An Approach to Penicillin Allergy

Around 10% of subjects report that they are allergic to penicillin. More than 90% of them are found not to be allergic to penicillin on skin testing. It is estimated that only 0.02%-0.04% of the population has severe (anaphylactic) penicillin allergy.

Strictly speaking, the term "allergy" connotes an IgE mediated process, but in practice, intolerance, idiosyncracy and pseudo-allergy are all lumped under the sobriquet of "allergy." This is unhelpful for a lifesaving medication such as penicillin.

It would be useful to recall the Gel-Coombs classification of hypersensitivity reactions and recollect specific examples.

Gel-Coombs Classification

Type I- IgE mediated, e.g. urticaria, angioedema, bronchoconstriction, hypotension, syncope. i.e. anaphylaxis. Occurs within minutes to an hour (sometimes up to 2 hours, if only oral exposure)
Type II- Antibody mediated cytotoxicity. e.g. Haemolytic anaemia. Occurs within hours to days.
Type III- Immune Complex reaction, e.g. serum sickness- maculopapular rash, fever, joint pains, low C3, C4, low CH50. Occurs from 7-21 days after exposure
Type IV- Delayed hypersensitivity. e.g. maculopapular rash without pruritus, SJS, TEN, DRESS, occurs after days to weeks

It is important to differentiate between these various processes as it is only the Type I (IgE mediated) reaction that lends itself to skin testing, graded dose challenge and desensitisation. These procedures should not be attempted in subjects with non-IgE medited reactions, that is Types II, III or IV hypersensitivity.

Further, it is important to remember that hypersensitivity to skin testing declines with time @ 10% per year. Therefore, 10 years after an index episode of penicillin allergy, 80-100% of subjects would have lost IgE mediated hypersensitivity to penicillin.

The likelihood of developing penicillin allergy is higher after intravenous dosing, frequent dosing, as opposed to oral or infrequent dosing. Atopy itself does not increase risk of penicillin allergy, but atopic subjects are likely to have more severe anaphylactic reactions if they do develop it.

Subjects with EBV developing a maculopapular rash with an aminopenicillin are not penicillin allergic. They can receive penicillin and beta lactams if indicated.

The cross reaction between penicillin and other beta lactam antibiotics is low. There is estimated to be <2% cross-reaction with amino-peicillins, 3% cross-reaction with cephalosporins (less with 3rd and 4th generation than with 1st and 2nd), 0% with monobactams such as aztreonam and <1% with carbapenems. Aztreonam and ceftazidime cross react with each other. There is 10-40% cross reaction between aminopenicillins such as amoxycillin or ampicillin and cephalosporins. Cross reaction occurs due to shared side chains and is non-IgE in character. It is best not to use one if there is a history of insensitivity to the other. It is important to quiz the patient regarding the type of reaction they had with penicillin. The most important arbiter is the speed with which the adverse reaction occurred. If the hypersensitivity was within minutes to an hour, it was likely to have been IgE mediated. Reactions occurring after days are non-IgE medated. For severe delayed reactions such as SJS, TEN, AIN, DRESS, haemolytic anaemia or serum sickness, repeat use of penicillin and other beta-lactams is best avoided. Penicillin is the only antibiotic for which skin prick testing is reliable. There are two antigens that are used to test for penicillin allergy- a major determinant- penicilloyl polylysine, also called Prepen, and a minor determinant- penicillin G itself. Both must be injected. Intradermal administration is necessary only if there is no reaction to skin prick testing. A negative control (normal saline) and positive control (histamine) is used simultaneously. Results are read at 15 minutes and a wheal 3mm or bigger compared with the negative control is considered to be evidence of Type I penicillin hypersensitivity. Other beta lactams are not used for skin testing. The results are read at 15 minutes. The PPV of skin prick test for penicillin allergy is 50% while the NPV is 97%. Thus, a subject with negative skin prick test is very unlikely to have penicillin allergy, but half of those who test positive may not have allergy. Skin prick testing is best delayed for 4-6 weeks after a severe allergic (anaphylactic) reaction.

If skin test is positive, it is best to use an alternative antibiotic. If penicillin or a related beta lactam must absolutely be used as there are no effective alternative, then densitisation may be attempted. This is attempted by giving progressively increasing doses of penicillin every 15-20 minutes S/C or IV or every 30 minutes, orally. It is customary to begin with 1/10,000 to 1/1000 of the therapeutic dose. Success rates are high. For example, between 75% to 100% of subjects with cystic fibrosis, who generally have high rates of drug intolerance, are rendered penicillin tolerant.

