Category Archives: Infectious disease

Blood Culture

Clinical, General paediatrics, Infectious disease

Essential investigation in sepsis, particularly where unusual organisms or deep seated infection eg endocarditis.

The volume of the sample is important. Small volumes have higher false negative rate, and are slower to become positive – 6ml superior to 2ml [j Peds 1996].

Traditionally, thought to be most effective when done at time of pyrexia, but there is little evidence for this.  In a study of 1,436 adult patients with bacteremia and fungemia, the likelihood of documenting bloodstream infections was not significantly enhanced by collecting blood specimens for culture at the time that patients experienced temperature spikes. Nor was there any benefit for any subgroup eg patient age, gender, white blood cell count and specific cause of bacteremia. [J Clin Microbiol. 2008 Apr; 46(4): 1381–1385.  doi:  10.1128/JCM.02033-07]

Also traditionally, considered negative at 48 hours. Canadian study of 98 positive blood cultures in babies up to 90 days of age found 96% of true pathogenic cultures were positive at 24 hours, with 100% positive at 36 hours. Mean time to positivity was 14.4 hours in pathogenic bacteria and 23.2 hours in contaminants.  [DOI: 10.1093/jpids/piv078]

US study of 256 non-critically ill babies up to 60 days of age found median time to positive blood cultures of 16.6 hours for pathogens cf 25.1 for contaminants, for CSF cultures 14 hours for pathogens cf 40 for contaminants. 82% of pathogens positive within 24hrs for both blood and CSF [can’t see figures for 36/48hrs yet, full text embargoed?][Hosp Peds 2020]

Another US study of 392 cases (outside of PICU) found 96% of pathogens positive by 36hrs (95% CI 95-98), and 99% at 48hrs. But not clear how many of these would have been well enough to go home at 36 hours.  Estimated that observation >36hrs would identify 1 bacteraemic infant for 1250-2778 infants [Biondi, JAMAped2014]. Note that there were significant differences between organisms (E coli faster, staph slower), and between sites (sample volumes? time to inoculation?). No correlation with degree of fever, interestingly.

Current Western Australian guideline, FeBRILe3, appears to be safe.

Canadians have published a new position statement too.

In a tertiary neonatal unit, 72 hours was considered necessary. [ADC Fetal & Neonatal 2001]

Haemolytic Uraemic Syndrome

Gastro, General paediatrics, Infectious disease, Renal

Or HUS for short.  Mainly caused by VTEC (Verocytotoxin producing E coli), esp serotype O157.  But note also:

  • Occasionally Pneumococcal
  • Atypical HUS – not infective, but a genetic complement disorder
  • D- HUS is the shorthand for HUS which manifests in absence of diarrhoeal illness.  Still worth looking for E coli O157, but need to look at other possibilities.

Clinically

What it says on the tin!

  • Haemolysis
  • Uraemia

Mechanism is Thrombotic Microangiopathy, with microthrombi circulating that affect not just kidneys (producing uraemia) but also:

  • Thrombocytopenia,
  • MI/stroke/infarction
  • Encephalopathy

Differential

  • Acute dysentery eg campylobacter, shigella
  • Intussusception
  • Atypical HUS
  • Acute colitis (Ulcerative Colitis)

Although atypical HUS has a genetic cause, it is typically triggered by infection, esp respiratory tract, else diarrheal illness in 80% of kids, so may be difficult to exclude.  Consider in young infants, severe cases, non-colitis. Low C3 levels are a clue.

Acute colitis will usually have more extensive history or other clues.  The emphasis on managing these cases is on identifying toxic megacolon, and surgical intervention if necessary.  Antibiotics are recommended if high risk of infection (eg signs of sepsis) and/or immediately pre-surgery.

Diagnosis

Features of established disease are:

  • Microangiopathic haemolysis
    • Falling Hb, Plts – clinically pallor, petechiae and bruising
    • Fragmented rbc’s on film
    • High LDH
    • Blood/protein on urinalysis (if there’s any urine being produced to collect)
  • Rising Urea/Creatinine

But ideally you get the diagnosis early, before too much damage has been done.  Clues are:

  • Rising LDH
  • Falling Plts
  • Oliguria
  • Blood/protein on urinalysis

Stool results, to confirm E coli O157, take 24-48hrs (culture and toxin test). Discuss with microbiology if stool culture negative, consider gene PCR, serology.

