Panton Valentine Leucocidin

General paediatrics, Infectious disease

PVL for short.

Cytotoxin associated with Staph SCCmec type IV (this is the cassette that contains mecA), which is the one sensitive to most non-beta lactam antibiotics, but in the US many MRSA too.

Causes lysis of neutrophils and macrophages.  But clinical effects probably through immune dysregulation.

Associated with higher virulence eg necrotizing, multifocal disease eg osteomyelitis, sepsis, multiorgan failure.

Should be treated with combination of beta lactam and protein synthesis blocking antibiotic (clindamycin, linezolid, rifampicin or gentamycin).  Some evidence to support addition of daptomycin.

Surgery often required to remove foci of infection in necrotic tissue.

Decolonisation therapy with chlorhexidine body wash and mupirocin nasal cream recommended.

Chronic Recurrent Multifocal Osteomyelitis

General paediatrics, Infectious disease, Orthopaedic

Adolescents, longbones, probably 1% of all osteomyelitis. ?mech – biopsies usually negative on culture! Pain, ?arthritis if adjacent to focus. Associated with:

  • pyoderma gangrenosum
  • uveitis
  • palmar plantar pustulosis (as in psoriasis)
  • IBD (may come later)

ie inflammatory, autoimmune sounding. Osteolytic & sclerotic lesions on XR, hotspots on bone scan. Histology not characteristic. Differential diagnosis is Langerhans cell histiocytosis.

Rx NSAIDs, steroids if severe/recurrent, ?pamidronate, ?infliximab.

Self limiting but relapsing over 2-4 yrs. 1 case series showed high rate of deformity, but the largest found no long term complications at all!

Osteomyelitis

General paediatrics, Infectious disease, Orthopaedic

Bone infection.  Caused either by haematogenous spread (from distant site), direct innoculation (trauma) or spread from adjacent focus (eg otitis media).

Can be acute or more indolent eg 2/52+ symptoms (Brodie abcess). Mostly femur, tibia, humerus but can be anywhere. Up to 20% multifocal. Pelvic disease often presents with abdo/lumbar pain!

Septic arthritis – similar to OM, usually due to bacteraemia, same organisms. Potential for growth plate or joint consequences. Can lead to OM and vice versa.

Discitis – same bugs (probably), generally under 3-5yrs only, due to persistence of blood vessels in cartilage that subsequently atrophy – can mimic vertebral OM. Well, blood culture neg (cf vertebral osteomyelitis – >3yr, toxic, blood culture pos). Rx clindamycin for 2/52 but no evidence! Likely that some of these would resolve spontaneously if untreated.

Note also Chronic recurrent multifocal Osteomyelitis (CRMO) – clue is in the name! Sterile. Treat with NSAIDS.

Neonatal

Neonatal cases have wider range of organisms and generally involve both bone and joint.  Approx 50% have no systemic features, present with pseudoparalysis alone.

Bugs

Epidemiology varies. MRSA predominant in US etc.

Staph aureus is the main cause, plus:

  • Neonates – GBS, candida, enterobacteriae
  • Infant – kingella, rarely pneumococc, GAS, haemophilus (type B and others), MRSA.
  • Penetrating injuries – risk of contamination, so odd organisms

Kingella, incidentally, is often resistant to vanc and clinda!

Beware salmonella (sickle cell), meningococcal (gonococcal too), TB and non tuberculous mycobateria.  But unknown in up to half, PCR vs culture…

Panton Valentine Leucocidin toxin positive associated with higher fever, higher inflammatory markers, multiple sites, chronic/recurrent.

Radiology

X-ray shows mixture of fast (cortical breach, lysis) and slow (sclerosis, periosteal reaction) changes – but non-specific.

Abscess with sinus extending into soft tissue is indicative of infection.

Fistula and sequestrum (isolated bit of dead bone) more suggestive but take 1-2 weeks to develop.