If the skin prick test is negative in a subject with a history of an adverse reaction to penicillin, a graded dose challenge is used as a precursor to giving the therapeutic dose. This is done using 1/100 to 1/10 of the therapeutic dose to start with, increasing the dose every 30 minutes.

It is important to mention again, that neither skin prick testing, nor graded dose challenge or desensitisation should be used for non-IgE mediated hypersensitivity reactions to penicillin. In such hypersensitivity reactions,if severe, penicillin is best avoided altogether.


Reference:

Gozalez-Estrada A, Radojicic C. Penicillin allergy: A practical guide for clinicians. CCJM 2015;82:295-300.

Fractional Excretion of Nitric Oxide in Assessment of Inflammatory Asthma

The National Institute of Clinical Excellence (NICE) in the United Kingdom recently recommended measurement of fractional excretion of Nitric Oxide (FeNO) in exhaled air as a surrogate for inflammatory, i.e. eosinophil driven asthma, which, by definition, would be corticosteroid responsive.(1)

Nitric Oxide is produced in response to Th2 lymphocyte driven inflammation. While a Cochrane review in 2009 could not find sufficient evidence to recommend this approach, subsequent studies have shown that the fraction of NO in exhaled air predicts response to anti-inflammatory therapy such as inhaled corticosteroids even in subjects with FEV1 >80% of predicted. Conversely, low FeNO levels indicate well controlled asthma, allowing reduction or discontinuation of oral/inhaled steroids.

Levels of NO in exhaled air of less than 25 parts per billion is characterised as "low", levels of 25-50 ppb as "intermediate" and >50 ppb as "high".

FeNo should be used in addition to standard PFTs such as FEV1, FEV1/FVC ratio and PEF. However, experience shows that these tests are imperfect predictors of response to inhaled steroid treatment. Observational studies show that 60% of subjects with putative asthma referred to secondary care and 30% of subjects diagnosed with asthma in primary care, have no evidence of airway dysfunction, and that in a majority of such subjects, inhaled steroid therapy can be stepped down without adverse consequences. (2)

Measurement of FeNO is therefore a welcome addition to the current diagnostic/monitoring modalities for inflammatory asthma. Following widespread adoption in the UK, I expect that this will now find acceptance elsewhere.

References:

1. Povard ID, Bush A, Holgate S. Asthma diagnosis: addressing the challenges. Lancet Respir Med 2015; 3: 184

2. Hawkins G, McMahon AD, Twaddle S, Wood SF, Ford I, Thomson NC.
Stepping down inhaled corticosteroids in asthma: randomised controlled
trial. BMJ 2003; 326: 1115.

Dealing With Low Flow, Low Gradient Aortic Stenosis

In deciding which symptomatic subjects with aortic stenosis (AS) need surgery, most authorities would agree that a subject with aortic valve area less than 1 cm^2 ( or <0.6 cm^2/m^2, if indexed to body surface area) on transthoracic echo (TTE), along with a mean transaortic gradient of >40 mm Hg, or a transaortic valve peak velocity of 400 cm/s have severe AS, and should proceed to surgery. But what of those symptomatic subjects, who have a valve area less than 1 cm^2 on echo, but have a peak velocity of flow or a mean transaortic gradient below the thresholds described above in association with reduced left ventricular ejection fraction (LVEF)? In such patients, it can be difficult to determine whether the reduced LVEF is, in fact, a consequence of AS itself (and who would therefore benefit from valve replacement) or whether the apparently reduced orifice of the aortic valve is due to the reduced transvalvular flow caused by low ejection fraction (EF) caused by the underlying heart failure. The latter subjects would obviously not benefit from valve replacement.

The difficulty in distinguishing between these two possibilities is not confined to echocardiographic methods. The tradional method of determing the severity of aortic stenosis has been Gorlin and Gorlin's seminal approach described in the 1950s, and described by the following equation:

Aortic Valve Area= Cardiac Output/Systolic Ejection Period*Heart Rate*44.3*Sqroot Mean Pressure Gradient.

The problem with the Gorlin formula is that it uses a constant that is flow dependent, i.e. it assumes a normal LVEF. It is therefore likely to be less accurate in subjects with heart failure. Most cardiologists would think long and hard before subjecting such subjects to the ordeal of cardiac catheterisation. It has also been pointed out that while measuring the left ventricular pressure (as part of the calculation of the pressure gradient), the catheter itself is occupying an already stenotic aortic valve orifice and might therefore confound pressure measurements.

