproducible) implicating certain infections as a trigger. Co-existing mood disorder in substantial proportion of patients, sometimes sleep-wake disorder – likely to perpetuate/exacerbate.

Brain imaging has identified alternations suggesting that it is a brain problem.

Investigations

[NICE 2007]

  • Urinalysis
  • FBC, LFTs
  • TFTs
  • Coeliac disease screening
  • CK
  • ESR/CRP
  • Glucose
  • Ferritin

NOT microbiology unless indicated: borrelia, HIV, Hepatitis viruses, EBV, CMV, toxoplasmosis

Management

Exercise

Cochrane review of graded exercise therapy – may benefit sleep, physical function, self-perceived general health, and no evidence that it worsens outcomes. Curiously, no evidence for loss of aerobic fitness! Perhaps graded exercise tackles a hyper-reactive CNS response to exercise-related physiological signals. Note that fear of physical activity becomes conditioned when it commonly exacerbates symptoms.

Warn that exercise programmes can make things worse rather than better. Exercise should only be done as part of supervised programme, with physiotherapist – don’t just tell them to go the gym more! Start below baseline activity level.

Other

Relaxation techniques recommended by NICE.

CBT – should only be offered to manage symptoms, improve functioning and reduce distress.  Again, not a “cure”. Analysis of both CBT and graded exercise suggests that benefit comes from reducing inactivity.

Sleep hygiene important.  Include rest periods in plan but avoid day time naps, especially since sleep doesn’t usually help anyway!

Many people find exclusion diets useful, esp bowel symptoms, not recommended but involve dietician if attempted anyway.

Equipment to maintain independence can improve quality of life and should be part of overall management.

Beware boom-bust! Many patients over do it when they have a period of relative wellness. Flares and relapses are to be expected.  Trigger? New medical problem? Adjust plan as necessary.

Pain and orthostatic intolerance are big issues for some people.

Severe CFS can increase risk of pressure ulcers, DVT, vitamin D deficiency and contractures.

Prognosis

Important to be honest at time of diagnosis.  More optimistic in young people.  Most adults improve, some are able to return to usual activities but others experience long term symptoms or relapse.

PACE trial aimed for less than full restoration of health as “recovery”, future trials should use clinically relevant improvement and patient self-perception.

[bmj 2015;350:h2087]

[NICE 2021] 

2010 Scottish Good Practice statement needs update.

Lyme Disease

Cardiology, General paediatrics, Infectious disease, Microbiology, Neurology, Rheumatology

Borrelia (spirochaete) infection, spread by ticks (Ixodes), common in localized areas of Europe and North America (forest environments).

Differential includes possible co-infection from other tick born organisms viz anaplasmosis, or babesiosis.

Vaccine available if likely to be at risk.

Clinical

Infection occurs a minimum of 48 hours after bite!

Skin – Erythema migrans is the classic skin lesion, a spreading ring usually at the site of the bite but can be multiple and at different sites.  Typically not hot, itchy or painful. Takes a while for central clearing to develop. Develops over 1-4 weeks (from 3 days to 3 months!), can last months.  Looks like erythema multiforme, but time scale different.  Insect bite hypersensitivity/superinfection looks similar but usually hot, itchy and/or painful, and develops/recedes within 48 hours!

Lyme lymphocytoma is a painless bluish red nodule or plaque, especially on the ear but also reported on the nipple and scrotum.  More common in children.  May persist for months, can precede other features.  Acrodermatitis chronica atrophicans (ACA) is almost exclusively seen in adults, predominantly women, and is an eruption with chronic, progressive red or bluish-red lesions, usually on the extensor surfaces, with later atrophic, fibroid or sclerodermic changes.

Consider Lyme as possible (but unlikely) cause for:

  • fever and sweats
  • swollen glands
  • malaise
  • fatigue
  • neck pain or stiffness
  • migratory joint or muscle aches and pain
  • cognitive impairment, such as memory problems and difficulty concentrating (sometimes described as ‘brain fog’)
  • headache
  • paraesthesia

Arthritis – uncommon, presents as recurrent inflammation of 1 or more large joints, usually the knee. Swelling can be disproportionate to pain.  Can become more persistent – in a minority, despite treatment, inflammation becomes chronic (presumably immune-mediated).

Carditis occurs rarely, and almost always with other clinical features.  Usually partial heart block, but can be complete, usually resolves within a week.

Neurological – isolated facial palsy, meningitis, other cranial nerve palsies, meningoencophalitis, polyradiculopathy.  There is a small proportion of children who can present with non-specific headache, fatigue, neck pain without clear neurological signs (and also the rare case of raised intracranial pressure).

