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.