Fortunately, it is possible to avoid such tricky situations by skillful use of stress TTE with dobutamine. Before we go there, it might be useful to summarise the principles of transvalvular pressure measurement on Echo.

Measurement of transaortic pressure depends on a simplification of the Bernoulli principle. Thus, the pressure gradient Delta P is described as:

Delta P = [4* (transaortic valve peak velocity)^2] - [4* (subaortic peak velocity)^2]

The rationale for subtracting the component contributed by subaortic flow may seem confusing until you consider what happens to a subject who has both AS and HOCM. The accelerated upward flow from HOCM boosts the aortic flow, and if we are not careful, will lead to an overestimation of the transaortic gradient. Fortnately, in most subjects, the contribution from subaortic flow is negligible, and can be ignored. The Bernoulli equation therefore boils down to:

Delta P = 4V^2, where V is the transaortic valve peak velocity.

Upon stimulation with dobutamine (5 microgram/min, increasing to 20 microgram/min), subjects with severe AS but normal LVEF, i.e. those with "true" stenosis, fail to increase their aortic valve area. However, their transaortic gradient , and with it, the valve resistance, increases. The concept of valve resistance requires an explanation.

Pressure = Flow*Resistance

or Resistance = Pressure/Flow

Flow is of course cardiac output in cm^3/s. The unit for pressure is dyne/cm^2. The unit for Resistance is therefore dyne.second.cm^-5.

Most cardiologists do not feel that measurement of valve resistance adds to information already gained from measurement of transvalvular pressure gradient.

In subjects who have reduced LVEF due to underlying myocardial failure rather than due to AS itself, stressing with dobutamine increases flow and therefore leads to an increased valve area on TTE. The transvalvular pressure gradient and vascular resistance falls. This is described as "Pseudo-stenosis".

Some authorities make a distinction between subjects who have reduced LVEF in association with concentric LVH, and those who have reduced LVEF but no LVH. The former group tend to have a worse prognosis.

Surgical outcomes tend to be good after valve replacement in subjects with "True" stenosis but poor in subjects with "Pseudostenosis". This distinction is therefore important.

In those with true stenosis, a further distinction may be based on a concept called "Contractile Reserve" (CR). CR is the increase in stroke volume with dobutamine stress. Those who have a CR>20%, i.e. those who increase their stroke volume by >20% with dobutamine, have better surgical outcomes than those subjects who have a CR<20%. However, it is important to mention that even these latter subjects have better prognosis with surgery than with medical management alone. Surgery should therefore not be witheld from such subjects. Sometimes the effective area of a heavily calcified, stenotic valve area can be difficult to determine on TTE. In such subjects, the continuity principle may be used. The continuity principle is an extension of Pascal's Law and assumes that flow in a (periodically) closed system such as the heart is the same throughout. Flow = Area*Velocity Since flow through the aortic valve equals flow in the aortic outflow tract (the vena contracta), it follows that Aortic Valve Area (AVA)*Transaortic velocity (TaV) = Area of aortic outflow tract (AO) * Velocity in aortic outflow tract (AoV). Thus AVA= AO*AoV/TaV In some subjects, the area of the aortic outflow tract is easier to measure than that of the aortic valve itself. The continuity principle is useful in such cases. Most cardiologists prefer to use the velocity time integral (VTI) rather than the instantaneous peak velocity in such calculations. Thus, effective Aortic Valve Area = Area of Aortic outflow tract* VTI in aortic outflow tract/ VTI through aortic valve. Subjects with similar valve areas can often have different clinical outcomes. It is thought that the extent to which the energy imparted by the left ventricle is dissipated as the blood passes through the stenotic aortic valve, predicts prognosis in such subjects even better than the area of the stenotic valve itself. This is epitomised by the Energy loss index. Energy Loss index (ELI)= (Aortic valve area*Area of the aorta at the sino-tubular junction/Area at the sinotubular junction-Aortic valve area)/ Body surface area. Subjects with an ELI< 0.52 cm^2/m^2 have a significantly poorer prognosis than those with a higher ELI. References: 1. Uptodate 2. Simultaneous Determination of Aortic Valve Area by the Gorlin Formula and by Transesophageal Echocardiography Under Different Transvalvular Flow Conditions: Evidence That Anatomic Aortic Valve Area Does Not Change With Variations in Flow in Aortic Stenosis. J Am Coll Cardiol. 1997;29(6):1296-1302. doi:10.1016/S0735-1097(97)00060-0 (Open access).