“Onion skin appearance” suggests chronic infection but is also seen in normal infants, malignancy and in retinoid therapy.

USS may show sub-periosteal oedema early on.

MRI standard for defining collections and guiding surgery: 92-97% sens cf 64-71% for bone scan (latter is also operator dependent).

Investigations

CRP better than ESR.  But can (like WBC) be normal.

Bone biopsy rarely done unless cancer suspected. Joint/pus aspiration can be useful, but generally diagnosis relies on blood culture, hence low identification rates. New PCR technique for Kingella from conventional culture media.

Treatment

Surgical drainage if collection identified or poor response after 48-72hrs in absence of resistance. But still not well defined – over 1 yr and delayed presentation seems to have worse prognosis but will also depend on virulence and resistance.

A septic hip should always be drained promptly, but less clear for other sites – some still advocate early intervention given potential for rapid joint destruction. Aspiration and irrigation probably adequate for most, with second line open arthrotomy (laparoscopic view is limited)

Immobilization +/- traction are considered good practice. For SA, window of 4hrs considered acceptable to get samples before starting antibiotics.

Poor evidence for antibiotic treatment.  Current recommendations:

Cefuroxime under <6yrs (non-neonatal) else Fluclox  or clinda. Beware PVL staph, Hib unimmunized and risk factors for MRSA.  Broad spectrum if neonate, immuncompromised or sickle cell disease.

For all antibiotics use the maximum dose. Never give rifampicin monotherapy as resistance quickly induced. Beware erythromycin resistant MRSA and clinda (inducible resistance). Teico good for bone (keep level>10).

Switch to oral when clinically improved +/- CRP response (eg<20 or down more than 2/3 of peak), median 4 days.  Under 3 months, give full 4/52 treatment course IV.

Failure to improve –

  • consider metastatic infection, DVT, unusual organism eg Fusobacterium. PVL pos
  • IV for 21 days minimum, total 6/52 minimum (even SA)
  • HPA recommend max dose clinda, rifamp AND linezolid. Max 4/52 linez – neuropathy.

Total duration 4-6 weeks for OM, in textbooks, 3 weeks for SA.

Recent HPA guidelines suggest initial therapy for deep seated PVL positive Staphylococcus aureus infections in children as intravenous clindamycin plus rifampicin and linezolid (linezolid maximum of 4 weeks due to the risk of development of peripheral neuropathy), followed by clindamycin plus rifampicin.  Beware thrombosis.

Shorter courses eg 10 days? Peltola’s Finnish studies of shorter courses may not be applicable, as possibly selected for milder infection, exclude culture negative but have high rates of positive diagnosis (staph). [Current Opinion in Pediatrics. 25(1):58-63, 2013 Feb. UI: 23283291] Howard-Jones & Isaacs in JPedsCH however feel evidence for 3/52 courses (grade 2B), emphasize QDS dosing. 1 small old study suggested nafcillin/methicillin inferior to cefuroxime, so Clinda preferable to Fluclox. [Jourrnal of Paediatrics and Child Health 49 (2013) 760–76 UI: 23745943]

[Saul Faust Arch Dis Child 2012;97:545–553. doi:10.1136/archdischild-2011-301089]

Codeine

General paediatrics,

A European review of the safety of codeine-containing medicines licensed for pain relief in children (age 0–18 years) began in October 2012. This review was triggered by concerns of an increased risk of morphine toxicity when susceptible children receive codeine for pain after surgery. These concerns follow the reporting of three fatalities and one life-threatening case of respiratory depression in children given codeine after tonsillectomy or adenoidectomy in the treatment of obstructive sleep apnoea.

Recommendation

Do not use codeine-containing medicines in children under 12 as it is associated with a risk of respiratory side effects related to opiate toxicity. Codeine is not recommended for adolescents (12 to 18) who have problems with breathing eg neurorespiratory problems.

Contraindicated in all patients of any age known to be CYP2D6 ultra-rapid metabolisers (esp common in Africans, else 1-2%) who convert codeine into morphine.