[Pediatr Int. 2009 Apr;51(2):216-9 PMID 19405919]

Progression

But not everyone who gets E coli O157 gets HUS. Some people get diarrhoea without progressing to colitis (prob the majority), some get colitis without progressing to HUS (only a minority).  Predictors of progression to HUS are:

  • Fever (usually not at presentation, but in history – not very specific)
  • WCC >11
    • Normal WBC provides reliable reassurance against progression to HUS in 9/10
    • WCC>11 predicts progression to HUS in 70–90% of children
  • Raised CRP

[Ikeda, Epid infection 2000; 124:343.  Archimedes, Arch Dis Child 2007]

Ikeda proposes scoring system of 2+ features of fever, high CRP and WCC – 32% sens cf 98% spec.

Public Health

Preventing further cases is as important as managing your case.  About 20% of cases in outbreaks are secondary, but this increases to over 50% of cases in under 6yrs.  Interestingly, secondary cases are usually other children in the nursery (but rarely adults) if pre-school, but family members if primary/secondary school age!  [BMC Infect Dis. 2009 Aug 28;9:144. doi: 10.1186/1471-2334-9-144] Notify Health Protection team on suspicion of E. coli O157 syndrome.

Antibiotics?

Controversial.  Would be considered for other infective dysenteries viz Clarithro for campylobacter, Cipro/cef for salmonella, Azithro for shigella.

But do they precipitate HUS in E coli O157? “Exposure to antibiotics (aOR 3.62; 95% CI, 1.23–10.6) in 1st week independently associated with development of HUS” [Wong 2012].  Current 2011 UK guidance states “The use of antibiotics should, therefore, be governed by good paediatric practice as indicated by needs other than the suspicion of enteric VTEC infection”.

Fluids etc

Loperamide has traditionally been associated with toxic megacolon in acute dysentery so is not advised.

Pain – can be significant with colitis.  Opiates, NSAIDs contraindicated given potential for megacolon or nephropathy.

IV fluid volume and sodium during E coli O157:H7 infections, esp in first 4 days of illness, associated with oligoanuric HUS:

  • 1.6x more likely to become oligoanuric if no IV fluids were given during the first 4 pre-HUS days

[Christina Hickey (St Louis) and Jim Beattie, prospective study Arch Pediatr Adolesc Med. 2011;165(10):884-889. doi:10.1001/archpediatrics.2011.152]

Hence, seems reasonable to:

  • Give 20ml/kg at presentation
  • Rehydrate aggressively eg correct over 6-8hrs
  • Repeat boluses if urine output reduces

Monitoring

Since onset of HUS is from 5 to a maximum of 13 days into diarrhoea illness, there is a need to monitor those with suspected or proven E coli O157 without HUS viz repeat bloods at 5-7 days or earlier if symptoms worsen.  Consider admission if significant infection control issues eg young children/siblings.

Advanced Measures

  • Renal replacement therapy
  • Plasmapheresis (not done in Glasgow)
  • Eculizumab – drug of choice for aHUS, recommended for children in whom plasma exchange is technically difficult
  • Monoclonal antibodies vs STX1/2

Eculizumab = Recombinant monoclonal anti-C5 antibody. Orphan drug.  No good evidence from Germany, but they had good results from plasma exchange anyway.  Evidence from severe TTP that it is effective in cases resistant to immunosuppression and plasma exchange.

 

E. coli O157

Gastro, General paediatrics, Infectious disease, Microbiology, Renal

Notorious STEC/VTEC producing strain of E coli. STEC is shigella toxigenic E coli, VTEC is verocytotoxin toxigenic E coli (same thing).

Cause of potentially fatal Haemolytic uraemic syndrome. But other strains also recognised.