An Approach to Myopathy in the Rheumatology Clinic

It's quite common to see a subject with raised CK in the Rheumatology clinic. Most of these subjects will not have one of the idiopathic inflammatory myopathies (IIM), the traditional forte of Rheumatologists, as these are quite rare disorders. While some of these cases will be undoubtedly, and correctly, passed to the Neurologists, it'd be helpful to formulate an approach to these subjects. No one individual can hope to have mastery of the hundreds of muscle disorders that can present in a tertiary clinic, and all too often one runs out of ideas when confronted by the patient with the raised CK. Failure to ask the right questions and to examine properly will result in an incorrect diagnosis. Here, therefore, is a brief approach, by no means comprehensive, but focusing on common muscle disorders seen in the clinic, with a suggested set of questions and helpful examination findings and investigations that might lead to a diagnosis. Certain obvious questions such as age and duration are deliberately ignored. Most experienced physicians will not miss out on such basics.

History

The three questions to ask to rule out metabolic myopathies

Is weakness or pain the main feature?
An overwhelming majority of subjects with IIM present with weakness. Pain in the absence of weakness often points to metabolic muscle diseases.

Are the symptoms related to exercise? How long does it take to appear?
Pain or cramps that is brought on by exercise, but is absent at rest, is typical of metabolic myopathies rather than IIM. In one series, the two commonest metabolic disorders that presented with exertional muscle pain were carnitine palmitoyl transferase II (CPT2) deficiency and myophosphorylase deficiency. While CPT2 deficiency typically causes pain after 30-60 minutes of exercise, myophosphorylase deficiency would be expected to cause pain within 5 minutes. (The next two commonest were phosphorylase kinase deficiency and myoadenylate aminase deficiency).

Does the patient pass dark urine during/after episodes of pain?
If so, this is due to myoglobinuria due to rhabdomyolysis, strongly associated with metabolic myopathies.

The four questions to rule out IIM

Raynaud?
Supports anti-synthetase syndromes.

Dysphagia?
IIM or overlap with scleroderma.

Joint pains?
Favours anti-synthetase syndromes

Weight loss?
Favours malignancy

Severe pain?
Makes IIM unlikely

Six questions to rule out toxin/drug induced myopathy

What is your alcohol intake?
Acute alcoholic myopathy often associated with low PO4, K.

Do you use any recreational drugs?
Cocaine, heroine, amphetamines, phencyclidine

Are you on statins or fibrates?

Are you on hydroxychloroquine?
Unpredictable myoneurotoxicity- not dose related. Can occur early or late. Can be associated with cardiomyopathy. Fully reversible with discontinuation. No pain. Reflexes diminished and loss of vibration in legs.

Are you on colchicine?
Usually dose related, prolonged use. Typically in subjects with renal impairment. No pain. Fully reversible with discontinuation.

Do you take nutritional supplements?
Creatine

Four questions to rule out adult onset muscular dystrophies/myopathies

Family history

Diabetes+ Hypogonadism+Cataracts
Myotonic dystrophy.

Diabetes+Deafness
Mitochondrial myopathy

Four questions to rule out MND (CK<1000)

Fasciculations?
Cramps?
Weight loss?
Nasal regurgitation?

One question to rule out parasitic muscle disease

Do you eat uncooked pork?
Trichinellosis

Examination

PM & DM causes symmetrical & proximal myopathy

IBM causes weakness of wrist and finger flexors- often asymmetrical

Expose the patient fully, so as not to miss shawl sign, V sign, Gottron's sign on knees, Holster sign and Flagellate erythema. Look for Gottron's papule and mechanics hands

Myotonia- handgrip and abductor pollicis
Myotonic Dystrophy 1 and 2.

Short stature? Ptosis and squint but no diplopia
Mitochondrial myopathy

Fasciculations, Babinski
MND

Typical DM rash?
Make sure patient is not on hydroxyurea.