Other rare disease manifestations include uveitis, iridocyclitis and keratitis.

Diagnosis

For erythema migrans, clinical diagnosis is adequate, and antibodies only positive in 30-70% anyway!

Use a combination of clinical presentation and laboratory testing to guide diagnosis and treatment in people without erythema migrans. Do not rule out diagnosis if tests are negative but there is high clinical suspicion of Lyme disease.

  • Offer an enzyme-linked immunosorbent assay (ELISA) test for Lyme disease – consider starting treatment with antibiotics while waiting for the results if there is a high clinical suspicion. (Test for both IgM and IgG antibodies)
  • If the ELISA is positive or equivocal, perform an immunoblot test for Lyme disease (again, consider starting treatment with antibiotics while waiting for the results if there is a high clinical suspicion). [Western blot increases specificity, but cut offs (for both serology and Western blot) can be an issue, with potential false positives for other acute infections and autoimmune conditions.  Definitely needs to be an approved lab…]
  • If ELISA negative and the person still has symptoms, review their history and symptoms, and think about the possibility of an alternative diagnosis.  If tested within 4 weeks from symptom onset, repeat the ELISA 4 to 6 weeks after the first test.
  • If Lyme disease is still suspected in people with a negative ELISA who have had symptoms for 12 weeks or more, perform an immunoblot test.  If negative, consider synovial fluid aspirate/biopsy, or lumbar puncture [PCR – culture is difficult – or CSF antibodies for neuroborreliosis; consider for isolated facial palsy]
  • If immunoblot negative and symptoms resolved, no treatment is required.

For early neuroborreliosis, antibodies 80% sensitive, rises to virtually 100% for late or ACA.

Early antibiotic treatment is also believed to potentially block antibody production.

Antibodies can then persist for months or even years after successful treatment of the infection, so repeat testing is not useful for monitoring treatment success.

First line ELISA test can have false positives for other spirochaetes, glandular fever and autoimmune conditions.

The idea that there are seronegative “chronic Lyme” cases has little evidence to support it, with only 2 possible cases reported (ACA and arthritis, not neuro).

NICE says “Discuss the diagnosis and management of Lyme disease in children and young people under 18 years with a specialist, unless they have a single erythema migrans lesion and no other symptoms. Choose a specialist appropriate for the child or young person’s symptoms dependent on availability, for example, a paediatrician, paediatric infectious disease specialist or a paediatric neurologist.”

Treatment [check NICE]

The most commonly recommended first-line treatments for different stages of Lyme borreliosis in Europe are:

  • Erythema migrans/borrelial lymphocytoma:  10-14 days Doxycycline if 9yr+ (initially 5 mg/kg in 2 divided doses on day 1, then 2.5 mg/kg daily in 1–2 divided doses, max dose 200mg, for a total of 21 days, option for higher dosing) – 10 days courses of doxy effective in US trials.  Else Amoxicillin 50mg/kg/d, max 500mg TDS (10-14 days)[BNFc says 30mg/kg/d, max 1g, TDS for 21 days].  Don’t delay treatment pending test results.  Scandinavia use 10 days Pen V (100mg/kg/d, max 1000mg TDS). BNFc says Azithromycin as alternative.
  • Isolated facial palsy: 14 days Oral doxycycline  – else as above.  Doesn’t probably help resolution but may prevent later complications.
  • Meningitis/radiculopathy: PO Doxycycline or IV Ceftriaxone  50-100mg/kg/d, max 2g daily (14-21 days). [BNFc talks about CNS disease separate from cranial/peripheral nerves]
  • Encephalitis, myelitis: Ceftriaxone (14 days)
  • Lyme arthritis: Doxycycline (28 days) else Amoxicllin (21-28 days)
  • Carditis: Ceftriaxone during pacing, else PO doxycycline (14 days)

Ceftriaxone is the most commonly preferred parenteral agent, with once-daily dosing facilitating outpatient treatment. Recent prospective studies have shown that oral doxycycline is noninferior to ceftriaxone in neuroborreliosis, and it is now recommended in Europe for the treatment of acute facial palsy (FP), meningitis and radiculoneuritis. Ceftriaxone currently remains the preferred choice for children with other presentations of neuroborreliosis and for those with contraindications to doxycycline.

Several recent EM treatment studies have incorporated noninfected control groups. Excellent responses were seen, with resolution of rash within 7–14 days. Nonspecific symptoms including headache, myalgia, arthralgia, fatigue and parasthesias were no more common in cases than controls at 6-month follow up.

[position statement by the British Infection Association, J Inf 2011;62:329]

[Pediatric Infectious Disease Journal Volume 33(4), April 2014, p 407–409]