Category Archives: Infectious disease

Group A Streptococcus

General paediatrics, Infectious disease

Various haemolytic groups, GAS is beta haemolytic.  Other groups of beta haemolytic identified by Rebecca Lancefield.

  • Beta haemolytic Group B is seen in the genitourinary tract of women and is an important pathogen in neonates.
  • Groups C and G both cause invasive disease, both have M proteins, more common throat carriage in developing countries. Maybe also responsible for acute rheumatic fever.
  • Alpha-haemolytic (strep viridans) are associated with line infections and endocarditis.
  • Gamma-haemolytic include enterococci, of which faecium is usually resistant to amoxicillin but faecalis is usually sensitive. Of note, some enterococci are now resistant to vancomycin (VRE).

Acute otitis media

Common, General paediatrics, Infectious disease

Probably 60% of infections are mixed viral/bacterial! Pneumococcus, Haemophilus (non capsulated), Moraxella catarrhalis. Group A Strep is characterized by older age, higher local aggressiveness (ie tympanic perforation and mastoiditis) but lower rates of fever and respiratory symptoms.

AOM is associated with dummy use, adenoids/tonsillitis.

60% of placebo treated children were pain free within 24 hours of presentation [Cochrane 2004, PMID 14973951]. Antibiotics do not increase this proportion. At 2-7 days after presentation, antibiotics reduce by a third the number of children who still have pain (only 14% of the original number), giving a NNT of 15. Too few cases of complications eg mastoiditis to be able to comment on whether antibiotics are useful for preventing such complications.NICE clinical knowledge summary gives NNT of 4000 to prevent 1 case of mastoiditis!

Management is therefore primarily good analgesia. No role for decongestants/antihistamines (Cochrane/NICE).

SIGN guideline 66 on AOM in primary care does not recommend routine antibiotics (but if used, Amoxicillin or co-amox for 5 days recommended). SIGN warns that evidence is poor in infants or in severe disease.

NICE clinical knowledge summary states that at initial presentation, pain and fever should be treated with paracetamol or ibuprofen, at maximum doses if necessary.  No benefit from using both (though poor quality evidence).  For most children antibiotics can be delayed until day 4 of illness (mean duration of illness is 4 days).

Eardrops containing analgesia and anaesthetic (phenazone and lidocaine = “Otigo”) work within 10 minutes – they also significantly reduce the number of people who go on to have antibiotics. Not to be used instead, however, and not to be used where perforation/discharge.

Antibiotics should be offered however at presentation to people who are systemically unwell. Depending on severity, antibiotics should be considered where child is under 2yrs with bilateral otitis media, or if there is perforation and/or discharge in the ear canal.  This advice is also reflected in the British National Formulary for children.

Delaying antibiotics certainly reduces prescriptions, metanalysis of 4 studies in Cochrane did not find any significant difference in pain at 3-7 days, although all but 1 reported some benefit in the immediate treatment group.

A study comparing delayed antibiotics with vs without a prescription (ER based) found high and comparable parental satisfaction rates with both approaches [Chao Peds 2008 PMID 18450878]. In the Cochrane review of delayed antibiotics for URTI, which looked at both adults and children, immediate antibiotics were felt to be more likely to confer modest benefits than delayed antibiotics, with no differences in complication rates between immediate vs delayed antibiotics. Immediate antibiotics had slightly higher levels of patient satisfaction than delayed antibiotics but of marginal clinical significance (92% versus 87%). Concluded that as no evidence for benefit of delayed vs no prescription, best to offer nothing (likely to result in the least antibiotic use). [Cochrane 2011 Delayed antibiotics in URTI, PMID 17636757]

BNFc does suggest antibiotics if:

  • no improvement after 72 hours,
  • clinical deterioration,
  • systemically unwell,
  • at high risk of serious complications (eg in immunosuppression, cystic fibrosis),
  • mastoiditis is present,
  • under 2 years of age with bilateral otitis media.

BNFc also suggests that perforation of the tympanic membrane usually heals spontaneously without treatment; but treat if there is no improvement (eg pain or discharge persists).