Listen to chest.
Velcro crackles favours anti-synthetase and CADM

Synovitis?
Anti-synthetase or overlap

Periorbital oedema?
DM, PM or Trichinellosis,

Investigations

Metabolic myopathy

Plasma acylcarnitines raised in CPT-2 deficiency and other fatty acid disorders (but not in long chain acyl coA dehydrogenase deficiency)
Ask specifically for immunohistochemical staining for myophosphorylase, phosphorylase kinase and myoadenylate deaminase when you request muscle biopsy
If necessary, genetic testing for myophosphorylase, CPT2, myoadenylate deaminase
Serum amino acids (includes alanine)
24-hour urine for organic amino acids

Mitochondrial myopathy

Fasting lactate

Myotonic dystrophy

Immunoglobulins (Hypogammaglobulinemia)
Blood sugar, HbA1c
FSH, LH, Testosterone
ECG
Genetic tests- No. of CTG repeats in DMPK (MD1) or CCTG repeats in ZNF9 (MD2)

Trichinellosis

Eosinophilia

Serology- ELISA, followed by Western Blot

Drug/Toxin induced Myopathy

Screen for drugs of abuse

EMG , Muscle biopsy & MRI

Request EMG in one leg and Muscle biopsy in other leg to avoid artefact. Muscle biopsy ideally done in leg opposite to the one in which EMG abnormalities were demonstrated, but on the same side as abnormal MRI

Ask for staining for dystrophin, merosin and sarcoglycans when you request muscle biopsy

Avoid biopsy of calf- risk of artefact. Quads and deltoids best. Vastus lateralis safest.

Ask for staining for SDH and cytochrome oxidase- abnormal in mitochondrial myopathy

EMG will pick up myotonic dystrophy.

PM causes inflammation of fascial planes on MRI, IBM entire muscles.

Pneumococcal Vaccination

There are two types of pneumococcal vaccines- the polysaccharide vaccine- Pneumovax®, and a conjugate vaccine- Prevenar13®. The 23-valent polysaccharide vaccine, PPSV 23, was first introduced in 1992 for “at-risk” adults. Its use was later extended to at-risk subjects above the age of 2 and to all subjects aged 65 or above.

To understand the need for 2 separate vaccines, and their applicability to subjects on biologics or DMARDs, a bit of background information is needed.

Children below the age of 2 do not make antibodies to polysaccharide antigens very well. This is because they are reliant entirely on their T-cells to prime their “usual” B-cells (also called B-2 or thymus-dependent cells). There is however, another type of B-cells, ontologically more primitive, called B-1 cells. These B-cells are thymus independent and therefore also called TI cells. It is these latter cells that are responsible for making antibodies to polysaccharide antigens. These B-1 cells are not well developed in children below the age of 2 years. Very young children thus do not respond to polysaccharide vaccines.

An ingenious way of getting around this problem is to conjugate the polysaccharide to a protein and thus make it recognisable to T cells. This principle has already been exploited in engineering vaccines against Meningococcus and H.influenzae, both of which have polysaccharide coats and affect very young children. The commonest protein conjugate used is a substance called CRM 197, a toxoid obtained by weakening the diphtheria toxin. UK was in fact the first country to introduce the conjugate vaccine against Meningoccus C.

In 2006, a 7-valent conjugate vaccine (PCV-7) was added to the childhood vaccination programme in the UK. In 2010, this was replaced by a conjugate vaccine containing 13 strains- PCV 13. One of the unexpected consequences of the introduction of conjugate Pneumococcal vaccines among children has been a fall in the incidence of Pneumococcal infections caused by vaccine serotypes among adults, and an increase in infections by serotypes not covered by the conjugate vaccines.

Further, it is important to note that the overall efficacy of PPSV23 in preventing pneumococcal bacteraemia is probably 50 to 70%. Current evidence suggests that PPV is not effective in protecting against non-bacteraemic pneumococcal pneumonia. It does not prevent otitis media or exacerbations of chronic bronchitis. The vaccine is relatively ineffective in patients with multiple myeloma, Hodgkin’s and non-Hodgkin’s lymphoma (especially during treatment) and chronic alcoholism.

Studies from Africa show that the conjugate vaccine offers protection against invasive pneumococcal infections in HIV positive patients. Head to head studies on the efficacy of PPSV 23 versus PCV13 are unfortunately lacking. To my knowledge, only one such study exists, and it did not show significant difference in efficacy.

There is some evidence that the use of methotrexate with certain biologics such as Tocilizumab reduces the immunogenicity of PPSV 23 compared with stand-alone use of the biologic, although this probably doesn’t translate into a difference in clinical protection.