CYP2D6 substrates include tricyclics, SSRIs, opioids, antipsychotics, beta-blockers, Chlorphenamine (!) among others. Rifampicin and dexamethasone are the only inducers, inhibitors include SSRIs. Effect depends on whether a drug needs cytochrome P450 to activate it in the first place, and whether oxidation products are more or less active than original form.

[MHRA]

Post streptococcal acute glomerulonephritis

General paediatrics, Renal

PSAGN for short.  Develops 7-14 days post streptococcal pharyngitis, longer if pyoderma.

Classic presentation is with acute nephritis viz

  • Oliguria
  • Hypertension
  • Haematuria

which leads to fluid overload.  But can be milder eg microscopic haematuria without oliguria.

Microscopic haematuria may persist 1yr+. Acute severe hypertension can present with symptoms of visual impairment, headache, encephalopathy.  Treat with labetolol or nitroprusside infusion.

Insensible losses = 400ml/m2/d.

Less than 2% have long term haematuria or hypertension.

IgA nephropathy

General paediatrics, Renal

Various presentations – usually presents as episode frank haematuria in otherwise well individual.

Can be microscopic haematuria post URTI but within 2-3 days, not delayed as in PSAGN.

Diagnosis requires biopsy – looks like HSP. IgA is found in kidney, no abnormality in blood levels!

Up to 20% progressive renal disease so not quite benign.

Glomerulonephritis

General paediatrics, Renal

Inflammation in the concentrating tissue of the kidney can produce a range of manifestations:

  • Proteinuria
  • Haematuria (microscopic, ie on dipstick/microscopy only, or frank macroscopic)
  • Nephrotic syndrome
  • Acute nephritis

Protein in urine is not usually symptomatic in itself, the urine may seem more frothy.  It would not be until the loss of a substantial amount of protein leads to hypoalbuminaemia and oedema (nephrotic syndrome) that it would be apparent.

Investigations

Accompanying symptoms will tend to guide you to a diagnosis eg purpuric rash (HSP), photodermatitis and/or arhtritis (SLE), heavy proteinuria without haematuria (minimal change glomerulonephropathy).

Dipstick testing is sensitive for proteinuria and haematuria, but urine protein/albumin:creatinine ratio is more reliable.  On microscopy, red and white cell casts are pathognomic.  Presence of red cells useful to exclude other causes of apparent haematuria.

Complement – some characteristic patterns.

If isolated low C3, and fits with PSAGN, diagnosis is clear.  But check it normalizes in 3/12, else biopsy.

Biopsy – for definitive diagnosis.  Although some conditions have patchy changes so sampling error possible.

Causes

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)

Lead toxicity

General paediatrics

No safe blood level has been identified and all sources of lead exposure for children should be controlled or eliminated.

Experts now use a reference level of 5 micrograms per deciliter to identify children with blood lead levels that are much higher than most children’s levels. This new level is based on the U.S. population of children ages 1-5 years who are in the highest 2.5% of children when tested for lead in their blood (National Health and Nutrition Examination Survey (NHANES))

CDC is no longer using the term “level of concern” and is instead using the reference value to identify children who have been exposed to lead and who require case management.

In the past, blood lead level tests below 10 micrograms per deciliter of lead in blood may, or may not, have been reported to parents. The new lower value means that more children will likely be identified as having lead exposure allowing parents, doctors, public health officials, and communities to take action earlier to reduce the child’s future exposure to lead.

What has not changed is the recommendation for when medical treatment is advised for children with high blood lead exposure levels. The new recommendation does not change the guidance that chelation therapy be considered when a child has a blood lead test result greater than or equal to 45 micrograms per deciliter.

Vitamin D

General paediatrics, Nutrition, OPD, Orthopaedic

=colecalciferol.  Essential for bone health.