Lancet 2006 [pmid 17055944] meta-analysis supports the idea of treating under 2s with bilateral signs (NNT=4), but unlike the BNFc supports treating otorrhoea (NNT=3), as does Cochrane!

Exponential increase in drug resistance and multiresistance. Given how effective placebo is, an effective drug has to do considerably better! Amoxicillin no longer useful (but still recommended by NICE), cefaclor and TMP-SMX not good for borderline resistant pneumococci, azithromycin does not achieve MIC for Hib/Pneumo in ear (although cure rates may not be all that bad…). Co-amox in double dose ie 90 mg/kg/d in 2 divided doses is effective, but increasing resistance.

Treatment leads to higher numbers of resistant species in nasopharynx, esp dually resistant bugs. Azithromycin persists in body for several weeks so is excellent for inducing resistance. Despite overall trend towards reducing antibiotic usage in AOM, most reduction in amoxicillin, with increased prescribing of quinolones and azithromycin. So don’t treat at all unless added features (unless under a year). [Ron Dagan, Beersheva]

Lots of potential complications:

  • Acute mastoiditis = a type of osteomyelitis, with potential for intracranial spread and meningitis/cerebral abscess formation.  Classic signs are erythema, swelling and tenderness behind the ear, with deviation of the pinna.
  • Gradenigo syndrome = intratemporal extension of AOM, causing VI nerve palsy (via apex of petrous temporal bone).
  • Grisel’s syndrome = non-traumatic subluxation of the atlanto-axial joint caused by inflammation of the adjacent tissues.  Clue is trismus and torticollis.

HIV/AIDS

Immunology, Infectious disease

2015 37m worldwide living with HIV, vast majority in Sub-Saharan Africa. Growth is N Africa and Middle East.

20 years since introduction of ART. Still over 1 m deaths per year. Only about a third have access to ART. $250 per child per year.

West Africa seroprevalence only 1-2%, S Africa 25% of sexually active!!!

Treatment for pregnant women actually very good coverage in South and East Africa, much poorer elsewhere.

WHO now recommends treatment for everyone at diagnosis, regardless of CD4, symptoms etc!

In UK 5000 new cases per year, peaked in 2005 (8000), pretty stable now, still mostly migrant associated. Average age of HIV pos child is now 13.6!!! No neonatal cases in Scotland for years.

Majority of known patients have undetectable viral load!

Maternal transmission

Previous advice to breast feed exclusively for 6/12 then stop, now WHO say at least 10-12 months, with no recommendation on stopping. Mixed feeding is now considered acceptable. But this weighs benefits of breast feeding against low rate of transmission of under 2%.

In UK, completely discourage breast feeding, but “not a child protection issue”! Still controversial. Check with your local team!

Transition

Focus now on optimisation of health status through childhood rather than survival! Worry that significant numbers of deaths in survivors of childhood HIV.

Future

Treatment interruptions (not good outcomes in adults)?  Reduction in lab monitoring? Still new (delayed) toxicities eg portal hypertension with DDI. Depot injections!

Treatment

Kaletra + nevirapine first line. Commissioning in England influences treatment recommendations. PENTA 2016 now recommends ART for all children.

Dolutegravir has best results, side effect profile and low interactions (Integrase strand transfer inhibitors (INSTIs)).

Complement deficiency

General paediatrics, Immunology, Infectious disease

Complement cascade can be triggered by classical (antibody binding to antigen, but also directly by C-reactive protein an other substances), lectin (mannan binding lectin, which recognise glycoproteins not typically found in higher order animals) or alternative pathways.  The alternative pathway is the oldest, and constitutes a constant low level autoactivation, at the ready to explode!  Properdin acts here, and may ineract directly with bacteria.

Deficiency can cause susceptibility to infection, but see also hereditary angioedema and atypical HUS.

C3 is the common factor, so deficiency leads to severe infection with encapsulated organisms eg Pneumococcus, Haemophilus, Meningococcus.  Deficiency in terminal and alternative pathways lead almost exclusively to problems with meningococcus!