The American Committee on Immunization Practices, ACIP, recommends the use of both PCV13 and PPSV23 in subjects receiving immunosuppressive therapy, including those on biologics (but excluding subjects on DMARDs, who are still recommended to receive PPSV 23 alone) In subjects on biologics or other powerful immunosuppressive drugs, the ACIP recommendation is that PCV 13 should be given first, followed ideally 6 months later, (but no earlier than 8 weeks) by PPSV 23. If PPSV 23 is given first, then one must wait for a minimum of 12 months before giving PCV 13. Further doses of PPSV 23 are recommended every 5 years, but no further doses of PCV 13 are recommended.

These biologic-specific recommendations have still not been adopted by the Joint Committee on Vaccination and Immunisation in the UK and do not appear in the BSR website. However, it is likely that these will be adopted.

Special considerations apply to subjects over the age of 65. Above this age, even if the subject is no longer on biologics (say, receiving DMARDs alone or on no treatment at all), he/she should still receive a single dose of PPSV 23 upon turning 65, or later, if a dose of PPSV 23 was given within the last 5 years, i.e. there should be a minimum period of 5 years since the last dose of PPSV 23 before re-administering this vaccine.

The UK, just as in the USA, has a policy of universal immunization of subjects over age 65 with a single dose of PPSV 23. In the UK, repeat doses of PPSV 23 are only indicated for subjects with asplenia or hyposplenia (regardless of age) and in those with CKD 4 or 5 or nephrotic syndrome (regardless of age), on the premise that the level of humoral immunity declines more rapidly in such subjects. Such subjects should receive PPSV 23 every 5 years even if they are not on immunosuppression. Revaccination is well tolerated.

However, in the USA, age related Pneumococcal vaccination guidelines changed in 2014. Based on the efficacy of PCV13 in a trial of 85,000 subjects in Netherlands aged 65 and above, the ACIP recommended this year that all subjects above 65 should receive both PCV 13 and PPSV 23. Typically, PCV 13 would be given first, followed at least 8 weeks later by PPSV 23.

Pneumococcal vaccines are not live vaccines and therefore are not contraindicated in pregnant women or those receiving biologics. However, as the vaccine takes around 2 weeks to produce immunity, it is desirable that the vaccine be given at least a couple of weeks before starting the biologic, if possible. If this is not possible, the vaccine can be given at any time after starting the biologic. The exception is Rituximab, which naturally compromises humoral immunity. It is therefore expedient to wait for 6 months post-Rituximab before administering the Pneumococcal vaccine.

Subjects who have had infection with Pneumococcus must still be immunized. Immunity will be strain-specific and will not protect the subject against other serotypes of Pneumococcus. The index infection suggests that the subject might be vulnerable to infection with other strains of Pneumococcus, and therefore it would be important to immunize.

Summary

1. Subject on DMARD, below 65 years of age- 1 dose of PPSV 23

2. Subject on DMARD, above 65- additional dose of PPSV 23 ASAP after turning 65, as long as 5 years have elapsed since last dose of PPSV 23.

3. Any subject with asplenia, hyposplenia (includes coeliacs) , CKD 4 or 5, or nephrotic syndrome, on DMARD, but not on biologic, regardless of age- PPSV23 every 5 years

4. Any subject on biologic, regardless of age or other co-morbidity- Initial PCV13, followed 6 months later by PPSV 23, and then repeat PPSV 23 every 5 years, as long as subject remains on biologic. If PPSV 23 has already been given, wait 12 months before giving PCV 13, and then repeat PPSV 23 after 5 years of initial dose of PPSV 23, and then every 5 years, as long as patient remains on biologic

5. Age over 65, biologic/DMARD discontinued- One-off dose of PPSV 23 ASAP after turning 65, provided at least five years have elapsed since last dose of PPSV 23.

The Changing Face of Acute Epiglottitis

Epiglottitis (also called supraglottitis) is more common in children, right?

You would be surprised. Since the introduction of the conjugate Haemophilus influenzae B vaccine in the early 1990s, the incidence of acute epiglottitis in children has fallen. As a result, epiglottitis is now 3 times more common in adults as in children.

Haemophilus influenzae remains the most commonly identified agent in both adults and children, but other bacteria such as S.aureus, streptococci, and viruses have been implicated. In immunosuppressed subjects such those with HIV, Candida and Pseudomonas can cause acute epiglottitis.