1996 Lanarkshire outbreak, traced back to meat pies from John Barr’s butcher’s in Wishaw.  21 deaths, 512 cases of HUS, esp Wishaw Parish Church Hall luncheon and a local pub birthday party. At the time it was the most deadly food related disease outbreak in world history.  As of 2023 it is still the 6th most deadly food related outbreak in history, and still the worst death toll from O157.

A sad claim to fame for the town.  John Barr was eventually fined £2500.

Emerged in late 80s, rates in Scotland have always been highest in UK until Northern Ireland outbreak with 140 cases in 2012. Odd because England has a lot more cows…

Scotland is said to have 2nd highest incidence globally, although not great data from many places, high regional variability, under-reporting…  Canada and Iran worse?

At the same time as the Lanarkshire outbreak, there was an outbreak in Sakai city, Japan – 12 000 cases of infection, mostly primary school kids.  121 developed HUS, 3 died.  Traced to white radish sprouts.

The most serious outbreak was in 2011, Northern Germany. O104 strain however, enteroaggregative plus toxin. 800 cases HUS (90% adults), 53 deaths.  Traced to organic fenugreek sprouts, although Spanish cucumbers blamed initially, exports dropped £120 million per week until consumer confidence returned.

In 2024, there was a UK wide outbreak of O145 related STEC, with 293 cases and 11 HUS cases. There were 2 deaths. Traced back to salad leaves in pre-packed sandwiches, although never proven.

Ratio of unreported human VTEC O157 infection to reports to national surveillance is estimated at 7.4 to 1.

Cows

E coli O157 is now commonly found in cattle, but causes no clinical effect, therefore no incentive for farmers to control. Supershedders are recognized, with one such cow able to contaminate a huge proportion of other animals’ hides.   Current FSA research project underway.  A vaccine has been developed.

Sheep have also been found to carry it…  Likely cause of outbreaks related to “Tough Mudder” events.

Pathology

Lots of acronyms!

  • EHEC = Enterohaemorrhagic E coli
  • O157:H7 = serotype
  • STEC = Shiga toxin producing E coli, same as VTEC (verocytotoxin)
  • STX1/2 genes (same as VTX) code for this toxin.
  • D+/- = Diarrhoeal illness associated (or not)
  • HUS – Haemolytic uraemic syndrome

More than 400 O:H serotypes – 6 account for most HUS.

Other genes are also relevant for virulence eg Intimin (an adherence factor, coded for by eae gene).

Diagnosis

  • Stool culture – should be collected and processed urgently.  State if bloody diarrhoea present and/or suspicion of STEC infection. Routinely tested for the presence of E. coli O157 at local laboratory, which takes 24-48 hours from sample receipt, but will miss non-O157 types. If positive, isolates are referred to SERL for confirmation of identity and typing.
  • PCR stool testing – if stool culture negative, and clearly bloody (or clinical info suggests likely STEC), then Scottish (SNERL) guidance is to send stool for PCR at the Scottish E. coli O157/ STEC Reference Laboratory (SERL), which detects both E. coli O157 and non-O157 STEC.
  • Serum serology – is used for suspected cases where culture/PCR negative.
  • Rectal swabs – may be submitted directly to SERL from cases of HUS who are unable to produce a stool sample.

Do not delay appropriate clinical and public health management while awaiting reference laboratory results.

Regarding laboratory processes:

  • Rapid referral of samples from diagnostic laboratories to SERL is important to improve the probability of culture confirmation.
  • Positive PCR results will be telephoned immediately to the referring diagnostic laboratory and culture results will follow.
  • The local diagnostic laboratory will inform the clinical team and the local public health team of positive PCR and culture results.
  • PCR (stool) may become available to local diagnostic laboratory, removing need for samples to be referred to SERL . However, if a patient presenting with HUS or acute bloody diarrhoea tests negative by local PCR and is causing clinical concern, please discuss referral of stools for further testing with SERL.

Ebola persistence and recrudescence

General paediatrics, Infectious disease

Now documented that Ebola can recur, or else persist (and therefore be transmissible) from survivors.

Only 2 documented cases of recurrence.  Must be v low risk.

Where blood/urine PCR positive, always ill. Detectable in urine, sweat for up to 40 days.