Properdin

Stabilizes C3/C5 convertase enzymes.  Deficiency (X-linked) associated with fulminant meningococcal infection, especially with unusual types eg W135, Y!  Phagocytosis more important for type B disease? Life time risk for affected individual is about 50%!  Interestingly, mean age of presentation is 14yrs.  Recurrence is actually unusual, presumably due to intact immune memory.

Subtypes characterized by absent, low level and dysfunctional properdin seen.  Standard screening with C3, C4 and CH50 are normal.  Good family history is more important.

Good antibody responses to Men ACWY vaccine.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1905414/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2952982/

 

https://www.ncbi.nlm.nih.gov/pubmed/19758139

Tuberculosis

General paediatrics, Infectious disease

[needs revising]

Contacts

Offer testing to close contacts of pulmonary or laryngeal TB treated for less than 2 weeks. Over 2yrs, start with Mantoux. If negative, repeat after 6 weeks with IGRA.

Smear positive get immediate assessment for active TB. Smear negative refer to specialist.

Neonates start isoniazid with pyridoxine. Mantoux at 6 weeks.

Mantoux>= 5mm positive regardless of BCG history.

If positive assess for active TB. If assessment negative, complete treatment for latent (6months). If negative reassess for active TB and consider IGRA test. If IGRA negative stop treatment and give BCG.

For under 2yrs, start isoniazid +/- rifampicin and do Mantoux. Latent treatment with rifampicin is just 3/12.

If Mantoux negative continue treatment, assess for active TB after 6/52 and repeat Mantoux. Consider IGRA as above.

IGRA should only be done alone if Mantoux not available or impractical(?!).

Diagnosing active disease

If clinical signs and suspicion, start treatment pending test results.

Do CXR and 3 cough swabs (including 1 early morning). Young children get induced sputum.

Other testing depends on age and whether suspected pulmonary.

  • If suspected pulmonary, then do rapid diagnostic nucleic acid amplification tests (PCR) – usually only 1 per specimen type (deep cough sputum, induced sputum or gastric lavage) AND IGRA+/or Mantoux
  • For extrapulmonary, after imaging, discuss pros/cons of both biopsy and needle aspiration (NOT into formalin…). Do CXR anyway.
  • if clinical suspicion, HIV Positive, need for rapid result or large contact tracing exercise.

[NICE guidance 2016, updated 2019 https://www.nice.org.uk/guidance/ng33]

Cefalosporins

General paediatrics, Infectious disease, Medical, Microbiology

Cefalosporins have a broader activity than penicillins, esp 3rd generation eg cefotaxime, ceftriaxone which are effective against most gram positives and gram negatives.

Good for meningitis (penetrate inflamed meninges at high dose) but not effective against pseudomonas, enterococcus, listeria, MRSA, and not that great against normal staphs so beware if possible line infection or neonatal meningitis. Some pneumococci can be resistant (1st line meningitis treatment in US is cef with vanc).

Ceftriaxone is drug of choice for Lyme with complications; it is not recommended for immediate treatment of meningococcal disease as any subsequent calcium containing infusions will reduce its plasma levels.

Ceftriaxone also eradicates meningococcal colonization – since cefotaxime is essentially equivalent, no reason to switch just for this indication.

Contraindications to ceftriaxone:

  • Concomitant treatment with intravenous calcium (including total parenteral nutrition) in premature and full-term neonates—risk of precipitation in urine and lungs (fatal reactions) ;
  • full-term neonates with jaundice, hypoalbuminaemia, acidosis, unconjugated hyperbilirubinaemia, or impaired bilirubin binding—risk of developing bilirubin encephalopathy;
  • premature neonates less than 41 weeks corrected gestational age

Chronic Granulomatous Disease

General paediatrics, Immunology, Infectious disease

A neutrophil defect, prediposes to certain characteristic organisms. Frustrated neutrophils cause granulomas, hence the name: these are responsible for some other characteristic features of the disease.