Typically, epiglottitis presents with sore throat, anterior tenderness over the neck in the region of the hyoid, drooling, dysphagia and odynophagia. While the triad of drooling, dysphagia and (respiratory) distress- 3D- is considered pathognomonic, respiratory distress is commoner in children because of the small size of the supraglottis. Symptoms can progress rapidly in children with respiratory obstruction and death within 12 hours of onset of symptoms, and therefore the paediatrician must have a high index of suspicion.

Children with epiglottitis look anxious, breath through an open mouth, with the neck hyperextended and the chin thrust forward. They often assume a posture where they bend forward, arms stretched, splinting their trunk, much as a subject with emphysema would (the tripod sign).

Stridor occurs in a minority of patients. Cough and hoarseness are not usual features and should raise suspicion of an alternative diagnosis such as croup in children, or laryngitis in adults. However, the voice can be muffled.

The most important clue on examination is the presence of sore throat with a normal appearing pharynx. Direct or indirect Laryngoscopic examination should be postponed, particularly in children as it carries a risk of respiratory arrest, and in both adults and children, should be carried out in a setting where emergency intubation is possible. Attention to airway takes primacy in all subjects, regardless of age, if epiglottitis is suspected.

An alternative, non-invasive way of diagnosing epiglottitis is through the lateral neck X-ray, which shows an enlarged epiglottis- called the thumb sign, along with swollen ary-epiglottic folds, often in association with straightening of the curvature of the normally slightly lordotic cervical spine (Figure 1).

Figure 1. The Thumb Sign in Acute Epiglottitis


Treatment should comprise a combination of 3rd generation cephalosporin such as cefotaxime or ceftriaxone with an anti-staph agent such as clindamycin or vancomycin.

In subjects who have developed epiglottitis despite immunisation, or whose immunisation history is not known, or in subjects who have had epiglottitis in the past and now present with another invasive infection possibly due to H.influenzae B such as cellulitis, osteomyelitis, meningitis or septic arthritis, it is easy to check for functional antibodies to H.influenzae B. If the titres are suboptimal, the subject should receive a single dose of Menitorix vaccine- a combination of conjugate vaccine against H.influenzae B and Meningococcus C.

Varicella & Shingles Vaccines, DMARDs & Biologics

Varcella vaccine and Zoster (Shingles) vaccine are both comprised of the same strain- Oka- but are not the same vaccine. While the varicella vaccine (Varivax®, Varilix®) contains 1350 Plaque forming units (PFU), the zoster vaccine (Zostavax®) contains 18,700-60,000 PFU, i.e. at least 14 times more virus. The varicella vaccine needs to be given in two doses 4-8 weeks apart, while only one dose of the Zoster vaccine need be given.


In Rheumatology, the varicella vaccine is indicated in subjects who are about to start immunosuppression and are non-immune. Although, a history of chicken-pox is a reliable indicator that the subject will have protective antibodies, it is customary to check the varicella serology before starting immune-suppressive treatment. It is estimated that 90% of adults in the UK will have had either clinical or sub-clinical exposure to varicella growing up and will be immune- i.e. have protective levels of antibodies to varicella in the serum.


In the minority of patients with auto-immune disease that do not have protective antibodies, 2 doses of the varicella vaccine are administered 4-8 weeks apart. This should ideally be done 4 weeks before starting DMARDs.