Circulating neutralizing antibody would reduce risk from blood, but “immune protected” sites different eg Eyes, Pregnancy / breast milk, semen, Central nervous system.

Only 2 cases of sexually transmitted ebola.

So far no evidence of persistence beyond 1yr.

 

Pharyngitis treatment

Common, General paediatrics, Infectious disease,

Pencillin is generally recommended, as resistance in group A streptococcus is unheard of, and risk of rash with amoxicillin if actually Epstein-Barr.  For group A streptococcus a 10 day course has better microbiological clearance but probably no benefit clinically to 5 days.

For scarlet fever, treat for 10 days with any antibiotic except azithromycin (5 days).

Comparative efficacy of antibiotics vs gp A strep pharyngitis – Seventeen trials (5352 participants) were included; mixed adults and kids?

  • no difference in symptom resolution between cephalosporins and penicillin (intention-to-treat (ITT) analysis; N = 5; n = 2018; odds ratio for absence of resolution of symptoms (OR) 0.79, 95% confidence interval (CI) 0.55 to 1.12).
  • Clinical relapse was lower with cephalosporins (N = 4; n = 1386; OR 0.55, 95% CI 0.31 to 0.99; overall number needed to treat to benefit (NNTB) 50), but found only in adults (OR 0.42, 95% CI 0.20 to 0.88; NNTB 33).
  • There were no differences between macrolides and penicillin. Children experienced more adverse events with macrolides (N = 1, n = 489; OR 2.33; 95% CI 1.06 to 5.15).

Evidence is insufficient to show clinically meaningful differences between antibiotics for GABHS tonsillopharyngitis. Based on these results and considering the low cost and absence of resistance, penicillin can still be recommended as first choice.  But not much logic in replacing any other antibiotic with penicillin! [Cochrane Database of Systematic Reviews. 4:CD004406, 2013. UI: 23633318]

Short courses (3-6 days) of amox, co-amox, cefuroxime/cefixime (cefalexin not studied), macrolides etc are actually better than standard 10 day course of penicillin, but more expensive.  [ Cochrane Database of Systematic Reviews 2012, Issue 8. Art. No.: CD004872.]

SAPG 2022 recommends penicillin but if shortage amoxicillin then flucloxacillin. For penicillin allergy, clarithromycin preferred, then erythromycin, then azithromycin. Third line cefalexin, then co-amoxiclav, then co-trimoxazole.

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]

Sepsis

Emergency medicine, Infectious disease

See also Sepsis6.

In reviews of child deaths, most significant recurrent avoidable factor is failure to recognize severe illness, most often at point of first contact with health services (Why children die, Pearson Arch Dis Child doi:10.1136/adc.2009.177071)

American College of critical care medicine 2007 shock update – central venous and arterial monitoring, dopamine within 15 mins, then warm vs cold shock, etc.  2009 Paed intensive care society audit in UK found majority of children (62%) targets were not met, for reasons that remain unclear. OR for death 3.8 where shock still present at time of PICU admission.

In 2011 goal directed therapy study, less intubations and inotropes, half the number of deaths. (But less severe group?) [Andrea Cruz, Pediatrics 2011;127;e758; DOI: 10.1542/peds.2010-2895]

Chinese study of antibiotic timing found reduced time to reversal of shock where given within 1 hour.

Definition of risk group – Paed CCM international consensus conference – at least 2 of the following 4, 1 must be abnormal temp (reported within 4 hours of admission if afebrile at presentation)

  • Core temp <36 or > 38.5
  • Tachycardia
  • Bradycardia
  • Tachypnoea
  • Leucocyte count elevated for age or >10% immature neutrophils

(Not clear why different criteria used for sepsis6)

Def of inappropriate tachycardia?

Studies continue to be done looking for predictive factors esp young infants.

Management

  • Give high flow O2, regardless of sats!
  • Titrate fluids over 5-10 mins, repeat if necessary. Aim to reverse shock.
  • Early inotropic support viz adrenaline (make up during 3rd bolus). 0.3mg/kg in 50ml 5% dextrose, 1ml/hr (0.1mcg/kg/min)
  • 15 mins ideal, within 60mins acceptable.