Due to NADPH oxidase mutations, causing reduced oxidative burst (needed by neutrophils to kill pathogens after phagocytosis). Various types depending on which subunit affected. X linked gp91phox def (ie NADPH OXidase, due to CYBB gene defect) is severe, p47phox is autosomal and milder (NCF1 gene, partial activity retained). Other gene defects are CYBA and NCF2, funnily enough, and RAC2. Phenotype varies even between mono twins (factors?). Since non-oxidative killing is then the only remaining immune mechanism, the most important pathogens are catalase positive (an enzyme to make bugs resistant to the peroxide and superoxide produced by neutrophils or by the bacteria themselves as a toxic byproduct). Register exists in UK.

Usually present by 2 yrs but occ not until adulthood. Most commonly lymphadenitis (often culture negative), skin infections (esp perianal), pneumonia. Hepatomegaly is a clue. Other sites of infection are osteomyelitis, liver abscesses (distinctive, fibrous capsule, septated, thick contents – vague presentation, blood cultures usually negative so low index of suspicion).

Probably not the superoxides themselves that are important; MPO deficiency does not tend to present with infections! Critical step is probably degranulation of primary granules, with release of elastases etc. Superoxides probably deal with toxic metabolites rather than doing the killing.

Chronic inflammatory problems occur (due to having intact upregulated phagocytic activity with reduced apoptosis):

  • BCG causes lymphadenitis in CGD, but does not disseminate.
  • colitis (characterized by pigment laden macrophages, quite specific for CGD but not very sensitive). Seen in 45% of X-linked, 10% of autosomal recessive. Tends to present with abdo pain rather than frank bleeding, often subclinical, may account for FTT.
  • lupus like rash and illness
  • Poor wound healing (classically dehiscence at 10/7 post op, non-purulent)
  • cystitis
  • pericarditis
  • chorioretinitis
  • Hollow organs may become obstructed by granulomas esp oesophagus, gastric outlet, bladder.
  • pulmonary fibrosis

Mums who are carriers of CGD can be symptomatic even with fairly decent percentages of functional neutrophils incl aspergillus! Due to lyonization.  Onset variable.

Diagnosis

Nitroblue tetrazolium (NBT) test now replaced by Dihydrorhodamine test on flow cytometer (false positive esp in preterm so always check with reference lab). Only takes 15 mins!

The organisms found are also characteristic:

  • Staphylococcus aureus – found in most liver abscesses as well as in skin
  • Enterobacteria – Enterobacter, E coli, Salmonella, Klebsiella, Aerobacter, Serratia, Yersinia, Proteus
  • Aspergillus – mostly fumigatus but A. nidulans is emerging in US, and Candida albicans, Scedosporium apiospernum and Chyrosporium zonatum reported. Can be acute, esp after inhalation eg digging in garden. Biopsy may be needed to make diagnosis. Steroids useful for severe inflammatory disease!!!
  • Burkholderia cepacia – looks identical to Pseudomonas, so any Ps not specified as aeruginosa should be considered suspect! (Pseudomonas itself is catalase positive but susceptible to non-oxidative killing so is not a problem).
  • Septicaemia is v rare ! – but may be seen with B. cepacia.
  • Nocardia common in US, rare in Europe – gram positive soil organism, forms filaments like a fungus. Usually pneumonia but also skin, CNS. Sensitive to co-trimoxazole.
  • Actinomycosis – even though catalase negative!

Note that you do NOT see PCP, strep, onychomycosis (despite susceptibility to fungus) or lymphomas (cf granulomas).

Patients are often anaemic with an iron-deficient pattern but resistant to iron supplementation (except in bowel disease, ?vitamin B12 def). ESR is often raised even when well. Less of a problem with CRP.

Management

Co-trimoxazole prophylaxis (daily dosing, not 3x weekly as in PCP prophylaxis) good because active against typical bugs, and intracellular. Itraconazole is prophylactic vs Aspergillus.

Avoid BCG because of tendency to form abscess.