For subjects who are already on DMARDs, it may not be too late to give the varicella vaccine. If the subject is on <0.4 mg methotrexate per kg body weight per week (equivalent to 25 mg weekly in a 60 kg subject), or receiving <3 mg azathioprine daily, or <1.5 mg 6-mercaptopurine daily, the varicella vaccine may still be administered. Similarly, those on low dose steroids (<20 mg daily for less than 2 weeks) are considered eligible. These are expert (level 3, not based on RCTs or case control studies) recommendations made by the Advisory Committee on immunization Practices (ACIP) based in the USA, an organisation that celebrates its 50th year in 2014. This is a body that has shaped immunisation guidelines worldwide. The Zoster or Shingles vaccine is recommended for subjects between 70 and 80 years in the UK. This year, the vaccine is being rolled out to subjects who are 70, 78 or 79 years old as of 1 September 2014, but not to other subjects. This is because it is quite expensive- each dose costs ~£100. A prior history of chickenpox or immunity to varicella is not considered necessary by the ACIP for giving the shingles vaccine. However the UK guidelines by the Joint Committee on Vaccination and Immunisation advice that such history be established before giving the shingles vaccine for fear of causing varicella in virus-naïve subjects late in life. The zoster vaccine provides only 50% protection to subjects from shingles, compared with no immunisation. While vaccinated subjects may still develop shingles, the disease is often attenuated. Live virus vaccines should never be given to subjects on biologics or pregnant women. Further, if the subject is about to receive, or has received rituximab, the vaccine must be given either 4 weeks before giving rituximab or 6 months after giving rituximab. With other biologics, varicella or zoster vaccines can be given 4 weeks before starting the biologic or approximately 5 half-lives after completing the biologic. What if a subject on immunosuppression is non-immune and has had a “significant” exposure to varicella or shingles? Significant exposure is defined as “face to face” contact or being in the same room or in the same 4-6 bedded bay. Exposure in more open wards or subjects living in a different part of the house or those exposed in a larger area such as a classroom are treated on a case to case basis. For such purposes, exposure to anybody with chickenpox is considered significant. Exposure to immunocompetent subjects with localised shingles in a covered area such as the thoracolumbar area is not considered significant. However exposure to shingles in an exposed area such as ophthalmic shingles is considered significant. Further, any exposure to shingles developing in an immunosuppressed subject, whether covered or not, is considered significant, as such subjects shed the virus at a much faster rate than immunocompetent subjects. Vulnerable subjects with such significant exposure are treated with varicella zoster immunoglobulin (VZIG). Currently, VZIG is prepared from pooled plasma accumulated from donors outside the UK. Donors from UK are not accepted for this purpose because of concerns about vCJD. Donors are screened for hepatitis B, hepatitis C and HIV, and the collected plasma is also screened for RNA and DNA from these viruses. Subjects who are considered eligible for VZIG are non-immune subjects with “significant exposure” as follows: 1. Immunosuppressed subjects- on biologics, high dose steroid therapy (>20 mg prednisolone for 4 weeks or longer), subjects with leukaemia, lymphoma, myeloma or generalised solid cancers, subjects who have had chemotherapy or have inherited disorders of immune deficiency. (Hopefully, most of these subjects would have been screened for varicella early in their illness trajectory).
2. Pregnant women in the first 20 weeks of pregnancy. Exposure in this period carries a risk of “congenital varicella syndrome” in the foetus, comprising microcephaly, maldeveloped limbs, skin lesions and other features.
3. In women who have been exposed to varicella during the last 7 days of their pregnancy or during the first 7 days after giving birth, the neonate must receive VZIG. During this period, the neonate is at risk of disseminated varicella. The risk lessens considerably after the first 7 days of life.



However, if the mother develops shingles rather than varicella during this period, VZIG need not be given to the neonate as it would have received pre-formed antibodies from the mother.



Prophylaxis still required if the neonate is exposed to chickenpox or shingles from another source apart from the mother in the first 7 days of life.



The dose of VZIG is as follows:
0-5 years- 500 mg
6-10 years- 1000 mg
11-15 years- 1500 mg
>15 years- 2000 mg


VZIG is given intramuscularly. If the subject has a bleeding diathesis and cannot receive IM injection, IVIG can be given in a dose of 0.2 mg/kg.


A subject receiving VZIG will not respond to the varicella vaccine if given concurrently. If VZIG has to be given within 4 weeks of giving the varicella vaccine, it is advisable to re-administer the vaccine after 3 months. VZIG also interferes with immunity to other viral vaccines with the exception of yellow fever, something that should be kept in mind for travellers.


There is no need to give VZIG in any subject who has protective levels of varicella antibodies in blood. The titre of such antibodies is not increased significantly by giving VZIG.


It is worth mentioning that many subjects will develop varicella despite receiving the VZIG. Only 50% of subjects are fully protected from chickenpox by VZIG. However, it is thought to attenuate the severity of chickenpox if it does develop.


VZIG must be given ideally within 7 days, and certainly within 10 days of exposure to provide protection. If the subject’s immune status is not known, it is possible to send off the serology and receive a report within a week under current arrangements. Therefore, in such cases, VZIG can still be given.


It is occasionally possible for immunosuppressed subjects to develop varicella despite having protective antibodies in blood. In such subjects, it is thought that a deficit in cellular immunity contributes to development of chickenpox.


Treatment with acyclovir should be promptly administered to immunosuppressed subjects who develop chickenpox or disseminated zoster despite immunisation or in non-immune immunosuppressed subjects who develop varicella despite receiving VZIG.