Obtained from sun exposure to the skin.  Only a few dietary sources – oily fish, cheese, egg yolk, fortified cereals. Diet more important for calcium, of course. Once you apply sun screen, you don’t make vitamin D any more so there is a conflict with the potential for skin solar damage including cancer.

Children under 5 considered a high risk group, along with pregnant, pigmented skin, northern latitudes, wearing concealing clothing, being housebound etc.

2021 Scottish government advice is that everyone consider taking a Vitamin D supplement, particularly between October and March, but that all year round supplementation should be taken by:

  • all pregnant and breastfeeding women
  • all infants and children under 5 years old
  • people who have low or no exposure to the sun, for example those who cover their skin for cultural reasons, are housebound, confined indoors for long periods or live in an institution
  • people from minority ethnic groups with dark skin such as those of African, African-Caribbean and south Asian origin, who require more sun exposure to make as much vitamin D

2017 chief medical officer (CMO) advice – all babies from birth up to one-year-of-age should be given a daily supplement of 8.5 to 10μg vitamin D with Healthy Start vitamin drops being the recommended choice of vitamin, other than babies who are formula fed getting at least 500ml per day, as infant formula already has added vitamin D.

Nonetheless, breastfeeding is preferred – supplementation needed for breastfed infants given lack of sunlight in the UK (probably only useful sun exposure in Scotland between April and September, and between 11 and 3pm).

Children aged 1-4 years old should be given a daily supplement containing 10mcg of vitamin D.

“Healthy Start” vitamins preferred – made for  NHS,  available free to those on income support,  contains recommended dose (approx 300 units) .

Standard prevention dose is 300-400u (10mcg) (neonates), between 400u and 1000u (over 1/12) per day.  Over the counter multivitamins often contain surprisingly little Vitamin D.  Drops, tablets, sprays all available.

Many vitamin D preparations around this dose contain calcium, which may improve efficacy in fracture prevention, but some people won’t like.  Fultium D3 capsules have 800u (20μg) vit D and no calcium.

Symptoms

Aches and pains, delayed walking, seizures and tetany, genu valgum/varum, muscle weakness (incl cardiomyopathy).  The classic features of rickets are bowed legs, rachitic rosary (expanded costochondral junctions), pectus carinatum, curvature of the spine, expansion of the metaphyses at the wrist/ankle, poor dentition.

Testing

Historically deficiency defined as 25hydroxyVitaminD below 25nmol/L. But debated what is optimal.  NICE CKS uses this figure, and defines ‘insufficiency’ as between 25 and 50 nmol/L.

Treatment

Vitamin D3 preferred – D2 sometimes used.

If rapid correction needed eg deficiency with symptoms, fixed loading dose used for 8-12 weeks:

  • 1-5 months: 3000 IU
  • 6 months -11 years: 6000 IU
  • 12yr+: 10 000IU. Single/divided oral dose totalling 300 000IU can be considered if compliance issues.
  • After that, standard prevention dose as above unless significant lifestyle changes to improve Vitamin D status.

Otherwise 400-600IU daily from age 1 month to 18 years. Buy over the counter unless for chronic condition that leads to deficiency.

Assess need for calcium supplementation eg milk allergy. Online calcium calculators available.

Colecaciferol liquid available (3000u/ml), tablets come in 1000u doses and higher.  The combined VitD/Cal tablets tend to have lower Vit D doses and may not be tolerated.

Weekly doses, or single megadoses (30x daily dose) have been recommended where compliance a concern. Intramuscular ergocalciferol 7.5mg (300,000 units, 1ml) can be given in special situations.

Alfacalcidol is used in chronic kidney disease, needs specialist advice and careful monitoring.

Monitoring

Repeat measurement of serum 25 OH vitamin D is not usually necessary, and certainly not within 3 months of starting treatment unless agreed with the duty biochemist.  Check compliance eg empty bottles?

Continue supplementation until child has stopped growing.

Vitamin D deficiency in children | Health topics A to Z | CKS | NICE