Cipro and Fluclox good for first line – effective against typical organisms, and cipro acts intracellularly. In serious pneumonia, empirical treatment should consist of Ceftazidime/Meropenem, Fluclox and Amphotericin. Because of the range of possible organisms, bacteriological diagnosis should not be delayed and tissue biopsy sought if non-invasive methods unsuccessful.

Steroids for colitis, cystitis and obstructive granulomatous disease. Also for poor wound healing!

Other adjuncts:

  • Voriconazole is an effective oral antifungal, so useful when no tissue diagnosis (beware accumulation of amphotericin with long term use, causing permanent renal damage).
  • Interferon (IFN) gamma – effective as prophylaxis in large Multicentre study, but strong centre effect with less benefit in Europe (in fact the lowest incidence seen with antibiotic prophylaxis) so not universally used (but safe). Less evidence in established infection but that’s when it tends to get used! Increases NO production by neutrophils, by improved RNA splicing efficiency(?). Give three times a week by subcut injection; side effect is fever and flu-like symptoms. Better antifungals mean it is used less now.
  • Granulocyte infusions (apheresed from donors after GCSF priming) can be done every 1-2 days (or instilled directly into lesions) but rarely needed now with better antifungals. Increases risk of reaction to Ambisome, plus you become sensitized, which will hinder transplant prospects. Can support infected kids through BMT.
  • Surgery may be necessary to remove infected tissue, may help get positive culture.
  • BMT is indicated at diagnosis if a matched donor is available.
  • Gene therapy has produced transient improvements only.

Median survival 30 years – NB compliance with prophylaxis by adolescents. So consider transplant.

[Clin Exp Imm 122(1); October 2000 pp 1-9 GOLDBLATT, D; THRASHER, AJ]

Recurrent boils

General paediatrics, Immunology, Infectious disease, Microbiology

Potentially symptom of diabetes, chronic granulomatous disease, Hyper IgE syndrome – but more usually just an individual thing, or a nasty strain of staphlycoccus aureus.

GOS says if otherwise well (no other abscesses, no colitis, no weird organisms eg Serratia) then consider eradication with:

  • Naseptin – a medication taken four times a day for a period of 10 day.s
  • Chlorhexidine shower or bath and hairwash every day for a period of 14 days.
  • Keep a separate towel for each member of the family, change for a clean towel every two days and wash the dirty towels on a hot wash cycle.

[http://www.gosh.nhs.uk/medical-information-0/search-medical-conditions/recurrent-boils]

Antibiotic resistance

General paediatrics, Infectious disease, Microbiology

Penicillin resistance

Resistance to penicillin is usually due to Beta lactamase enzymes.  Therefore adding a  beta-lactamase inhibitor eg clavulanate (as found in co-amoxiclav) overcomes the resistance and extends the spectrum.

An alternative resistance mechanism however is production of defective Penicillin Binding Proteins – this is the mechanism of resistance in Pneumococci.  Beta lactamase inhibitors therefore do not help.

Macrolide resistance

Variable resistance seen; sometimes effective against penicillin resistant staphylococci including some MRSA, but poor activity against Haemophilus. Variable resistance seen in streptococcus, pneumococcus. Resistant mycoplasma are rare but do exist – try cipro, else tetracycline.

Using Azithromycin probably improves efficacy in Haemophilus (more active) but pneumococci that are resistant to erythromycin (approximately 5 to 20% of strains currently) will also be resistant to azithro, and no difference in in vitro activity between the newer and old macolides against other common respiratory pathogens.

Multiresistant organisms

In theory, you should use a combination of antibiotics (if possible) to treat a multiresistant organism, to prevent resistance developing (as in TB).  However there is no good clinical data to support this, beyond TB treatment (which is slow growing, so probably different).  On the contrary, meta-analyses demonstrate no difference in clinical outcomes between the two treatment strategies (for infections with Gram-negative bacteria), but there are well-documented increased toxicities with combination therapy.

Having said that, given the greater mortality associated with delays in appropriate and effective antimicrobial treatment, starting with combination therapy in critically ill patients seems sensible.

If there is poor response to treatment, rather than simply adding a second agent, consider:

  • dose, frequency – are you achieving adequate time above MIC?  Consider prolonged antibiotic infusion strategy
  • route – give IV if not already
  • duration – extended treatment course?

[doi: 10.1128/CMR.05041-11 Clin. Microbiol. Rev. July 2012 vol. 25 no. 3 450-470]

ESBL – extended spectrum beta lactamase

Scenario 1: lower renal tract infection with ESBL producing Gram negative

Bacteriuria with urinary symptoms but minimal systemic symptoms and no fever

  • Treatment duration 3 days
  • First line – trimethoprim / nitrofurantoin  (not used in under 3 months)
  • Depending on sensitivities and age alternative options include ciprofloxacin, single dose aminoglycoside, pivmecillinam or fosfomycin

Scenario 2: upper renal tract infection with ESBL producing Gram negative

Bacteriuria with urinary symptoms and associated systems symptoms including fever

  • Treatment duration 7-10 days (as per NICE)
  • Always consult with infection management specialist
  • First line – if seriously unwell or under 3 months carbapenem  + consider one dose of aminoglycoside
  • Alternative: tazocin and consider one dose of aminoglycoside (if sensitive and not seriously unwell and after discussion with local microbiologist)
  • OPAT : Ertapenem
  • Daily IVOST review required
  • Potential IVOST options when afebrile, clinically improving, falling CRP and able to take and absorb oral medicines: ciprofloxacin, trimethoprim
  • There was less consensus on the role of pivmecillinam and its ability to penetrate renal tissue. It should be considered only to offer an oral option to finish a course of antibiotics in a clinically improving child

Scenario 3 – infection with ESBL producing Gram negative outside the renal tract (except for meningitis)

  • As per IDSA – carbapenem, meropenem (especially if child unwell)
  • Stepdown co-trimoxazole or ciprofloxacin (would consider fosfomycin on rare occasion)
  • Temocillin not empirical therapy until we understand PK/PD profile better plus expensive and difficult to obtain – consider not including
  • Recommendation would need caveat, how unwell, age of child.  Not experienced discuss with infection specialist. BNFC reference
  • Ertapenem OPAT

Scenario 4 – meningitis complicating ESBL producing Gram negative

  • Carbapenem, limited ability to step down
  • Treatment duration – 3 weeks
  • Lumbar puncture to ensure infection cleared.

[Conor Docherty]

Enterovirus

Common, General paediatrics, Infectious disease

Mild: fever +/- rash, hand/foot/mouth, herpangina, pleurodynia, pharyngitis, conjunctivitis, croup.

Serious: meningitis, encephalitis, acute paralysis, neonatal sepsis, myo/pericarditis, hepatitis, chronic infection (immunocompromised).

Meningo-encephalitis in neonates usually associated with other organ involvement. In adolescents headache can be severe and symptoms last several weeks! Early CSF can show around 1000 neutrophils! Prognosis good, although some subtypes with encephalitis highly aggressive eg EV-71 outbreak in Taiwan in assoc with hand/foot/mouth (78 deaths).

Acute flaccid paralysis can occur cf polio. Particularly Enterovirus EV-D68 (also associated with respiratory disease), some clusters.  Increased incidence across Europe including Wales since April 2016.

Neonatal disease can be severe, mimicking bacterial sepsis or HSV. Maternal history is often elusive.

Virus is shed in throat and stool (rectal swab quicker than stool!), can also be detected in CSF, blood and urine.

Role of IVIG is unproven but antibody plays an important role in immune response to EV. Pleconaril in enteroviral meningitis RCT, 38% to 50% improvement in symptoms in the drug-treated group with improvement noted as early as 24 hours after initiation of therapy – no longer available.

[Current Opinion in Pediatrics. 13(1):65-9, 2001]

Human Parechovirus has been described in Japan, Canada and now the Netherlands, causing neonatal sepsis or encephalitis in about 10% of cases where culture suggests enterovirus but PCR is negative. [Clin Infect Dis. 2006 Jan 15;42(2):204-10]